Infectious Diseases, Second Edition (EXPERT GUIDE SERIES- AMERICAN COLLEGE OF PHYSICIANS)

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BK6016A IDFinalcover

11/26/07

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Page 1

Infectious Diseases

Tan File Salata Tan

Second Edition

• Features new chapters on antimicrobial agents and prosthetic joint infections. • Includes individual chapters on HIV, herpes virus, Lyme disease, and malaria. • Puts key information at your fingertips with diagnostic and treatment tables throughout the text. • Reviews the clinical manifestations of each infection as well as recent advances in clinical microbiology. • Focuses on the common and uncommon diseases most often seen in primary care practices. Infections comprise a sizable proportion of the conditions encountered in the office setting. Manage them easily and effectively with this thorough, yet practical, guide.

Infectious Diseases

• Examines infections of the central nervous system, heart and blood vessels, gastrointestinal tract, genitourinary system, respiratory tract, skeletal system, and skin.

Second Edition

Find the expert guidance you need to evaluate, diagnose, and treat the most commonly encountered infections in the primary care setting. Infectious Diseases, 2nd Edition keeps you current with new etiologic agents, the most appropriate diagnostic tests, and the most effective management options. This New Edition:

ACP

Infectious Diseases Second Edition

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Expert Guide to

INFECTIOUS DISEASES SECOND EDITION

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Expert Guide to

INFECTIOUS DISEASES SECOND EDITION Edited by James S. Tan, MD, MACP Professor and Vice Chairman, Department of Internal Medicine Northeastern Ohio Universities College of Medicine Head, Infectious Diseases Section Chairman, Department of Internal Medicine Summa Health System

THOMAS M. FILE, JR., MD, MSC, MACP Professor, Department of Internal Medicine Head, Infectious Diseases Section; Master Teacher Northeastern Ohio Universities College of Medicine Chief, Infectious Diseases Service Summa Health System

ROBERT A. SALATA, MD, FACP Professor and Vice-Chair, Department of Medicine Chief, Division of Infectious Diseases & HIV Medicine Case Western Reserve University University Hospitals Case Medical Center

MICHAEL J. TAN, MD, FACP Assistant Professor, Department of Internal Medicine Northeastern Ohio Universities College of Medicine Clinical Physician, HIV and Infectious Diseases Summa Health System

ACP Press American College of Physicians • Philadelphia

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Clinical Consultant: David R. Goldmann, MD Associate Publisher and Manager, Books Publishing: Tom Hartman Developmental Editor: Victoria Hoenigke Production Supervisor: Allan S. Kleinberg Senior Editor: Karen C. Nolan Editorial Coordinator: Angela Gabella Indexer: Kathleen Patterson Copyright © 2008 by the American College of Physicians. All rights reserved. No part of this book may be reproduced in any form by any means (electronic, mechanical, xerographic, or other) or held in any information storage and retrieval systems without written permission from the publisher. Manufactured in the United States of America Composition by SPI, India Printing/Binding by Versa Press Inc. ISBN: 978-1-930513-85-3

The authors have exerted reasonable efforts to ensure that drug selection and dosage set forth in this volume are in accord with current recommendations and practice at the time of publication. In view of ongoing research, occasional changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This care is particularly important when the recommended agent is a new or infrequently used drug. ACP is not responsible for any accident or injury resulting form the use of this publication.

08 09 10 11 12 / 9 8 7 6 5 4 3 2 1

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In Memoriam James S. Tan, MD, MACP

O

ur renowned colleague, James Tan, died May 25, 2006, in Akron, Ohio. He was 67. Jim was the editor of the first edition of Expert Guide to Infectious Diseases, and through his efforts it was a great success. At the time of his death, he was coordinating this second edition, which we dedicate to him. Jim graduated in 1965 from the University of the Philippines College of Medicine, and he trained in infectious diseases at the University of Cincinnati College of Medicine. In 1974, he moved from a faculty position at the University of Cincinnati to Akron, Ohio to be the first Head of Infectious Diseases at Akron City Hospital (now Summa Health System). He was the first infectious diseases specialist to bring clinical expertise to the community setting in northeastern Ohio. In 1979, he was named Chairman of the Department of Medicine at Akron City Hospital, a position he held until his death. At that time, he had completed the longest term as program v

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In Memoriam

director of an internal medicine residency program in the nation and was involved in the training of countless physicians. He was also the first Chairman of the Infectious Diseases Section of Northeastern Ohio Universities College of Medicine (NEOUCOM) in Rootstown, Ohio and he held this position since 1977. Through his leadership, he organized the development of the infectious diseases curriculum for medical students at the College of Medicine. Jim will be forever remembered as a consummate infectious diseases clinician and educator. Jim was a Master of the American College of Physicians. He was former Governor of the Ohio Chapter of the American College of Physicians, and further served the College in many additional capacities. He was also a Fellow of the Infectious Diseases Society of America (IDSA) and served as the secretary-treasurer (aka, ‘executive director’) of the Infectious Diseases Society of Ohio for five years. He was a member of the IDSA Clinical Guideline Panel for the Diagnosis and Treatment of Diabetic Foot Infections. Jim was exceptionally active in research. He was particularly interested in the evaluation of the pharmacokinetics of antimicrobials: one of his significant achievements in this field was his improvement of a skin window technique to measure the interstitial fluid concentrations of antimicrobials. This work has been published in numerous journal articles and textbook chapters. His many awards include the Liebelt/Wheeler Award from NEOUCOM for faculty excellence and the American College of Physicians Ohio Chapter Laureate and Master Teacher Awards. He received the Watanakunakorn Clinician of the Year Award at the annual meeting of the Infectious Diseases Society of America meeting in San Francisco in October 2005. Twice he was named teacher of the year by the house staff of Akron City Hospital (Summa Health System). He authored and co-authored more than 180 scientific publications. Throughout Jim’s distinguished career, the care of patients was always his primary interest. Even while he excelled at research, teaching medical students, residents, and colleagues, and administering at a large teaching medicine program, patient care remained his passion. His friendly personality and warm smile endeared him to his patients. He truly improved the lives of thousands with his compassionate care. Jim Tan is survived by his wife, June; his children, Stephanie Tan, MD, Rowena Tan, PhD, and Michael Tan, MD (co-editor of this edition of Expert Guide to Infectious Diseases); and his grandchildren, Drew, Allison, Hannah, Nicholas, and Jameson. TMF Jr. RAS MJT

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Contributors

Keith B. Armitage, MD, FACP Professor of Medicine Vice Chair for Education, Department of Medicine Division of Infectious Diseases & HIV Medicine Case Western Reserve University University Hospitals Case Medical Center Cleveland, OH

David Bobak, MD Associate Professor of Medicine Department of Medicine Division of Infectious Diseases & HIV Medicine Case Western Reserve University University Hospitals Case Medical Center Cleveland, OH

Manmeet S. Ahluwalia, MBBS Department of Medicine Fairview Hospital Cleveland, OH

Hector Bonilla, MD Assistant Professor of Internal Medicine Northeastern Ohio Universities College of Medicine Summa Health System Akron, OH

Johan S. Bakken, MD, PhD, FACP Associate Professor Department of Family Medicine Duluth School of Medicine University of Minnesota Duluth, MN

Robert A. Bonomo, MD Associate Professor of Medicine Department of Medicine Division of Infectious Diseases & HIV Medicine Section Chief, Louis Stokes VA Medical Center Case Western Reserve University Cleveland, OH

Richard H. Beigi, MD, MSc Assistant Professor of Reproductive Biology Department of OB/GYN University of Pittsburgh Medical Center Pittsburgh, PA

Rebecca A. Brady, PhD Research Associate Department of Microbiology and Immunology University of Maryland School of Medicine Baltimore, MD

Anthony Berendt, MD Medical Director & Consultant Physicianin-Charge Bone Infection Unit Nuffield Orthopaedic Centre Headington, Oxford, United Kingdom

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Contributors

Itzhak Brook, MD, MSc Professor of Pediatrics & Medicine Georgetown University Georgetown University School of Medicine Washington, DC Jason H. Calhoun, MD J. Vernon Luck Distinguished Professor Chair, Department of Orthopaedics University of Missouri Columbia, MO Rafael E. Campo, MD Associate Professor of Medicine Leonard M. Miller School of Medicine University of Miami Associate Director for Inpatient Services Infectious Diseases Research Unit Jackson Memorial Hospital Miami, FL David Canaday, MD Assistant Professor of Medicine Division of Infectious Diseases & HIV Medicine Case Western Reserve University University Hospitals Case Medical Center Cleveland, OH Joseph C. Chan, MD Associate Professor of Medicine Leonard M. Miller School of Medicine University of Miami Mt. Sinai Medical Center Miami Beach, FL Jason W. Chien, MD Assistant Professor of Medicine University of Washington Fred Hutchinson Cancer Research Center Seattle, WA Gordon Christensen, MD, FACP Professor of Medicine University of Missouri-Columbia School of Medicine Columbia, MO Catherine Markin Colecraft, MD Dorn VA Medical Center Primary Care/Subspecialty Medicine Columbia, SC Blaise L. Congeni, MD Professor of Pediatrics Professor of Microbiology & Immunology

Northeastern Ohio Universities College of Medicine Children’s Hospital Medical Center Akron, OH Curtis J. Donskey, MD Assistant Professor of Medicine Department of Medicine Division of Infectious Diseases & HIV Medicine Louis Stokes VA Medical Center Cleveland, OH J. Stephen Dumler, MD Professor of Pathology Department of Pathology Division of Medical Microbiology The Johns Hopkins University School of Medicine Baltimore, MD Jack Ebright, MD, FACP Associate Professor of Internal Medicine Wayne State University School of Medicine Detroit, MI James Fanning, DO Chairman, Department of Obstetrics & Gynecology Medical Director, Women’s Health Services Summa Health System Akron, OH Bradford W. Fenton, MD, PhD, FACOG Faculty, Department of Obstetrics & Gynecology Summa Health System Northeastern Ohio Universities College of Medicine Comprehensive Women’s Specialty Physicians Akron, OH Thomas M. File, Jr., MD, MSc, MACP Professor of Internal Medicine Northeastern Ohio Universities College of Medicine Chief, Infectious Diseases Service Summa Health System Akron, OH Robert F. Flora, MD, MBA Residency Program Director Head, Urogynecology & Reconstructive Pelvic Surgery

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Contributors

Summa Health System Associate Professor of Obstetrics & Gynecology Vice Chair, Clinical Associate Professor of Urology Northeastern Ohio Universities College of Medicine Akron, OH Scott A. Fulton, MD Assistant Professor of Medicine Department of Medicine Division of Infectious Diseases & HIV Medicine Case Western Reserve University University Hospitals Case Medical Center Cleveland, OH William G. Gardner, MD, MACP Consulting Professor in Community and Family Medicine Duke University Director of Internal Medicine Duke Southern Regional AHEC Family Medicine Residency Durham, NC K.V. Gopalakrishna, MD, FACP Chair, Department of Medicine Chief, Infectious Diseases Fairview Hospital Associate Clinical Professor Case Western Reserve University Clinical Professor & Chairman Ohio State University Department of Medicine Chief, Infectious Diseases Fairview General Hospital Cleveland, OH Barbara M. Gripshover, MD Associate Professor of Medicine Department of Medicine Division of Infectious Diseases & HIV Medicine Case Western Reserve University University Hospitals Case Medical Center Cleveland, OH Daniel P. Guyton, MD Professor and Chairman, Department of Surgery Northeastern Ohio Universities College of Medicine Chairman, Department of Surgery

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Akron General Medicine Center Akron, OH Jennifer A. Hanrahan, MD Assistant Professor of Medicine Division of Infectious Diseases Case Western Reserve University MetroHealth Medical Center Cleveland, OH John L. Johnson, MD Professor of Medicine Department of Medicine Division of Infectious Diseases & HIV Medicine Tuberculosis Research Unit Case Western Reserve University University Hospitals Case Medical Center Cleveland, OH Warren S. Joseph, DPM, FIDSA VA Medical Center - Coatesville, PA Huntingdon Valley, PA Carol A. Kauffman, MD, FACP Chief, Infectious Diseases Veterans Affairs Ann Arbor Professor of Internal Medicine University of Michigan VA Medical Center Ann Arbor, MI Charles H. King, MD, FACP Associate Professor of International Health Center for Global Health and Diseases Case Western Reserve University School of Medicine Cleveland, OH Richard B. Kohler, MD, MACP Vice Chair for Education Professor of Medicine Department of Medicine Indiana University School of Medicine Indianapolis, IN Donald P. Levine, MD, FACP Professor of Medicine Chief, General Internal Medicine Wayne State University Health Center Detroit, MI Michelle V. Lisgaris, MD Assistant Professor of Medicine Department of Medicine Division of Infectious Diseases & HIV Medicine

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Contributors

Case Western Reserve University University Hospitals Case Medical Center Cleveland, OH

Carlos R. Ramírez-Ramírez, MD Infectious Diseases Consultant Pavia Hospital San Juan, PR

Scott Mahan, MD Assistant Professor of Medicine Department of Medicine Division of Infectious Diseases Case Western Reserve University MetroHealth Medical Center Cleveland, OH

Carlos H. Ramírez-Ronda, MD, MACP Professor of Medicine University of Puerto Rico School of Medicine Department of Medicine San Juan VA Medical Center San Juan, PR

Thomas J. Marrie, MD, MACP Dean, Faculty of Medicine & Dentistry University of Alberta Edmonton, Alberta Canada

Allan R. Ronald, MD, FRCPC, MACP Section of Infectious Diseases St. Boniface General Hospital Winnipeg, Canada

Farid F. Muakkassa, MD, FACS Professor of Surgery Northeastern Ohio Universities College of Medicine Chief, Trauma/Surgical Critical Care Akron General Hospital Akron, OH

Heather Rupe, DO Chief Resident Department of Obstetrics & Gynecology Summa Health System Northwestern Ohio Universities College of Medicine Akron, OH

Joseph P. Myers, MD, FACP Chair, Department of Medicine Summa Health System Professor of Internal Medicine Infectious Diseases Section Northeastern Ohio Universities College of Medicine Akron, OH

Robert A. Salata, MD, FACP Professor and Vice Chair Department of Medicine Chief, Division of Infectious Diseases & HIV Medicine Case Western Reserve University University Hospitals Case Medical Center Cleveland, OH

Michael S. Niederman, MD, FACP Professor of Medicine SUNY at Stony Brook Chairman Department of Medicine Winthrop University Hospital Mineola, NY

Louis D. Saravolatz, MD, MACP Chair, Department of Internal Medicine St. John Hospital & Medical Center Detroit, MI

William C. Papouras, MD, FACS Clinical Assistant Professor of Surgery Director of Surgery Clerkship Northeastern Ohio Universities College of Medicine Akron General Medical Center Akron, OH

Mark E. Shirtliff, PhD Assistant Professor, Department of Biomedical Sciences Dental School Adjunct Professor Department of Microbiology and Immunology School of Medicine University of Maryland-Baltimore Baltimore, MD

Timothy R. Pasquale, PharmD Clinical Lead, Infectious Diseases Department of Pharmacy Summa Health System Akron, OH

Gary I. Sinclair, MD Assistant Professor of Medicine The University of Texas Southwestern Medical Center Dallas, TX

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Contributors

Lavinia F. Smultea, DO Infectious Disease Fellow Case Western Reserve University Cleveland, OH Jack D. Sobel, MD, FACP Professor of Medicine Chief Division of Infectious Diseases Wayne State University School of Medicine Harper Hospital Detroit, MI Dennis L. Stevens, MD, PhD, FACP Professor, Department of Medicine University of Washington, Seattle Chief, Infectious Diseases Section VA Medical Center Boise, ID James S. Tan, MD, MACP Professor and Vice Chairman of Internal Medicine Head, Infectious Diseases Section Northeastern Ohio Universities College of Medicine Chairman and Residency Director Department of Internal Medicine Summa Health System Akron, OH Michael J. Tan, MD, FACP Assistant Professor of Internal Medicine Northeastern Ohio Universities College of Medicine Summa Health System Akron, OH

Richard B. Thomson, Jr., PhD Professor of Pathology Director, Microbiology & Virology Laboratory Northwestern University Feinberg School of Medicine Evanston Hospital Evanston, IL Jose A. Vasquez, MD, FACP, FIDSA Professor of Medicine Henry Ford Hospital Senior Staff Wayne State University School of Medicine Detroit, MI Arjun Venkataramani, MD, MPH Assistant Professor of Internal Medicine Northeastern Ohio University College of Medicine Akron, OH Kathryn Wright, MD Resident Summa Health System Akron City Hospital Akron, OH Mohamed Yassin, MD, MBBS Attending Physician Maryland General Hospital Internal Medicine Department Infectious Diseases Section University of Maryland Baltimore, MD

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Preface to the First Edition

T

he purpose of this newest volume in the ACP Expert Guide series is to provide up-to-date information on common infectious diseases encountered in the office of the primary care physician. Infections comprise a sizable proportion of the common, and less common, diseases seen in the office as well as in the hospital. Physicians are expected to know not only the basic clinical manifestations of each infection but also the names of the etiologic agents, the new diagnostic tests, and the new therapies. With the number of new antimicrobial agents increasing yearly, it has been ever more difficult for practicing physicians to distinguish and master all the treatments and therapies that could be useful to their patients. Many physicians have not kept up with advances in clinical microbiology since their graduation from medical school. The first chapter introduces the proper use of clinical microbiology and discusses some of the recent advances in diagnostic techniques. The most appropriate and practical diagnostic tests for the more commonly encountered diseases are reviewed. Richard Thomson, a clinical microbiologist with extensive experience, was asked to write this chapter because of his ability to clearly convey clinical microbiology information to the practicing physician. The discussion of individual diseases begins with common central nervous system infections, with emphasis on bacterial infections such as meningitis and brain abscess. Two chapters are then devoted to heart and vascular infections. The first, on endocarditis, was written by Chatrchai Watanakunakorn, one of the most active researchers in this field. Sadly, this close friend and colleague passed away in July 2001. Because of the increased use of vascular devices, the second chapter in this section considers native vascular and device-associated infections. Infections in the gastrointestinal tract, including diarrhea, hepatitis, and surgical diseases, continue to be commonly encountered in the primary care practice, and five chapters are devoted to them here. The following xiii

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section focuses on genitourinary infections, including sexually transmitted diseases and papillomavirus, the latter meriting a separate chapter because of its increasing importance in the detection of cervical cancer. Respiratory tract infections are one of the most common reasons for prescription of antimicrobial agents in the United States. Itzhak Brook, Thomas Marrie, and Thomas File, all members of guidelines committees of important medical societies, were among the contributors to this section, the longest in the book. Bone infections and skin infections are commonly seen in patients; however, diagnosis does not always come easy. Without intending to be exhaustive, the chapters in these two sections provide important principles that will guide physicians in their management of these problems. HIV infection is one of leading causes of death in the world. Because of rapid advances in the diagnostic and therapeutic fields, the clinician is urged to consult the most recent literature and specialists in treating HIV patients. Our purpose herein has been to give the basic information the physician needs to manage the patient with this infection. Opportunistic fungal, mycobacterial, viral, and Pneumocystis infections are next reviewed. The final two chapters discuss Lyme disease (included because of its prevalence in certain geographic areas of the United States) and malaria (representing the parasitic infections). The authors have written with clarity and conciseness. For the convenience of the reader, helpful tables on diagnosis and treatment recommendations have been provided throughout the text. Expert Guide to Infectious Diseases cannot be the final word on a subject so vast. Its aim is more modest but of equal importance: to be the best source for the essential information sought by the primary care physician. James S. Tan, MD

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Preface to the Second Edition

A

s co-editors of the Expert Guide to Infectious Diseases, second edition, we are honored to contribute to an update of the first edition that was so expertly edited by James Tan, MD, MACP. Sadly, Jim passed away in May 2006; a brief description of some of his many accomplishments is included on the In Memoriam page. At the time of his passing, Jim was actively supervising this second edition, and he kindly asked us to assist with its completion. We are pleased and privileged to have done so, and believe we have preserved Jim’s desire for a concise, complete guide for the primary care physician. As stated in the Preface to the first edition, the primary purpose of this volume of the ACP Expert Guide series is to provide up-to-date information on common infectious diseases encountered within the office and hospital setting by the practicing primary care physician. We have added Key Learning Points to every chapter, and separate New Developments boxes highlighting important changes and advances within each subject area that have particular relevance for the primary care provider. Additionally, we have created a large Appendix that summarizes, in convenient table form, recommended antimicrobial therapy for the most common pathogens and infections discussed within this book. The compilation of this table was largely done by one of the contributing authors, Tim Pasquale, PharmD, to whom we are very grateful. We feel this appendix provides an easy-to-use, quick reference for all practitioners in primary care practice. We thank all of the contributing authors for their expertise and excellent discussions. We are confident that this new edition of Expert Guide to Infectious Diseases will be a useful source of essential infectious disease

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information for primary care practitioners and help them provide the best care for their patients. We wish to thank Betty Loucks for her administrative assistance for this, as well as the first edition. TMF, Jr. RAS MJT

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Contents

PA R T I

ANTIMICROBIALS AND L A B O R AT O R Y T E S T S

1. Antimicrobial Agents for the Primary Care Physician. . . . . . . . . . 3 Timothy R. Pasquale and James S. Tan 2. Use of Microbiology Laboratory Tests in the Diagnosis of Infectious Diseases . . . . . . . . . . . . . . . . . . . . . . . 15 Richard Thomson, Jr.

PA R T I I

CENTRAL NERVOUS SYSTEM INFECTIONS

3. Bacterial Meningitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 Carlos H. Ramírez-Ronda and Carlos R. Ramírez-Ramírez 4. Viral Meningitis and Viral Encephalitis . . . . . . . . . . . . . . . . . . . 80 K.V. Gopalakrishna and Manmeet S. Ahluwalia 5. Brain Abscess . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 Scott A. Fulton and Robert A. Salata

PA R T I I I

HEART

AND

VA S C U L A R I N F E C T I O N S

6. Infective Endocarditis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 Jack Ebright and Donald P. Levine 7. Vascular Infections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126 Louis D. Saravolatz

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PA R T I V

GASTROINTESTINAL INFECTIONS

8. Infectious Diarrhea and Gastroenteritis . . . . . . . . . . . . . . . . . 143 Keith B. Armitage and Robert A. Salata 9. Biliary Tract Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168 Lavinia F. Smultea and Curtis J. Donskey 10. Viral Hepatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185 Hector Bonilla and Arjun Venkataramani 11. Peritonitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204 Jennifer A. Hanrahan and Robert A. Bonomo 12. Intra-Abdominal Abscess . . . . . . . . . . . . . . . . . . . . . . . . . . . 223 Farid F. Muakkassa, William C. Papouras, and Daniel P. Guyton

PA R T V

GENITOURINARY INFECTIONS

13. Urinary Tract Infections in Adults . . . . . . . . . . . . . . . . . . . . . 245 Allen R. Ronald 14. Prostatitis and Epididymitis . . . . . . . . . . . . . . . . . . . . . . . . . 266 Keith B. Armitage and Catherine Markin Colecraft 15. Common Sexually Transmitted Diseases . . . . . . . . . . . . . . . . 284 Richard Beigi and Barbara M. Gripshover 16. Pelvic Inflammatory Disease . . . . . . . . . . . . . . . . . . . . . . . . 313 Robert F. Flora, Heather Rupe, and James Fanning 17. Vaginitis and Cervicitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326 J. D. Sobel 18. Papilloma Virus and Cervical Cancer . . . . . . . . . . . . . . . . . . 352 James Fanning, Kathryn Wright, Bradford W. Fenton, and Robert F. Flora

PA R T V I

R E S P I R AT O R Y T R A C T I N F E C T I O N S

19. Pharyngotonsillitis, Peritonsillar, Retropharyngeal, and Parapharyngeal Abscesses, and Epiglottitis . . . . . . . . . . . . . . 365 Itzhak Brook

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20. Sinusitis and Otitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387 David H. Canaday and Robert A. Salata 21. Acute Bronchitis and Exacerbations of Chronic Bronchitis . . . 401 Richard B. Kohler and James S. Tan 22. Influenza and Other Viral Respiratory Tract Infections. . . . . . 417 Jason W. Chien and John L. Johnson 23. Community-Acquired Pneumonia . . . . . . . . . . . . . . . . . . . . . 450 Thomas J. Marrie 24. Nosocomial Pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . 480 Thomas M. File, Jr. and Michael Niederman 25. Tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495 Scott Mahan and John J. Johnson

PA R T V I I

DEEP FUNGUS INFECTIONS

26. Blastomycosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 521 Carol A. Kauffman 27. Candidiasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 527 Carol A. Kauffman 28. Coccidioidomycosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 541 Carol A. Kauffman 29. Histoplasmosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 549 Carol A. Kauffman 30. Aspergillosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 559 Jose A. Vasquez

PA R T V I I I

SKIN, BONE INFECTIONS

AND

JOINT

31. Septic Athritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 581 William G. Gardner 32. Prosthetic Joint Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . 599 Anthony R. Berendt

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33. Osteomyelitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 609 Jason H. Calhoun, Rebecca A. Brady, and Mark E. Shirtliff 34. Superficial Skin Infections (Pyodermas) . . . . . . . . . . . . . . . . 629 Thomas M. File, Jr. and Dennis L. Stevens 35. Necrotizing Soft Tissue Infections. . . . . . . . . . . . . . . . . . . . . 643 Thomas M. File, Jr. and Dennis L. Stevens 36. Foot Infections in Patients with Diabetes Mellitus . . . . . . . . . 663 Warren S. Joseph and James S. Tan 37. Bite-Wound Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 680 Joseph P. Myers 38. Viral Exanthems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 699 Blaise L. Congeni

PA R T I X

I M M U N O C O M P R O M I S E D - R E L AT E D INFECTIONS

39. HIV Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 723 Joseph C. Chan and Rafael E. Campo 40. Opportunistic Infections in Patients with AIDS . . . . . . . . . . . 760 Michael J. Tan 41. Opportunistic Infections in the Immunocompromised Host . . 777 David A. Bobak and Robert A. Salata 42. Herpes Virus Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . 800 Michelle V. Lisgaris and Gary I. Sinclair

PA R T X

MISCELLANEOUS INFECTIONS

43. Tick-Borne Infections: Lyme Borreliosis, Ehrlichiosis and Anaplasmosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 833 Johan S. Bakken and J. Stephen Dumler

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Contents

44. Malaria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 853 Keith B. Armitage and Charles H. King Appendix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 871 Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 909

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Part I

Antimicrobials and Laboratory Tests

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Chapter 1

Antimicrobial Agents for the Primary Care Physician TIMOTHY R. PASQUALE, PHARMD JAMES S. TAN, MD

Key Learning Points 1. Several reports have described the association of patients receiving inappropriate antimicrobial therapy with increased morbidity and mortality. 2. Goal of antibiotic prophylaxis in surgical patients is to have drug concentrations in the serum and tissue exceeding the MIC of the organism likely to be encountered for the duration of the operation. 3. Appropriate empirical antimicrobial usage requires consideration of a number of factors, including knowledge of the most likely pathogens. 4. Pharmacokinetics is simply what the host does to the drug. 5. Pharmacodynamics is the relationship between concentration and pharmacological/toxicological effects of a drug. 6. A drug must not only reach the site of infection, but achieve adequate concentration in order for an optimal effect to occur. 7. The minimal inhibitory concentration (MIC) is a good predictor of the potency of an antimicrobial agent against an infecting organism, but does not always equate to treatment success. 8. The goal for optimal dosing in time-dependent agents (i.e., penicillins, cephalosporins, vancomycin, etc.) is to achieve drug concentration above the MIC for at least 40-50% of the dosing interval. 9. The goal for optimal dosing in concentration-dependent agents is to maximize the AUC/MIC ratio (i.e., fluoroquinolones) or the peak/MIC ratio (i.e., aminoglycosides). 3

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Expert Guide to Infectious Diseases

New Developments in Antimicrobial Therapy • An advisory statement from the National Surgical Infection Prevention Project recommends the first antimicrobial prophylactic dose should be given within 60 minutes before surgical incision, and the prophylactic antimicrobial should be discontinued within 24 hours after the end of surgery. • A recent review found that bactericidal antimicrobials are not considered superior to bacteriostatic agents except in certain infections such as endocarditis, meningitis, and neutropenia.

Antimicrobial Therapy Empirical Antimicrobial resistance is an ongoing problem that has plagued institutions over the last several decades. In addition, awareness of antimicrobial resistance in the community is increasing with the emergence of communityacquired methicillin-resistant Staphylococcus aureus infections. Over the last decade several reports described the association of patients receiving inappropriate antimicrobial therapy with increased morbidity and mortality (1-5). Inappropriate antimicrobial therapy is defined as failure to provide an antimicrobial agent with activity against the causative pathogen based on the results of in-vitro susceptibility testing (3). Considering these two significant factors, the issue of appropriate antimicrobial therapy has emerged to the forefront for clinicians. An appropriate empirical antimicrobial regimen requires a clinician to consider a number of factors. First, the antimicrobial agent chosen is based on the likelihood of a specific infection. Second, the clinician must have knowledge regarding the most likely pathogens that are encountered in the specific infection. Third, the clinician must have awareness to the most likely predicted susceptibility patterns of the pathogen. A fourth factor to consider is the characteristics of the host (e.g., site of infection, age, renal and hepatic function, pregnancy, and drug interactions). Finally, the characteristics of the drug—concentration-dependent killing, time-dependent killing, bactericidal versus bacteriostatic, route of administration, and halflife—should be taken into consideration. Recommended antimicrobial regimens for adults for specific infections are listed in the Appendix. These recommendations were obtained from the chapters within this edition of the Expert Guide to Infectious Diseases.

Antimicrobials for Surgical Prophylaxis Surgical site infections remain a common cause of nosocomial infections and are associated with increased morbidity and mortality. Primary care physicians often have patients that have surgery and require preventative

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antimicrobial therapy. The goal of antibiotic prophylaxis in surgical patients is to have drug concentrations in the serum and tissue exceeding the MIC of the organism likely to be encountered for the duration of the operation (6). Appropriate selection and timing of antimicrobial prophylaxis in surgical patients is crucial. Recommendations for antibiotic prophylaxis in patients undergoing common surgical procedures are listed in Table 1-1.

Table 1-1 Recommendations for Antibiotic Prophylaxis for Common Surgical Procedures (6, 25-27). Type of Surgery

Common Pathogens

Prophylaxis1

Cardiothoracic Surgery

Prosthetic valve, coronary Staphylococcus aureus artery bypass, other Staphylococcus epidermidis open-heart surgery, pacemaker, or defibrillator

Cefazolin 1-2 g IV2 or cefuroxime 1.5 g IV2 or vancomycin 1 g IV3 or clindamycin 600-900 mg IV

Gastrointestinal Surgery

Esophageal, gastroduodenal6 Biliary tract Colorectal

Appendectomy, nonperforated

Enteric gram-negative bacilli, Cefazolin 1-2 g IV4 gram-positive cocci Enteric gram-negative bacilli, Cefazolin 1-2 g IV5 enterococci, clostridia Enteric gram-negative bacilli, Oral: neomycin plus enterococci, anaerobes erythromycin base7 Parenteral: cefoxitin or cefazolin 1-2 g IV + metronidazole 500 mg IV Enteric gram-negative bacilli, Cefoxitin 1-2 g IV enterococci, anaerobes

Gynecologic and Obstetric

Vaginal or abdominal hysterectomy Cesarean section

Enteric gram-negatives, Cefazolin 1-2 g IV or anaerobes, group B cefoxitin 1-2 g IV or streptococcus, enterococci cefotetan 1-2 g IV Enteric gram-negatives, High risk only8: cefazolin anaerobes, Group B 1-2 g IV after cord

clamping Abortion

Streptococcus, enterococci Enteric gram-negatives, First trimester, high risk9: anaerobes, group B penicillin G 2 million streptococcus, enterococci units IV or doxycycline 300 mg PO10 Second trimester: cefazolin 1 g IV

Head and Neck Surgery

Incisions through oral or pharyngeal mucosa

S. aureus, enteric gramClindamycin 600-900 mg negative bacilli, anaerobes IV + gentamicin 1.5 mg/kg IV or cefazolin 1-2 g IV Continued

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Table 1-1 Continued Type of Surgery

Common Pathogens

Prophylaxis1

Neurosurgery

Craniotomy, cerebrospinal S. aureus, S. epidermidis fluid shunting

Cefazolin 1-2 g IV or vancomycin 1 g IV3

Ophthalmic Surgery

S. epidermidis, S. aureus, Topical gentamicin, streptococci, enteric gramtobramycin, ciprofloxacin, negative bacilli, ofloxacin, or neomycinPseudomonas species gramicidin-polymyxin B (multiple drops topically over 2 to 24 hours) or cefazolin 100 mg subconjunctivally Orthopedic Surgery

Total joint replacement, internal fixation of fractures

S. aureus, S. epidermidis


S. aureus, S. epidermidis

Cefazolin 1-2 g IV or cefuroxime 1.5 g IV or vancomycin 1 g IV3 + gentamicin 3 mg/kg IV

S. aureus, S. epidermidis, Streptococci, enteric gram-negative bacilli

Cefazolin 1-2 g IV or cefuroxime 1.5 g IV or vancomycin 1 g IV3

Spine Surgery

Thoracic (noncardiac)

Pulmonary surgery

Vascular Surgery

Arterial surgery S. aureus, S. epidermidis involving a prosthesis, enteric gram-negative the abdominal aorta, bacilli or a groin incision Lower extremity S. aureus, S. epidermidis amputation for ischemia enteric gram-negative bacilli, Clostridia



Urologic Surgery

High-risk patients only: Enteric gram-negative Urine culture positive bacilli, enterococci or unavailable, presence of preoperative urine catheter, or transrectal biopsies

Ciprofloxacin 500 mg PO or 400 mg IV

Contaminated Surgery11

Ruptured viscus

Enteric gram-negative bacilli, Cefoxitin 1-2 g q 6 h IV or anaerobes, enterococci cefotetan 1-2 g q 12 h IV ± gentamicin 1.5 mg/kg q8h Continued

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Table 1-1 Continued Type of Surgery

Traumatic wound

Common Pathogens

S. aureus, group A streptococcus, Clostridia

Prophylaxis1

IV or clindamycin 600 mg q 6 h IV + gentamicin 1.5 mg/kg q 8 h IV Cefazolin 1-2 g IV q 8 h

Abbreviations: IV, intravenous; PO, orally; q, every. 1. Recommended for prophylactic antibiotics to be given as a single intravenous dose completed 30 minutes or less before operation. Additional intraoperative doses should be given every 4 to 8 hours for the duration of the operation. 2. An additional dose when patients are removed from bypass during surgery is recommended. 3. Recommended only when methicillin-resistant S. aureus (MRSA) and methicillin-resistant Staphylococcus epidermidis (MRSE) are a frequent cause of wound infection. 4. Recommended for high-risk patients such as those with morbid obesity, esophageal obstruction, decreased gastric acidity, or gastrointestinal motility. 5. Recommended for high-risk patients such as those older than 70 years of age, or with acute cholecystitis, nonfunctioning gallbladder, obstructive jaundice, or common duct stones. 6. Placement of percutaneous endoscopic gastrostomy (PEG) tube. 7. After appropriate diet and catharsis, one gram of each at 1 p.m., 2 p.m., and 11 p.m. the day before an 8 a.m. operation. 8. Active labor or premature rupture of membranes. 9. Patients with previous pelvic inflammatory disease, previous gonorrhea, or multiple sex partners. 10. Divided into 100 mg 1 hour before the abortion and 200 mg 30 minutes after. 11. Antimicrobial agents for these operations are considered therapy rather than prophylaxis and should be continued postoperatively for several days.

Pharmacokinetics and Pharmacodynamics Over the past several decades, knowledge of the interactions between antimicrobial agents and the microbes in the host has become clearer. In order for an antimicrobial agent to exert its effect on the bacterial cell, the antimicrobial must have the ability to reach the target site, achieve adequate concentration at the site, and remain there for a sufficient time to accomplish its mission. This drug-host-microbe system is very complex and involves the interaction of multiple factors. Two distinct components of this drug-host system are pharmacokinetics and pharmacodynamics. Pharmacokinetics involves the absorption, distribution, metabolism, and excretion of a drug or simply what the host does to the drug. Pharmacodynamics encompasses the relationship between serum concentrations as well as tissue concentrations and the pharmacological and toxicological effects of the drug on the host and microbe. In simple terms, pharmacodynamics is what the drug does in the host to the bacteria. The integration of these principles can be used to optimize dosing to maximize the clinical efficacy of antimicrobials and minimize any potential adverse toxicities. A brief review of the general principles of pharmacokinetics and pharmacodynamics and their clinical application will be provided.

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Pharmacokinetics Absorption Absorption of a drug is a dynamic process that occurs at different sites of administration (e.g., intramuscular, subcutaneous, topical, rectal, or oral) other than a physiologic fluid component (e.g., intravenous). The rate and extent of absorption can vary among different drugs and different formulations of the same drug. The percentage of the total amount of drug that reaches systemic circulation is the drug bioavailability. The route of administration can have a significant affect on the bioavailability of a medication. A drug administered via intravenous tends to have a 100% bioavailability, although drugs administered via other routes such as oral, intramuscular, subcutaneous, and rectal have reduced bioavailability ( MIC) (11). These agents are most effective when the serum drug concentrations remain greater than the MIC of the infecting bacteria (11). The efficacy of these agents is not greatly enhanced by increasing drug concentrations above the minimal bactericidal concentration (11). However, when drug concentrations at the site of infection fall below the MIC, residual bacterial populations can regrow quickly (especially for beta-lactams because they lack or have no PAE) (11). The

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rate and extent of killing stays essentially constant once the concentration is approximately four times the MIC of the pathogen. The efficacy of these agents can be maximized by the dosing to ensure the optimal duration of drug exposure. The optimal time to be above the MIC is variable depending on the pathogen, infection site, and drug. Studies done in animal infection models show that antibiotic concentrations do not have to exceed the MIC for 100% of the dosing interval. It is generally accepted that the T > MIC be at least 40% to 50% of the dosing interval for optimal effect (13,15). The relationship between efficacy and the T > MIC in clinical situations was assessed. The bacteriologic cure for beta-lactam antibiotics against Streptococcus pneumoniae and Haemophilus influenzae was evaluated in patients with acute otitis-media infections. These studies demonstrated a T > MIC of greater than 40% was necessary to achieve an 85% to 100% bacteriologic cure rate (11,16-19). The principle in using timedependent killing agents is to maintain levels above the MIC for at least 40% to 50% of the time between dosing intervals. This can be achieved with continuous infusion, extended infusion (e.g., extending the infusion time of the agent given intermittently from 30 minutes to 3 hours), or using drugs with long half-lives. Agents that exhibit concentration-dependent killing include aminoglycosides, fluoroquinolones, azalide, ketolides, and metronidazole. The goal of therapy for these agents is to maximize the concentration and attain the highest concentration possible at the site of infection without producing toxicity. The greater the concentration above the MIC, the greater killing these agents produce. Two good parameters to indicate the extent of antibiotic exposure or maximal concentration are the area under the serum concentration curve (AUC) and peak drug concentration as they are dependent on dose, absorption, and clearance of a drug. The pharmacodynamic parameters that correlate with clinical and bacteriologic efficacy are the 24-hour AUC to MIC ratio (AUC:MIC), or peak drug concentration to MIC ratio (peak:MIC). There are two pharmacodynamic parameters associated with the aminoglycosides. Animal and in-vitro models show the 24-hour AUC to MIC ratio as an important parameter (20). The 24-hour AUC:MIC ratio of 80:100 produced maximum effects against a strain of Escherichia coli (20). Although, the pharmacodynamic parameter generally accepted to be associated with aminoglycosides is the peak:MIC ratio. Several studies supported the correlation between peak:MIC ratio and clinical efficacy. Kashuba and others demonstrated in patients with nosocomial pneumonia caused by gram-negative bacteria that a peak:MIC ratio of 10 or greater within the first 48 hours of aminoglycoside therapy was associated with a 90% probability of a therapeutic response by day 7 (21). The aminoglycosides are also associated with adaptive resistance (22). A short-term decrease in drug uptake and bactericidal activity of bacteria occurs when it is initially exposed to low drug concentrations. Thus, the

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goal of aminoglycosides is to optimize the dosage to produce higher drug concentrations. The 24-hour AUC:MIC ratio is the best pharmacodynamic parameter associated with efficacy of fluoroquinolones. The targeted AUC:MIC ratio for fluoroquinolones varies for gram-positive and gram-negative pathogens. For gram-negative pathogens, the accepted AUC:MIC ratio is greater than or equal to 125. Forrest and others demonstrated that a 24-hour AUC:MIC ratio of greater than or equal to 125 was associated with a satisfactory outcome for seriously ill patients treated with intravenous ciprofloxacin (23). Lower values resulted in clinical and bacteriologic cure rates at less than 50% (22). In addition, AUC:MIC ratios of less than 100 are associated with the development of antimicrobial resistance (24). For gram-positive pathogens (specifically Streptococcus pneumoniae), an AUC:MIC of 30 is the breakpoint that is generally accepted to maximize killing and minimize the development of resistance (12,14,15). The principle in using concentration-dependent killing agents is to give a high-dose bolus of the agent at a twice- or once-a-day interval depending on the drug.

Summary The information to date suggests that the dose is not a good predictor of outcome. Pharmacokinetic and pharmacodynamic characteristics are probably a better predictor of outcomes as they play a vital role in the efficacy of antimicrobial therapy. Over the past several decades, knowledge of antimicrobials’ pharmacokinetic and pharmacodynamic properties has increased significantly and has provided a better understanding of the complex drug-host interaction that occurs. Pharmacokinetics and pharmacodynamics are two distinct components of this complex interaction, but go hand in hand with each other. A drug must not only reach the site of infection, but achieve adequate concentration at the site of infection for an optimal effect to occur. Most of the pharmacodynamic data available has been generated through the use of in-vitro models. More patient experience is warranted to validate the information that has been obtained from experimental models. REFERENCES 1. Leone M, Bourgoin A, Cambon S, Dubuc M,Albanèse J, Martin C. Empirical antimicrobial therapy of septic shock patients: adequacy and impact on the outcome. Crit Care Med. 2003;31:462-7. 2. Luna CM, Vujacich P, Niederman MS, Vay C, Gherardi C, Matera J, et al. Impact of BAL data on the therapy and outcome of ventilator-associated pneumonia. Chest. 1997;111:676-85. 3. Kollef MH, Sherman G,Ward S, Fraser VJ. Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients. Chest. 1999;115:462-74. 4. Ibrahim EH, Sherman G,Ward S, Fraser VJ, Kollef MH. The influence of inadequate antimicrobial treatment of bloodstream infections on patient outcomes in the ICU setting. Chest. 2000;118:146-55.

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5. Cosgrove SE, Sakoulas G, Perencevich EN, Schwaber MJ, Karchmer AW, Carmeli Y. Comparison of mortality associated with methicillin-resistant and methicillin-susceptible Staphylococcus aureus bacteremia: a meta-analysis. Clin Infect Dis. 2003;36:53-9. 6. Surgical Infection Prevention Guidelines Writers Workgroup. Antimicrobial prophylaxis for surgery: an advisory statement from the National Surgical Infection Prevention Project. Clin Infect Dis. 2004;38:1706-15. 7. Wilkinson GR. Pharmacokinetics: The dynamics of drug absorption, distribution and elimination. In: Hardman JG, Limbird LE, Gilman AG, eds. The Pharmacological Basis of Therapeutics. 10th ed. New York: McGraw-Hill; 2001:3-30. 8. Amsden GW, Ballow CH, Bertino Jr. JS, Kashuba ADM. Pharmacokinetics and pharmacodynamics of anti-infective agents. In: Mandell G, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Disease. 5th ed. New York: Churchill Livingstone; 2000:271-81. 9. Nicolau DP, Quintiliani R, Nightingale CH. Antibiotic kinetics and dynamics for the clinician. Med Clin North Am. 1995 May;79(3):477-95. 10. Pankey GA, Sabath LD. Clinical relevance of bacteriostatic versus bactericidal mechanisms of action in the treatment of Gram-positive bacterial infections. Clin Infect Dis. 2004;38:864-70. 11. Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis. 1998;26:1-10; quiz 11-2. 12. Levison ME. Pharmacodynamics of antibacterial drugs. Infect Dis Clin North Am. 2000 Jun;14(2):281-91. 13. Jacobs MR. Optimisation of antimicrobial therapy using pharmacokinetic and pharmacodynamic parameters. Clin Microbiol Infect. 2001;7:589-96. 14. Gunderson BW, Ross GH, Ibrahim KH, Rotschafer JC. What do we really know about antibiotic pharmacodynamics? Pharmacother. 2001;21(10 pt 2):302S-18S. 15. Craig WA. Does the dose matter? Clin Infect Dis. 2001;33(suppl 3):S233-7. 16. Howie V. Eradication of bacterial pathogens from middle ear infections. Clin Infect Dis. 1992;14(suppl 2):S209-11. 17. Klein JO. Microbiologic efficacy of antibacterial drugs for acute otitis media. Pediatr Infect Dis J. 1993;12:973-5. 18. Dagan R,Abramson D, Leibovitz E, et al. Impaired bacteriologic response to oral cephalosporins in acute otitis media caused by pneumococci with intermediate resistance to penicillin. Pediatr Infect Dis. 1996;15:980-5. 19. Hoberman A, Paradise JL, Block S, Burch DJ, Jacobs MR, Balanescu MI. Efficacy of amoxicillin/clavulanate for acute otitis media: relation to Streptococcus pneumoniae susceptibility. Pediatr Infect Dis J. 1996;15:955-62. 20. Vogelman B, Gudmundsson S, Leggett J,Turnidge J, Ebert S, Craig WA. Correlation of antimicrobial pharmacokinetic parameters with therapeutic efficacy in an animal model. J Infect Dis. 1988;158:831-47. 21. Kashuba AD, Nafziger AN, Drusano GL, Bertino JS Jr. Optimizing aminoglycoside therapy for nosocomial pneumonia caused by gram-negative bacteria. Antimicrob Agents Chemother. 1999;43:623-9. 22. Rodvold KA. Pharmacodynamics of antiinfective therapy: Taking what we know to the patient’s bedside. Pharmacother. 2001;21(11 pt 2):319S-30S. 23. Forrest A, Nix DE, Ballow CH, Goss TF, Birmingham MC, Schentag JJ. Pharmacodynamics of intravenous ciprofloxacin in seriously ill patients. Antimicrob Agents Chemother. 1993;37:1073-81. 24. Schentag JJ, Gilliland KK, Paladino JA. What have we learned from pharmacokinetic and pharmacodynamic theories? Clin Infect Dis. 2001;32(suppl 1):S39-46. 25. Antimicrobial prophylaxis in surgery. Med Lett Drugs Ther. 2001;43:92-7. 26. ASHP Therapeutic Guidelines on Antimicrobial Prophylaxis in Surgery. American Society of Health-System Pharmacists. Am J Health Syst Pharm. 1999;56:1839-88. 27. Brown EM, Pople IK, de Louvois J, et al for the British Society of Antimicrobial Chemotherapy Working Party on Neurosurgical Infections. Spine update: Prevention of postoperative infection in patients undergoing spinal surgery. Spine. 2004;29(8):938-45.

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Chapter 2

Use of Microbiology Laboratory Tests in the Diagnosis of Infectious Diseases RICHARD THOMPSON, JR., PHD

Key Learning Points 1. Communication of the suspected diagnosis with the microbiology lab will help the laboratory professional select appropriate media and look for particular organisms. 2. Available testing modalities are constantly changing; there should be open communication between the clinician and the laboratory to ensure appropriate tests are ordered and to explain nuances that are not conveyed through reporting. 3. Specimens submitted to the microbiology laboratory need to be collected on appropriate media and handled correctly while being delivered to the laboratory in a timely fashion. 4. Quality of the results will often depend on the quality of the specimen and clinical information submitted. 5. Interpretation of results by the clinician may vary, and clinical information must be taken into consideration. 6. Antigen detection, serology, and molecular assays can aid with diagnosis but negative results often will not be enough to exclude a diagnosis.

T

he microbiology laboratory has changed in recent years. Automation, the use of molecular testing, new or reemerging infectious diseases, regulation and cost controls, and consolidation of laboratory services has changed the face of microbiology. Medical school education has moved away from teaching lists of microorganisms and diseases that prepare future physicians for laboratory reports. In addition, primary care physicians and other laboratory users are too busy to keep up with the changing science 15

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New Developments in Laboratory Testing and Diagnosis • Many newer methods, including polymerase chain reaction and antigen detection, can aid in the detection of microorganisms. These methods may speed detection and diagnosis; however, they are not 100% sensitive. • Changes to the microbiology laboratory in recent years include more use of automation and molecular testing, more newly available diagnostic tests, and the increasing presence of new or reemerging infectious disease. These changes require the clinician to have open communication with the microbiology lab.

of laboratory testing. All these developments have resulted in widespread misunderstanding of laboratory testing. This chapter serves as a reminder and an update of important clinical microbiology principles that enable full and appropriate use of microbiology tests and test results. The laboratory diagnosis of infectious diseases requires the detection of etiologic microorganisms or antibodies specific for the etiologies. Microorganisms can be detected by staining and recognition of characteristic morphology and tissue histopathology, by culture and identification of the isolate, and by detection of antigens or nucleic acid (RNA or DNA) unique to the pathogen. Serologic testing for specific antibodies can be performed by many different methods, all of which are designed to detect the presence or absence of antibody, the relative amount of specific antibody, and the class of antibody or immunoglobulin (IgM, IgG, etc.) present. Table 2-1 summarizes the use of microbiology tests in the diagnosis of infectious diseases. Regardless of the diagnostic approach used, communication between the laboratory professional and clinician is essential to proper selection and interpretation of tests and results (1). Evolving technology, emerging infec-

Table 2-1 Summary of Laboratory Tests for the Detection of Infectious Diseases Test

Detects

Use

Microscopic examination Histopathologic examination Culture

Inflammatory cells and microorganisms Inflammatory reaction and microorganisms Microorganisms

Rapid etiologic diagnosis

Antigen detection (EIA, FA, latex) Nucleic acid detection (e.g., PCR) Serology

Microorganisms Microorganism DNA or RNA Antibody

Pathologic reaction and microorganism morphology Isolate for definitive identification and antimicrobial testing Rapid etiologic diagnosis Rapid detection or detection of microorganism that does not grow in culture Establish immune status or active disease

Abbreviations: EIA, enzyme immunoassay; FA, fluorescent antibody; Latex, latex agglutination; PCR, polymerase chain reaction.

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tious diseases, and the need to provide rapid, economical testing fuel the need for communication. Communication can be accomplished by wellorganized test requisitions and clearly formatted computer reports but often requires verbal exchange to convey important nuances. The need for a primary care physician to discuss a radiograph with a radiologist or for a surgeon to review a surgical pathology slide and report with a pathologist is a well-established practice that improves the clinician’s understanding of diagnostic and treatment options. Reviewing specific laboratory data with a laboratory pathologist or scientist, beyond checking normal values, is a step in the diagnostic process that has been lost during recent years as laboratories have moved off site and as work schedules have become more hectic. The responsibility for establishing channels of communication lies with both the clinician and the laboratorian. Issues in the laboratory diagnosis of infectious diseases that are enhanced by communication over and above the usual test requisitions and preliminary and final computer reports include the following: ●

●

● ●

●

●

●

Selecting the correct test including those for the detection of unusual pathogens (e.g., Leptospira) Selecting among the available multiple tests (e.g., detecting influenza using rapid culture or PCR testing) Collecting and transporting specimens Choosing the appropriate specimen (e.g., urethral, cervical, or urine specimen for the detection of Chlamydia trachomatis) Ensuring the quality of the specimen (e.g., the results of microscopic screening can indicate an inferior specimen) Interpreting the results (e.g., determining if the positive result represents contaminating flora or pathogen) Choosing antimicrobial testing of unusual pathogens for which standard methods are not available

Laboratory Processing Laboratory processing, simply speaking, includes performing all the tests ordered. However, laboratory processing also requires the verification of proper labeling of the specimen, the clear indication of the test(s) that have been requested, the clinical diagnosis or diagnosis code according to the International Classification of Diseases, 9th Edition, and complete billing information. All laboratories have protocols that must be followed for unlabeled specimens to ensure compliance with licensing regulations (2). Specimens that are not labeled with patient-identifying characters or have been mislabeled cannot be processed. Additionally, it is illegal for laboratories to perform tests that have not been requested. Improper test requests cannot be changed without a physician’s written order.

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The clinical diagnosis helps the laboratory technician select appropriate media for a requested culture. Although standard media with inocula from a specific site grow pathogens typical for that site, unusual or fastidious microorganisms can be missed unless specific tests for them are requested or are indicated by the clinical diagnosis. Enterohemorrhagic Escherichia coli, Vibrio species, and Cyclospora cayetanensis are examples of causes of enterocolitis that can go undetected if clinical suspicion is not conveyed to the laboratory.

Principles of Culture Culture represents the century-old gold standard for detecting microorganisms and remains essentially unchanged except for nutritional modifications that allow for growing a wider variety of bacterial species. Bacteria grow by binary fission, with average strains requiring 30 to 60 minutes for one cell to become two or for the total organism count to double. This process, which cannot be accelerated, results in at least an overnight delay before growing bacteria are detected by colony formation. Some microorganisms, such as the mycobacteria, have doubling times that approach 24 hours, resulting in detection times of many weeks. Viruses grow only within other living cells and therefore are isolated in cell cultures that consist of living cells. Cell cultures serve as hosts for the propagation and detection of pathogenic viruses. The average times to detection of microbial colonies (turn-around times) for common microbial cultures and viruses in cell culture are listed in Table 2-2. Table 2-2 Average Turnaround Times for Microbial Cultures and Virus Isolation* Test

Average Time to Detection

Aerobic bacterial culture

16–24 hours

Anaerobic bacterial culture

24–48 hours

Mycobacterium tuberculosis and other slowly growing mycobacteria Mycobacteria—rapidly growing (e.g. M. fortuitum)

1–2 days 3–14 days 3–6 weeks 2–7 days

Fungi—yeasts and molds Fungi—dimorphic pathogens (e.g. Histoplasma, Blastomyces, Coccidiodes) Virus detection

1–5 days 3 days–3 weeks

1 day 1–7 days 2–4 weeks

Comment

Longer if antimicrobials in specimen slow growth Actinomyces spp., can require 1–2 weeks before growth is detected Molecular methods Broth culture methods Solid medium methods Can grow on bacterial culture media (e.g., Mycobacterium fortuitum) (e.g., Histoplasma, Blastomyces, Coccidioides) Molecular methods Virus isolation Some CMV and VZV strains

Abbreviations: CMV, Cytomegalovirus; VZV, varicella-zoster virus. * For culture, time until colonies appear or virus replication in cell culture can be detected.

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Although culture and virus isolation tests can delay the detection or confirmation of an infectious disease, they have many important advantages. Positive cultures provide the following: definitive proof of the presence of a pathogen, organisms for typing in cases of suspected outbreaks, and, most importantly, isolates for antimicrobial testing. Non–culture-based tests for the presence of pathogens (e.g., antigen detection by enzyme or fluorescence methods, and antibody detection in serum) are subject to misleading false-positive and false-negative results. Diagnosis by molecular methods (e.g., detection of pathogen DNA or RNA by PCR) provides results similar to those of culture but cannot provide antimicrobial susceptibility test results. It is for these reasons that culture remains essential for the diagnosis of most infectious diseases.

Specimens for Culture Specimens for culture require specific clinical material collected, stabilized, and transported according to exacting specifications to ensure valid results (3). Table 2-3 lists appropriate and inappropriate microbiology specimens

Table 2-3 Selection of Common Clinical Specimens Disease

Appropriate

Inappropriate

Bronchitis and pneumonia Sinusitis

Sputum (expectorated mucus and inflammatory cells) Secretions, washes, curettage and biopsy material collected during endoscopy procedure Midstream, straight catheterization, suprapubic, and cystoscopy urine Aspiration of pus or local irrigation fluid (nonbacteriostatic saline). Swab of purulence from beneath the dermis Freshly passed stool. Washes and feces collected during endoscopy

Saliva (oropharyngeal material) Nasal or nasopharyngeal secretions, sputum and saliva

Urinary tract infection

Wound infection

Diarrhea

Bacteremia/sepsis

Two to three blood specimens collected from separate venipunctures, before initiation of antibiotics, each containing 20 mL of blood

Urine from Foley catheter collection bag Swab of surface material or specimen contaminated with surface material Rectal swab. Specimen for bacterial culture if diarrhea developed after patient hospitalization for >3 days Clotted blood. One or more than three blood specimens collected within 24 h period. Volume of blood 1 h Freeze during transport Expose to sunlight

Purulence or secretions (swab)

Fluid or purulent aspirate

Urine

Stool

Blood for culture

Blood for serology tests

Clotted blood in sterile tube Refrigerate for delays of 1-4 h Separate serum within 4 h

Use dry container No holding medium Delay >48 h Expose to temperature extremes Do not send to lab in syringe with needle. No anaerobic transport if anaerobes are suspected Delay >48 h before culture

Room temperature holding and transport without using boric acid preservative Expose to temperature extremes No holding medium used Temperature extremes Blood transported in syringe Clotted blood Blood in collection tube containing anticoagulant other than SPS Expose to temperature extremes Blood in nonsterile tube Blood hemolyzed Expose to temperature extremes

Abbreviation: SPS, sodium polyanetholesulfonate.

for the diagnosis of different types of diseases. Table 2-4 lists specimen holding and transportation conditions that are required to maintain viable microorganisms in the relative quantities in which they are found at the time of collection. Poor specimen quality is the single greatest obstacle to the accurate diagnosis of infectious diseases. Diagnoses are missed, and over-diagnoses are made from inaccurate culture reports that stem from improper specimen collection methods or transport conditions. In general, specimens for culture should be collected as soon as possible after the onset of acute disease and before the initiation of antibiotic

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therapy. Collecting a second specimen for culture can be necessary because of poor specimen quality or inadequate transport conditions that affect a first specimen, but it is rarely required in other situations. Exceptions include the collection of multiple blood specimens for culture, additional stool cultures from patients with chronic diarrhea, and additional specimens if unusual or fastidious pathogens need to be added to the list of suspected causes.

Screening to Ensure Specimen Quality Most specimens that are submitted for bacterial culture can be screened to check for quality (4). Table 2-5 lists common specimens and results of

Table 2-5 Screening Specimens to Ensure Quality Specimen

Screening Method

Sputum

Acceptable

Unacceptable

Microscopic

25 SEC/10 × field

Endotracheal aspirate

Microscopic

Bronchoalveolar lavage

Microscopic

1% of cells are SEC

Urine

Superficial wound Stool for bacterial pathogens

Other specimens

Action if Unacceptable

Do not culture without consultation Do not culture without consultation

Culture results can represent oropharyngeal contamination Urinalysis 3+ SEC with Recollect urine. LE+ and/ LE and Infection less or NIT+ NIT − likely Gram stain Leukocytes 3+ or predom- Recollect urine if and bacteria inant SEC infection suspected present present Gram stain 2+ SEC, no Culture results can leukocytes leukocytes represent present contamination Patient Outpatient or In hospital Consider Clostridium location, inpatient >3 days and difficile testing duration of 105 CFU/mL in quantitative culture

Isolate not seen in Gram stain and 102 CFU/mL Urine LE positive

Isolate equal to or less than contaminating flora

Urine— midstream, patient with asymptomatic bacteriuria Urine— midstream, male with UTI

Urine—“straight” catheter, all patients Urine—Foley catheter, all patients Superficial wound

Isolate >105 CFU/mL Urine LE positive

Additional Data Suggesting Isolate Is a Pathogen

Gram stain shows potential pathogen within leukocytes (intracellular bacteria) Gram stain shows potential pathogen within leukocytes (intracellular bacteria). For patients with prior antimicrobials, clinical judgment rather than quantitative counts Gram stain shows potential pathogen within leukocytes and/or casts Confirm by repeating urine culture

Isolate 105 CFU/mL LE positive or negative mL and equal to potential pathogen or less than conwithin leukocytes taminating flora and/or casts (when present) Isolate 103 CFU/mL Urine LE positive mL and equal to potential pathogen or less than conwithin leukocytes taminating flora and/or casts (when present) Isolate 103 CFU/mL and LE positive in mL and LE potential pathogen symptomatic patients negative within leukocytes and/or casts Isolates detected Do not culture if Isolate >103 CFU/mL; multiple pathogens in asymptomatic patient can be present patients asymptomatic Urine LE positive Isolate predominates SEC present and Gram stain shows in Gram stain and neutrophils potential pathogen culture absent within leukocytes Neutrophils abundant, (intracellular no SEC bacteria) Continued

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Table 2-6 Continued

Specimen

Potential Pathogen

Fluids (e.g., CSF) and deep tissue biopsy

Neutrophils present Isolate in Gram stain and culture If Gram stain is negative, multiple colonies of isolate present on culture plates Isolate in one or more cultures

Blood

Not Potential Pathogen

Additional Data Suggesting Isolate Is a Pathogen

Neutrophils absent. Gram stain shows If Gram stain is potential pathogen negative, single within leukocytes colony on plate or growth in broth only

Detection of Pathogen coagulasematching blood negative isolate detected staphylococci, at primary site Corynebacteof infection (e.g., rium, Bacillus, urinary tract) and saprophytic Neisseria in one culture only

Abbreviations: CFU, colony forming units; CSF, cerebrospinal fluid; LE, leukocyte esterase; SEC, squamous epithelial cells.

nation of stained smears; microbial antigen detection by fluorescent antibody staining, or enzyme immunoassay or latex agglutination (LA); and detection of microbial genes by molecular methods such as nucleic acid probing or amplification (e.g., PCR) (6).

Microscopic Examination Microscopic examination of wet mounts and stained smears is the easiest and one of the quickest non–culture-based detection methods. Bacterial infection is detected best with the Gram stain; mycobacterial infection with the auramine–rhodamine fluorescent acid-fast stain; fungal infections with the potassium hydroxide (KOH)/calcofluor wet mount; and parasitic infections with Giemsa stain for intracellular and blood parasites, iodine wet mount for helminths, trichrome stain for protozoans, and Kinyoun acid-fast stain for stool coccidians (Cyclospora and Cryptosporidium). Table 2-7 summarizes the common morphologies reported using the Gram stain and the specific bacteria or yeast corresponding to each morphology. These are especially important when interpreting Gram stains for empiric antimicrobial selections.

Fluorescent Antibody Staining Microbial antigen detection is nearly as quick as microscopic examination and is more specific, because microorganisms can be identified by unique

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Table 2-7 Interpretation of Gram Stained Smears Morphology Observed/Reported

Interpretation

Gram-positive Gram-positive Gram-positive Gram-positive Gram-positive Gram-positive Gram-positive

Staphylococci Streptococci/Enterococci Pneumococci Corynebacterium/Propionibacterium Bacillus/Clostridium Nocardia/Actinomyces Lactobacillus, Listeria, and other Gram-negative bacilli Neisseria/Moraxella catarrhalis Haemophilus, Bacteroides Enteric and Pseudomonas-like Gram-negative bacilli Yeast (e.g., Candida and Cryptococcus) Molds (filamentous fungi, e.g., Aspergillus)

cocci, clusters cocci, chains cocci, diplococci/lancets bacilli, diphtheroid bacilli, boxcar bacilli, filamentous-branching bacilli, other

Gram-negative diplococci Gram-negative coccobacilli Gram-negative bacilli Yeast cells with and without pseudohyphae Hyphae

antigens. However, microbial antigen detection does not allow the examination of specimen cellularity (e.g., neutrophils, contaminating epithelial cells) that is inherent in conventional microscopy. Fluorescent antibody stains require the use of an expensive fluorescence microscope and a trained microscopist. Moreover, smear preparation for fluorescent staining can require centrifugation to concentrate the specimen as well as specimen washing to eliminate nonspecific fluorescence. Fluorescent stains are less sensitive than culture but require only 2 to 4 hours for completion.

Enzyme Immunoassays Enzyme immunoassays (EIAs) are available as conventional and membrane (handheld) tests. Conventional tests formatted for microtiter trays must be performed by trained personnel, can require expensive instrumentation, and are best for testing large batches of specimens at one time. Membrane tests, such as the rapid Streptococcus tests available for detecting Streptococcus pyogenes, can be performed by personnel with minimal training and are designed for individual rather than batch use. Common EIAs are 50% to 90% sensitive with turnaround times of hours for conventional formats and minutes for handheld formats.

Latex Agglutination Latex agglutination (LA) testing, a less common method for antigen detection, is limited to testing for bacterial antigens in body fluids such as cerebrospinal fluid. Bacterial antigens that can be detected include those of Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, and Streptococcus agalactiae (group B Streptococcus). After decades of use, it has been concluded that bacterial antigen testing has little usefulness in

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the diagnosis of serious disease. Laboratory evaluations show antigen-testing results to be equivalent to those of the Gram stain, and clinical evaluations show that no change in antibiotic therapy occurs until culture results are available. In a climate of limited testing resources, bacterial antigen tests should be used infrequently, if at all (7). An approach to limiting the use of antigen tests is to test only specimens from patients who have taken antibiotics that might interfere with culture results.

Molecular Assays Molecular methods for detecting pathogenic organisms have emerged as essential components for the diagnosis of many infectious diseases (8). Common molecular methods include detection without target amplification using probes, and detection with target amplification using the PCR or related assays. Probes detect specific microbial genes (DNA sequences). The higher the concentration of specific microorganism present in the specimen, the more copies of the target gene there will be, and the more sensitive the probe detection test. Detection of papilloma viruses in skin biopsies is an example of a DNA probe assay. Although PCR and related assays also detect specific genes, detection occurs after amplification or multiplication of the gene up to 1 million times, increasing significantly the sensitivity of detection. PCR methods allow detection of DNA and RNA, the latter is necessary for viruses with RNA genomes. Currently, molecular methods are used for the detection of microorganisms in cases in which culture methods are not available, not sensitive, or relatively slow. Table 2-8 summarizes molecular tests used for the diagnosis of infectious diseases. Table 2-8 Molecular Tests for the Diagnosis of Infectious Diseases Microorganism Detected

Method

Specimen

Methicillin-resistant Staphylococcus aureus (MRSA) Neisseria gonorrhoeae Chlamydia trachomatis Bordetella pertussis Mycobacterium tuberculosis Herpes simplex virus Varicella-Zoster virus Other herpes viruses (EBV, HHV 6-8) Human immunodeficiency virus (HIV)

PCR

Nasal swab

PCR, molecular probe PCR, molecular probe PCR PCR, molecular probe PCR PCR PCR PCR and others

Hepatitis C virus (HCV)

PCR and others

Parvovirus Human papilloma virus

PCR Molecular probe

Genital Genital Nasopharyngeal Respiratory/CSF Skin/CSF Skin/CSF Skin/Blood/CSF Blood (detection and viral load) Blood (detection and viral load) Amniotic fluid Skin

Abbreviations: CSF, cerebrospinal fluid; EBV, Epstein-Barr virus; HHV 6-8, human herpes viruses 6-8; MRSA, methicillin-resistant S. aureus; PCR, polymerase chain reaction (for the detection of RNA and DNA).

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Principles of Identification Bacteria Isolated bacteria are identified by immunologic testing, which reveals the presence of unique antigens, and biochemical testing, in which a characteristic pattern of substrate utilization is obtained (9). Identification by immunologic methods, such as LA, can be accomplished in minutes but is restricted to Staphylococcus aureus, beta-hemolytic streptococci, the Salmonella and Shigella groups, and a few other organisms. Biochemical testing is the mainstay of bacterial identification, and is accomplished by spot, same-day, or overnight testing. Spot testing requires only minutes to complete, and involves rubbing the unknown microorganism on a substrate-impregnated paper. Large amounts of preformed bacterial enzyme degrade the substrate, which is signaled by a colored indictor. Spot testing is inexpensive and rapid (usually minutes to complete) but works only with bacteria that produce excessive amounts of enzyme and have unique substrate patterns. The advantage of same-day testing is the relative speed of identification. More than 80% of bacteria detected in the usual hospital clinical laboratory can be identified using LA and rapid spot testing. Overnight testing is required for bacteria that produce small quantities of enzyme or whose enzymes require induction before detectable substrate degradation occurs. Overnight testing is, in general, costly and time consuming but more comprehensive and accurate than is same-day testing. Automated identification of bacterial isolates is accomplished by biochemical testing that uses unique signals to identify substrate utilization. For example, the Vitek System (bioMerieux Vitek, Hazelwood, Missouri) detects early growth and substrate utilization through the use of colorimetry and nephelometry (light scattering). The Microscan System (Dade Microscan, Inc., West Sacramento, California) uses colorimetry and spectrophotometry (light transmission) to detect growth and reactions that involve a color change. In both instruments, identification is accomplished by computer software that matches the substrate-utilization profiles of unknown organisms with databases of known utilization profiles (10). Identification by automated methods can require as little as 2 hours or can need overnight incubation. Terminology used to characterize bacteria in preliminary reports, before definitive identification has been completed, is not standardized among all microbiology laboratories and can be confusing. It is helpful for the clinician to understand this terminology to better interpret preliminary culture results. For example, an oxidase-positive, gram-negative rod growing from a blood culture will not be an E. coli or related enteric-type gram-negative rod, because all of the Enterobacteriaceae are oxidase-negative. The most common oxidase-positive, gram-negative rod in blood cultures is Pseudomonas aeruginosa. Empiric therapy needs to cover P. aeruginosa and other oxidasepositive pathogens in this example. In other preliminary reports, one can

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encounter a lactose-fermenting, gram-negative rod. The most common lactose fermenters encountered are E. coli and Klebsiella and Citrobacter species. None of the opportunistic, nonfermenting gram-negative rods, such as Acinetobacter, Stenotrophomonas, and Pseudomonas, are lactose fermenters. Tables 2-9 through 2-12 organize common and important bacteria according to official classification schemes using laboratory jargon.

Table 2-9 Classification and Terminology Used to Describe Gram-Positive Aerobic and Facultative Bacteria Gram-Positive Cocci (GPC)

GPC pairs and chains (streptococci, enterococci, Abiotrophia) Beta-hemolytic streptococci Group A (S. pyogenes) Group B (S. agalactiae) Group C Group G Group F (S. milleri/anginosis group) Streptococcus pneumoniae (pneumococcus with more than 80 serotypes) Enterococci (contains Group D antigen) E. faecalis E. faecium Viridans streptococci S. milleri/anginosis group S. mitis group S. mutans group S. salivarius group S. sanguinis group Nutritionally variant streptococci (satelliting streptococci) Abiotrophia defectiva Granulicatella adiacens Streptococcus bovis group S. gallolyticus (formerly S. bovis I) S. infantarius (formerly S. bovis II 1) S. pasteurianus (formerly S. bovis II 2) GPC clusters (staphylococci) S. aureus (coagulase-positive) Coagulase-negative staphylococci S. epidermidis S. capitis S. hominis S. haemolyticus S. saprophyticus Many others Gram-Negative Bacilli (GNB)

Arcanobacterium haemolyticum Bacillus species (produce endospores, many species) B. anthracis B. cereus Continued

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Table 2-9 Continued Gram-Negative Bacilli (GNB)

Corynebacterium species (aerobic diphtheroid, many species) C. diphtheriae C. jeikeium C. urealyticum Erysipelothrix rhusiopathiae Lactobacillus species (lactobacilli, many species) Listeria monocytogenes

Table 2-10 Classification and Terminology Used to Describe Gram-Negative Aerobic and Anaerobic Bacteria Gram-Negative Cocci

Neisseria species (many species, including) N. gonorrhoeae (gonococci) N. meningitides (meningococci) Moraxella catarrhalis Gram-Negative Bacilli

Glucose-fermenters, oxidase-negative Enterobacteriaceae Lactose-fermenters E. coli K. pneumoniae Non-lactose fermenters Proteus mirabilis Salmonella species Shigella species Lactose or non-lactose fermenters Enterobacter species Serratia species Citrobacter species Glucose-fermenters, oxidase-positive Vibrio cholerae V. parahaemolyticus V. vulnificus Vibrio (many other species) Aeromonas hydrophilia A. caviae Aeromonas (many other species) Glucose non-fermenters, oxidase-negative Acinetobacter species A. baumannii A. lwoffii Stenotrophomonas maltophilia Glucose non-fermenters, oxidase-positive Pseudomonas aeruginosa Pseudomonas, other species Continued

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Table 2-10 Continued Gram-Negative Bacilli

Alcaligenes species Burkholderia cepacia Burkholderia, other species Gram-Negative Bacilli—Fastidious (fastidious means no growth on selective Gramnegative media such as MacConkey Agar)

Haemophilus influenzae (H. flu) HACEK group (Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, Kingella) Bordetella pertussis Pasteurella multocida Legionella pneumophila

Table 2-11 Classification and Terminology Used to Describe Bacteria That Are Uncultivable or Difficult to Cultivate Bartonella henselae (cat scratch bacillus) Chlamydia trachomatis Chlamydophila (formerly chlamydia) pneumoniae Coxiella burnetii (Q-fever bacterium) Ehrlichia/Anaplasma species Rickettsia species Spirochetes Borrelia burgdorferi (Lyme disease spirochete) Borrelia recurrentis Leptospira species Treponema pallidum (syphilis spirochete) Tropheryma whippelii (Whipple disease bacterium)

Mycobacteria The mycobacteria are identified by molecular probe technology, substrate utilization studies that are similar in principle to those used with the common bacteria discussed earlier, and sequencing of certain mycobacterial genes. Commercially available nucleic acid probes can be used to rapidly identify Mycobacterium tuberculosis, M. avium, M. kansasii, and M. gordonae. Once in-vitro growth occurs, probe identification requires 2 to 4 hours. Some mycobacteria are identified by biochemical utilization studies, which can require 2 weeks or longer to complete. The number and diversity of mycobacteria have increased so greatly in the past 20 years that accurate identification of some isolates is accomplished only by gene sequencing. This technology requires 1 to 2 days following growth. Terminology used to classify clinically significant mycobacteria is summarized in Table 2-13 (11).

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Table 2-12 Classification and Terminology Used to Describe Anaerobic Bacteria Gram-Positive Bacilli (non-spore-forming)

Gram-Negative Bacilli

Actinomyces species Propionibacterium (anaerobic diphtheroid) Eubacterium species Lactobacillus species Bifidobacterium species

Bacteroides fragilis group B. fragilis B. thetaiotaomicron B. vulgatus B. distasonis B. uniformis B.ureolyticus Bilophila species Porphyromonas species Prevotella species Fusobacterium species

Gram-Positive Bacilli (spore-formers)

Clostridium perfringens C. septicum C. difficile C. botulinum C. tetani Clostridium, many other species Cocci

Gram-positive cocci Peptostreptococcus species Peptococcus species Gram-negative cocci Veillonella species

Table 2-13 Classification and Terminology Used to Describe the Mycobacteria Category

Mycobacterium

Mycobacterium tuberculosis complex

M. tuberculosis M. bovis M. kansasii M. marinum M. scrofulaceum M. szulgai M. thermoresistable M. xenopi M. avium complex (MAC) M. genavense M. haemophilum M. fortuitum M. chelonei M. abscessus M. leprae

Photochromogens (colony pigment following exposure to light) Scotochromogens (colony pigment in light and dark)

Nonchromogens (no colony pigment)

Rapid Growers (colonies in 1 month) should be at −70˚C. Serum specimens should not be stored in frost-free freezers with repeated freezing and thawing because this can aggregate IgM-type antibodies and denature all antibodies resulting in false-negative tests. Specimens that are frozen and need to be transported to another office or laboratory for analysis should be sent in the frozen state. Immunity, especially to viral diseases, can be established by detecting antibody—an indication that infection has occurred sometime in the past. Serologic tests for immunity must be performed with sensitive methods that detect IgG-type antibodies (e.g., enzyme-based assays rather than complement fixation-type assays). Serologic diagnosis of disease can be accomplished by detecting either pathogen-specific IgM or a rise in the titer of pathogen-specific IgG. IgM can be detected as early as 1 week after the onset of disease. The presence of pathogen-specific IgM in a single serum specimen suggests current or very recent infection by that particular pathogen. Rising IgG titers are detected by collecting and assaying acute and convalescent serum specimens. The acute specimen is collected as soon as possible after the onset of disease, and the convalescent specimen is collected 3 to 6 weeks later. A significantly greater antibody titer in the convalescent specimen than that detected in the acute specimen suggests current infection by the specifically infecting pathogen. In some clinical situations, both convalescent and postconvalescent serum specimens are collected. In such instances, a significant decrease in serum antibody titer from the convalescent to the postconvalescent specimen can indicate recent infection. This approach and interpretation should be

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confirmed with the laboratory performing the test. Serologic diagnosis of infection by detection of IgM or IgG antibody is more effective for some infectious agents than for others. Drawbacks to serologic testing include the persistence of IgM for months after acute infection, the need to wait for a convalescent specimen when testing for IgG, and interference with diagnostic antibody levels after vaccination. In general, serological testing is not practical for the initial management of an acute infectious disease because of the delay between onset of disease and appearance of diagnostic antibodies.

Interpreting Biopsy Specimens Microorganisms can be detected in thin sections of biopsy tissue through characteristic histopathologic reactions and by identifying microbial morphologies with histologic stains. In either case, unfixed tissue from the same biopsy specimen as that submitted for microscopic examination by the pathologist should be aseptically dissected and submitted to the microbiology laboratory for culture. Detecting microorganisms in culture is more sensitive than is microscopic examination, serves to confirm morphologic findings and to provide more complete identification of an organism, and provides organisms for antimicrobial susceptibility testing or microbial typing in epidemiologically related cases. Histopathologic inflammatory responses to infection depend on both the pathogenic properties of the infectious agent and the immune status of the host, and can be divided into the following categories as reviewed by Woods and Walker (16). The microorganisms responsible for each inflammatory category also are listed. ●

●

●

●

Acute inflammation characterized by an exudative and suppurative response, which can result in abscess formation is caused by pyogenic bacteria such as Nocardia species, Candida species, Aspergillus species; and Zygomycetes, such as Rhizopus species. Caseating granulomatous inflammation is caused by Mycobacterium tuberculosis, nontuberculous mycobacteria (especially Mycobac-terium marinum, Mycobacterium szulgai, and Mycobacterium leprae), Histoplasma capsulatum, Coccidioides immitis, and Cryptococcus neoformans. Noncaseating granulomatous inflammation is caused by M. tuberculosis, nontuberculous mycobacteria as in the preceding for caseating granulomas, H. capsulatum, Brucella species, Toxoplasma gondii, Coxiella burnetti, Ehrlichia species, cytomegalovirus, Schistosoma species, and Dirofilaria immitis. Mixed suppurative and granulomatous inflammation is caused by nontuberculous mycobacteria, Blastomyces dermatitidis, Sporothrix schenckii, Paracoccidioides brasiliensis, fungal agents

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●

●

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of chromoblastomycosis and phaeohyphomycosis, Acanthamoeba species, Yersinia species, Francisella tularensis, Bartonella henselae, and C. trachomatis strains causing lymphogranuloma venereum. Nonorganizing, mixed acute and chronic or chronic inflammation is caused by Legionella species, Helicobacter pylori, Cryptosporidium species, microsporidia, and Treponema pallidum. Aggregates or diffuse infiltrates of histocytes are caused by Mycobacterium avium complex, M. genavense, M. leprae, Leishmania species, and Listeria monocytogenes.

Use and Interpretation of In-Vitro Antimicrobial Susceptibility Tests In-vitro antimicrobial susceptibility tests are used to help predict whether a specific antimicrobial agent will eradicate a pathogen from the site of infection. Laboratories perform in-vitro susceptibility tests when they isolate a likely pathogen that has an unpredictable antimicrobial profile, and proven methods exist for determining the pathogen’s susceptibility and resistance. The methods used to test antimicrobial susceptibility are established by the Clinical Laboratory Standards Institute (CLSI), a consensus group composed of representatives from industry, government, clinical laboratories, and appropriate medical specialties. The CLSI publishes annual updated procedures, and all laboratories are required by licensing regulations to follow CLSI methods and interpretations. The antimicrobial agents to be tested by the laboratory should be determined by local resistance patterns, cost, and the preferences of physicians who are knowledgeable in antimicrobial therapy. Physician, pharmacy, and laboratory representatives commonly form the nucleus of the hospital committee responsible for determining the batteries of antimicrobials to be tested. These batteries of tests need to be reviewed and changed on a periodic basis.

The Minimum Inhibitory Concentration Test and the Breakpoint The backbone of in-vitro antimicrobial susceptibility testing is the minimum inhibitory concentration (MIC) test (17), which determines the lowest concentration of an antimicrobial agent needed to inhibit the growth of a microorganism. Reported in micrograms per milliliter (µg/mL) of antimicrobial agent, MIC values are established at concentrations that range from 0.1 µg/mL to as high as 64 µg/mL, depending on the antimicrobial agent being tested. The MIC value is compared with the quantity of antimicrobial agent that can be achieved in the patient at the site of infection. In general,

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when the MIC is lower than the concentration at the infected site, the infecting organism is considered susceptible to the antimicrobial agent being tested. When the MIC is higher, the microorganism is considered resistant. The specific concentration of antimicrobial agent at the infection site that is used to differentiate between susceptible and resistant is referred to as the breakpoint. Antimicrobials are used in various dosages and dosing schedules because they have different pharmacologic properties in the body and, therefore, can have different breakpoints. In practice, the breakpoint for a particular antimicrobial agent is set using many different criteria, such as the results of clinical trials, resistance mechanisms of bacteria, animal studies, pharmacokinetic and pharmacodynamic properties, and concentrations of the agent at important sites of infection (e.g., cerebrospinal fluid). An understanding of the MIC and breakpoint should make it clear that selecting an antimicrobial agent from a list of MIC values is not simply a matter of selecting the drug with the lowest MIC. One must know the breakpoint concentration for each antimicrobial agent to ensure that the MIC value of the agent for a particular pathogen is below this concentration. The goal of antimicrobial therapy is to kill a patient’s pathogen. Can an inhibitory test be used in the laboratory to predict the killing of a pathogen in the patient? The answer is “Yes” (18). Although methods for bactericidal testing (measure killing rather than inhibition) are available to the laboratory, the MIC test has proven to be an accurate predictor of clinical response through decades of clinical use. In most patients, a susceptible MIC test result implies that the pathogen is likely to be eradicated from the site of infection, increasing the likelihood of a favorable outcome. A resistant MIC test result suggests that the pathogen is less likely to be eradicated. A laboratory report indicating an intermediate result means that the concentration of antimicrobial agent at the infected site is at or near the MIC of the infecting pathogen. In most such cases, an alternative drug that yields a susceptible MIC test result is selected. The term intermediate also implies that the infecting organism can be interpreted as susceptible if higher-thannormal doses of the specific antimicrobial agent are used or if the antimicrobial agent is concentrated at the site of infection (e.g., in the urinary tract, where drugs excreted by the kidneys become concentrated). Increasing the dose and concentration of an antimicrobial agent at various body sites increases the breakpoint of the agent for a particular pathogen, transforming intermediate MIC test results into susceptible ones.

Methods Used to Determine the Minimum Inhibitory Concentration Laboratories use many manual and automated methods to determine the MICs of antimicrobial agents for various pathogens. The microbroth dilu-

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tion method is the commonly used gold standard. In this technique, dilutions of antimicrobial agents prepared in microtiter trays are inoculated with a standard concentration of the microorganism which is to be tested for susceptibility. After overnight incubation, quantitative MIC results are determined and reported in micrograms per milliliter (µg/mL), with a qualitative interpretation of susceptible, resistant, or intermediate susceptibility. Commercially available automated methods are adjusted to meet the microbroth dilution standard. Disk diffusion is performed using disks containing the antimicrobial agent to be tested, which are placed on the surface of a standard agar plate that has been inoculated with a carefully adjusted lawn of bacteria. The antimicrobial agent diffuses into and across the agar surface, creating a concentration gradient that mimics the dilutions one uses in the broth microdilution procedure, with a high concentration near the disk and progressively lower concentrations at increasing distances from the disk. Bacteria grow toward the disk until they reach the surrounding region that contains the test antibiotic at their MIC value, producing a circular zone of inhibited growth around the disk. The disk-diffusion test, in effect, is a MIC test performed on the surface of an agar plate. Statistical analysis has been used to determine MIC and breakpoint equivalents for disk diffusion. Results of disk-diffusion testing are reported as being susceptible, intermediate, or resistant, without including the MIC equivalent value. The E-test (AB Biodisk, Piscataway, New Jersey) is an agar-gradient method that uses an antimicrobial agent applied in gradient concentrations to a strip. The strip is marked to show the exact decreasing concentrations of the antimicrobial agent from one end to the other. The strip is placed onto an agar surface that has been inoculated with the bacterium to be tested. Bacterial growth occurs around the strip in an elliptical pattern, with a larger area of growth inhibition at the high-concentration end of the strip and a narrowing area of inhibition toward the low-concentration end. The MIC value is read from the concentration marking on the strip at the point at which the concentration of antimicrobial agent is low enough to permit growth of bacteria right up to the strip. Results are reported as quantitative MIC values with a susceptible, resistant, or intermediate interpretation.

Special Methods Used to Detect Specific Resistance Standard MIC and disk-diffusion methods do not detect all resistant bacteria accurately (19). Supplementary methods are used to ensure accurate results. Table 2-18 lists combinations of bacteria and antimicrobials that require supplementary testing.

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Table 2-18 Bacterial-Antimicrobial Combinations that Require Supplementary Testing to Confirm In-Vitro Susceptibility Microorganism

Antimicrobial

Mechanism of Resistance

Supplementary Test

Gram-Positive Cocci

Staphylococcus aureus

Penicillin

All Staphylococci

Methicillin, and related drugs

Vancomycin

Clindamycin

Enterococci

Vancomycin

Beta-lactamase production Altered penicillinbinding proteins

Beta-lactamase assay Mec-A gene analysis, or a combination of agar and broth dilution testing with increased concentrations of NaCl Broth dilution MIC or agar dilution. Disk diffusion should not be used. D-test

Altered cell wall morphology that binds excess drug Induced by erythromycin or mutation Altered cell wall Broth dilution MIC or morphology agar dilution. Disk that prevents diffusion should not binding of drug be used.

Gram-Negative Bacilli

Escherichia coli/ Klebsiella

Cephalosporins

Haemophilus influenzae

Ampicillin

ExtendedReview overall spectrum antimicrobial beta-lactamase pattern. Compare production cephalosporin (e.g., (ESBL) ceftazidime) MIC or zone diameter to cephalosporin plus clavulanate MIC or zone diameter. Beta-lactamase Beta-lactamase assay production

Gram-Negative Cocci

Moraxella catarrhalis

Ampicillin

Neisseria gonorrhoeae

Penicillin

Beta-lactamase production Beta-lactamase production

Beta-lactamase assay Beta-lactamase assay

Abbreviations: D-test, erythromycin and clindamycin disk approximation test on agar plate that detects inducible clindamycin resistance. A D-test positive Staphylococcus is considered resistant to clindamycin. A D-test negative Staphylococcus is considered susceptible to clindamycin. MIC, minimum inhibitory concentration; mec-A, staphylococcal gene encoding altered penicillin binding protein (referred to as PBP2a) that confers methicillin resistance. Absence of mec-A implies methicillin susceptibility; NaCl, sodium chloride.

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Synergy Testing The term synergy describes an inhibitory or cidal test result representing the combination of two antimicrobial agents that exceeds that expected when individual results of each tested alone are added together. Combinations of antimicrobial agents are commonly used with the expectation that synergy will occur, although laboratory testing is rarely needed to prove that synergy is present (20). Even if synergy does not occur, the two antimicrobial agents in a particular combination can be necessary either to broaden the spectrum of organisms covered by therapy or to ensure that mutant organisms that are resistant to one antimicrobial agent will be inhibited by the second agent. Synergy is expected with the following regimens: ●

●

●

A beta-lactam drug plus an aminoglycoside is used in treating infections caused by many gram-negative bacilli, especially Pseudomonas aeruginosa. An antistaphylococcal beta-lactam drug plus an aminoglycoside is used when treating S. aureus. Ampicillin (or an equivalent drug) or vancomycin plus an aminoglycoside is used when treating enterococci or viridans streptococcus.

Only the combinations of antimicrobials that are needed to treat enterococcal infections require laboratory testing to confirm synergy. Enterococci are not routinely killed by therapy with a single antimicrobial agent. Enterococcal endocarditis requires bactericidal therapy to ensure a high probability of bacteriologic cure. Combinations of inhibitory, cell-wall–active antimicrobials (e.g., ampicillin or vancomycin), plus gentamicin are synergistic because the cell-wall–destroying antimicrobial agent augments the penetration of gentamicin into the cytoplasm where gentamicin binds to ribosomes and kills the bacterial cell. A surrogate test for synergy in this instance is to perform an MIC test at a single concentration of gentamicin. The enterococcus sample to be tested is inoculated onto an agar plate or into broth medium that contains 500 µg/mL of gentamicin, a concentration so high that gentamicin is forced across the enterococcal cell wall and into the cell’s cytoplasm. If the gentamicin is not inactivated by enterococcal aminoglycoside–inactivating enzymes, the organism will be inhibited, that is, it will be susceptible to the 500 µg/mL concentration of the drug, and synergy can be expected. If the gentamicin is inactivated by enterococcal enzymes, growth is not inhibited, the isolate is resistant to the 500 µg/mL concentration of gentamicin, and synergy will not occur. This high-level gentamicin test should be performed whenever combination antimicrobial therapy is used for the treatment of enterococcal infection.

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Antimicrobial Assays Assays of antimicrobial agents are used to measure the concentrations of these drugs in the blood. These assays can be used to document compliance with a prescribed regimen, to ensure that concentrations of a drug are adequate to effectively treat a serious infection, and to document that concentrations are not at toxic levels. In practice, measurements of aminoglycoside and vancomycin concentrations are the only assays needed routinely. Measurements of both drugs are used to ensure therapeutic and nontoxic levels (21,22). The recommended target levels for the aminoglycosides will depend on the dosing schedule (i.e., the previously traditional every 8 hours or the more commonly used once daily dosing for gram-negative bacilli) and whether used for synergy for enterococci (for this latter indication gentamicin peak levels of 3-4 µg/mL are recommended). For the once daily dosing of gentamicin or tobramycin (7 mg/kg), a peak level is usually not required because the peak levels with this dose are relatively high; trough levels of less than 1 µg/mL are usually the target level recommended. For vancomycin, target levels will depend on the site of infection and MIC of the pathogen. Newer recommendations are pending, but many authorities recommend a trough level of 10 to 15 µg/mL, with higher levels (15-20 µg/mL) for selected infections (e.g., a central nervous system [CNS] infection or methicillin-resistant Staphylococcus aureus [MRSA] pneumonia).

Antibiograms Antibiograms are compilations of antibiotic testing results over a defined period (23). In general, antibiograms list the percentage of bacteria susceptible to antimicrobial agents during the preceding 1-year period. Antibiograms are used to assess the overall activity of antimicrobial agents against a pathogen. Every hospital or community has a different antibiogram. Commonly used antibiograms include those for gram-negative bacilli, S. aureus, and enterococci. Focused antibiograms, with data limited to specific microorganism–antimicrobial combinations, are useful in the management of emerging antimicrobial resistance. Antibiograms for vancomycin-resistant enterococci, Viridans group streptococci, coagulase-negative staphylococci, pneumococci, anaerobes, yeasts, and M. tuberculosis also can be useful. Antibiograms for groups of pathogens isolated from various anatomic sites (e.g., community-wide respiratory pathogens and stool pathogens) provide another way of representing antimicrobial susceptibility data. Table 2-19 is an example of a focused antibiogram for the viridans group streptococci.

9 11 38 0 29

0.015

Abbreviation: MIC, minimum inhibitory concentration.

S. milleri/anginosus group (115) S. mitis group (163) S. mutans group (15) S. salivarius group (32) S. sanguinis group (39)

Organism (number of strains tested) 45 26 100 6 28

0.03 94 41 100 31 39

0.06

Susceptible

Table 2-19 Penicillin Antibiogram for Viridans Group Streptococci

98 60 100 47 62

0.12 99 71 100 53 80

0.25 100 78 100 75 90

0.5

100 80 100 88 95

1.0

Intermediate

100 85 100 91 97

2.0

Cumulative Percent Inhibited by Penicillin MIC of:

100 92 100 94 100

100 100 100 100 100

8.0

Resistant

4.0

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U s e o f M i c r o b i o l o g y L a b o r a t o r y Te s t s 45

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REFERENCES 1. Thomson RB, Peterson LR. Role of the clinical microbiology laboratory in the diagnosis of infections. In: Noskin GA, ed. Management of Infectious Complications in Cancer Patients. Boston: Kluwer Academic Publishers; 1998:143-65. 2. College of American Pathologists. Compliance Guidelines for Pathologists. Northfield, IL: College of American Pathologists; 1978:57-61. 3. Wilson ML. General principles of specimen collection and transport. Clin Infect Dis. 1996;22:766-77. 4. Bartlett RC, Mazens-Sullivan M,Tetreault JZ, Lobel S, Nivard J. Evolving approaches to management of quality in clinical microbiology. Clin Microbiol Rev. 1994;7:55-88. 5. Morris AJ, Smith LK, Mirrett S, Reller LB. Cost and time savings following introduction of rejection criteria for clinical specimens. J Clin Microbiol. 1996;34:355-7. 6. Holland CA, Kiechle FL. Point-of-care molecular diagnostic systems—past, present and future. Curr Opin Microbiol. 2005;8:504-9. 7. Kiska DL, Jones MC, Mangum ME, Orkiszewski D, Gilligan PH. Quality assurance study of bacterial antigen testing of cerebrospinal fluid. J Clin Microbiol. 1995;33:1141-4. 8. Espy MJ, Uhl JR, Sloan LM, Buckwalter SP, Jones MF, Vetter EA, et al. Real-time PCR in clinical microbiology: applications for routine laboratory testing. Clin Microbiol Rev. 2006;19:165-256. 9. Forbes BA, Sahm DF,Weissfeld AS. Bailey and Scott’s Diagnostic Microbiology. 11th ed. St. Louis: Mosby; 2002:1148-68. 10. Miller JM, O’Hara CM. Manual and automated systems for microbial identification. In: Murray PR, Baron EJ, Pfaller MA, et al, eds. Manual of Clinical Microbiology. 7th ed. Washington, DC: ASM Press; 1999:193-201. 11. Diagnosis and treatment of disease caused by nontuberculous mycobacteria. This official statement of the American Thoracic Society was approved by the Board of Directors, March 1997. Medical Section of the American Lung Association. Am J Respir Crit Care Med. 1997;156:S1-25. 12. McGinnis MR, Rinaldi MG. Some medically important fungi and their common synonyms and obsolete names. Clin Infect Dis. 1997;25:15-7. 13. Garcia LS. Classification of human parasites. Clin Infect Dis. 1997;25:21-3. 14. Forbes BA, Sahm DF,Weissfeld AS. Bailey and Scott’s Diagnostic Microbiology. 11th ed. St. Louis: Mosby; 2002:799-863. 15. Weinstein AJ, Farkas S. Serologic tests in infectious diseases. Clinical utility and interpretation. Med Clin North Am. 1978;62:1099-117. 16. Woods GL,Walker DH. Detection of infection or infectious agents by use of cytologic and histologic stains. Clin Microbiol Rev. 1996;9:382-404. 17. Jorgensen JH, Ferraro MJ. Antimicrobial susceptibility testing: general principles and contemporary practices. Clin Infect Dis. 1998;26:973-80. 18. Jacobs MR. How can we predict bacterial eradication? Int J Infect Dis. 2003;(suppl 1): S13-20. 19. Kiska, DL. In vitro testing of antimicrobial agents. Semin Pediatr Infect Dis. 1998;9:281-91. 20. Eliopoulos GM, Eliopoulos CT. Antibiotic combinations: should they be tested? Clin Microbiol Rev. 1988;1:139-56. 21. Cantú TG, Yamanaka-Yuen NA, Lietman PS. Serum vancomycin concentrations: reappraisal of their clinical value. Clin Infect Dis. 1994;18:533-43. 22. Rogers MS, Cullen MM, Boxall EM, Chadwick PR. Improved compliance with a gentamicin prescribing policy after introduction of a monitoring form. J Antimicrob Chemother. 2005;56:566-8. 23. Ernst EJ, Diekema DJ, Boots Miller BJ,Vaughn T,Yankey JW, Flach SD, et al. Are United States hospitals following national guidelines for the analysis and presentation of cumulative antimicrobial susceptibility data? Diagn Microbiol Infect Dis. 2004;49:141-5.

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Part II

Central Nervous System Infections

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Chapter 3

Bacterial Meningitis CARLOS H. RAMIREZ-RONDA, MD CARLOS R. RAMIREZ-RAMIREZ, MD

Key Learning Points 1. Early recognition of meningitis is essential for better prognosis. 2. Blood cultures should be obtained before therapy is started. 3. Cerebrospinal fluid should be sent for examination including gram stain and culture. 4. The common etiologies are Streptococcus pneumoniae and Neisseria meningitides in areas where Haemophilus influenzae vaccine routine used. 5. Antimicrobial therapy should be instituted as soon as possible after blood cultures have been taken. 6. Consider using adjunctive corticosteroids in patients with suspected or proven bacterial meningitis as recommended by IDSA guidelines.

B

acterial meningitis is a relatively infrequent disease with serious consequences. Central nervous system (CNS) infections account for approximately 1% of hospital admissions. Athough bacterial meningitis is a rare disease, it requires prompt diagnosis and treatment. The morbidity and mortality from bacterial meningitis remain unacceptably high. A 1993 report observed that 61% of infants who survived gram-negative bacillary meningitis had developmental disabilities and neurologic sequelae (1). In 493 episodes of bacterial meningitis in adults, the overall case fatality rate was 25% (2). The increased frequency of isolates of Streptococcus pneumoniae that are resistant to penicillin makes the prompt diagnosis and treatment of bacterial meningitis an urgent requirement (3-13).

49

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New Developments in Bacterial Meningitis • New pathogens are being observed as causes of community-acquired bacterial meningitis including methicillin resistant Staphylococcus aureus. • Recent studies have identified factors associated with a worse outcome in meningitis in adults caused by Streptococcus pneumoniae including Glasgow coma score, cranial palsies, cerebral spinal fluid WBC < 100 cells/mm3, and markedly elevated erythrocyte sedimentation rate. • Molecular diagnostic techniques are becoming available to enable rapid and accurate diagnosis of bacterial meningitis.

Infection of the CNS can present in a great variety of forms, ranging from acute benign forms of viral meningitis to rapidly fatal bacterial meningitis; in other cases CNS infection can present with slow progressive mental deterioration that can be related to fungal, mycobacterial, or persistent viral infection (Figure 3-1). The most common infectious diseases of the CNS are viral and bacterial meningitis, with the cumulative risk for CNS infection through 80 years of age being 2.3% for men and 1.5% for women (14). Prompt treatment is usually effective for many of the severe presentations of CNS infections. The outcome is often determined by the efficacy and appropriateness of the treatment. Most deaths from bacterial infection occur at an early point, and usually within the first 48 hours of hospitalization. Because of its potential lethality, CNS infection must be recognized early and the probable infecting agent determined as rapidly as possible, either through laboratory examination or clinical diagnosis. Proper initial assessment of the patient requires a careful history, with attention to the evolution of the patient’s disease, the history of exposures to infectious agents, and host factors that can result in increased susceptibility to certain infections. The physical examination is directed at localizing the neurologic disease and identifying evidence of systemic infection. These assessments are supplemented by examination of the cerebrospinal fluid (CSF) and imaging studies.

Epidemiology The frequency of meningitis in children caused by Haemophilus influenzae has declined dramatically in the past 5 to 10 years because of widespread vaccination against H. influenzae type b with the protein conjugated vaccine. From 1985 to 1991 there was an 82% reduction in incidence of H. influenzae meningitis in children < 5 years of age (4,15). This reduction means S. pneumoniae and Neisseria meningitidis have become the predominant causes of meningitis in non-neonates. Another important trend is the worldwide increase in infection with antibiotic-resistant strains of S. pneumoniae. Although penicillin-resistant strains of S. pneumoniae were first identified in the late 1960s, and meningitis caused by such strains was first diagnosed

No

Meningitis

Yes

Focal deficit

Meningitis Encephalitis Meningitis Encephalitis Abscess Abscess encephalitis

Absent

Cranial nerve palsy

Alert Obtunded Coma Present

Level of consciousness

Yes

Meningitis

No

Abscess

No

Meningismus

Meningitis encephalitis abscess

Yes

No

Intracranial presion

Figure 3-1 Algorithm for the evaluation and management of community-acquired or nosocomial meningitis. Clinical presentations are those seen in the acute clinic or emergency room or in hospitalized patients. The community-acquired diseases are divided into those that present with and without prior antibiotic treatment. In those with prior treatment, empirical therapy is started in patients with more than 48 hours of pretreatment, irrespective of the CSF findings. If treatment was for less than 48 hours, empirical treatment is started only on those whose CSF examination shows a protein level of ≥150 mg/dL, a glucose level of ≤40 mg/dL, or a leukocyte count of ≥1200 cells/mL.

Meningitis

Yes

Cranial trauma

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Bacterial Meningitis 51

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in 1974, the incidence of infection with S. pneumoniae resistant to penicillin and other beta-lactam antibiotics has increased worldwide in the past decade (4,16,17). The new findings are in contrast to the 1990 Centers for Disease Control and Prevention (CDC) report of a multistate surveillance study of bacterial meningitis based on data collected in 1986 (18). H. influenzae was the pathogen most commonly identified. The majority of cases were caused by three species of bacteria: H. influenzae (45%), S. pneumoniae (18%), and N. meningitidis (14%). The incidence rates of infection with specific pathogens were most influenced by age. Case fatality rates varied according both to type of bacteria and age group. For example, the overall case fatality rate for infection was higher for S. pneumoniae (19%) than for either N. meningitidis (13%) or H. influenzae (3%), but that for S. pneumoniae meningitis was much lower in children younger than 5 years of age (3%) than in adults older than 60 years of age (31%) (18). Antibiotic-resistant strains of S. pneumoniae have emerged as a major problem in the United States. For example, in metropolitan Atlanta, from January through October 1994, isolates from 25% of patients with invasive pneumococcal infection were resistant to penicillin (5% were highly resistant, with minimum inhibitory concentrations [MIC] > 2 µg/mL), and isolates from 9% were resistant to cefotaxime (4% were highly resistant) (18).

Etiology The most frequent bacterial pathogens of meningitis (S. pneumoniae, N. meningitidis, H. influenzae) were responsible for approximately 80% of reported cases in the United States. Until the 1990s, H. influenzae was the leading cause of bacterial meningitis, accounting for almost 50% of cases. The position of H. influenzae as the chief cause of bacterial meningitis in infants and young children was changed by the widespread use of H. influenzae type b (Hib) conjugate vaccines. As a result, the relative frequencies of S. pneumoniae and N. meningitidis as agents of meningitis have increased among children (5,6,8,10,11,13,19). Other bacterial causes of meningitis are group B streptococci, Listeria monocytogenes, and enteric gram-negative bacilli. L. monocytogenes has become important in bacterial meningitis as the result of the increasing numbers of immunocompromised and otherwise vulnerable persons at risk, such as transplant recipients, patients undergoing hemodialysis, and patients with liver disease. In New York City, cases of Listeria meningitis increased from 0.9% to 3.4% of all reported cases between 1972 and 1979. Similarly, gram-negative bacillary meningitis (excluding cases caused by H. influenzae) increased in New York City from 5.6% to 7.0% of reported cases between 1972 and 1979 (20). The frequencies of the bacterial agents in meningitis are age related. In neonatal meningitis, Escherichia coli and group B streptococci predominate,

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Bacterial Meningitis

53

but other streptococci and L. monocytogenes also have significant roles. After the neonatal period in children, the predominant position of H. influenzae as a cause of meningitis in the first few years of life declined dramatically since 1990 in the United States as a result of widespread immunization with Hib-protein conjugate vaccines. N. meningitidis is the second most frequent cause of childhood bacterial meningitis. For adult meningitis, S. pneumoniae is the principal bacterial agent, causing approximately 40% of cases. In adults with bacterial meningitis treated in tertiary care institutions, cases of nosocomial as well as community origin are seen. Among community-acquired cases, S. pneumoniae, N. meningitidis, and L. monocytogenes are the leading causes, accounting for approximately 40%, 15%, and 10% of cases, respectively. Among nosocomial cases, gram-negative bacilli, various streptococcal species, Staphylococcus aureus, and coagulase-negative staphylococci are the principal infecting microorganisms, accounting for approximately 40%, 15%, and 10% of cases, respectively. Gram-negative bacillary meningitis is commonly a postneurosurgical (nosocomial) complication, but can be spontaneous (in hospitalized patients or in the community setting) (11,13,21). S. aureus is the pathogen in 1% to 9% of cases of bacterial meningitis overall. Cases occur in several categories, based on predisposing circumstances: CNS disorders (usually involving prior neurosurgery) in approximately 50%, endocarditis in approximately 20%, and bacteremia from other sites of infection (often in the setting of diabetes, cancer, or alcoholism) in approximately 25% (22). Obligate anaerobic bacteria rarely cause meningitis. Approximately 1% of cases of bacterial meningitis are polymicrobial infections. The common predisposing factors for mixed bacterial meningitis have become cerebrospinal fluid (CSF) fistulae; neoplasms in proximity to the CNS, such as carcinoma of the rectosigmoid colon eroding through the sacrum to the subarachnoid space; and contiguous sites of infection (23).

Pathogens and Pathophysiology A common feature among the bacterial meningeal pathogens is their polysaccharide capsules. These are present on S. pneumoniae, H. influenzae, N. meningitidis, E. coli K1, and Streptococcus agalactiae (group B streptococcus). Such encapsulation inhibits phagocytosis by neutrophils and antibody-independent, complement-mediated bactericidal activity in different ways. The capsular sialic acid of N. meningitidis seems to facilitate binding of complement factor H to C3b, and this interferes with the binding of factor B and activation of the alternative pathway (24). In the case of S. pneumoniae, factor B binds poorly to C3b on the capsular surface of the organism, and the poly-ribosyl phosphate capsule of Hib cannot serve as an acceptor for covalent C3 deposition (24).

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The initial site of entry of H. influenzae into the CNS is the vascular choroid plexus, which shows the earliest histopathologic evidence of inflammation. After exiting the inflamed plexus capillaries, the organisms enter the lateral ventricles and the subarachnoid space. Once infection is introduced into the CSF, bacteria multiply rapidly because of inadequate local defenses in the form of lack of complement-mediated lysis, opsonizing antibody, and neutrophil phagocytosis. A number of pathophysiologic changes develop as a consequence of bacterial meningitis, and involve the brain, its lining, cranial nerves, meningeal and other intracranial blood vessels, and the spinal cord (24). In experimental animal models, specific bacterial subcapsular components (in the case of S. pneumoniae, peptidoglycan or lipoteichoic acid; in the case of Hib, lipopolysaccharide) are the major inducers of the meningeal inflammation that follows bacterial entry and multiplication in the CSF. Ampicillin-induced lysis of pneumococci in the CSF results in a transient increase in polymorphonuclear cell pleocytosis, consistent with the release of cell-wall debris (24). This inflammatory response is caused by the release into the subarachnoid space of various proinflammatory cytokines, such as interleukin-1 (IL-1), IL-6, and tumor necrosis factor (TNF) from meningeal cells. By inducing the expression of several families of adhesion molecules on endothelium that interact with corresponding leukocytic receptors, these cytokines promote increased adherence and transendothelial movement of neutrophils (24). A leukocyte adhesion of molecule (AM-1) belonging to the selectin family mediates adhesion to endothelium even under conditions of flow; its binding affinity for its endothelial receptor is increased by exposure to cytokines (TNF, granulocyte-macrophage colony-stimulating factor), thus furthering neutrophil trafficking into the subarachnoid space. Once within the subarachnoid space, activated neutrophils release prostaglandins and toxic oxygen metabolites that increase vascular permeability and can cause direct neurotoxicity. Early in the course of meningitis, as observed in animal models, changes take place in meningeal and cerebral capillaries. These vessels, by virtue of their tight intercellular endothelial junctions and their meager rate of pinocytosis, constitute the blood-brain barrier (BBB). They undergo morphologic changes (opening of tight junctions, enhanced pinocytosis) and become permeable to proteins. In experimental Hib meningitis, the increase in permeability in the BBB seems to correlate principally with the bacterial titer in the CSF, but is augmented by increasing pleocytosis. A variety of mediators of the inflammatory response, such as IL-1, IL-6, TNF, complement components, and arachidonate metabolites probably contribute to the breakdown of the BBB and the cerebral manifestations of bacterial meningitis. The major physiologic consequence of altered vascular permeability is (vasogenic) cerebral edema (24). This edema can also have cytotoxic and interstitial components. Increased intracranial pressure (ICP) caused by cerebral edema and reduced reabsorption of CSF produces vomiting and obtundation (24).

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55

Cerebral blood flow (CBF) seems to be enhanced in the early stages of bacterial meningitis, but it subsequently declines in accordance with the severity of the inflammatory process. Focal areas of marked hypoperfusion (attributable to local vasculitis or thrombosis) can occur in patients with normal overall CBF. In some patients, impaired autoregulation of CBF can contribute to the development of cerebral edema or ischemia or altering cerebral perfusion pressure (24). With the spread of meningeal inflammation over the cerebral hemispheres and into the basal cisterns, superficial pial arteries and veins can be subject to thrombosis. Decreased CBF caused by cerebral edema or vascular thrombosis, plus any element of hypoxia caused by pneumonia or respiratory insufficiency results in enhanced glucose metabolism via the anaerobic glycolytic pathway, with ensuing lactate accumulation in the brain and CSF. This central lactic acidosis can contribute considerably to the obtundation and coma of patients with severe meningitis (24).

Diagnosis Clinical Evaluation Figure 3-2 summarizes the steps in the diagnosis and management of bacterial meningitis.

General Manifestations Headache or backache and fever are common, but not universal, indications of bacterial meningitis. Fever can accompany acute meningitis but can be absent. The initial physical evaluation should include evaluation for level of consciousness, cranial nerve palsy, focal deficits, meningismus, increased ICP and critical trauma (14). Antecedent upper-respiratory tract infection is common in bacterial meningitis (40% of cases), and another 10% to 15% of patients have an illdefined prior illness (often diagnosed as otitis media). Between 25% and 75% of patients have a headache, lethargy, and confusion (meningeal symptoms) of rapid onset (within 24 hours). Other patients have more prolonged (1 to 7 days) respiratory tract or otic symptoms, with meningeal symptoms that develop and progress more slowly. In patients with L. monocytogenes meningitis, the prodromal symptomatic period tends to be longer than in patients with other types of pyogenic meningitis (12,25,26). Kerning and Brudzinski signs, along with fever, vomiting, irritability, lethargy, and headache, are features found on physical examination in most patients. Neck stiffness is a symptom in less than half of patients, but nuchal rigidity of some degree is noted as a sign in more than 80%. Myalgias (especially in meningococcal diseases) and backache occur less frequently. Reduced cognitive function is also seen. Photophobia is more often associated with viral meningitis.

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Headache, Fever, Confusion, Vomiting, Lethargy, Irritability, ± Nuchal rigidity, + Kerning signs, + Brudzinski signs, etc.

Community

Nosocomial Hx:

Neurosurgery Head trauma Sepsis Other site

Neurologic localizing signs or Papilledema

< 48 hrs CSF Exam Protein Glucose WBC count WBC differential Gram-Stain Culture or gluc < 40 + glucose < 40 protein > 150 WBC > 1200 observe Gram stain + −

+ Neurology/ Neurosurgery Consult

> 48 hrs

Localizing signs321 −

+

CSF Exam Empiric Rx 3rd Gen CPS

Repeat Empiric Rx CSF exam CPS 3rd or in 8–24 hrs CPS 4th* ± Vancomycin ± Aminoglycoside

*If Listeria possible Ampicillin, if using dexamethasone consider rifampin.

< 48 hrs CSF Prot > 150

All with > 48 hrs

Ampicillin

Empiric Rx or WBC > 1200

CT

−

Not pre-treated

Antibiotics for

No localizing signs

Empiric Antibiotic Therapy CPS3 3rd Gen AP/ CPS4 4th Gen ± ± Vancomycin ± Aminoglycoside

CT

Pre-treated

+ Neurology

−

+

− Observe

Repeat CSF exam in 8–24 hrs

− Observe

+

Figure 3-2 Algorithm for the patient who presents with granulomatous meningitis.

A petechial or purpuric rash, predominantly on the extremities, in a patient with meningeal signs carries the high probability of a meningococcal cause, and requires immediate treatment because of the rapidity with which this type of infection can advance. Approximately 50% of patients with meningococcal meningitis have such skin lesions. In more severe meningococcal infections, large purpuric areas develop, usually accompanying hypotension or shock and evidence of disseminated intravascular coagulation (DIC). Petechial and purpuric skin lesions sometimes occur in

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patients with acute S. aureus endocarditis who have meningeal signs and CSF pleocytosis (either from staphylococcal meningitis or cerebral embolic infarction). In this setting, one or two of the purpuric lesions often contain a purulent center, and aspirated material reveals gram-positive cocci in clusters (Staphylococci) on Gram-stain examination. Macular and petechial skin lesions accompanied by meningeal signs can occur with enteroviral aseptic meningitis in summer outbreaks (12). Infections of the leptomeninges can present with signs and symptoms of meningeal irritation and altered mental status. Inflammation of the meninges causes reflex paraspinous muscle spasm, which is reflected in an opisthotonic posture as nuchal rigidity, inability to straighten a raised leg, and flexion of the leg when the neck is flexed, or opisthotonic posture. Most patients with acute bacterial meningitis after the neonatal period have signs of meningeal irritation at the time of presentation (14). Those without such signs are more likely to be elderly and to have gram-negative meningitis. Neonates usually exhibit listlessness but no clear CNS signs. Seizures are common. Disease within the brain parenchyma can result in seizures, altered states of consciousness, acute changes in personality or behavior, or focal neurologic deficits. The hypothalamic–pituitary axis can be involved, causing severe hypothermia and diabetes insipidus. The evidence of CNS infection in meningitis can be masked in elderly persons by other disease processes. Fever can be attributed to a recognized infection elsewhere, such as pneumonia, cellulitis, endocarditis, otitis, or sinusitis, and altered CNS function can be blamed on alcoholism, head trauma, stroke, brain tumor, subarachnoid hemorrhage, or metabolic abnormalities. Treatable CNS infection, particularly bacterial meningitis, must be ruled out in such patients. This is usually done by careful neurologic examination, including lumbar puncture.

Neurologic Manifestations In adults the most frequent neurologic complications of bacterial meningitis are cerebrovascular, occurring in approximately 37% of patients with intracranial complications, followed in frequency by brain swelling, which is detected by computed tomography (CT) (in 34% of cases, and hydrocephalus in 29%) (27). BRAIN SWELLING As noted earlier, cerebral edema can occur in acute bacterial meningitis. Manifestations include obtundation and coma, palsies of cranial nerve VI, abnormal reflexes, hypertension, decerebrate posturing, an abnormal respiratory pattern, and bradycardia. Brain edema causes increased ICP, which in older infants has been shown to reduce cerebral blood flow velocity. The resulting decrease in cerebral perfusion is another potential cause of brain injury. Papilledema is rare because of the relatively brief duration of the meningeal process and increased CSF pressure.

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A markedly increased ICP from meningitis can lead to herniation. The following are signs of herniation: bradycardia and an abnormal respiratory pattern; midposition, nonreactive pupils; unequally sized or dilated, nonreactive pupils; a skew deviation or dysconjugate movements of the eyes; decorticate or decerebrate posturing (12). Marked hyperpnea sometimes occurs in patients with severe bacterial meningitis; in this condition, CSF acidosis, caused mainly by increased lactic acid levels, provides much of the respiratory drive.

FOCAL CEREBRAL SIGNS Focal cerebral signs (hemiparesis, quadriparesis, visual field defects, disorders of conjugate gaze, dysphasia) occur in 10% to 20% of patients with meningitis, more frequently with pneumococcal than with other types of meningitis. These signs can appear early in the course of meningitis, or, less frequently, later in the course of the disease as a result of cortical arteritis or phlebitis. CRANIAL NERVE DYSFUNCTION Cranial nerve dysfunction has been reported in 10% to 20% of patients with bacterial meningitis. Cranial nerves III, VI, and VIII are most often involved. The highest frequency of involvement is associated with S. pneumoniae meningitis. Vasculitis-induced infarction of cranial nerve VIII and necrosis of cells in the organ of Corti can be responsible for permanent deafness. Involvement of the inner ear is not a result of direct extension of infection from the middle ear to the inner ear, even when otitis media precedes meningitis (12,28). SEIZURES Seizures in meningitis can be focal or generalized. Early seizures occur in 15% to 30% of cases of bacterial meningitis. In a study of adults with meningitis, S. pneumoniae was the cause of seizures in a greater percentage of those patients who had them, but alcoholism was a confounder. Seizures that occur early in hospitalization do not herald the onset of a permanent seizure disorder, but those that persist beyond the first few days or that develop later during hospitalization can do so (29). Non-Neurologic Complications SEPTIC COMPLICATIONS Because of the early treatment of acute bacterial meningitis, endocarditis is an uncommon complication of the bacteremia associated with such meningitis. In the rare instance in which endocarditis develops, it usually involves the aortic valve. Pyogenic arthritis caused by the common agents of meningitis can complicate the presentation early in the course of CNS infection. COAGULOPATHIES In patients with meningitis, coagulation disorders (thrombocytopenia, DIC) can complicate bacteremia and hypotension. The coagulopathy can be mild and consist only of thrombocytopenia, but in patients with more profound bacteremia the clinical features and laboratory findings can be typically those of DIC.

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SHOCK Shock can develop early in the course of acute bacterial meningitis as a consequence of intense bacteremia, and this can also occur in meningococcemia-meningitis or in pneumococcal bacteremia in asplenic patients. PROLONGED FEVER Most patients with the common types of bacterial meningitis become afebrile within 2 to 5 days of initiation of appropriate antimicrobial therapy. Occasionally, fever persists for 8 to 10 days or longer, or recurs after initial defervescence. Such a febrile course, accompanied by persisting headache, a stiff neck, a depressed sensorium, and focal cerebral signs, suggests that antimicrobial therapy has been inadequate or that a neurologic complication (e.g., cortical vein thrombophlebitis and arteritis, ventriculitis, ventricular empyema, subdural effusion or empyema, sagittal sinus thrombosis) has supervened. Reevaluation of CSF findings, particularly Gramstained smears and cultures, is of paramount importance; the appearance of new focal cerebral signs would be an indication for cranial CT. (Examination of CSF is described in the following section, Laboratory Diagnosis.) Drug fever or a serum sickness-like syndrome should be considered in a patient with persistent fever whose clinical course and CSF findings show continued improvement.

Laboratory Diagnosis CSF Examination Examination of CSF is the basis of the diagnostic approach to CNS infection. Normally, CSF is crystal clear, contains less than five mononuclear cells per cubic millimeter; has a protein content of less than 4.5 g/L, of which 14% or less is g-globulin; has a glucose concentration approximately two thirds that of the blood; and is under a pressure of less that 180 mm H2O (21). CNS infection usually produces changes in the CSF. These can include an increased number of cells, increased protein concentration, and decreased glucose concentration. Total and differential cell counts should be made. Mononuclear cells usually predominate in nonbacterial (mycobacterial, fungal, rickettsial, and viral) infections; predominance of polymorphonuclear leukocytes (PMN) is typical of bacterial infections, but can also be seen in amebic infections and early in viral infections. One PMN or more than five mononuclear cells in an uncentrifuged CSF specimen are abnormal. Early in any of these diseases there can be no increase in the cell number. Repeated examination of the CSF after 8 to 24 hours in patients suspected of having a viral process is often useful. A pleocytosis can be found in subacute bacterial endocarditis, after severe seizures, and during systemic viral infections such as measles. Large numbers of erythrocytes can be found in the CSF in herpes virus infection and in postinfectious and amebic encephalitis (12,19,30,31). A CSF specimen should be stained and cultured for the possible infecting organism in meningitis. Because CNS infection is frequently a complication of

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systemic diseases, other body fluids (e.g., blood, stool, throat scrapings, sputum, and urine) should also be cultured. Short-term antibiotic treatment before hospital admission does not significantly alter the total or differential cell count or CSF protein or glucose values; however, it does reduce the frequency of positive cultures and diagnostic Gram stains (12). Some fungal and bacterial antigens (e.g., Cryptococcus, Haemophilus, pneumococcus, and meningococcus) can be detected by immunodiagnostic techniques, providing a rapid clue to diagnosis and a potential mechanism for identifying the infecting organism in previously treated persons. The polymerase chain reaction (PCR) is increasingly useful for the diagnosis of viral infections of the CNS (32-35). The CSF protein level increases with most infections, and in chronic infections an increased proportion of this protein can consist of locally synthesized immunoglobulin. The increase in protein concentration can be slight with viral infections, but is usually greater with bacterial, fungal, or tuberculous infections. An increased protein value can be the only CSF abnormality in brain abscess or parameningeal infection. The immunoglobulin present is often directed against the infecting agent. The CSF glucose value is usually low in untreated bacterial meningitis, and is often also low in fungal, tuberculous, and amebic meningitis. The CSF glucose value can best be interpreted if a plasma glucose level is also available from a sample taken at approximately the same time. The CSF glucose value can be depressed in some encephalitides of viral meningitis (mumps, lymphocytic choriomeningitis viruses, herpes virus infection), and CNS sarcoid, tumors, and subarachnoid hemorrhage (36). Infection at the site where the puncture will be performed is a contraindication to lumbar puncture. The major risk in performing a lumbar puncture occurs when there is evidence of increased ICP from a mass lesion in the brain. With removal of CSF, the ICP dynamics can be altered, and the brain can shift and herniate through the tentorial notch or foramen magnum. If a mass lesion is suspected on the basis of the history or physical examination, or if increased ICP is evident on funduscopic examination, an imaging technique such as CT or magnetic resonance imaging (MRI) should be used before lumbar puncture. If this occurs after culture, empiric antibiotic therapy should be begun. In other situations, lumbar puncture should not be delayed, because the information gained from examining the CSF is crucial for the differential diagnosis and early institution of treatment (19,37).

Other Laboratory Studies Blood cultures from patients with meningitis often reveal the pathogen, disclosing 90% of H. influenzae, 80% of S. pneumoniae, and 90% of N. meningitidis (34).

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Bacteremic skin lesions associated with highly invasive organisms can reveal the agent on a Gram-stained smear. Thus, for example, aspiration of the whitish center of one of the cutaneous purulent purpura associated with S. aureus or N. meningitides bacteremia can reveal the pathogen. The purely petechial lesions of the skin in bacterial meningitis, however, are unlikely to be revealing on Gram-stain examination. Gram-stain examination and a culture of fluid aspirated from a middleear effusion can provide a clue to bacteriologic diagnosis when the findings of CSF smear examination are equivocal. The peripheral leukocyte count is commonly increased in patients with bacterial meningitis, ranging from 14,000 to 24,000 cells/mm3, and is generally higher in pneumococcal and meningococcal than in H. influenzae disease (12). Hyponatremia in the course of bacterial (or tuberculous or fungal) meningitis is commonly caused by either the complicating syndrome of inappropriate antidiuretic hormone secretion (SIADH) or by inappropriate fluid administration.

Radiologic Studies Chest radiographs should be made in cases of bacterial meningitis to discover any predisposing pulmonary portal of infection. Films of the air sinuses and mastoids should be made at an appropriate time after commencing antimicrobial therapy if the history or findings suggest infection of these structures. When the history, clinical setting, or physical signs (papilledema, focal cerebral findings) suggest a suppurative intracranial fluid collection, cranial CT should be done without delay, and before lumbar puncture (but after blood for cultures has been taken, and therapy with appropriate antimicrobials for meningitis of unknown bacterial cause has been instituted) (12). Patients with bacterial meningitis rarely have clinically significant CT findings without concomitant focal neurologic abnormalities. A CT done during the second week of meningitis is most sensitive for cerebral infarction. In the course of meningitis in children, CT is most valuable when focal neurologic findings persist, when CSF cultures remain positive, or when meningitis is recurrent (38,39). In approximately 30% of adults with meningitis, CT shows abnormalities related to meningitis or its complications. Cerebral edema and dural enhancement are abnormalities seen on scans done within 72 hours of admission, whereas cerebral infarcts are seen on later scans. Ventriculomegaly is the most common CT abnormality in adult meningitis, occurring in 15% of all cases, of which 15% require a shunting procedure. In the study of adult meningitis in which this was found, 19 (49%) of the 39 patients who exhibited focal

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neurologic deficits or seizures had CT abnormalities related to meningitis. In contrast, of the 48 patients with nonfocal findings, only eight (17%) had CT abnormalities. Thus, CT in meningitis should not be routine, but should be employed as indicated by the clinical setting, neurologic findings, and clinical course (12,21).

Differential Diagnosis The clinical manifestations of meningeal inflammation in bacterial meningitis (headache, fever, stiff neck, obtundation) are common to various other types of meningitis (viral, fungal mycobacterial, treponemal, borrelial, parasitic, hypersensitivity), as well as to acute pyogenic bacterial meningitis and to parameningeal infections. Analysis of CSF findings is central to development of the differential diagnosis.

Nonbacterial Meningitis A retrospective analysis of the predictive value of initial clinical and laboratory observations was performed with 422 patients who had meningitis seen at one hospital between 1969 and 1980 (4). Five CSF values were found to be individual predictors of bacterial infection with 99% or greater certainty: 1. 2. 3. 4. 5.

The CSF glucose level is less than 1.9 mmol/L (34 mg/dL). The CSF/blood glucose ratio is less than 0.23. The CSF protein level is more than 2.2 g/L. There is more than 2000/mm3 CSF. There is more than 1180 CSF neutrophils per mm3.

Although any one of the foregoing tests could rule in bacterial meningitis with a high likelihood, none could exclude it. However, a logistic multiple regression model, utilizing the following parameters: patient age, month of onset, total CSF neutrophil count, and CSF/blood glucose ratio could be used to exclude acute bacterial meningitis with more than 95% confidence in patients whose CSF Gram stains were negative. Aseptic enteroviral meningitis usually can be distinguished from bacterial meningitis by its epidemiology, more gradual onset, rare occurrence of outbreaks, accompanying macular or petechial rash, and lymphocytic pleocytosis without hypoglycorrhachia (9). Aseptic echovirus meningitis can present with an initial pleocytosis of up to 1000 cells per mm3 and neutrophil predominance, which shifts in the following 12 to 36 hours to a predominance of lymphocytes. In nonbacterial meningitis, the CSF glucose level is usually greater than 40 mg/dL, but can be slightly reduced in occasional patients if the pathogen is the virus of lymphocytic choriomeningitis,

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mumps, or herpes simplex. Aseptic meningitis can be associated with the acute human immunodeficiency virus (HIV) mononucleosis-like syndrome. Acute aseptic herpes simplex virus type 2 (HSV-2) meningitis occurs in sexually active persons, and can be distinguished from bacterial meningitis by the presence of clustered vesicular lesions in the genital area or inguinal lymphadenopathy and by its lymphocytic pleocytosis. The aseptic meningitis of neuroborreliosis can be distinguished from acute pyogenic meningitis by its more subacute onset, exposure of the patient to an area endemic for Lyme disease, positive serologic test result for Lyme disease, lymphocytic pleocytosis, and history of erythema chronicum migrans. Leptospiral meningitis might be suggested by a biphasic illness, conjunctivitis, and lymphocytic pleocytosis occurring in a person exposed to rodents, dogs, or cows. Diagnosis of this disease is usually made by serologic testing. Tuberculous meningitis occurs in a setting of either past tuberculous infection (breakdown of an old meningeal tuberculoma) or recently acquired infection with miliary dissemination to the meninges in an immunocompetent or immunocompromised (e.g., HIVinfected) patient. The onset of tuberculous meningitis tends to be less abrupt than that of acute pyogenic meningitis. The characteristic CSF changes are lymphocytic pleocytosis, hypoglycorrhachia, and an increased protein concentration. Bilateral palsies of cranial nerve VI suggest a basilar meningitis, and with the CSF algorithm described earlier, strongly suggest tuberculous meningitis. Fungal meningitides are almost always more subacute in onset than is bacterial meningitis, produce a lymphocytic pleocytosis with hypoglycorrhachia, and are suggested by epidemiologic clues. Fungal meningitides— such as Cryptococcus neoformans—most commonly present the clinical picture of chronic meningitis, and are diagnosed by culture and antigen detection in the CSF, or by antibody determination in the CSF and serum. Rarely, chronic meningitis can be characterized by a predominantly neutrophilic CSF according to the algorithm previously described, for which any of several bacterial and mycotic agents can be responsible. Parameningeal infections (particularly brain abscess, subdural empyema, and cranial and spinal epidural abscess) should be considered in the differential diagnosis of acute bacterial meningitis. These processes might be suspected in a patient with features of meningeal inflammation who also has a chronic ear, sinus, or lung infection. Focal cerebral signs and neurologic symptoms antedating the onset of the acute meningitis suggest a space-occupying intracranial infection, such as a brain abscess. In a patient with presumed bacterial meningitis whose CSF algorithm shows an atypical neutrophilic pleocytosis, a normal glucose level, and no demonstrable organisms on a Gram-stained smear, parameningeal infections warrant particular attention in the differential diagnosis. Isolation of anaerobic bacteria from CSF, especially in mixed culture, suggests parameningeal infection.

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Naegleria fowleri can rarely produce a fulminant, acute, and usually fatal purulent meningitis. This diagnosis would be considered for a patient who had recently swum in warm freshwater. Early symptoms can include an altered sense of smell and taste. In addition to a neutrophilic pleocytosis with a low to normal glucose level, the CSF often contains numerous erythrocytes. The diagnosis is made by finding motile amoebic trophozoites in fresh preparations of uncentrifuged CSF. The clinical picture of acute meningitis can develop in bacterial endocarditis. It can represent true bacterial meningitis caused by a pyogenic organism (e.g., S. pneumoniae, S. aureus), or it can result from cerebral embolic infarction from endocarditis caused by a nonpyogenic organism. The CSF findings of cerebral infarction in this latter situation include a pleocytosis of several hundred cells, with varying numbers of neutrophils, a normal glucose level, and absence of bacteria. In occasional patients with meningeal symptoms caused by small cerebral embolic infarctions from acute S. aureus endocarditis, the diagnosis can be made by examining Gram-stained smears of purulent cutaneous purpura lesions.

Chemical Meningitis Chemical meningitis occasionally results from leakage into the subarachnoid space of debris from an intracranial tumor, commonly a craniopharyngioma or an epidermoid tumor of the posterior fossa. This can produce the picture of recurrent meningitis. The CSF findings include an initial neutrophilic (or lymphocytic) pleocytosis, with or without hypoglycorrhachia. Birefringent material (keratinized debris) from an epidermoid tumor or a craniopharyngioma can be observed under polarized light microscopy (40). Another rare, noninfectious cause of meningitis is systemic lupus erythematosus. The CSF in such cases usually shows a lymphocytic pleocytosis with a normal glucose concentration, although rarely, numerous neutrophils and hypoglycorrhachia are features. Antinuclear antibodies are present in high titers. Rarely, unusual acute, recurrent episodes of nonbacterial meningitis of unknown cause are part of the course of Behçet syndrome, Mollaret meningitis (believed to be caused by recurrent herpes meningitis), or familial Mediterranean fever. Hypopyon, oral and genital lesions, and pathergic skin changes would be indicative of Behçet syndrome.

Hypersensitivity Meningitis Occasionally, meningitis is the principal manifestation of hypersensitivity to drugs such as sulfonamides and nonsteroidal antiinflammatory agents. The pleocytosis in such cases can be predominantly neutrophilic or lymphocytic, and some eosinophils can be present, but the glucose level in CSF is normal. Mollaret meningitis, characterized by self-limited episodes of fever, meningeal

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findings, mononuclear pleocytosis (sometimes neutrophilic at inception), and the presence in the CSF of unusual cells variously described as epithelial or endothelial, has been associated in some instances with underlying Herpes simplex virus type 1 (HSV-1) infections or with epidermoid cysts of the CNS (6,8,12,13,19,30,41-43).

Treatment The efficacy of antimicrobial therapy in bacterial meningitis depends on a variety of factors, including the antimicrobial susceptibility of the organism, bactericidal activity of the antimicrobial agent, capacity of the antimicrobial agent to penetrate BBB, and effectiveness of various modes of antimicrobial drug administration in achieving desired concentrations of the drug in the CSF. Because there is a lack of intrinsic opsonic and antibacterial activity in the CSF early in bacterial meningitis, bactericidal rather than bacteriostatic agents are needed for treatment (44). The CSF concentration of beta-lactam antibiotics, vancomycin, or aminoglycosides must be 10 to 20 times higher than the minimal bactericidal concentration for the infecting organism if optimal bactericidal effects are to be achieved. The low pH and abundance of nucleic acids in purulent CSF inhibit rapid bacterial killing by aminoglycosides. Most antimicrobial agents used in treating bacterial meningitis, with the exception of chloramphenicol, do not penetrate well through the normal BBB. Beta-lactam antibiotics penetrate only to the extent of 0.5% to 2.0% of their peak serum concentrations, although higher concentrations are achieved when the meninges are inflamed. Clindamycin, erythromycin, and first- and second-generation cephalosporins should not be used to treat bacterial meningitis because effective bactericidal levels in the CSF cannot be obtained with these drugs. For antimicrobial drugs such as beta-lactam drugs, aminoglycosides, and vancomycin, which poorly penetrate even inflamed meninges, intermittent bolus parenteral administration is preferred because higher peak levels are achieved (19). The Infectious Diseases Society of America (IDSA) has prepared recently the treatment guidelines for bacterial meningitis, which we recommend to be used as reference (45).

Why Bactericidal Activity in Cerebrospinal Fluid? “Bacterial meningitis is an infection in an area of impaired host resistance” (19). Specific antibody and complement are frequently absent from the CSF in patients with this disease, resulting in inefficient phagocytosis and in rapid bacterial multiplication (to concentrations of 10 million or more colonyforming units per milliliter of CSF (46). Optimal antimicrobial treatment requires that the drug being used have a bactericidal effect in the CSF.

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Patients with pneumococcal and gram-negative bacillary meningitis who are treated with bacteriostatic antibiotics have poor clinical outcomes (12,19,47).

Factors Influencing Bactericidal Activity in Cerebrospinal Fluid The major factors affecting the bactericidal activity of an antimicrobial drug in CSF are its relative degree of penetration into the fluid, its concentration there, and its intrinsic activity in infected CSF. The penetration of an antimicrobial drug into CSF is primarily influenced by the characteristics of the drug and the integrity of the BBB (Table 3-1). When the barrier is intact, penetration is limited because vesicular transport across cells is minimal, and

Table 3-1 Empiric Selection of Antibiotics for the Treatment of Suspected Bacterial Meningitis Group of Patients

Likely Pathogen

Choice of Antibiotic

Neonate < 1 month

S. agalactiae, E. coli, Group D Other enterobacteriae Listeria S. pneumoniae, N. meningitidis + neonatal pathogens or L. monocytogenes N. meningitidis, S. pneumoniae

Ampicillin plus cefotaxime or ceftriaxone Ampicillin plus cefotaxime, ceftriaxone; dexamethasone if H. influenzae Cefotaxime/ceftriaxone ± dexamethasone + vancomycin ± rifampin if DRSP suspected Cefotaxime/ceftriaxone + Dexamethasone Vancomycin + rifampin if pneumococci Ampicillin plus cefotaxime or ceftriaxone plus dexamethasone plus rifampin if pneumococci Ampicillin plus ceftazidime or cefepime or meropenem

Infant 1–3 months

Age, 3 mo to 50 years

S. pneumoniae, L. monocytogenes, or gram-negative bacilli (rare) L. monocytogenes or gram-negative bacilli including P. aeruginosa

With impaired cellular immunity (alcoholics, other, primary or secondary) With head trauma, neurosurgery, or cerebrospinal fluid shunt With recurrent episodes of meningitis

Staphylococci, gram-negative bacilli, P. aeruginosa, or S. pneumoniae

Vancomycin plus ceftazidime or meropenem

S. pneumoniae (most common)

Broad-spectrum cephalosporins Cefotaxime/ceftriaxone Vancomycin plus dexamethasone plus rifampin

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the junctions between the endothelial cells of the cerebral microvasculature are tight. However, during meningitis there is an increase in vesicular transport across cells in meningeal arterioles and complete separation of the tight junctions between endothelial cells in meningeal venules. These changes result in increased permeability of the BBB, increasing the penetration of many microbial drugs (such as beta-lactam drugs) into the CSF to 5% to 10% of their serum concentrations. For other antibiotics more highly soluble in lipids (such as chloramphenicol, rifampin, and trimethoprim), penetration into CSF is high (reaching 30% to 40% of their serum concentration) even when the meninges are not inflamed (1). The CSF concentration of an antimicrobial agent needed for maximal bactericidal activity is unknown. In experimental meningitis, maximal bactericidal activity occurs when the concentration of drug is 10 to 30 times the minimal bactericidal concentration against the organism in vitro (48). One explanation for this difference is that infected CSF decreases the activity of an antimicrobial drug (19). Because the activity of a beta-lactam drug such as penicillin G on bacterial cell-wall synthesis depends on bacterial cell division, fever can impair its bactericidal effect in vivo (49).

Hazards of Antimicrobial Therapy Bactericidal therapy often results in bacteriolysis of the pathogen. As a result, treatment can promote the release of biologically active cell-wall products (e.g., the lipopolysaccharide of gram-negative bacteria and the teichoic acid and peptidoglycan of streptococci) into the CSF. This release of cell-wall fragments can increase the production of cytokines (IL-1, IL-6, and tumor necrosis factor-α [TNFα]) in CSF, exacerbating inflammation and further damaging the BBB. Achieving a rapid bactericidal effect in CSF remains a primary goal of therapy for meningitis (19,30).

When Should Treatment Be Started? It is important to promptly institute antibiotic therapy for bacterial meningitis, and the accusation of failure to promptly treat the disease is a common reason for malpractice litigation (19). The intuitive assumption is that a delay in therapy of even a few hours affects the prognosis adversely, although the clinical data on this are inconclusive (19). One of the most important factors contributing to delayed diagnosis and treatment of bacterial meningitis is the decision to perform cranial CT imaging before lumbar puncture is done. If imaging is indicated, investigators have suggested obtaining blood cultures, instituting empirical antimicrobial therapy, and performing lumbar puncture immediately after imaging if it

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discloses no intracranial mass lesion (5,12,19). Instituting antimicrobial therapy 1 to 2 hours before lumbar puncture will not decrease the diagnostic sensitivity if the culture of CSF is done in conjunction with testing of CSF for bacterial antigens and with blood cultures (19,45,50,51).

Empiric Antimicrobial Therapy When lumbar puncture is delayed or a Gram stain of CSF is nondiagnostic, empirical therapy is essential and should be directed at the most likely pathogens on the basis of the patient’s age and underlying health status (see Table 3-1 and Figure 3-3). For most patients, the IDSA treatment guidelines and most authors recommend therapy with vancomycin and a broadspectrum cephalosporin (cefotaxime or ceftriaxone), supplemented with ampicillin in neonates (younger than 1 month of age) and in young infants (1 to 3 months of age), because in these groups infections with S. agalactiae and L. monocytogenes are more prevalent. These recommendations require modification under special circumstances (2,8,13,19,30,45,50). For immunocompromised patients, treatment should include ampicillin (for possible Listeria) and vancomycin plus a broad-spectrum cephalosporin (such as ceftazidime or cefepime) that has more inclusive activity against gramnegative organisms, and specifically P. aeruginosa. Patients with recent head trauma or neurosurgery, and those with CSF shunts, should be given broadspectrum antibiotics effective against both gram-positive and gram-negative organisms, such as a combination of vancomycin and ceftazidime. For patients with identifiable bacteria on a Gram stain of CSF, microbial therapy should be directed toward the presumptive pathogen (Table 3-2). For all patients, therapy should be modified when the results of CSF culture and antibiotic susceptibility testing become available (12,19).

Empiric Glucocorticoid Therapy The IDSA guidelines state that consideration should be given to administration of adjunctive dexamethasone in certain patients with suspected or proven bacterial meningitis. The rationale for use is derived from experimental animal models of infection, which have shown that the subarachnoid space inflammatory response during bacterial meningitis is a major factor contributing to morbidity and mortality (45,52-55). The IDSA guidelines state that, at present, there are insufficient data to make a recommendation on the use of adjunctive dexamethasone in neonates with bacterial meningitis. For infants and children the recommendation is derived from a retrospective study involving children with pneumococcal meningitis that showed that in the dexamethasone group, there was a

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Modification for Age Empiric Therapy

Neonate < 1 mo S. agalactiae E. coli L monocytogenes

Ages 1 mo–7 years H. influenzae N. meningiditis S. pneumoniae

Ages 7–50 N. meningitidis S. pneumoniae

Ages > 50 S. pneumoniae N. meningitidis Listeria

Cefotaxmine or ceftriaxone plus Ampicillin

Cefotaxime or Ceftriaxone*



*If suspect DRSP consider adding vancomycin and or rifampin

Look at Results of Cultures/Serologies Studies of bacterial antigens Evaluate Clinically

Clinical Evaluation

No improvement or Deterioration

Improvement

Consider Repeat Continue Therapy CSF Exam and Follow up

Figure 3-3 Algorithm for the empirical therapy and follow-up guidelines for bacterial meningitis based on the age of the patient.

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Table 3-2 Recommendations for Antibiotic Therapy in Patients with Bacterial Meningitis Who Have a Positive Gram Strain or Culture of Cerebrospinal Fluid* Type of Bacteria

Choice of Antibiotic

By Gram stain

Cocci Gram-positive Gram-negative

Vancomycin plus cefotaxime or ceftriaxone, plus dexamethasone plus rifampin Penicillin high dose (300,000 U/kg up to 24 million U)

Bacilli

Gram-positive

Gram-negative

Ampicillin 100 mg/kg every 18 hours in children and 12 g/day in adults (or penicillin G) plus gentamicin 1.5 mg/kg every 1.8 hours Cefotaxime/ceftriaxone/ceftazidime or meropenem if P. aeruginosa likely

By culture

S. pneumoniae H. influenzae N. meningitidis L. monocytogenes S. agalactiae Enterobacteriaceae Pseudomonas aeruginosa, Acinetobacter

Vancomycin plus cefotaxime or ceftriaxone plus dexamethasone plus rifampin Ceftriaxone or cefotaxime Penicillin G high dose Ampicillin plus gentamicin—see gram-negative bacilli Penicillin G (some add gentamicin in neonates) Broad-spectrum cephalosporin or meropenem plus aminoglycoside (intravenous gentamicin; may need intrathecal) Ceftazidime or meropenem with or without aminoglycoside susceptibility studies

* Modified from Quagliarello VJ, Scheld WM. Treatment of bacterial meningitis. N Engl J Med. 1997;336:708–16.

higher incidence of moderate or severe hearing loss (46% vs. 23%; P = .016) or any neurologic deficits (55% vs. 33%; P = .02) (56). In a recently published randomized, placebo-controlled, double-blind trial of adjunctive dexamethasone in children in Malawi (57), the overall number of deaths (31% vs. 31%; P = .93) and presence of sequelae at final outcome (28% vs. 28%; P = .97) were not significantly different in the children who received adjunctive dexamethasone. The guidelines state that adjunctive dexamethasone does not reverse the CNS damage that develops as a result of existent cerebral edema, increased intracranial pressure, or neuronal injury that is present at diagnosis. Despite some variability in result of published trials, the IDSA guideline authors believe the available evidence supports the use of adjunctive dexamethasone in infants and children with H. influenzae type b meningitis. Dexamethasone should be initiated 10 to 20 minutes prior to, or at least concomitant with, the first antimicrobial dose, at 0.15 mg/kg every 6 hours for 2 to 4 days. Adjunctive dexamethasone should not be given to infants and children who have already received antimicrobial therapy, because administration of dexamethasone in this cir-

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cumstance is unlikely to improve patient outcome. In infants and children with pneumococcal meningitis, there is controversy concerning the use of adjunctive dexamethasone therapy. The guidelines state that “For infants and children 6 weeks of age and older, adjunctive therapy with dexamethasone can be considered after weighing the potential benefits and possible risks. Experts vary in recommending the use of corticosteroids in pneumococcal meningitis; data are not sufficient to demonstrate clear benefit in children” (58). For adults the IDSA guideline recommendations (45) are based on a recent published prospective, randomized, placebo-controlled, double-blind multicenter trial that did provide important data on the use of adjunctive dexamethasone in adults with bacterial meningitis (59). At 8 weeks after enrollment, the percentage of patients with an unfavorable outcome (15% vs. 25%; P = .03) and death (7% vs. 15%; P = .04) was significantly lower in the dexamethasone group. The IDSA guidelines (45) establish that on the basis of the available evidence on the use of adjunctive dexamethasone in adults, the use of dexamethasone is recommended (0.15 mg/kg every 6 hours for 2-4 days with the first dose administered 10-20 minutes before, or at least concomitant with, the first dose of antimicrobial therapy) in adults with suspected or proven pneumococcal meningitis. The authors of the guidelines recommend that adjunctive dexamethasone should be initiated in all adult patients with suspected or proven pneumococcal meningitis, because assessment of the score can delay initiation of appropriate therapy. Dexamethasone should only be continued if the CSF Gram stain reveals gram-positive diplococci, or if blood or CSF cultures are positive for S. pneumoniae. Adjunctive dexamethasone should not be given to adult patients who have already received antimicrobial therapy, because administration of dexamethasone in this circumstance is unlikely to improve patient outcome. The IDSA guidelines recommend that adjunctive dexamethasone be administered to all adult patients with pneumococcal meningitis, even if the isolate is subsequently found to be highly resistant to penicillin and cephalosporins; in patients with suspected pneumococcal meningitis who receive adjunctive dexamethasone, the addition of rifampin to the empirical combination of vancomycin plus a third-generation cephalosporin can be reasonable pending culture results and in vitro susceptibility testing.

Treatment of Specific Infections Common Pathogens Streptococcus Pneumoniae In treating meningitis caused by penicillin-susceptible strains of S. pneumoniae, penicillin G and ampicillin are similar in effectiveness and are the drugs of choice. For patients with suspected S. pneumoniae meningitis (for

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which the susceptibilities are unknown) and patients known to have antibiotic-resistant S. pneumoniae, the choices of drug are problematic. This is because the CSF concentrations of penicillin may not be bactericidal and second, because clinical failures have been reported with broadspectrum cephalosporins (cefotaxime or ceftriaxone) even though they can be effective against penicillin-resistant strains. Almost all failures have occurred in children with strains of S. pneumoniae for which the MIC of cefotaxime or ceftriaxone is 2 µg/mL or greater, although some reports suggest that treatment can fail when the MICs of the two drugs are 1.0 µg per milliliter (60). As the MIC of penicillin for S. pneumoniae increases, resistance increases to other antimicrobial agents, including cephalosporins, chloramphenicol, trimethoprim–sulfamethoxazole, and erythromycin, but not vancomycin. Therefore, vancomycin can be the most effective treatment agent for S. pneumoniae meningitis in the era of beta-lactam resistance. However, concern about the penetration of vancomycin into the CSF in adults has promoted studies of combination regimens. In experimental S. pneumoniae meningitis, the combination of vancomycin and ceftriaxone was synergistic even against strains for which the MIC of ceftriaxone was greater than 4 µg/mL (61). However, in animals given dexamethasone concomitantly, the penetration of vancomycin into the CSF was reduced, and sterilization of the CSF was delayed (62). Only the combination of ceftriaxone and rifampin effectively sterilized the CSF with respect to highly resistant strains of S. pneumoniae when dexamethasone was given concomitantly (62). In children, vancomycin has been used in a dose of 15 mg/kg; the data for adults with higher double doses of vancomycin are not strong, but many clinicians recommend this practice, especially when suspected drug resistant S. pneumoniae are found or when the infection is documented. Although these regimens have not yet been studied in humans, and recommendations for the management of bacterial meningitis are evolving, the increasing prevalence of antibiotic-resistant S. pneumoniae warrants the combination of ceftriaxone plus vancomycin in patients with a Gram stain of CSF that suggests the presence of S. pneumoniae (19). This regimen should be continued if the S. pneumoniae isolate is resistant to penicillin (MIC 0.1 µg/mL) and to ceftriaxone and cefotaxime (MIC > 0.5 µg/mL). In adults treated with adjunctive dexamethasone, ceftriaxone plus rifampin is the preferred combination regimen pending studies of susceptibility (19). Because the penetration of vancomycin into CSF is not reduced in children treated with dexamethasone, ceftriaxone plus vancomycin can still be given (63). Unless the isolate of S. pneumoniae is known to be susceptible to penicillin, many authors recommend a second lumbar puncture within 24 to 48 hours to document bacteriologic cure, because adjunctive dexamethasone therapy can prevent adequate clinical assessment of the response to therapy (62).

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Neisseria Meningitidis Penicillin and ampicillin are effective treatment agents for meningitis caused by N. meningitidis, although rare isolates of beta-lactamase–producing strains have high-level resistance (MIC 250 µg/mL). Clinical isolates with altered penicillin-binding proteins and intermediate resistance to penicillin (MIC 0.11.0 µg/mL) have been identified in Europe and South Africa, and recently in North Carolina. The clinical importance of such resistance is unclear, because most patients with meningitis caused by these intermediately resistant strains can be treated effectively with penicillin. At present, penicillin is the drug of choice for meningitis caused by N. meningitidis the bacterial isolates from patients who do not have adequate responses should be formally tested, and the treatment should be changed to ceftriaxone (or cefotaxime) if the isolate is resistant to penicillin (MIC 0.1 µg/mL) (5,12,13,19).

Less Common Pathogens Listeria Ampicillin and penicillin are the treatments of choice for L. monocytogenes meningitis (13,19). However, neither drug is bactericidal against Listeria in vitro, and mortality rates as high as 30% have been reported with the use of these drugs in Listeria. These observations, and the enhanced bactericidal activity in experimental Listeria meningitis when penicillin (or ampicillin) is combined with gentamicin, have prompted many to recommend these latter combinations. Some authors recommend ampicillin (or penicillin) plus gentamicin for patients of all ages who have Listeria meningitis (12,13,19). Trimethoprim–sulfamethoxazole is bactericidal against Listeria in vitro, and has been a successful alternative agent in specific patients. Despite being effective in vitro, chloramphenicol and vancomycin have proved ineffective in patients with systemic Listeria infection. Meropenem is active in vitro and in laboratory animals with Listeria meningitis, but there are inadequate data to recommend its use in humans (19). Streptococcus Agalactiae For neonates with meningitis caused by S. agalactiae (group B streptococcus), the combination of ampicillin and gentamicin is the regimen of choice because of the in-vitro synergy of these drugs and reports of penicillintolerant strains of S. agalactiae. In adults with group B streptococcal meningitis, the benefit of the combination regimen over penicillin (or ampicillin) is unproved, and mortality is influenced primarily by the presence of underlying illness (12,13,19). Gram-Negative Bacterial Meningitis With the advent of the broad-spectrum cephalosporins (cefotaxime, ceftriaxone, ceftazidime, and cefepime), clinical outcomes in bacterial meningitis have improved remarkably (success rate, 85%-90%) because of the high level

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of activity of these antibiotics against gram-negative pathogens, and their high degree of penetration into CSF. Ceftazidime in particular has enhanced activity against P. aeruginosa, and has proved very effective (cure rate 70%-75%, with or without concomitant systemic aminoglycoside therapy). Other promising antimicrobial agents are aztreonam, trimethoprim–sulfamethoxazole, ciprofloxacin, cefepime, and meropenem. Although no results are available from comparative trials, some authors (19) recommend ceftazidime combined with a parenterally administered aminoglycoside as first-line therapy for gramnegative bacillary meningitis. In patients who do not have a response, they recommend a repeat lumbar puncture with CSF culture and antibiotic susceptibility testing. If gram-negative bacilli continue to grow in cultures of CSF and resistance develops to cephalosporin during therapy, intrathecal (or intraventricular) therapy with aminoglycosides or alternative systemic antimicrobial agents can be given on the basis of the results of susceptibility studies. Chloramphenicol has been found ineffective in gram-negative bacteria because its effect against gram-negative bacilli in CSF is only bacteriostatic. Although aminoglycosides are bactericidal in vitro, systemic therapy with gentamicin and amikacin was not highly effective because of inadequate penetration into CSF. Unfortunately, in neonates with gram-negative meningitis, the intrathecal administration of aminoglycosides was ineffective, and the mortality rate for patients given intraventricular aminoglycoside therapy was higher than for patients given intravenous aminoglycoside therapy. Subsequent smaller case series suggested that individualized dosing of aminoglycosides through an intraventricular reservoir can lead to better outcomes.

Staphylococcus Aureus Treatment of S. aureus meningitis involves the use of intravenous nafcillin or oxacillin. For meningitis caused by methicillin-resistant S. aureus, or when such methicillin-resistant organisms are likely, or for patients who are allergic to penicillin, vancomycin is the alternative drug of choice (12,13,19). Some investigators recommend the addition of rifampin to either nafcillin or vancomycin when the therapeutic response to these latter two drugs has been inadequate, or from the beginning when the infection is severe (13,19). Because coagulase-negative staphylococci are the most frequent causes of CSF shunt infections (and complicating meningitis), and because more than one third of such nosocomial strains of staphylococci are methicillin resistant, vancomycin is the initial drug of choice for treating shunt infections, although its penetration is limited in the absence of marked meningeal inflammation. If the response to treatment is unsatisfactory, rifampin (which readily penetrates the CSF) might be added.

Duration of Antibiotic Therapy The optimal duration of antibiotic therapy for patients with bacterial meningitis is undefined (3,4,6-10,12,13,19,30,43,45,63). Most texts recommend a

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Table 3-3 Guidelines for the Duration of Antibiotic Therapy Pathogen

Suggested Duration of Thearpy (Days)

H. influenzae N. meningitidis S. pneumoniae L. monocytogenes Group B streptococci Gram-negative bacilli (other than H. influenzae)

7 7 10–14 14–21 14–21 21

* Modified from Quagliarello VJ, Scheld WM. Treatment of bacterial meningitis. N Engl J Med. 1997;336:708-16.

range of 7 to 10 days for meningococcal meningitis, and longer courses (1021 days) for meningitis caused by other pathogens (Table 3-3). In a randomized trial of therapy with ceftriaxone in children with nonmeningococcal meningitis (primarily H. influenzae disease), 7 days of therapy was as effective as 10 days of therapy (12,19,64). Clinical trials involving patients with meningococcal meningitis showed that 7-day treatment regimens (including penicillin, cefotaxime, ceftriaxone, and chloramphenicol) were very effective, and the vast majority of patients were cured in 4 or 5 days (12,19,65). No comparative studies have been done on the duration of treatment in patients with meningitis caused by S. pneumoniae, L. monocytogenes, S. agalactiae, or enteric gram-negative bacilli. We recommend that the duration of therapy be tailored to the individual patient on the basis of the clinical and microbiologic response.

Prevention Meningococcal Diseases The risk of meningococcal disease for household contacts of an initial case is 500 to 800 times greater than the endemic rate for meningococcal disease in the general population (12). Chemoprophylaxis is indicated for close contacts (e.g., household or day care center personnel, medical personnel in close direct contact with the patient) of patients with meningococcal disease. Rifampin is 80% to 90% effective in eliminating asymptomatic nasopharyngeal carriage of N. meningitidis and is the recommended drug for chemoprophylaxis of meningococcal meningitis. The dose is 600 mg given orally every 12 hours for 2 days for adults, 10 mg/kg every 12 hours for children older than 1 month of age, and 5 mg/kg every 12 hours for children younger than 1 month of age. Because the carrier state can recur shortly after discontinuation of treatment with high doses of penicillin, rifampin should also be administered to patients with meningococcal disease before their discharge from the hospital. Minocycline has been almost as effective as rifampin in eliminating N. meningitidis from nasopharyngeal carriers, but is not commonly used

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because of reports of vestibular side effects. Oral ciprofloxacin reaches concentrations in nasal secretions that are greater than the MIC for N. meningitidis. Single-dose oral ciprofloxacin, 500 or 750 mg for adult patients, is approximately 90% effective in eradicating pharyngeal carriage of N. meningitidis. Ceftriaxone (250 mg intramuscularly in adults and 125 mg in children) was reported to eliminate the carriage of serogroup A meningococci in more than 90% of patients for up to 2 weeks. Immunoprophylaxis of meningococcal disease currently involves use of a quadrivalent (A/C/Y/W-135) polysaccharide vaccine. It is used in the military, in travelers to countries with hyperendemic or epidemic disease, in aborting outbreaks caused by meningococcal serogroups covered by the vaccine, and for persons at high risk, such as asplenic patients or those who have terminal complement-component deficiencies. Meningococcal vaccines are important in quelling epidemics in developing countries where they are used as a component to prophylactic chemotherapy in neighborhood or school outbreaks.

Haemophilus Influenzae Infection The risk of secondary spread of invasive Hib infection from infected persons to nonimmunized household contacts younger than 4 years of age is 2% to 6% during the 30-day period after exposure (12). The highest rate occurs in contacts younger than 1 year of age. The majority of secondary cases occur within a week of onset of disease in the index case. Rifampin is effective in eliminating nasopharyngeal carriage of Hib. If another child (whether previously given Hib vaccine or not) younger than 4 years of age resides in the household, rifampin prophylaxis is recommended for all household contacts, including adults (except pregnant women) of any index case. The dose is 20 mg/kg given orally once daily for 4 days (maximal daily dose is 600 mg). Because nasopharyngeal carriage can reappear after discontinuation of antimicrobial therapy for systemic Hib infection, the index patient should receive rifampin before hospital discharge. Current recommendations of the American Academy of Pediatrics Committee on Infectious Diseases call for vaccination of all infants beginning at 2 months of age with one of three licensed Hib PRP (or PRP oligomer) protein-conjugate vaccines: 1. HbOC (HibTITER) is a diphtheria CRM 197 protein conjugate. 2. PRP-OPM (PedvaxHIB) is a N. meningitidis serogroup B outer membrane protein complex conjugate. 3. PRP-T (ActHIB, OmniHIB) is a tetanus toxoid protein complex. A primary series of HbOC or PjRP-T consists of three doses given at 2, 4, and 6 months of age, whereas for PjR-OMP, only two doses, given at 2

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and 4 months, are recommended. An additional booster dose of a conjugate vaccine should be given at 12 to 15 months of age. A fourth vaccine, PRP-D (ProHIBIT), a diphtheria toxoid-protein conjugate vaccine, is recommended only for use in children 12 months of age and older, and can be substituted at that time for one of the other vaccines as the booster dose.

REFERENCES 1. Unhanand M, Mustafa MM, McCracken GH Jr., Nelson JD. Gram-negative enteric bacillary meningitis: a twenty-one-year experience. J Pediatr. 1993;122:15-21. 2. Durand ML, Calderwood SB,Weber DJ, Miller SI, Southwick FS, Caviness VS Jr., et al. Acute bacterial meningitis in adults. A review of 493 episodes. N Engl J Med. 1993;328:21-8. 3. Hosoglu S, Ozen A, Kokogly OF, et al. Acute bacterial meningitis in adults: Analysis of 218 episodes. Indian J Med Sci. 1997;166:231-4. 4. Schuchat A, Robinson K,Wenger JD, Harrison LH, Farley M, Reingold AL, et al. Bacterial meningitis in the United States in 1995. Active Surveillance Team. N Engl J Med. 1997;337:970-6. 5. Andersen J Wandall JH, Skinhoj P, et al. Acute meningococcal meningitis: Analysis of features of the disease according to the age of 255 patients. J Infect Dis. 1997;34:227-35. 6. Segreti J, Harris AA. Acute bacterial meningitis. Infect Dis Clin North Am. 1996;10:797-809. 7. Sigurdardóttir B, Björnsson OM, Jónsdóttir KE, Erlendsdóttir H, Gudmundsson S. Acute bacterial meningitis in adults. A 20-year overview. Arch Intern Med. 1997;157:425-30. 8. Tunkel AR, Scheld WM. Acute bacterial meningitis in adults. Curr Clin Top Infect Dis. 1996;16:215-39. 9. Andersen J,Wandall JH,Voldsgaard P, et al. Acute meningitis of unknown etiology: Analysis of 219 cases admitted to the hospital between 1977 and 1990. J Infect Dis. 1995;31:115-22. 10. Townsend GC, Scheld WM. Infections of the central nervous system. Adv Intern Med. 1998;43:403-47. 11. Pruitt AA. Infections of the nervous system. Neurol Clin. 1998;16:419-47. 12. Swartz M. Acute bacterial meningitis. In: Gourbach SL, Barlett JG, Blacklow NR, eds. Infectious Diseases. 2nd ed. Philadelphia, PA: WB Saunders; 1998:1377-81. 13. Roos KL,Tunkel AR, Scheld WM. Acute bacterial meningitis in children and adults. In: Scheld WM, Whittey RJ, Durack DT, eds. Infections of the Central Nervous System. 2nd ed. Philadelphia, PA: Lippincott-Raven; 1997:297-312. 14. Griffin DE. Approach to the patient with infections of the central nervous system. In: Gourback SI, Bartlett JG, Blacklow NR, eds. Infectious Diseases. 2nd ed. Philadelphia, PA: WB Saunders; 1998:1377-1381. 15. Adams WG, Deaver KA, Cochi SL, Plikaytis BD, Zell ER, Broome CV, et al. Decline of childhood Haemophilus influenzae type b (Hib) disease in the Hib vaccine era. JAMA. 1993;269:221-6. 16. Naraqi S, Kirkpatrick GP, Kabins S. Relapsing pneumococcal meningitis: isolation of an organism with decreased susceptibility to penicillin G. J Pediatr. 1974;85:671-3. 17. Fenoll A, Martín Bourgon C, Muñóz R,Vicioso D, Casal J. Serotype distribution and antimicrobial resistance of Streptococcus pneumoniae isolates causing systemic infections in Spain, 19791989. Rev Infect Dis. 1991;13:56-60. 18. Wenger JD, Hightower AW, Facklam RR, Gaventa S, Broome CV. Bacterial meningitis in the United States, 1986: report of a multistate surveillance study. The Bacterial Meningitis Study Group. J Infect Dis. 1990;162:1316-23. 19. Quagliarello VJ, Scheld WM. Treatment of bacterial meningitis. N Engl J Med. 1997;336:708-16. 20. Cherubin CE, Marr JS, Sierra MF, Becker S. Listeria and gram-negative bacillary meningitis in New York City, 1972-1979. Frequent causes of meningitis in adults. Am J Med. 1981;71: 199-209. 21. Durand ML, Calderwood SB,Weber DJ, Miller SI, Southwick FS, Caviness VS Jr., et al. Acute bacterial meningitis in adults. A review of 493 episodes. N Engl J Med. 1993;328:21-8. 22. Schlesinger LS, Ross SC, Schaberg DR. Staphylococcus aureus meningitis: A broad-based epidemiologic study. Medicine (Baltimore). 1987;66:148. 23. Swartz MN. Central nervous system infection. In: Finegold SM, George WL, eds. Anaerobic Infections in Humans. San Diego, CA: Academic Press; 1989:155-212.

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24. Tunkel AR, Scheld WM. Pathogenesis and pathology of bacterial infections of the central nervous system. In: Scheld WM, Whitley RJ, Durack DT, eds. Infections of the Central Nervous System. Philadelphia, PA: Lippincott-Raven; 1997:297-312. 25. Carpenter RR, Petersdorf RG. The clinical spectrum of bacterial meningitis. Am J Med. 1962;33:262-75. 26. Salwén KM,Vikerfors T, Olcén P. Increased incidence of childhood bacterial meningitis. A 25year study in a defined population in Sweden. Scand J Infect Dis. 1987;19:1-11. 27. Pfister HW, Borasio GD, Dirnagl U, Bauer M, Einhäupl KM. Cerebrovascular complications of bacterial meningitis in adults. Neurology. 1992;42:1497-504. 28. Eavey RD, Gao YZ, Schuknecht HF, Gonzalez-Pineda M. Otologic features of bacterial meningitis of childhood. J Pediatr. 1985;106:402-7. 29. Bohr VA, Rasmussen N. Neurological sequelae and fatality as prognostic measures in 875 cases of bacterial meningitis. Dan Med Bull. 1988;35:92-5. 30. Tunkel AR, Scheld WM. Issues in the management of bacterial meningitis. Am Fam Physician. 1997;56:1355-62. 31. Hoen B, Canton P, Gerard A, et al. Multivariate approach to differential diagnosis of acute meningitis. Eur J Clin Microbiol Infect Dis. 1996;15:252-4. 32. Ferraro MJ. Rapid immunologic diagnosis of meningitis—Is there a future? In: Balows A, Tilton RC, Turano A, eds. Rapid Methods and Automation in Microbiology and Immunology. Italy: Brixia Academic Press; 1988:481-7. 33. Martin WJ. Rapid and reliable techniques for the laboratory detection of bacterial meningitis. Am J Med. 1983;75:119-23. 34. Bohr V, Rasmussen N, Hansen B, Kjersem H, Jessen O, Johnsen N, et al. 875 cases of bacterial meningitis: diagnostic procedures and the impact of preadmission antibiotic therapy. Part III of a three-part series. J Infect. 1983;7:193-202. 35. Wilson CB, Smith AL. Rapid tests for the diagnosis of bacterial meningitis. Curr Clin Top Infect Dis. 1986;7:134. 36. Koskiniemi M, Vaheri A, Taskinen E. Cerebrospinal fluid alterations in herpes simplex virus encephalitis. Rev Infect Dis. 1984;6:608-18. 37. Bryan CS, Reynolds KL, Crout L. Promptness of antibiotic therapy in acute bacterial meningitis. Ann Emerg Med. 1986;15:544-7. 38. Packer RJ, Bilaniuk LT, Zimmerman RA. CT parenchymal abnormalities in bacterial meningitis: clinical significance. J Comput Assist Tomogr. 1982;6:1064-8. 39. Bodino J, Lylyk P, Del Valle M,Wasserman JP, Leiguarda R, Monges J, et al. Computed tomography in purulent meningitis. Am J Dis Child. 1982;136:495-501. 40. Crossley GH, Dismukes WE. Central nervous system epidermoid cyst: a probable etiology of Mollaret’s meningitis. Am J Med. 1990;89:805-6. 41. Prasad K, Haines T. Dexamethasone treatment for acute bacterial meningitis: how strong is the evidence for routine use? J Neurol Neurosurg Psychiatry. 1995;59:31-7. 42. Wubbel L, McCracken GH Jr. Management of bacterial meningitis: 1998. Pediatr Rev. 1998;19:78-84. 43. Rockowitz J, Tunkel AR. Bacterial meningitis. Practical guidelines for management. Drugs. 1995;50:838-53. 44. Simberkoff MS, Moldover NH, Rahal J Jr. Absence of detectable bactericidal and opsonic activities in normal and infected human cerebrospinal fluids. A regional host defense deficiency. J Lab Clin Med. 1980;95:362-72. 45. Tunkel AR, Hartman BJ, Kaplan SL, Kaufman BA, Roos KL, Scheld WM, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis. 2004;39:1267-84. 46. Zwahlen A, Nydegger UE,Vaudaux P, Lambert PH,Waldvogel FA. Complement-mediated opsonic activity in normal and infected human cerebrospinal fluid: early response during bacterial meningitis. J Infect Dis. 1982;145:635-46. 47. Crane LR, Lerner AM. Nontraumatic gram-negative bacillary meningitis in the Detroit Medical Center, 1964-1974. Medicine (Baltimore). 1978;57:197. 48. Strausbaugh LJ, Sande MA. Factors influencing the therapy of experimental pneumococcal meningitis in rabbits. Infect Dis. 1978;137:251-60. 49. Small PM, Täuber MG, Hackbarth CJ, Sande MA. Influence of body temperature on bacterial growth rates in experimental pneumococcal meningitis in rabbits. Infect Immun. 1986;52: 484-7. 50. Coant PN, Kornberg AE, Duffy LC, Dryja DM, Hassan SM. Blood culture results as determinants in the organism identification of bacterial meningitis. Pediatr Emerg Care. 1992;8:200-5.

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51. Kanra GY, Ozen H, Seçmeer G, Ceyhan M, Ecevit Z, Belgin E. Beneficial effects of dexamethasone in children with pneumococcal meningitis. Pediatr Infect Dis J. 1995;14:490-4. 52. Tunkel AR. Bacterial meningitis. Philadelphia, PA: Lippincott Williams &Wilkins; 2001. 53. Tunkel AR, Scheld WM. Pathogenesis and pathophysiology of bacterial meningitis. Clin Microbiol Rev. 1993;6:118-36. 54. Scheld WM, Koedel U, Nathan B, Pfister HW. Pathophysiology of bacterial meningitis: mechanism(s) of neuronal injury. J Infect Dis. 2002;186 Suppl 2:S225-33. 55. van der Flier M, Geelen SP, Kimpen JL, Hoepelman IM,Tuomanen EI. Reprogramming the host response in bacterial meningitis: how best to improve outcome? Clin Microbiol Rev. 2003;16:415-29. 56. Arditi M, Mason EO Jr., Bradley JS,Tan TQ, Barson WJ, Schutze GE, et al. Three-year multicenter surveillance of pneumococcal meningitis in children: clinical characteristics, and outcome related to penicillin susceptibility and dexamethasone use. Pediatrics. 1998;102:1087-97. 57. Molyneux EM, Walsh AL, Forsyth H,Tembo M, Mwenechanya J, Kayira K, et al. Dexamethasone treatment in childhood bacterial meningitis in Malawi: a randomised controlled trial. Lancet. 2002;360:211-8. 58. American Academy of Pediatrics. Pneumococcal infections. In: Pickering LK, ed. Red book: 2003 report of the Committee on Infectious Diseases. 26th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2003:490-500. 59. European Dexamethasone in Adulthood Bacterial Meningitis Study Investigators. Dexamethasone in adults with bacterial meningitis. N Engl J Med. 2002;347:1549-56. 60. Friedland IR, Shelton S, Paris M, Rinderknecht S, Ehrett S, Krisher K, et al. Dilemmas in diagnosis and management of cephalosporin-resistant Streptococcus pneumoniae meningitis. Pediatr Infect Dis J. 1993;12:196-200. 61. Friedland IR, Paris M, Ehrett S, Hickey S, Olsen K, McCracken GH Jr. Evaluation of antimicrobial regimens for treatment of experimental penicillin- and cephalosporin-resistant pneumococcal meningitis. Antimicrob Agents Chemother. 1993;37:1630-6. 62. París MM, Hickey SM, Uscher MI, Shelton S, Olsen KD, McCracken GH Jr. Effect of dexamethasone on therapy of experimental penicillin- and cephalosporin-resistant pneumococcal meningitis. Antimicrob Agents Chemother. 1994;38:1320-4. 63. Klugman KP, Friedland IR, Bradley JS. Bactericidal activity against cephalosporin-resistant Streptococcus pneumoniae in cerebrospinal fluid of children with acute bacterial meningitis. Antimicrob Agents Chemother. 1995;39:1988-92. 64. Knockaert DC. Bacterial meningitis: diagnostic and therapeutic considerations. Eur J Emerg Med. 1994;1:92-103. 65. Lin TY, Chrane DF, Nelson JD, McCracken GH Jr. Seven days of ceftriaxone therapy is as effective as ten days’ treatment for bacterial meningitis. JAMA. 1985;253:3559-63.

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Chapter 4

Viral Meningitis and Viral Encephalitis K.V. GOPALAKRISHNA, MD MANMEET S. AHLUWALIA, MD

Key Learning Points: 1. Enteroviruses are the most common cause of aseptic meningitis syndrome. 2. It is important to recognize herpes simplex virus (HSV) encephalitis early, as the mortality of untreated disease is high. 3. West Nile virus has caused wide spread outbreaks of encephalitis (WNE) in United States since 1999. 4. Diagnosis of viral encephalitis is aided by CSF analysis, detection of viral antigen by polymerase chain reaction (PCR) and radiologic imaging techniques. 5. The only form of viral encephalitis for which effective treatment exists is that caused by HSV.

Aseptic Meningitis Aseptic meningitis syndrome is a self-limiting disease characterized by meningeal symptoms of acute onset, cerebrospinal fluid (CSF) pleocytosis (usually with a mononuclear cell predominance), and the inability to isolate a bacterial agent. At least 300,000 cases of this syndrome occur each year in the United States (1). Aseptic meningitis is commonly caused by an infectious agent but may be of noninfectious origin (2). Viruses are the most common identifiable agents of this syndrome, and enteroviruses are responsible for more than 80% of cases (3). Outbreaks of enteroviral meningitis are seasonal. Table 4-1 shows the common and uncommon causes of acute aseptic meningitis syndrome. The most commonly affected 80

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New Developments in Viral Meningitis and Encephalitis • Japanese encephalitis and West Nile virus have spread into new habitats and

environments. • This illustrates the need for continued international surveillance to meet

emerging disease threats.

Table 4-1 Causes of Acute Aseptic Meningitis Syndrome More Common Infectious Causes Viral Enteroviruses (nonpolio) HIV Mumps virus Herpes simplex virus type 2 Vector-borne viruses (e.g., mosquitoand tick-borne) Lymphocytic choriomeningitis virus (arenavirus) Spirochetes Leptospira species Borrelia burgdorferi Mycobacteria Mycobacterium tuberculosis Less Common and Rare Infectious Causes Viral Adenovirus Herpes simplex virus type I Varicella-zoster virus Cytomegalovirus Epstein-Barr virus Influenza virus types A and B Parainfluenza virus Measles virus Rubella virus Poliovirus Rotavirus Encephalomyocarditis virus Attenuated vaccine strains of poliovirus, mumps, measles, and vaccinia Spirochetes Treponema pallidum Borrelia recurrentis Bartonella henselae

Chlamydia Chlamydia psittaci Chlamydia trachomatis Rickettsia Rickettsia rickettsii Coxiella burnetii R. prowazekii R. typhi R. tsutsugamushi Ehrlichia species Mycoplasma Mycoplasma pneumoniae M. hominis Ureaplasma urealyticum Other Bacteria Brucella species Listeria monocytogenes Nocardia species Actinomycetes Fungi Cryptococcus neoformans Coccidioides immitis Histoplasma capsulatum Blastomyces dermatidis Sporothrix schenkii Zygomycetes Pseudoallescheria boydii Cladosporium species Parasites Angiostrongylus cantonensis Strongyloides stercoralis Taenia solium Schistosoma species Trichenella spiralis Paragonimus species Echinococcus granulosus Continued

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Table 4-1 Continued Multiceps multiceps Gnathostoma spinigerum Toxoplasma gondii Naegleria/Acanthomoeba species Trypanosoma species Other Infections Partially treated bacterial meningitis Parameningeal focus of infection Endocarditis or bacteremia Bacterial toxins Viral postinfectious syndromes Postvaccination for mumps, measles/mumps, poliovirus, pertussis, rabies, or vaccinia Noninfectious Causes Medications NSAIDs (e.g., ibuprofen, naproxen, tolmetin, diclofenac, ketoprofen) Antimicrobial agents (e.g., sulfisoxazole, isoniazid, ciprofloxacin, beta-lactam agents, metronidazole, pyrazinamide) Muromonab-CD3 (OKT-3) Azathioprine Carbamazepine Phenazopyridine Ranitidine Immunoglobulin Intracranial Tumor and Cysts Craniopharyngioma Dermoid/epidermoid cyst Pituitary adenoma Astrocytoma Glioblastoma multiforme

Medulloblastoma Pinealoma Ependymoma Teratoma Lymphomatous Meningitis, Carcinomatous Meningitis, Leukemia Neurosurgery-Related Illness Intrathecal injections (e.g., air, isotopes, antimicrobial agents, antineoplastic agents, steroids, radiographic contrast media) Chymopapain injection Systemic Illness Systemic lupus erythematosis Sarcoidosis Behçet disease Sjo˙gren’s syndrome Mixed connective-tissue disease Rheumatoid arthritis Polymyositis Wegener granulomatosis Lymphomatoid granulomatosis Polyarteritis nodosa Granulomatous angiitis Cerebral vasculitis Familial Mediterranean fever Kawasaki disease Multiple sclerosis Vogt–Koyanagi–Harada syndrome Serum sickness Heavy-metal poisoning (e.g., lead, mercury) Procedure-related complications (e.g., spiral anesthesia)

NSAIDs = nonsteroidal anti-inflammatory drugs; TMP-SMX = trimethoprim–sulfamethoxazole. Modified from Hasbun R. The acute aseptic meningitis syndrome. Curr Infect Dis Rep. 2000;3:345–51; and Connolly KJ. Hammer SM. The acute septic meningitis syndrome. Infect Dis Clin North Am. 1990;4:599–622.

age groups are infants and children (4). The discussion in this chapter includes the clinical manifestations of aseptic meningitis syndrome in older children and adults. The clinical manifestations of acute bacterial meningitis and those of aseptic meningitis are difficult to distinguish from one another. In older children and adults, both conditions present with fever of acute onset (usually with a temperature of 38˚C–40˚C), severe headache, and meningismus. Neck

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Table 4-2 Cerebrospinal Fluid Findings in Patients Who Present with Meningeal Signs

Diagnosis

Glucose Pressure Leukocytes PMNLs (CSF:blood (cm H2O) (105/L) (per mm3) ratio)

Normal 20 meningitis Chronic meningitis Variable Aseptic (viral) 1000

50

>0.5 1000 2 0.5 µg/mL, and Enterococcus species

Staphylococcus aureus, methicillin susceptible,in absence of prosthetic material

Penicillin, 24 million U/24 h, IV or Ceftriaxone, 2 g, once daily, IV plus Gentamicin, 3 mg/kg once daily IV/IM§ or Vancomycin, 30 mg/kg/ 24 h in 2 divided doses, IV Ampicillin, 12 g/24 h, IV or Penicillin, 18-30 million U/24 h, IV plus Gentamicin, 3 mg/kg/ 24 h in 3 divided doses, IV/IM or Vancomycin, 30 mg/kg/ 24 h in 2 divided doses, IV plus Gentamicin, 3 µg/kg/ 24 h in 3 divided doses, IV/IM Nafcillin or oxacillin, 12 g/24 h, IV with optional use of Gentamicin, 3 mg/kg/ 24 hin 3 divided doses, IV/IM or cefazolin, 6 g/24 h in 3 divided doses, IV with optional use of gentamicin, 3 mg/kg/ 24 h in 3 divided doses, IV/IM

Comments

Only for patients intolerant of penicillin/ cephalosporins

4

4 2

4

4-6 4-6

Only for patients intolerant of penicillin/ cephalosporins 6 wk for patients with symptoms for ≥3 mo

4-6

6

6

6 3-5 d

6 3-5 d

6 wks recommended because of reduced activity against enterococci

For complicated rightsided IE and for left-sided IE; for uncomplicated right-sided, treat IE with nafcillin with or without gentamicin for 2 wk** For penicillin-allergic (nonanaphylactic) patients Continued

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Table 6-4 Continued Infecting Organisms

Regimen†

S. aureus, Vancomycin, 30 mg/kg/ methicillin24 h in 2 divided resistant, in doses, IV absence of prosthetic material Prosthetic Valve IE Nafcillin or oxacillin, caused by 12 g/24 h, IV methicillinplus rifampin 900 mg/ susceptible 24 h in 3 divided staphylococci doses, PO/IV plus gentamicin 3 mg/kg/ 24 h in 3 divided doses, IV/IM Prosthetic valve IE Vancomycin, 30 mg/kg/ caused by 24 h in 2 divided methicillin-doses, IV resistant staphylo plus rifampin 900 mg/ cocci 24 h in 3 divided doses, PO/IV plus gentamicin, 3 mg/ kg/24 h in 3 divided doses, IV/IM HACEK microCeftriaxone, 2 g, once organisms daily, IV or Ampicillin-sulbactam, 12 g/24 h in 4 divided doses, IV or Ciprofloxacin, 1000 mg/ 24 h, PO, or 800 mg/ 24 h, IV in 2 divided doses

Duration (wk)

Comments

6

≥6 ≥6

2 ≥6 ≥6

2

4

4

4

Fluoroquinolone therapy recommended only if penicillin or cephalosporin are not an option

Adapted from Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis diagnosis, antimicrobial therapy, and management of complications: Statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association. Circulation. 2005;111:e394-433. † Dosages recommended for adults with normal renal function. ‡ Vancomycin peak of 30-45 µg/mL and trough 10-15 µg/mL. § Gentamicin peak of 3-4 µg/mL and trough < 1 µg/mL. Note: In treating prosthetic valve endocarditis caused by streptococci/enterococci, duration is at least 6 wks; penicillin dosage is at least 24 million units/24 h; Gentamicin is given for 6 wks for streptococci with MIC* of penicillin > 0.12 µg/mL and for enterococci. For streptococci with MIC* of penicillin 10 mm) on anterior leaflet of mitral valve during first 1-2 wks of therapy Valve dehiscence, perforation, rupture, fistula, or large perivalvular abscess Prosthetic valve endocarditis Fungal endocarditis IE caused by aggressive, antibiotic-resistant bacteria

* Remaining vegetation possibly increasing concern. Abbreviations: IE = infective endocarditis; wk = week.

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for prosthetic valve endocarditis is approximately 10% to 15%. Other microorganisms such as S. aureus, Enterobacteriaceae, and fungi are more likely to be associated with treatment failure during the primary course of therapy (1). After cessation of antibiotic therapy, the patient should be seen every 2 weeks for the first month and monthly for 2 more months. Blood cultures should be taken if the patient’s temperature increases to more than 38ºC more than once and there is no obvious reason for fever. Relapse is unlikely after 3 months.

Antimicrobial Prophylaxis Although there is no proof that the prophylactic use of antibiotics in humans can prevent bacterial endocarditis, it is justified on theoretical and experimental grounds. The aim is to provide high serum concentrations of effective antibiotics during procedures associated with a high incidence of transient bacteremia in patients predisposed to infection and with cardiac and intravascular defects. Only 1 dose of appropriate antibiotics is necessary, given shortly before the performance of a high-risk procedure.

Conclusion Endocarditis is a challenging disease with protean manifestations. Few patients present with findings suggestive of intracardiac infection, yet it is the responsibility of the primary care physician to recognize the significance of their complaints and to arrive at the proper diagnosis. Careful attention to details of history, physical examination, and properly selected laboratory tests ultimately lead to a successful approach. The recently modified Duke criteria help make the diagnosis, and the updated antibiotics provide the latest information to assist with making the correct therapeutic decision.

REFERENCES 1. Mylonakis E, Calderwood SB. Infective endocarditis in adults. N Engl J Med. 2001;345:1318-30. 2. Berlin JA, Abrutyn E, Strom BL, Kinman JL, Levison ME, Korzeniowski OM, et al. Incidence of infective endocarditis in the Delaware Valley, 1988-1990. Am J Cardiol. 1995;76:933-6. 3. Tleyjeh IM, Steckelberg JM, Murad HS,Anavekar NS, Ghomrawi HM, Mirzoyev Z, et al. Temporal trends in infective endocarditis: a population-based study in Olmsted County, Minnesota. JAMA. 2005;293:3022-8. 4. Hogerik H, Olaison L, Andersson R, Lindberg J, Alestig K. Epidemiologic aspects of infective endocarditis in an urban population: A 5-year prospective study. Medicine (Baltimore). 1995;74:324-39. 5. Frontera JA, Gradon JD. Right-side endocarditis in injection drug users: review of proposed mechanisms of pathogenesis. Clin Infect Dis. 2000;30:374-9. 6. Watanakunakorn C, Burkert T. Infective endocarditis at a large community teaching hospital, 1980–1990: A review of 210 episodes. Medicine (Baltimore). 1993;72:90-102. 7. Cabell CH,Abrutyn E. Progress toward a global understanding of infective endocarditis. Early lessons from the International Collaboration on Endocarditis investigation. Infect Dis Clin North Am. 2002;16:255-72, vii.

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8. ICE Investigators. Staphylococcus aureus endocarditis: a consequence of medical progress. JAMA. 2005;293:3012-21. 9. Weinstein L, Schlesinger JJ. Pathoanatomic, pathophysiologic and clinical correlations in endocarditis (first of two parts). N Engl J Med. 1974;291:832-7. 10. Fowler VG, Scheld MW, Bayer AS. Endocarditis and intravascular infections. In Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 6th ed. Philadelphia, PA: Elsevier Churchill Livingstone, 2005; 975-1022. 11. Gould K, Ramirez-Ronda CH, Holmes RK, Sanford JP. Adherence of bacteria to heart valves in vitro. J Clin Invest. 1975;56:1364-70. 12. Watanakunakorn C, Kim J. Mitral valve endocarditis caused by a serum-resistant strain of Escherichia coli. Clin Infect Dis. 1992;14:501-5. 13. Yao L, Bengualid V, Lowy FD, Gibbons JJ, Hatcher VB, Berman JW. Internalization of Staphylococcus aureus by endothelial cells induces cytokine gene expression. Infect Immun. 1995;63:1835-9. 14. Gallagher PG, Watanakunakorn C. Group B streptococcal endocarditis: report of seven cases and review of the literature, 1962-1985. Rev Infect Dis. 1986;8:175-88. 15. Klein RS, Recco RA, Catalano MT, Edberg SC, Casey JI, Steigbigel NH. Association of Streptococcus bovis with carcinoma of the colon. N Engl J Med. 1977;297:800-2. 16. Fernández-Guerrero ML, Verdejo C, Azofra J, de Górgolas M. Hospital-acquired infectious endocarditis not associated with cardiac surgery: an emerging problem. Clin Infect Dis. 1995;20:16-23. 17. Ellner JJ, Rosenthal MS, Lerner PI, McHenry MC. Infective endocarditis caused by slow-growing, fastidious, Gram-negative bacteria. Medicine (Baltimore). 1979;58:145-58. 18. Caputo GM, Archer GL, Calderwood SB, DiNubile MJ, Karchmer AW. Native valve endocarditis due to coagulase-negative staphylococci. Clinical and microbiologic features. Am J Med. 1987;83:619-25. 19. Fowler VG Jr., Li J, Corey GR, Boley J, Marr KA, Gopal AK, et al. Role of echocardiography in evaluation of patients with Staphylococcus aureus bacteremia: experience in 103 patients. J Am Coll Cardiol. 1997;30:1072-8. 20. Smyth EG, Pallett AP, Davidson RN. Group G streptococcal endocarditis: two case reports, a review of the literature and recommendations for treatment. J Infect. 1988;16:169-76. 21. Teong HH, Leo YS,Wong SY, Sng LH, Ding ZP. Case report of Staphylococcus lugdunensis native valve endocarditis and review of the literature. Ann Acad Med Singapore. 2000;29:673-7. 22. Drancourt M, Mainardi JL, Brouqui P, Vandenesch F, Carta A, Lehnert F, et al. Bartonella (Rochalimaea) quintana endocarditis in three homeless men. N Engl J Med. 1995;332:419-23. 23. Levine DP, Crane LR, Zervos MJ. Bacteremia in narcotic addicts at the Detroit Medical Center. II. Infectious endocarditis: a prospective comparative study. Rev Infect Dis. 1986;8:374-96. 24. Baddour LM, Wilson WR. Infections of prosthetic valves and other cardiovascular devices. In Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 6th ed. Philadelphia, PA: Elsevier Churchill Livingston; 2005, 1022-44. 25. Crawford MH, Durack DT. Clinical presentation of infective endocarditis. Cardiol Clin. 2003;21:159-66, v. 26. Wallace SM,Walton BI, Kharbanda RK, Hardy R,Wilson AP, Swanton RH. Mortality from infective endocarditis: clinical predictors of outcome. Heart. 2002;88:53-60. 27. Heidenreich PA, Masoudi FA, Maini B, Chou TM, Foster E, Schiller NB, et al. Echocardiography in patients with suspected endocarditis: a cost-effectiveness analysis. Am J Med. 1999;107:198-208. 28. Beeson PB, Brannon ES, Warren JV. Observations on the sites of removal of bacteria from the blood of patients with bacterial endocarditis. J Exp Med. 1945;81:9-23. 29. Hoen B, Selton-Suty C, Lacassin F, Etienne J, Briançon S, Leport C, et al. Infective endocarditis in patients with negative blood cultures: analysis of 88 cases from a one-year nationwide survey in France. Clin Infect Dis. 1995;20:501-6. 30. Pazin GJ, Saul S,Thompson ME. Blood culture positivity: suppression by outpatient antibiotic therapy in patients with bacterial endocarditis. Arch Intern Med. 1982;142:263-8. 31. Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America. Circulation. 2005;111:e394-434. 32. Li JS, Sexton DJ, Mick N, Nettles R, Fowler VG Jr., Ryan T, et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis. 2000;30:633-8.

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33. Investigators of the Multicenter Aspirin Study in Infective Endocarditis. A randomized trial of aspirin on the risk of embolic events in patients with infective endocarditis. J Am Coll Cardiol. 2003;42:775-80. 34. Blumberg EA, Robbins N, Adimora A, Lowy FD. Persistent fever in association with infective endocarditis. Clin Infect Dis. 1992;15:983-90. 35. Olaison L, Pettersson G. Current best practices and guidelines indications for surgical intervention in infective endocarditis. Infect Dis Clin North Am. 2002;16:453-75, xi. 36. Morris AJ, Drinkovifá D, Pottumarthy S, MacCulloch D, Kerr AR,West T. Bacteriological outcome after valve surgery for active infective endocarditis: implications for duration of treatment after surgery. Clin Infect Dis. 2005;41:187-94.

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Chapter 7

Vascular Infections LOUIS D. SARAVOLATZ, MD

Key Learning Points 1. Vascular infections are usually associated with bactereremia and significant morbidity and mortality. 2. The microbial etiology may be similar to endocarditis and rarely includes a variety of less common organisms. 3. Magnetic resonanance angiography for arterial studies and high resolution computed tomography for venous studies are most helpful. 4. Antimicrobial therapy needs to be prolonged, parenteral and guided by susceptibility and local resistance patterns. 5. A combined surgical and medical approach is needed for the management of endovascular infections.

V

ascular infections are uncommon infections that can arise from the deposition of bacteria circulating in the bloodstream onto the vascular endothelial surface, or from contiguous spread of bacteria to a vessel wall. These infections are associated with significant illness and death. This chapter will address mycotic aneurysms, infected pseudoaneurysms, and septic thrombophlebitis.

Mycotic Aneurysms Mycotic aneurysms were described in 1885 by Sir William Osler in association with bacterial endocarditis arising in a patient with multiple aneurysms of the aorta (1). Osler described a case of endocarditis and its association 126

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New Developments in Vascular Infections • Advances in diagnostic imaging including use of magnetic resonance angiography and contrast-enhanced computerized tomography of the veins have improved diagnostic accuracy • The increase in community-associated methicillin-resistant Staphylococcus aureus

(MRSA) reinforces the need for anti-MRSA therapy in these infections. • The role of anticoagulation in these infections remains controversial.

with an aneurysm as a consequence of hematogenous seeding of bacteria through the vascular supply to the large blood vessels. However, mycotic aneurysms had in fact originally been noted as many as 30 years earlier by Edward Koch, who described a superior mesenteric artery aneurysm associated with rheumatism (2). Although the term mycotic was used to describe the appearance of the vegetation, most of these aneurysms are caused by bacteria not fungi. Mycotic aneurysms can involve a normal vessel or infect a preexisting aneurysm. These aneurysms were traditionally described as primary and secondary. Primary aneurysms were those that were considered cryptogenic. These develop from a primary intravascular focus of infection, without any evidence of an inflammatory process in the surrounding tissue. A primary mycotic aneurysm is suspected when the patient presents clinically with evidence of infection as the result of bacteremia from an obscure focus of infection. The clinician’s suspicion of this diagnosis would be increased if the bacteremia were antedated by an illness caused by the same bacterial agent. Primary infections arise from bacterial embolic seeding to the vasa vasorum of the media of arterial walls. Secondary mycotic aneurysms are associated with another focus of infection and sometimes with an inflammatory process in the adjacent tissue. These latter forms of aneurysm are often referred to as pseudoaneurysms, and will be addressed separately.

Clinical Manifestations The clinical manifestations of mycotic aneurysms can vary substantially according to the virulence of the organism. Often characterized by a long, febrile course that eludes the diagnostic acumen of the clinician, a mycotic aneurysm becomes clinically apparent when the affected blood vessel ruptures. In 75% of cases, rupture is the initial presentation. If the site is intracranial, the presentation is headache and rapid neurologic deterioration. If the site is intrathoracic, a catastrophic aortic rupture is the presentation with fever and back and abdominal pain as presenting symptoms. In the case of an intra-abdominal site, retroperitoneal hemorrhage is commonly found. Leukocytosis occurs in most patients, and blood cultures are positive in 50% to 85% of patients (3,4). Primary mycotic aneurysms are associated with

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atherosclerosis, cystic medial necrosis, or syphilitic aortitis. The underlying disease process generally involves the intima of the vessel wall. The microbial cause of mycotic aneurysms includes Streptococcus viridans and Staphylococcus aureus, and to a lesser extent Salmonella species, enterococci, and Streptococcus pneumoniae. There are also reports of Mycobacterium tuberculosis causing mycotic aneurysm as well as many other organisms that rarely cause this disease (5). In a series of 330 patients, bacterial endocarditis was the disease most commonly associated with infectious aneurysms and occurred in 294 cases (2). Coarctation of the aorta occurred in approximately 15% of cases. Pneumonia, osteomyelitis, lung abscess, primary bacteremia, otitis media, urinary sepsis, and meningitis each occurred in less than 5% of cases. The average age at presentation was 33 years. Blood vessels involved were most commonly the aorta, followed by superior mesenteric, cerebral, femoral, hepatic, pulmonary, splenic and even coronary arteries.

Diagnosis The diagnosis of a mycotic aneurysm requires a high index of suspicion in unexplained bacteremias associated with systemic signs of sepsis, or in the case of systemic sepsis in the bacteremic patient. The existence of infective endocarditis in the year before presentation, or of other recent serious bacterial infections, should heighten suspicion of the possibility of a mycotic aneurysm. Laboratory findings are generally nonspecific and are those associated with sepsis. Radiographic evaluations can help. A palpable aneurysm is rarely seen, and unfortunately a diagnosis is established before rupture in only slightly more than half of cases. Ultrasonography can be useful, but computed tomography with enhancement is preferred (4). Angiography of the site of suspected involvement is the definitive test before surgical exploration. For intracranial mycotic aneurysms, magnetic resonance angiography and intravenous digital subtraction angiography are promising techniques (6,7).

Treatment Optimal treatment of mycotic aneurysms requires surgical excision and concomitant antimicrobial therapy (8). In the case of rupture of aneurysms of large vessels such as the abdominal aorta, survival is infrequent even for patients who undergo emergency surgery. Even in the case of elective surgery, excision of an aneurysm and revascularization can be associated with severe perioperative illness and death. During the operative procedure, affected tissue should be collected for both histology and culture. Adequate excision of all infected material and establishment of adequate drainage is essential. Unfortunately, this is extremely difficult to do when a large vessel is involved, and particularly if there is preexisting prosthetic material that cannot be removed. Several investigators have shown that placing arterial

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homografts or plastic prosthesis through contaminated tissues, even in the face of systemic antibiotic coverage, can result in persistent infection and frequent disruption of the graft anastomoses. In contrast, arterial bypass reconstruction through clean tissue planes has produced healing with favorable results. In the surgical approach to the peripheral vessels, a bypass is created with an uninvolved vessel. In such cases, a vein graft can also be used. In these cases, there has been greater success in eradicating infection even in the face of persistent infection in the adjacent tissue (9,10). Optimal antimicrobial therapy for infectious aneurysms requires selection of bactericidal antimicrobial agents that can be given in high doses for prolonged periods. These requirements are general, and there are no controlled studies that provide objective evidence for an optimal duration of therapy. The dose, selection, and duration of antimicrobial therapy are similar to those for infective endocarditis. Some clinicians use an even longer duration because of the potential contamination of prosthetic material that can be implanted into an infected surgical site. In such cases it would be prudent to administer antimicrobial therapy for a minimum of 6 weeks by means of a parenteral route, and combination therapy should be considered for more resistant organisms, as is the case in the treatment of infective endocarditis (11). Moreover, even though the infection can seem to be brought under control, the patient’s clinical course can deteriorate rapidly and terminate in early disruption of the arterial suture line with associated hemorrhage. In such cases, the patient can develop hemorrhagic shock, and death is to be expected. Such complications can occur at any time from 1 to 2 months after surgery, thus necessitating careful long-term follow-up to permit intervention on an emergent basis. Even though embolic complications can occur, anticoagulation should not be used in these patients. The role of anticoagulation in general in patients with associated endocarditis remains controversial (12).

Prognosis and Prevention Today, the overall prognosis in the case of a mycotic aneurysm is generally poor. Medical management alone is almost always fatal (96%) versus a much more favorable survival rate (38%) when a combined medical and surgical approach is used (3). There is often an abrupt onset making a rapid diagnosis difficult at best. The use of magnetic resonance angiography should be considered in place of traditional angiography. Once the diagnosis is made, the challenge is to excise the infected tissue and eradicate any organisms in the vascular suture line or that are clinically inapparent on areas of the blood vessel wall. Some organisms are more virulent than others, making it even more difficult to eliminate them and necessitating prolonged antibiotic therapy. In addition, penetration of antimicrobial agents into atherosclerotic plaques and thrombi is poor. These areas tend to be avascular resulting in subtherapeutic levels of antimicrobial agents.

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Thus, antimicrobial therapy for indefinite periods can be given consideration in some infections because of the fear of relapse and its devastating consequences. Prevention of such infections is best achieved by eradicating the primary focus of infection, which will be either infective endocarditis or bacterial infection at another site. With available therapy and the high cure rate in infective endocarditis, most cases of infectious aneurysm can be prevented. The clinician should monitor patients for evidence of relapse of these infections and promptly treat them. There is no evidence for primary prophylaxis for infectious aneurysms. If a prosthetic graft is present some clinicians can treat these patients in a similar way as those with a cardiac valve graft in place, and give antimicrobial prophylaxis for high-risk procedures such as dental and genitourinary procedures.

Infected False Aneurysms (Pseudoaneurysms) Various terms have been associated with infected mycotic aneurysms involving the major or peripheral vessels and resulting in destruction of the vessel wall, aneurysm formation, and aneurysm rupture (13). False aneurysms, in contrast to true mycotic aneurysms, almost always involve a blood vessel that was normal before the infection. Thus, there is no intimal involvement, and the lesion does not result in embolomycotic events. These false or pseudoaneurysms are usually triggered by an unsuccessful attempt at femoral vein access, often for use of illicit injectable drugs. Failure to use aseptic technique establishes a perivascular infection. There is inadvertent trauma to the arterial wall resulting in a vascular or perivascular hematoma, which in turn leads to the formation of a false aneurysm. As the infection continues to spread, there is a destructive process involving the blood vessel wall, and eventual rupture leading to rapid clinical deterioration and demise within a relatively short ensuing period.

Etiology Infected false aneurysms are most often associated with parenteral drug abuse as a risk factor, although other techniques, such as intravascular catheter placement and angiography, can be associated with mycotic aneurysms. However, because aseptic technique is generally used during these procedures, the risk for such complications is extremely low. Nonetheless, there are reports of hematoma with local infection resulting in contiguous spread and infected aneurysm formation in association with cardiac catheterization. Thus, the evolution of a false aneurysm involves trauma to the outer layer of the arterial wall, or externa, resulting in perivascular hematoma and infection leading to aneurysm formation with intimal sparing.

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Clinical Manifestations The history and physical findings made by McIlroy and colleagues in a series of 60 patients with infected false aneurysms of the femoral artery included groin swelling and/or a mass in the femoral artery area in more than 90% with pain and tenderness in 80% (13). Fever and chills were found in 62%; other symptoms were nonspecific and included nausea, vomiting, paresthesias, and purulent drainage in less than 15% of patients. A pulsatile mass in the groin or femoral artery area was found in only 63% of the patients in this series, but its presence should alert the clinician to the high probability of an infected aneurysm. Fever and/or groin tenderness were present in only slightly more than half of the patients on admission. Other findings, such as an audible bruit over the palpable mass, were made in only 27% of the cases. Associated cellulitis, erythema, and purulent drainage were found in less than 25% of the patients. Absence of a pulse distal from the involved artery was present in less than 10% of the patients, and distal emboli were found in only 1 of the 60 patients. The history of groin swelling, pain, and tenderness with the finding on physical examination of a mass in cases of mycotic aneurysm of the femoral artery make the clinical presentation indistinguishable from that of a groin abscess or phlegmon evolving into an abscess. The findings that one would like to make, such as bruit, diminished pulses, distal emboli, and even a pulsatile mass, are often absent, thus making the diagnosis extremely difficult to establish.

Diagnosis As in the case of mycotic aneurysms, laboratory findings in cases of infected false aneurysm are nonspecific. Leukocytosis is present in many cases, but is not always found. Blood cultures should be done, but were positive in only 60% of the 60 patients in the McIlroy and colleagues series. Nonetheless, the organisms were discovered in the blood vessels at the time of surgery in more than 90% of these patients. The most common isolated pathogen was S. aureus, in 80% of the latter patients; other organisms that were noted, which included Streptococcus pyogenes, other streptococci, and anaerobes, were each found in 20% of the patients. The anaerobes included Bacteroides, Fusobacterium, and Peptococcus. Gram-negative aerobic bacilli occurred in 15% of the patients, with no single predominant organism, but included Pseudomonas aeruginosa, Proteus mirabilis, Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, and Citrobacter freundii. The procedures used to diagnose false aneurysms include digital subtraction angiography (DSA), conventional arteriography, ultrasonography (US), and computed tomography (CT). Figure 7-1 demonstrates by intravenous digital subtraction angiogram a bilobed false aneurysm in the medial aspect of the distal left common femeral artery. In addition, small

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Figure 7-1 Digital subtraction angiogram of a bilobed false aneurysm in the medial aspect of the distal left common femoral artery.

numbers of patients have false aneurysms diagnosed at the time of surgical intervention for drainage of an abscess when surgeons discover that they are inadvertently dissecting into the blood vessel wall. In the case of DSA and arteriography, the sensitivity is 90% to 96% (14). US is considerably less effective, with a diagnostic sensitivity of only 24%. The value of US is that it can quite accurately reveal the presence of a perivascular abscess, which, if detected, might arouse suspicion of contiguous spread of infection leading to a mycotic aneurysm.

Treatment Treatment of infected false aneurysms requires a combined medical and surgical approach (3,13,15). The empiric treatment used before organisms are identified should include vancomycin, gentamicin, and metronidazole for beta-lactam–resistant S. aureus, gram-negative bacilli, and anaerobes. Once the organisms are identified and appropriate susceptibility testing has been done, a specific antimicrobial regimen can be prescribed. In a large published series, the mean duration of effective antibiotic therapy for infected false aneurysms was 24 days for patients who were successfully cured (13). Bacteriologic treatment failure was accompanied by a recur-

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rence rate of 10% (6 of 60 patients) for cellulitis and/or wound infection at the site of the aneurysm. However, these six patients had initially received short-term (less than 15 days) parenteral antibiotic therapy, versus the other patients who were cured with more than 16 days of therapy ( p = 0.002, Fisher exact test). In this series, in contrast to findings with mycotic aneurysms, all treatment failures occurred within the first month after discharge from the hospital. There was no one predominant organism among the cases of treatment failures, with S. aureus being most common both in cases of treatment failure and treatment success. Interestingly, none of the patients who experienced bacteriologic treatment failure required amputation, and all were subsequently cured with the second course of antimicrobial treatment. We can therefore conclude that prolonged antimicrobial therapy for at least 3 weeks and even as long as 6 weeks will provide a reasonable margin of safety. For false aneurysms that manifest as swelling in the groin and with evidence of overlying infection, management requires a combined medical-surgical approach. Initial antimicrobial therapy should be broad spectrum, to treat beta-lactam–resistant S. aureus, anaerobes, and gram-negative bacilli. Thus, combination therapy with vancomycin, gentamicin, and metronidazole should be considered. In cases in which the groin is not involved, anaerobes are less relevant and metronidazole can be avoided. Perivascular abscesses and infected hematomas should be appropriately excised. Interestingly, in the large published series mentioned earlier (13), various surgical approaches were taken, including grafting and/or reanastomotic procedures involving saphenous vein grafts and prosthetic grafts (Dacron). Graft failures did occur, and in the case of femoral mycotic aneurysms, 10% of the patients required above-knee amputation. Interestingly there were no deaths in this series of 60 aneurysms with the current availability of optimal antimicrobial therapy and vascular surgical techniques. Infected false aneurysms need to be ligated and removed, with the wound left open, and adequate surgical debridement of the infected perivascular tissue. Surgical management is an area for future investigation in terms of defining the extent of debridement, optimal graft material, and revascularization procedures (3,15). State-of-the-art vascular surgery and advances in this discipline with prosthetic or homologous graft procedures will determine the surgical management.

Prevention Among the 169 cases of infected false aneurysm reported in the United States literature between 1966 and 1988, the overwhelming majority occurred in intravenous drug users, and the main mechanism for preventing these lesions is therefore dealing with socioeconomic considerations of illicit drug use, which is not within the scope of this chapter (13). To prevent infected false

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aneurysms associated with cardiac catheterizations, optimal aseptic technique should be used during the catheterization procedures. Antimicrobial therapy for infected hematomas and consideration of pressure decompression for noninfected pseudoaneurysms should be given before surgical intervention is needed.

Suppurative Septic Thrombophlebitis Suppurative septic thrombophlebitis evolves from an infected venous thrombosis that becomes associated with venous obstruction, high-grade bacteremia and metastatic seeding. This is a serious condition resulting in significant illness and death.

Etiology Suppurative septic thrombophlebitis has changed with time from chiefly involving intracranial veins and the dural sinus, both of which are now rarely involved, to mainly consisting of suppurative phlebitis of cannulated and great veins as a complication of intravenous therapy (16-18). Other sites at which the condition can occur, but again relatively rarely, include pylephlebitis and pelvic septic thrombophlebitis. Local infection is the major factor predisposing to septic thrombophlebitis. Major risk factors for suppurative thrombophlebitis are intravenous catheters, steroids, burns, and intravenous drug use (19,20). Suppurative septic thrombophlebitis arises from thrombus suppuration within the vein wall that develops because of stasis, hypercoagulability, and endothelial injury. These risk factors are all increased when there is adjacent inflammation. If the inflammatory process is associated with microorganisms, the latter migrate by means of lymphatics or the vascular supply to the wall of the vein resulting in suppuration within the vein wall. The associated infection can be anywhere in the body, including intracranial veins, neck veins, great veins of the thorax, abdominal veins, pelvic veins, and peripheral veins. In addition to the periphlebitic method of acquisition, a more common current route for the development of septic thrombophlebitis is the endovascular route, by means of an intravenous cannula, especially if the latter is left in place for more than 48 hours. However, cannula-associated infections usually have both perivascular and endovascular components, and it is often unclear which route initiated the infection in such cases. A third possible route is hematogenous seeding from a distant site. Certain pathogens, such as streptococci, Bacteroides fragilis, and Campylobacter fetus have a higher rate of occurrence in septic phlebitis than do other pathogens that are isolated more frequently from the primary source of infection. There is evidence that these organisms can release substances that inhibit the coagulation cascade.

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Clinical Manifestations The clinical manifestations of septic thrombophlebitis are local inflammation and infection, sepsis, and embolic manifestations. The latter include fever, rigors, diaphoresis, confusion, tachycardia, tachypnea, hypotension, abdominal pain, and ecchymoses. The local process varies with the site of involvement. Patients with suppurative thrombophlebitis generally present with fever (70%-90%). The signs and symptoms are described in Table 7-1 on the basis of the site of involvement. Understanding the anatomy of the site of involvement in the case of intracranial veins and dural sinuses can assist the clinician in understanding what to expect in terms of clinical manifestations (Fig. 7.2).

Table 7-1 Clinical Manifestations of Intracranial Septic Thrombophlebitis Vein

Predisposing Illness

Cavernous sinus

Chronic sinusitis, diabetes mellitus, facial cellulitis

Symptoms/Signs

Headache (ophthalmic and maxillary branch CN V), periorbital edema, unilateral progressing to bilateral eye findings, diplopia, photophobia, tearing, ptosis, and mental status changes. Hemiparesis, and seizures are less common. Sinus tenderness to palpation, exophthalmus, chemosis, ophthalmoplegia CN III, IV, and VI), papilledema, V1 and V2 deficit. Lateral sinus Usually absent other than Subacute onset with headache chronic otitis media (fronto-occipital and temporal occipital) nausea, vomiting, vertigo, signs of ear infection, ruptured tympanic membranes (40%), posterior auricular swelling (Cresinger sign 50%), papilledema (15%), CN VI palsy (33%), nuchal rigidity (33%). Superior sagittal sinus Bacterial meningitis, Similar to bacterial meningitis: extension from cavernous headache, nausea, vomiting, or lateral sinus septic seizure, coma, hemiparesis, phlebitis, sinusitis brain stem compression, and (ethmoid and maxillary), papilledema scalp infection. Less common: pulmonary or odontogenic infections. Cortical Bacterial meningitis and Seizures, focal deficits and signs sinusitis and symptoms of meningitis

Abbreviations: CN, cranial nerve; V1, fifth cranial nerve (ophthalmic division); V2, fifth cranial nerve (maxillary division).

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Cortical veins

Inferior sagittal sinus

Superior sagittal sinus

Great vein of Galen

Falx cerebri

Straight sinus Cavernous sinus

Sphenoid sinus Transversa sinus

Superior petrosal sinus Tentorium cerebelli

Inferior petrosal sinus

Figure 7-2 Intracranial veins and ducal sinuses.

Diagnosis The laboratory findings in cases of suppurative septic thrombophlebitis are those of sepsis. An increased leukocyte count with a left shift and laboratory evidence of disseminated intravascular infection are common. Blood cultures are usually positive and essential in the diagnosis of septic thrombophlebitis. Two sets of cultures should be obtained initially, and two additional sets after 24 to 48 hours. If bacteremia persists despite appropriate empiric antimicrobial therapy, this can suggest the need for surgical intervention. Aspiration of the vein or direct culture of the excised vein can be useful in identifying the etiologic organism. Careful examination of initial and subsequent chest radiographs can disclose evidence of septic pulmonary emboli. Irregularly defined pulmonary infiltrates progressing to cavitation suggest this complication. High-resolution CT can be more sensitive than plain radiography, and can be done if the diagnosis is strongly considered in the face of a negative chest radiograph. The diagnosis of suppurative septic phlebitis is definitively established by venotomy with histologic and microbiologic examination of the thrombus. When this is done, the laboratory must be asked for aerobic, anaerobic, and fungal cultures. In seeking a specific site of infection as the source of suppurative septic thrombophlebitis, the clinician should order cultures appropriate for probable sites. If, for example, an intracranial focus is suspected, cerebrospinal fluid should be obtained, culture of which will reflect either meningitis or a parameningeal inflammatory process (increased leukocyte count with both

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polymorphonuclear leukocytes and mononuclear cells, a normal glucose, a slightly elevated protein concentration and culture negativity). Radiographic assessment with high-resolution CT or magnetic resonance imaging (MRI) can be helpful. If used, contrast-enhanced CT or MRI with gadolinium can be very sensitive modalities in demonstrating filling defects consistent with thrombus caused by septic phlebitis (21,22).

Treatment Antimicrobial therapy with high-dose intravenous antibiotics should be initiated empirically for septic thrombophlebitis on the basis of the site of the lesion and most likely pathogens (Table 7-2). The optimal duration of

Table 7-2 Microbial Etiology and Treatment Considerations for Suppurative Septic Phlebitis Site

Microbial Agents

Empiric Treatment Options*

Cavernous sinus

Staphylococcus aureus (70%), group A streptococci, Streptococcus pneumoniae, gram-negative bacilli, anaerobes Group A streptococcus, S. aureus, Bacteroides, gram-negative (Proteus mirabilis and Escherichia coli) S. aureus, Group A streptococci S. pneumoniae, Haemophilus influenzae, Neisseria meningitis

Vancomycin, ceftriaxone (or cefotaxime) plus metronidazole

Lateral sinus

Sagittal sinus Cortical

Internal jugular vein

Great vein

S. aureus, gram-negative bacilli, candida If candida is suspected S. aureus, gram-negative bacilli

Pelvic veins

Anaerobes (Bacteriodes fragilis), microaerophilic, steptococci, gram-negative bacilli

Pylephlebitis

Anaerobes (Clostridium), gramnegative bacilli S. aureus, Group A streptococci

Peripheral

Ceftriaxone (or cefotaxime), vancomycin, plus metronidazole Vancomycin Vancomycin plus ceftriaxone if brain abscess or sinus source add metronidazole Vancomycin and ceftriaxone or aminoglycosides Add amphotericin B As in internal jugular sources Metronidazole plus an aminoglycoside or carbapenems or betalactam/beta-lactamase inhibitors plus an aminoglycoside As in pelvic veins Vancomycin. Add an aminoglycoside if patient had prolonged hospitalization or prior antimicrobial agents.

* Dosing with normal renal and hepatic function: Ceftriaxone 2 g IV every 12 h; cefotaxime 2 g IV every 4 to 6 h; aminoglyosides: gentamicin/tobramycin 1.5 mg/kg IV every 8 h; amphotericin 0.6-1.0 mg/kg every 24 h; beta-lactam/beta-lactamase inhibitors; ticarcillin/clavulunate 3.1 g every 4 h; ampicillin-sulbactam 3.0 g every 6 h; piperacillin-tazobactam 3.375 g every 6 h.

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therapy has not been established, but 2 weeks of therapy would be a minimum, with at least 4 weeks if S. aureus is the pathogen (23). If the vein is accessible and the patient demonstrates persistent bacteremia or perivascular infection, surgical excision of the infected clot should be considered (24). Other ancillary measures include drainage of any primary focus of infection such as a contiguous abscess. The involved area should be elevated to a 45-degree angle to enhance venous drainage. The use of anticoagulation remains controversial. There is some anecdotal evidence for a benefit of anticoagulation in the case of internal jugular vein involvement and pelvic septic phlebitis. In cases involving other sites, the risk of hemorrhage and complications of therapy must be carefully weighed before anticoagulation is instituted, in the view of the lack of convincing evidence to support such therapy. Some experts have considered anticoagulation if there is evidence of the extension of the thrombosis while on therapy (25).

Prevention and Future Developments Prompt and appropriate treatment of bacterial infections of the skin, ear, dentition, sinuses, and pelvis is the main measure that can be effective in preventing septic thrombophlebitis. In case a venous cannula is in place, its removal should occur within 48 to 72 hours whenever possible, and more promptly when there is development of local infection or sepsis of unknown source. A detailed discussion of strategies for preventing infected emboli from vascular catheters has been published by the Centers for Disease Control and Prevention (26). As for further research, the role of anticoagulants should be critically evaluated in a randomly assigned, placebo-controlled trial, which has not been done to date. Unfortunately, the difficulty in agreeing on diagnostic criteria, and the low rate of septic thrombophlebitis at most sites can make such a trial difficult if not impossible to do.

REFERENCES 1. Osler W. The Gustonian lecture on malignant endocarditis. Br Med J. 1885;1:4672-70. 2. Goadby HK, McSwiney RR, Rob CG. Mycotic aneurysm. St. Thomas Hospital Report. 1949;5: 44-52. 3. Johnson JR, Ledgerwood AM, Lucas CE. Mycotic aneurysm. New concepts in therapy. Arch Surg. 1983;118:577-82. 4. Suravia-Dunand VA, Lou VG, Salit IE. Aortitis due to salmonella; report of 10 cases and comprehensive review of the literature. Clin Infect Dis. 1999;29;862. 5. Long R, Guzman R, Greenberg H. Tuberculous mycotic aneurysms of the aorta: Review of published medical and surgical experience. Chest. 1999;115:52. 6. Tunkel AR, Kaye D. Neurologic complications of infective endocarditis. Neurol Clin. 1993;11:419-40. 7. Kimura I, Okumura R,Yamashita K, Shibata T, Hayashi N, Hayakawa K, et al. Mycotic aneurysm. Radiat Med. 1989;7:121-3.

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8. Mundth ED, Darling RC,Alvarado RH, Buckley MJ, Linton RR,Austen WG. Surgical management of mycotic aneurysms and the complications of infection in vascular reconstructive surgery. Am J Surg. 1969;117:460-70. 9. Johansen K, Devin J. Mycotic aortic aneurysms. A reappraisal. Arch Surg. 1983;118:583-8. 10. Bitseff EL, Edwards WH, Mulherin JL Jr., Kaiser AB. Infected abdominal aortic aneurysms. South Med J. 1987;80:309-12. 11. Cina CS,Arena, CO, Fiture SO. Ruptured mycotic thoracoabdominal aortic aneurysms: A report of 3 cases and a systematic review. J Vasc Surg. 2001;33:361. 12. Kamalakannan D, Beeai M, Gardin J, Saravolatz L. Anticoagulation in infective endocarditis: A survey of infectious disease specialists and cardiologists. Infect Dis Clin Pract. 2005;13: 122-26. 13. McIlroy MA, Reddy D, Markowitz N, Saravolatz LD. Infected false aneurysms of the femoral artery in intravenous drug addicts. Rev Infect Dis. 1989;11:578-85. 14. Shetty PC,Krasicky GA,Sharma RP, Vemuri BR,Burke MM. Mycotic aneurysms in intravenous drug abusers: the utility of intravenous digital subtraction angiography. Radiology. 1985;155:319-21. 15. Reddy DJ, Smith RF, Elliott JP Jr., Haddad GK,Wanek EA. Infected femoral artery false aneurysms in drug addicts: evolution of selective vascular reconstruction. J Vasc Surg. 1986;3:718-24. 16. Maki DG. Septic thrombophlebitis. Hosp Med. 1976:36-49. 17. Southwick FS. Septic thrombophlebitis of major dural venous sinuses. Curr Clin Top Infect Dis. 1995;15:179-203. 18. Rupp ME. Infections of intravascular catheters and vascular devices. In: Crossley KB, Archer GL, eds. The staphylococci in human disease. New York: Churchill Livingstone; 1997:379-99. 19. Andes DR, Urban AW,Acher CW, Make DG. Septic thrombosis of the basilie, axillary, and subclavian veins caused by a peripherally inserted central venous catheter. Am J Med. 1998;105:446. 20. Arnow PM, Quimosing, EM, Beach M. Consequences of intravascular catheter sepsis. Clin Infect Dis. 1993;16:778. 21. Ellie E, Houang B, Louail C, Legrain-Lifermann V, Laurent F, Drouillard J, et al. CT and high-field MRI in septic thrombosis of the cavernous sinuses. Neuroradiology. 1992;34:22-4. 22. Komiyama M. Magnetic resonance imaging of the cavernous sinus. Radiat Med. 1990;8:136-44. 23. Raad I, Narro J, Khan A, Tarrand J, Vartivarian S, Bodey GP. Serious complications of vascular catheter-related Staphylococcus aureus bacteremia in cancer patients. Eur J Clin Microbiol Infect Dis. 1992;11:675-82. 24. Verghese A,Widrich WC,Arbeit RD. Central venous septic thrombophlebitis—the role of medical therapy. Medicine (Baltimore). 1985;64:394-400. 25. Golpe R, Marín B, Alonso M. Lemierre’s syndrome (necrobacillosis). Postgrad Med J. 1999;75: 141-4. 26. Centers for Disease Control and Prevention. Part 1. Intravascular device-related infection: An overview: Part 2. Recommendations for prevention of intravascular device-related infections. Fed Regist. 1995;60:4997-8.

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Part IV

Gastrointestinal Infections

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Chapter 8

Infectious Diarrhea and Gastroenteritis KEITH B. ARMITAGE, MD ROBERT A. SALATA, MD

Key Learning Points 1. With the notable exception of C. difficile associated diarrhea and illness in immunosuppressed patients, most diarrhea acquired in developing countries is self-limited. 2. Diarrhea in travelers is often due to bacterial pathogens, and responds to appropriate antimicrobial therapy. 3. Noroviruses are a common cause of self-limited gastrointestinal illness in developed countries. 4. Nosocomial diarrhea is almost never related to bacterial pathogens other than C. difficile, and should always raise concerns for this pathogen.

I

nfectious gastroenteritis is one of the most common infections throughout the world and is a leading worldwide cause of infant death, with 4 million to 6 million deaths per year. In the United States, most cases of infectious gastroenteritis are self-limited, a sharp contrast to the state of affairs in the developing world where cases are more often chronic and debilitating. Diarrhea may be the most common symptom for travelers, immigrants, and refugees. The pathogens that cause diarrhea range from viruses that cause self-limited illness in adults and more serious syndromes in children to bacterial and protozoan pathogens that may cause significant illness and death in healthy and immunocompromised adults and children alike. New and emerging pathogens (e.g., Escherichia coli serotype 0157:H7, Cryptosporidium, Cyclospora) have received much attention from the lay press and the medical community. In this chapter, a general approach to the adult patient with acute diarrhea is followed by 143

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New Developments in Infectious Diarrhea and Gastroenteritis • Newer agents such as nitazoxanide (for giardiasis and cryptosporidiosis) and rifaximin (for traveler’s diarrhea) show promise as therapeutic alternatives. • Antimicrobial resistance among pathogens causing traveler’s diarrhea complicates the choices for presumptive therapy. • The incidence and morbidity of Clostridium difficile infection appears to be increasing; this appears to be related to the emergence of an epidemic strain that is more pathogenic and is highly resistant to fluoroquinolones and other antibiotics. • Recent studies have suggested a link between traveler’s diarrhea and the development of IBS. Abbreviation: IBS = irritable bowel syndrome.

a discussion of selected pathogens that cause diarrhea. Chronic diarrhea, food poisoning, and traveler’s diarrhea are discussed separately. The discussion generally excludes infectious diarrhea in patients with AIDS and/or HIV infection.

Epidemiology In the United States, most cases of infectious gastroenteritis go unreported, and the incidence of the disease is based on estimates. On average, adults in the United States and Europe have approximately 1 episode per year of infectious gastroenteritis (1). Annually in the United States, infectious diarrhea accounts for approximately 8 million visits to physicians, 250,000 hospitalizations, and 10,000 deaths (2). Together, gastroenteritis and acute diarrhea account for 1.5% of hospitalizations for inpatients younger than 20 years of age. In the developed world, most of the illness and death from infectious gastroenteritis occurs in the elderly. Exceptions to this rule occur with infection by E. coli 0157:H7, which produces hemolytic uremic syndrome [HUS] in children, and by rotavirus, which causes diarrhea leading to dehydration in young children. Although the United States has an average of 1 case of infectious gastroenteritis per adult, these cases are unevenly distributed in the population. Groups at special risk include adults who have small children in day care centers, international travelers, homosexual men, immunosuppressed patients, and individuals living in poor hygienic conditions. These risk groups account for a disproportionate number of cases of infectious gastroenteritis. Animal populations are the primary reservoir for most bacterial enteropathogens in the United States. Salmonella, Campylobacter, and pathogenic strains of E. coli usually enter humans from poultry, bovine, or porcine sources; and the route of illness is usually by means of undercooked or contaminated food. Infectious agents that rely on a human reservoir and are spread directly from one person to another or by human fecal contamination and include

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Salmonella typhi, Shigella, and Vibrio cholerae are much less common in the United States than in the developing world.

Pathogenesis Most microorganisms found in the human intestine are not pathogenic, but those that are rely on various virulence factors to produce disease. Microbial virulence factors include enterotoxins that alter intestinal salt and water transport mechanisms, adherence (and colonization) factors, and invasive and penetrability properties. Enterotoxins usually act in the upper small intestine to provoke fluid and electrolyte secretion and either cause no significant alteration in mucosal histology (e.g., cholera toxin) or are cytotoxins that can alter mucosal histology to the point of epithelial cell death (e.g., clostridial and staphylococcal enterotoxins). Adherence to the intestinal surface is required for many enteropathogens and involves specific cell-surface determinants. Invasive bacteria primarily colonize the colon and have the ability to invade and survive in host cells and bring about cell death. Gross mucosal ulceration can occur, particularly in shigellosis, and is responsible for dysenteric stools in that disease. In the case of systemic pathogens such as S. typhi, virulence factors include the ability to infect and persist in host immune cells, which permits access to the circulation and leads to extraintestinal disease. The role of host factors in the susceptibility to infectious gastroenteritis is discussed in the following text.

Etiology Infectious diarrhea can be classified as inflammatory or noninflammatory (2). This classification has practical application for the clinician, because examining the stool for fecal leukocytes (see Figure 8-1) can help distinguish the 2 conditions, and this distinction can alter the diagnostic and therapeutic approach. Noninflammatory diarrhea most often results from interference with absorption of fluid and electrolytes and does not involve pathogenic invasion of the intestinal mucosa. Virtually all viral and most protozoan pathogens give rise to a noninflammatory diarrhea. In most cases, these pathogens cause disease by interfering with the absorptive functions of enterocytes in the small intestine through the production of toxins that alter the handling of fluids and electrolytes (e.g., as in cholera, discussed in a later section) or cause villous damage. These processes result in the delivery of excess fluid and electrolytes to the large intestine. Once the absorptive capacity of the large intestine is exceeded, a high-volume, watery diarrhea results. In contrast with the aforementioned viruses and protozoans, many bacterial pathogens invade the intestinal mucosa (usually the colon), provoking

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Figure 8-1 Fecal leukocytes as seen on microscopy.

an inflammatory response that results in colonic malabsorption and the presence of leukocytes and blood in the stool. This diarrhea is characterized by mucus and blood and by a smaller volume of stool than is seen with noninflammatory diarrhea. E. coli can produce either syndrome, depending on the strain of the infecting organism (discussed in a later section). Other bacterial pathogens also cause noninflammatory diarrhea by producing preformed toxins that are ingested in contaminated food (see Food Poisoning Syndromes in the following text).

Diagnosis The risk of acquiring a gastrointestinal infection varies with the host and the potential for exposures to infectious agents. Host factors that influence susceptibility to infection include age, intestinal dysmotility, integrity of the normal intestinal flora, gastric acidity, and intestinal mucosal immunity. Potential for exposure to infectious agents varies with socioeconomic conditions and sanitation, travel to areas endemic to intestinal pathogens to which the host lacks immunity, and the occurrence of food- or water-borne outbreaks of disease caused by these agents. When evaluating a patient with diarrhea, it is impossible to overemphasize the importance of a careful history that focuses on issues such as travel, antibiotic use, illness in close contacts, exposure to potentially contaminated food or water, and the presence of decreased gastric acidity or gastrointestinal motility. A careful history also helps differentiate patients who are likely to have a self-limited viral process that requires only symptomatic therapy from

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those who have a bacterial or protozoan pathogen that might necessitate further testing and specific therapy. In adults, viral gastroenteritis typically lasts 24 to 36 hours and no longer than 72 hours. The illness usually is not associated with significant abdominal pain, and there is no (or only a lowgrade) fever. Viral gastroenteritis is associated with watery stools without blood or pus. In infants and small children, some viral pathogens (rotavirus, most notably) may produce a prolonged illness. Risk factors for infection by bacterial or protozoan pathogens also can be determined from a history of potential exposures. In tropical countries, acute diarrhea occurs endemically and epidemically, and any recent travel in a tropical country increases the likelihood of infection by a nonviral pathogen. In the United States, camping and hiking may be associated with exposure to Giardia. Exposure to imported fruits and undercooked meats or poultry products may be associated with infection by bacterial pathogens or Cyclospora. Antibiotic use, achlorhydria, or an immunocompromised state may influence the risk of infection by a bacterial pathogen. Patients whose history suggests either a bacterial process or risk factors for the acquisition of bacterial pathogens should have their stool examined for fecal leukocytes (see Figure 8-1); patients at risk for acquiring protozoan or other intestinal parasites should have a fresh stool specimen examined for ova and parasites. The presence of fecal leukocytes should prompt a stool culture and may lead to the initiation of specific therapy (see Treatment section in the following text). This approach is illustrated in Figure 8-2.

Treatment When treating patients with diarrhea, be aware that an otherwise healthy individual with a history that suggests a self-limited viral process and no risk factors for acquiring other pathogens does not require any further workup and should be treated with oral rehydration and symptomatic support. For patients with acute inflammatory diarrhea or those from whom a pathogen has been isolated, the decision to institute specific antimicrobial therapy is based on host factors and the specific pathogen. For most healthy adults, antimicrobial therapy has a limited role in the management of acute diarrhea. For many enteropathogens, such as Salmonella, and enterohemorrhagic E. coli, antimicrobial therapy has not been proven to have a benefit and may prolong the carrier state in Salmonella infection. Furthermore, antimicrobial resistance is a growing problem with some enteropathogens, such as Shigella and Salmonella. In contrast, antimicrobial therapy is indicated for dysentery caused by Shigella or Entamoeba histolytica; in cholera, antimicrobial therapy can decrease the volume of fluid lost and shorten the clinical syndrome. However, patients who are at high risk for bacteremia and other complications of bacterial gastroenteritis (e.g., the elderly, immunocompromised patients, patients with vascular grafts, patients with

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Evaluate severity and duration Obtain history and physical examination Treat hydration Report suspected outbreaks

Check all the following that apply

A. Community-Acquired or Traveler's Diarrhea (especially if accompanied by significant fever or blood in stool)

Culture or test for: Salmonella Shigella Campylobacter Escherichia coli O157:H7 (if there is blood in stool, also test for Shiga toxin; refer isolates if positive) Clostridium difficile toxins A±B (if patient has received antibiotics or chemotherapy in recent weeks)

Consider quinolone for suspected shigellosis in adults (e.g., fever, inflammation) Consider macrolide for suspected resistant strains of Campylobacter Avoid antimotility and certain antimicrobial drugs if suspected STEO (e.g., afebrile, bloody diarrhea)

B. Nosocomial Diarrhea (onset > 3 days in hospital)

Test for: C. difficile toxins A±B (in suspected nosocomial outbreaks, in patients with bloody stools, and in infants; also add hosts in panel A)

C. Persistent Diarrhea (lasting > 7 days, especially in immunocompromised patients)

Consider parasites: Giardia Cryptosporidium Cyclospora Isopora belli Plus inflammatory screen If HIV positive, also test for the following: Microsporida (Gram chromotrope) Mycobacterium avium complex All in panel A

Discontinue antimicrobials if possible Consider metronidazole if illness worsens or persists

Treat per test results

Figure 8-2 Approach to diagnosis and treatment when presence of fecal leukocytes has been determined.

sickle cell disease) benefit from antibiotic therapy. In these patients, empirical therapy is warranted in the setting of acute inflammatory diarrhea. In crowded conditions, such as refugee camps or areas of poor hygiene, epidemics of acute diarrhea caused by enteropathogens are common. In such settings, take steps to ensure the safety of the water supply, improve hygienic conditions, and decrease the interpersonal spread of disease. As with noninflammatory diarrhea, patients with inflammatory diarrhea require adequate hydration. In the past quarter century, oral rehydration ther-

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apy has revolutionized the treatment of various acute diarrheal illnesses. Oral rehydration formulas in which the addition of glucose increases the efficiency of absorption of fluid and electrolytes have decreased the need for intravenous hydration. Antimotility agents should be used with caution in patients with inflammatory diarrhea, particularly in children. In a small minority of patients with severe colitis, especially in the setting of infection with Shigella or E. histolytica, antimotility agents are associated with complications such as colonic perforation and death. Most experts advise caution in the use of antimotility agents in patients with fever and bloody diarrhea and do not recommend their use without concomitant antimicrobial therapy. The use of biotherapeutic agents to prevent and treat intestinal infections has been studied but not widely applied (3). Lactobacillus and Saccharomyces species have shown potential in placebo-controlled studies to effectively prevent or treat antibiotic-associated colitis, acute infantile diarrhea, recurrent Clostridium difficile diarrhea, and other diarrheal illnesses (4). These agents have not gained widespread use, but they have potential benefit in selected patients.

Specific Pathogens Viruses Norovirus or Norwalk-Like Viruses A family of viral pathogens known as Norwalk-like viruses or norovirus are the major cause of viral gastroenteritis in adults worldwide (5,6). They can be distinguished both clinically and epidemiologically from rotavirus (which is discussed in the following section). Noroviruses cause illness in adults and children and usually produce a mild clinical syndrome characterized by nausea, vomiting, and diarrhea that lasts no more than 24 to 36 hours. The diarrhea is watery and noninflammatory, and abdominal pain and fever are usually mild or absent. There have been large, well-documented outbreaks of such illness caused by interpersonal transmission of noroviruses as well as common-source outbreaks caused by food handlers. Norovirus-associated illness in schools, hospitals, and cruise ships and a multistate outbreak caused by contaminated oysters are testimony to the highly contagious and ubiquitous nature of these enteric viral pathogens (6). Illness caused by Noroviruses has a higher incidence in the winter and is often referred to as “wintervomiting disease.” Treatment consists of rehydration and symptomatic relief with antimotility agents. Rotavirus Rotavirus infection is much more common in children than is infection by Norwalk-like agents and produces a longer and more severe illness. Most studies show that rotavirus is the most common cause of pediatric diarrhea. An estimated 75 to 125 deaths and 65,000 to 75,000 hospitalizations for

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rotavirus infection occur each year in the United States. By the age of 2 years, most children are immune to rotavirus (7). Unlike the large, antigenically heterogeneous Norwalk virus family, only a few strains of rotavirus are antigenically heterogeneous; thus, infection leads to protective immunity. Trials of a rotavirus vaccine seem promising (8). In addition to infecting children, rotavirus has been associated with illness in parents of infected children and travelers, and water-borne and nosocomial outbreaks of rotavirus disease have been reported. Treatment consists of hydration and supportive care.

Bacteria Salmonella In the developed world, salmonellosis is primarily a food-borne gastrointestinal disease. Outside the developed world, systemic illness caused by S. typhi and Salmonella paratyphi is unusual (and is discussed briefly later in the text). Approximately 40,000 culture-proven cases of Salmonella gastroenteritis are reported to the Centers for Disease Control and Prevention each year (9). However, this is believed to represent only a small fraction of cases, because for each reported case 10 to 100 cases go unreported. Gastroenteritis related to different Salmonella species can be differentiated by a serotyping system; approximately 10 of these serotypes are responsible for most cases in the United States. Most Salmonella infections in the United States arise from an animal reservoir, and specific species of Salmonella are associated with particular food types and animals. Poultry, beef, and pork frequently have been associated with Salmonella. Undercooking meat products and inoculating food-preparation surfaces, which leads to cross-contamination, are common sources of Salmonella gastroenteritis. Although such gastroenteritis is associated most often with meat products and eggs, 2 recent large outbreaks were described in connection with ice cream and dry oat cereal, and there are case reports of other food products and animals having been contaminated with Salmonella (9). Interpersonal spread plays a small role in the transmission of Salmonella gastroenteritis. Clinically, Salmonella gastroenteritis is characterized by inflammatory diarrhea that may be accompanied by abdominal pain and fever. The illness may be more severe in the very young, the elderly, and the immunosuppressed (10). Clinically significant bacteremia associated with Salmonella gastroenteritis is unusual in healthy adults but is seen in elderly and, most significantly, in immunosuppressed persons. Severe and prolonged illness, including bacteremia, has been well described in patients with AIDS (11). Most cases of Salmonella gastroenteritis in otherwise normal hosts do not require antibiotic treatment. Antibiotic therapy has not been shown to have a significant benefit in such cases and has been associated with relapses and prolonged carriage of Salmonella. Very young, elderly, and immunosup-

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pressed persons and those with underlying illnesses (e.g., severe vascular disease, sickle cell disease) are at risk for complications or prolonged illness in Salmonella gastroenteritis and benefit from antibiotic therapy. Antimicrobial resistance is an increasing issue, but the fluoroquinolones, such as ciprofloxacin, and third-generation cephalosporins usually are reliable (12). S. typhi and related species produce a prolonged systemic illness characterized by invasion of the reticuloendothelial system and bacteremia. Patients may not have diarrhea during the illness, or it may be present only at the outset and may be mild. In contrast to nontyphoidal species of Salmonella, S. typhi and related species are highly adapted human pathogens and have no animal reservoir. Infection is based on humanto-human spread through direct contact or, more often, through fecal contamination of food and water. Typhoid fever is unusual in the United States, with fewer than 500 cases reported per year (70% or more of which occur in travelers or immigrants) (11). In addition to having fever, patients with typhoid fever can present with hepatosplenomegaly and a rash. The diagnosis is made by serology or by culturing S. typhi from the blood, stool, urine, or bone marrow. Antimicrobial therapy with quinolones or other agents improves survival and shortens the duration of illness (13). Most patients respond clinically to antimicrobial therapy within a week. Antimicrobial resistance is increasing worldwide, and knowledge of local resistance patterns should be used in selecting therapy for typhoid fever. From 1% to 3% of patients may become chronic fecal carriers of S. typhi. The fluoroquinolones or ampicillin (for ampicillin-sensitive strains) may be used to attempt eradication of the chronic carrier state in selected individuals such as health care workers and food preparers. Avoiding contaminated food and water supplies can prevent typhoid fever. Several vaccines for typhoid fever are available and have an efficacy of approximately 70% to 80%. In the United States, vaccination is given most often to travelers to areas where S. typhi is endemic, which includes most tropical destinations.

Campylobacter Before the 1970s, when selective culture media simplified the isolation of several enteropathogens, infection with Campylobacter was thought to be unusual. It is now recognized as the most common cause of bacterial gastroenteritis in the developed world. An estimated 2 million to 4 million cases occur every year in the United States, with a summer to fall seasonality (14). Campylobacter is by far the most common cause of bacterial gastroenteritis in young adults, causing gastroenteritis 10 times more often than does Salmonella. The primary animal reservoir of Campylobacter is the chicken, and most cases of infection with the organism are associated with undercooked poultry or cross-contamination of other foodstuffs. Contact with animals other than chickens, including kittens, also has been associated with Campylobacter infection. Most cases are sporadic, and large outbreaks and interpersonal spread are unusual.

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Campylobacter causes an acute inflammatory colitis that is indistinguishable from that caused by Salmonella or other bacterial enteropathogens. Diarrhea, abdominal pain, and fever are present in most patients. The illness usually lasts from 4 to 7 days. Severe prolonged colitis that mimics inflammatory bowel disease has been reported. Campylobacter also has been associated with pseudoappendicitis, and in rare instances has been believed to cause appendicitis. Hepatitis and pancreatitis also have been reported infrequently in association with campylobacteriosis. Bacteremia occurs in approximately 2% of culture-confirmed cases, and immunocompromised patients are at increased risk. Additionally, Campylobacter is associated with the Guillain-Barré syndrome and is by far the most common identified infection preceding this syndrome, with evidence of antecedent Campylobacter infection found in 20% to 40% of Guillain-Barré cases (14a,14b). The overall incidence of Guillain-Barré syndrome is much lower than that of campylobacteriosis, and the individual risk of acquiring the syndrome after this enteric infection is low. Most patients with Campylobacter enteritis require only supportive therapy with rehydration. In clinical trials, antimicrobial therapy has not been shown to be of benefit when given after several days of illness. However, when given at the onset of illness, antimicrobial therapy shortens the duration of illness and is clearly beneficial for patients with severe or prolonged disease, which can occur in immunosuppressed patients. Campylobacter is resistant to trimethoprim and most cephalosporins. Fluoroquinolones showed early promise as therapeutic agents against Campylobacter; however, resistance has developed during therapy and is spreading in fields in which quinolones are heavily used, such as animal husbandry. In Thailand, greater than 90% of strains of Campylobacter are quinolone resistant. Azithromycin remains the antimicrobial agent of choice for the treatment of Campylobacter enteritis.

Escherichia coli E. coli is the predominant nonpathogenic bacterial species in the human intestinal flora, but some strains have developed the ability to cause gastrointestinal disease. Diarrheagenic strains of E. coli cause disease through various mechanisms and produce varying clinical syndromes, including traveler’s diarrhea, hemorrhagic colitis, HUS, persistent watery diarrhea in infants, and persistent diarrhea (15). The genetic information responsible for the pathogenesis is often carried by plasmids or phages. During the past decade, the detailed pathogenic mechanisms associated with specific strains of E. coli have been perceived, but their details are beyond the scope of this chapter (15). We focus on the most common and clinically significant diarrheal syndromes caused by E. coli. Enterotoxigenic E. coli strains are responsible for more than one third traveler’s diarrhea cases. They produce diarrhea by the elaboration of a toxin that induces secretion of fluid and electrolytes by the small bowel.

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The strains are noninvasive and noninflammatory and are acquired by ingesting contaminated food and water. The illness that they cause is characterized by watery diarrhea (mild or severe) that usually lasts approximately 5 days but can be prolonged (rare). The illness is usually self-limited; but antimicrobial therapy, such as trimethoprim-sulfamethoxazole or quinolones, has been shown to significantly shorten the duration of illness. Antimotility agents used with antibiotics also have been shown to decrease the frequency of stools. (For treatment of traveler’s diarrhea, see section on Diarrhea in Travelers.) E. coli 0157:H7 and other enterohemorrhagic E. coli strains have gained prominence in the past 15 years by producing a severe syndrome in children characterized by bloody diarrhea and subsequent HUS (16). These strains also produce a nonbloody diarrhea and a hemorrhagic colitis (which may be severe, particularly in the elderly) without HUS. E. coli 0157:H7 and related strains produce 2 toxins that account for the intestinal and systemic pathogenesis of disease. Cattle are the primary reservoir for E. coli 0157:H7, and most cases of illness caused by the organism can be traced to the consumption of contaminated beef or of food products contaminated with bovine fecal matter. Interpersonal spread of the organism also has been documented. Diagnosis of E. coli 0157:H7 gastroenteritis is made by isolating the organism from stool. Managing the illness caused by E. coli 0157:H7 and related strains consists of supportive care. Antimicrobial therapy has not been shown to shorten the duration of illness, and there are inconclusive reports that suggest that antimicrobial therapy may increase the risk for HUS. Pending large clinical trials, no rational recommendation can be made for or against antimicrobial therapy. However, dialysis instituted early in the course of E. coli 0157:H7–related HUS may provide a survival advantage, increasing the importance of early recognition of the syndrome. Recent reports have indicated that the type of grain given to cattle in feedlots may dramatically increase the amount of E. coli 0157:H7 in the animals’ intestines, and many efforts are underway to prevent or minimize this. Preventing E. coli 0157:H7–related illness by thoroughly cooking meat and avoiding contamination of beef or other food products is also critical and is receiving increasing government attention. Two other types of pathogenic E. coli deserve brief mention. Enteroinvasive E. coli strains are pathogenically related to Shigella (see section in the following text) and produce a similar colitis or dysentery syndrome. Enteropathogenic E. coli strains are a heterogeneous subset of pathogenic E. coli strains. They have been responsible for large outbreaks of diarrhea in both the developed and developing world. Management of diarrhea caused by either of these types is similar to that for diarrhea caused by other bacterial enteropathogens. Decisions about the use of antimicrobial therapy for disease caused by these types of E. coli are based on the severity of illness at presentation and the characteristics of the host.

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Vibrio cholerae Cholera is a scourge of antiquity and an infection of immense historical significance that remains a major public health issue today. The seventh cholera pandemic, caused by the 01 El Tor strain of V. cholerae, began in 1961 and continues today. The World Health Organization (WHO) estimates that more than 3 million cases have occurred in the past 40 years (17). The Western Hemisphere was free of cholera for almost 100 years, but the disease has gained a foothold in the past decade, spreading from the coast of Peru to other areas of South and Central America (18). In the United States, cases have been seen in travelers and in consumers of raw food imported from South America. Cholera causes an acute and explosive diarrhea that can lead rapidly to loss of up to 10% of the body’s fluids and electrolytes. V. cholerae produces a toxin that acts on the enterocytes of the small bowel, causing derangement of the normal handling of solute and water, leading to hypersecretion of fluid and electrolytes. The resultant voluminous rice water diarrhea can lead to dehydration and death. The diagnosis is made by isolating the organism from the stool. The use of oral rehydration solutions, which contain glucose and electrolytes, has been associated with a marked decrease in illness and death from cholera. Intravenous or oral rehydration is the mainstay of therapy, along with use of antibiotics (particularly fluoroquinolones). Vibrio parahaemolyticus is a worldwide cause of food-borne illness, and is the most common pathogen associated with food in Japan (19). V. parahaemolyticus is a salt water–loving organism, and the illness it causes is associated with the consumption of seafood and exposure to salt water. In addition to producing gastrointestinal illness, V. parahaemolyticus causes the infection of wounds exposed to salt water and can produce a severe sepsis syndrome, particularly in patients with liver disease or other impaired host defenses. Shigella Shigella species differ from other common bacterial enteropathogens because it lacks an animal reservoir and relies instead on human-to-human contact or human fecal contamination for spread of the infection. As a result, Shigella infection is more common in areas of the world where living conditions are poor and have insufficient infrastructures for handling human waste and delivering safe drinking water. In the United States, children who attend day care facilities and homosexual men are identified as risk groups for shigellosis. There are 4 species of Shigella—Shigella dysenteriae, Shigella flexneri, Shigella boydii, and Shigella sonnei—all of which vary in their epidemiology and pathogenicity. S. sonnei is the major species that causes illness in the developed world. Shigella causes a spectrum of enteritis that ranges from mild self-limited disease to fulminant dysentery. Shigella requires the smallest inoculum size (102 organisms) to cause infection of any of the major bacterial entero-

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pathogens. In addition to severe dysentery, HUS, and bacteremia, obtundation and seizures are known complications of shigellosis. The diagnosis can be made by isolating the organism in stool culture. Empirical therapy should be considered when patients have dysentery. The other common infectious cause of dysentery syndrome in travelers and immigrants is amebiasis, which should be ruled out, particularly in adults. Resistance to antibiotics (e.g., ampicillin, trimethoprim-sulfamethoxazole, fluoroquinolones [less common]) among Shigella species is increasing around the world (20). If determining the antimicrobial resistance of an isolate is not possible, patients who fail to respond to antibiotic treatment within 48 hours should be switched to another antibiotic. There is no effective vaccine for Shigella.

Yersinia enterocolitica Infection with Yersinia enterocolitica most often leads to inflammatory diarrhea but also can produce septicemia, arthritis, and abdominal pain that mimics appendicitis (21). In the United States, infection with Y. enterocolitica is less common than infection with the bacterial enteropathogens discussed previously and accounts for approximately 1% of bacterial gastroenteritis cases. Swine are an important animal reservoir for Y. enterocolitica, and the consumption of undercooked pork or chitterlings (raw pork intestines) is an important epidemiologic clue to the presence of Y. enterocolitica. Cows and other animals are also hosts for the organism, and its spread from dogs to humans and from humans to humans has been documented. The diarrheal illness caused by Y. enterocolitica is similar to that caused by Salmonella or Campylobacter. Pseudoappendicitis is more common in older children and adults. In clinical trials, antimicrobial therapy was not helpful in self-limited cases of Y. enterocolitica infection in otherwise healthy individuals; however, in most studies, antibiotic therapy was not started until several days into the illness. Antibiotic therapy is indicated for severe presentations, patients with medical complications, or cases of septicemia. Y. enterocolitica is resistant to ampicillin and first-generation cephalosporins and is sensitive to doxycycline, aminoglycosides, fluoroquinolones, and trimethoprim-sulfamethoxazole. Another species of Yersinia, Yersinia pseudotuberculosis, is an animal pathogen that occasionally produces diarrheal illness in humans similar to that caused by Y. enterocolitica. Clostridium difficile The first decade of the new millennia has seen an epidemic of Clostridium difficile in North America, with the spread of strains that may be more pathogenic (22). C. difficile is harmless under normal environmental conditions in the colon, its growth suppressed by the normal colonic flora. Disruption of the normal colonic flora permits C. difficile to proliferate and produce cytopathic toxins that cause mild to severe diarrhea. Asymptomatic

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carriage of C. difficile is found in 7% of all patients admitted to hospitals (22). The carriage rate increases to more than 20% after hospitalization, with the organism being spread from 1 patient to another by the hands of health care workers. Therefore, C. difficile is both a community-acquired and a nosocomially acquired organism. Broad-spectrum antimicrobial agents, particularly those that are active against anaerobes, are the most common causes of alterations in the ecology of the colon that lead to C. difficile disease. The illness can develop after a single dose of antibiotics or at any time up to 2 months after cessation of therapy. Chemotherapeutic agents that alter the intestinal flora also have been implicated in C. difficile disease. Not all patients who carry C. difficile and receive antibiotics develop diarrhea, and most mild cases of antibiotic-associated diarrhea (75%) are not caused by C. difficile but instead result from alterations in the flora or other effects of the antibiotics that are given. Clinically, C. difficile diarrhea ranges from a mild, self-limited illness to the severe but less frequent syndrome of pseudomembranous colitis. The latter condition is characterized by the development of whitish-yellow plaques in the colon that can become confluent (23); and it can lead to colonic perforation, necrosis, and death. Patients with this syndrome are often febrile and seem ill. Although occurring in a minority of patients, extreme leukocytosis (with peripheral leukocyte counts more than 40,000 cells/mm3) can be an important clue to the presence of pseudomembranous colitis, particularly in elderly patients. The diagnosis of C. difficile diarrhea is made by the demonstration of toxin in a patient’s stools; several different assays exist for this purpose. Isolating the organism from the stool of symptomatic patients is considered presumptive but not definitive evidence of infection, because carriage of C. difficile is not always associated with illness. Fecal leukocytes may or may not be present (sensitivity 30%-60%). Endoscopic examination can be used to establish a diagnosis of pseudomembranous colitis, and the findings in computed axial tomographic scans of the abdomen are often characteristic. Treatment of mild cases of C. difficile diarrhea can consist of simply stopping the offending antibiotic, if possible. In more severe cases, antibiotic therapy with oral vancomycin or oral or intravenous metronidazole should be used. Oral vancomycin is not absorbed and is effective in inhibiting the growth of C. difficile. An oral dose of 125 mg given 4 times daily is recommended except for the most severe cases. Oral vancomycin therapy is expensive compared with metronidazole and has been linked to colonization of vancomycin-resistant enterococcus. Intravenous vancomycin does not reach measurable levels in the bowel and is not an effective treatment agent for colitis caused by C. difficile. Metronidazole is also active against C. difficile and has the advantages of lower cost and availability for intravenous delivery in patients who cannot take anything by mouth and/or have ileus. Clinical trials of vancomycin and metronidazole in severe cases of C. difficile diarrhea have been inconclusive; many experts favor oral

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vancomycin for the sickest patients; combinations of oral vancomycin and intravenous metronidazole have been used in severe cases. Oral vancomycin has not been shown to provide any advantage in less severe cases of C. difficile diarrhea, and most authorities recommend metronidazole as a cheaper alternative. Intravenous immunoglobulin has shown benefit in uncontrolled trials in treating patients with severe disease, and nitazoxanide has shown promise as an alternative to vancomycin and metronidazole. Probiotic therapy with Saccharomyces boulardii has shown promise in clinical trials but has not gained widespread popularity. Many experts recommend against antimotility agents because they may prolong exposure to C. difficile toxin. Relapsing C. difficile diarrhea occurs in 10% to 20% of patients (22). Neither vancomycin nor metronidazole is active against C. difficile spores. If the colonic milieu remains altered after successful therapy, C. difficile diarrhea may recur after sporulation and the production of metabolically active, toxinproducing bacteria. Many relapses are a particular problem in the elderly, perhaps because of the tendency for spores to persist in diverticula and to resist being removed from the bowel through normal peristalsis. Therapeutic approaches to relapsing C. difficile diarrhea have included long tapering or pulse-dosing courses of oral vancomycin (see Table 8-1) (24).

Protozoa Entamoeba histolytica Entamoeba histolytica is an enteric protozoan parasite that causes amebiasis, the third most deadly parasitic disease worldwide (after malaria and schistosomiasis). Infection with E. histolytica is highly endemic in Africa, South America, Mexico, and southern Asia. The infection is transmitted through contaminated food and water, and less frequently by direct fecal–oral contact with the cyst form of the organism. Although most infected individuals are asymptomatic, E. histolytica causes various intestinal and extraintestinal syndromes. The most common clinical presentation is a noninvasive colitis that is characterized by nonspecific abdominal pain and loose stools. Amebic colitis, which is caused when E. histolytica trophozoites invade intestinal epithelial cells, is characterized by abdominal pain and tenderness, with bloody stools and without fecal leukocytes. Fulminant amebic colitis, which may lead to toxic megacolon, is infrequent but can be seen in malnourished patients, children, and patients taking corticosteroids. This syndrome is characterized by fever, an outward appearance of toxicity, profuse diarrhea, and occasionally intestinal perforation. Intestinal amebiasis can be diagnosed by identifying amebic trophozoites and/or cysts in the stool; several stool specimens are often required for this, and at least 3 stool specimens should be examined before amebiasis is ruled out. Additionally, E. histolytica must be differentiated from nonpathogenic intestinal protozoans. The colitis caused by E. histolytica is inflammatory, but fecal

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Table 8-1 Recommended Antimicrobial Therapies for the Infectious Organisms That Cause Diarrhea Diseases

Infectious Organism Recommended Antimicrobial Therapy

Bacterial Shigellosis

Shigella species

Salmonellosis

Salmonella enteritidis

Campylobacteriosis

Campylobacter jejuni

ETEC, EPEC, EIEC EHEC

Adults: SXT 160–800 mg q12h for 3 days Fluoroquinolone: Ofloxacin 300 mg, norfloxacin 400 mg, or ciprofloxacin 500 mg q12h for 3 days Children: SXT 5–25 mg/kg/d in 2 divided doses for 3–5 days Adults*: SXT 160–800 mg q12h for 3 days (if susceptible); norfloxacin 400 mg, ciprofloxacin 500 mg, or ofloxacin 200 mg q12h for 5–7 days Children*: If ≤3 months of age, ceftriaxone 50 mg/kg/d; if >3 months and healthy, no treatment necessary; if >3 months with underlying illness, ceftriaxone 85% of patients with invasive infection), and imaging studies such as computed tomography and ultrasound. Treatment of amebiasis depends on the site of infection and other factors. Treatment of asymptomatic persons who pass cysts of E. histolytica in their stools is given only to patients who live in nonendemic areas or to those who are at high risk for colitis. Various luminal agents are available for treating asymptomatic persons who pass cysts of the organism, including diloxanide, paromomycin, and diiodohydroxyquin. Colitis is usually treated with a nitroimidazole, such as metronidazole, followed by a luminal agent to eradicate the cyst state. Metronidazole is the treatment of choice for extraintestinal amebiasis. Preventing amebiasis is an important consideration in situations of crowding and poor sanitation. The simple act of boiling water eliminates cysts of E. histolytica; however, treating drinking water with chlorine or iodine is ineffective.

Giardia lamblia Giardia lamblia is the most common parasitic cause of diarrhea in the developed world (25). Because most states in the United States do not mandate reporting giardiasis, data on the incidence of the disease in this country are not highly reliable. The annual incidence is estimated to be 50 cases per 100,000 population, with toddlers and young adults the major groups at risk. Infection is passed from person to person and by ingesting contaminated water or food. Outbreaks of waterborne G. lamblia infection have been well described and usually involve the ingestion of untreated river, lake, well, and occasionally municipal water. Giardiasis occurs in travelers, accounting for approximately 5% of cases of traveler’s diarrhea. G. lamblia is resistant to chlorine and can be reliably removed from water only by ultrafiltration. Person-to-person transmission of the organism has been demonstrated most often in day care centers. G. lamblia can be found in many large mammals; however, because the organism is difficult to subtype, the role of these animal reservoirs is unknown. G. lamblia causes a noninflammatory diarrhea characterized by watery stools, cramping, flatulence, and little or no fever. The illness usually lasts approximately 1 week but can persist in immunocompromised patients, including those with IgA deficiency who may otherwise not show manifestations of immunodeficiency. The diagnosis is made by demonstrating the organism in a wet mount of a fresh stool specimen. Some symptomatic patients may shed few organisms, and empirical therapy is warranted for

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patients in whom there is a high index of suspicion of giardiasis but who have negative stool specimens. Standard therapy consists of metronidazole in a dose of 250 to 750 mg orally thrice daily for 7 to 10 days. Lower doses are associated with treatment failure, and higher doses are associated with increased side effects. Nitazoxanide (Alinia) is a newer agent active against both G. lamblia and Cryptosporidium parvum and is an alternative to metronidazole. Other treatment options include quinacrine hydrochloride, furazolidone, and tinidazole, which is unavailable in the United States.

Microsporidia Microsporidia are an order of small, obligate, intracellular protozoal parasites found widely in animals and in the environment. In the past decade, they have been recognized as having a role in human disease, particularly in immunocompromised patients, including those with HIV infection and/or AIDS. At least 4 genera are known to cause human disease: Encephalitozoon, Enterocytozoon, Nosema, and Pleistophora (26). Cases of infection are most often recognized in residents of tropical countries and in travelers. The most common symptoms are chronic diarrhea and wasting. Infection also has been recognized at extraintestinal sites. Diagnosis requires electron microscopy of biopsy specimens. Clearly defined therapies are lacking; albendazole has been used successfully in some cases of infection with Enterocytozoon. Cryptosporidia Cryptosporidium parvum is a protozoan parasite found throughout the world but was not known as a human pathogen until the early 1980s. It is now recognized as a cause of sporadic cases of self-limited diarrhea in healthy individuals and of intractable diarrhea in immunocompromised patients (27). Groups at risk for acquiring the organism include travelers, animal handlers, and day care center personnel. In 1994, an outbreak of cryptosporidiosis in Milwaukee that was associated with contamination of the city’s water supply affected several hundred thousand residents. Illness caused by C. parvum follows the ingestion of spores and the infection of small-bowel enterocytes, leading to disruption of intestinal absorption and producing a watery, noninflammatory diarrhea. The duration of the illness is usually 10 to 14 days but can be chronic in immunocompromised patients; chronic cryptosporidial diarrhea has been well described in patients with HIV infection and/or AIDS. Cholecystitis has been reported in immunocompromised patients. Diagnosis is made by identifying oocysts in stool with a modified acid-fast stain. Treatment in immunocompetent patients consists of hydration and supportive care. Nitazoxanide has been shown to shorten the duration of illness, and may offer benefit in immunocompromised patients (28). Various other antimicrobial agents have been used in chronic, severe cases of cryptosporidiosis, with no consistent response.

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Cyclospora Cyclospora cayetanensis is a coccidian parasite recently recognized as a cause of acute and chronic diarrhea (29). Originally described in travelers and expatriates in Kathmandu who presented with prolonged diarrhea, Cyclospora has been linked to outbreaks of diarrhea in the United States associated with imported fruit, particularly berries. The clinical illness caused by Cyclospora is characterized by diarrhea, nausea, and weight loss that can persist for months or weeks if left untreated. Treatment with trimethoprim-sulfamethoxazole has been successful. An alternative therapy for patients with sulfa allergy has not been established (30).

Food-Poisoning Syndromes Food poisoning can result from the ingestion of various infectious agents, preformed bacterial toxins, and noninfectious substances; and it encompasses many clinical presentations. For the purposes of this section, food poisoning is defined as any illness occurring within 48 hours of food ingestion. Not all food poisoning syndromes produce gastrointestinal symptoms, and many (e.g., scombroid, ciguatera, shellfish, botulism) present with primarily neurological syndromes that are beyond the scope of this chapter. Bacteria cause 92% of food-borne illnesses for which a cause is identified (31). In the United States, most cases of food-borne illness go unreported, and the incidence of food-borne gastroenteritis is based on estimates. In 1996, the Centers for Disease Control and Prevention began active surveillance for Campylobacter, E. coli 0157:H7, Listeria, Salmonella, Shigella, Vibrio, Yersinia, Cyclospora, and Cryptosporidium in specific regions of the United States (the data include illnesses with onset after 48 hours). The incidence of illness was highest for Campylobacter (24.7 cases per 100,000 population), followed by salmonellosis (13.7) and shigellosis (7.8) (32). The major risk factors for foodborne disease are improper food storage and preparation, most often related to the temperature at which the food is stored before preparation or the temperature at which it is held between preparation and consumption. Poor personal hygiene of the food preparer, inadequate cooking, and contaminated equipment (including cross-contamination of food-preparation surfaces) are also important risk factors. Food poisoning syndromes are often suspected by patients who present with gastrointestinal illness. The presence of similar symptoms in 2 or more people who have consumed the same food should raise suspicion for food poisoning. Food poisoning syndromes can be categorized by incubation time and symptoms, such as the presence or absence of vomiting. Gastrointestinal symptoms that occur within 6 hours of food ingestion suggest the presence of a preformed bacterial toxin, such as those produced by Staphylococcus aureus or Bacillus cereus, or a chemical substance. Both S. aureus and

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B. cereus proliferate and produce toxins under conditions of improper food storage. Syndromes of food poisoning from both S. aureus and B. cereus present with prominent nausea and vomiting. S. aureus food poisoning occurs when food is contaminated with enterotoxin-producing strains of staphylococci under conditions favoring growth of the bacteria and with time for accumulation of enough toxin to produce illness. Because S. aureus enterotoxins are relatively heat stable, proper cooking is not protective against disease. Vomiting is the predominant symptom, but diarrhea and fever also can occur. The diagnosis is suggested by the history and time frame of illness occurrence and can be confirmed by isolating a toxinproducing strain of S. aureus from the suspected food. Large outbreaks of illness caused by S. aureus food poisoning have been well documented. Custards, other egg products, and potato salads are among the foods most commonly associated with staphylococcal food poisoning. B. cereus poisoning is similar to that caused by S. aureus and is frequently associated with the consumption of fried rice. The differential diagnosis of short-incubation food poisoning also includes Norwalk-like viral gastroenteritis, as discussed previously. The incubation period for this illness is usually longer than that for food poisoning caused by S. aureus or B. cereus (usually >8 hours), and diarrhea is usually a prominent feature of the illness. Heavy metal ingestion can produce upper intestinal symptoms within an hour of ingestion. Zinc ingestion caused by improper storage of acidic beverages in galvanized containers has been reported. Faulty fluoridation that results in high fluoride levels also has been shown to produce nausea and vomiting. Ingestion of poisonous mushrooms and raw fish containing helminths are also included in the differential diagnosis. The onset of nausea, vomiting, and abdominal pain within 8 to 16 hours after ingestion of food suggests illness caused by the ingestion of preformed toxins from Clostridium perfringens or B. cereus. The longer incubation time results from the production of toxins after the ingestion of food. Food poisoning caused by C. perfringens typically presents with abdominal cramping and noninflammatory diarrhea with little or no vomiting. The diagnosis of C. perfringens food poisoning is difficult to make because the organism is normally present in the intestinal flora. The diagnosis is based on the isolation of the toxin from stool. Food poisoning caused by C. perfringens resembles B. cereus food poisoning of long incubation. Diarrhea related to food-borne infection that occurs with an incubation period of more than 16 hours is usually caused by the bacterial enteropathogens discussed previously, including Salmonella, Campylobacter, E. coli, Yersinia, and V. parahaemolyticus. The management of food-borne gastroenteritis consists primarily of rehydration and supportive care. Treatment issues for bacterial pathogens have been discussed previously. Food-borne illnesses are largely preventable through proper handling, storage, and preparation of food.

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Diarrhea in Travelers A wide variety of enteropathogens cause diarrhea in travelers, including Salmonella, Shigella, E. coli, Campylobacter, rotavirus, and protozoan parasites. In the developing world, these enteric pathogens circulate in the community and, at times, are isolated from both symptomatic and asymptomatic individuals. Travelers are at increased risk for developing infectious gastroenteritis because they typically lack immunity to the local enteropathogens and are often exposed to infection by means of contaminated food or water. The increased incidence of bacteria and parasites in travelers should prompt a more aggressive approach should diarrhea or other gastrointestinal symptoms develop, especially if these are severe or chronic. Enterotoxigenic E. coli is the most common cause of diarrhea in travelers, followed by Salmonella, Shigella, and viral pathogens (33). G. lamblia is responsible for approximately 5% of cases of traveler’s diarrhea and should be suspected in patients who develop diarrhea after returning from short-term travel, have an illness characterized by bloating and flatulence, and have prolonged symptoms (>3 weeks). In counseling travelers about diarrhea, it is important to give advice that helps them avoid acquiring enteropathogens and develop a strategy in case they do develop illness. Travelers should be advised to drink only bottled or boiled water (and to use such water when brushing their teeth), to eat fruits and vegetables only if they have been cooked or if they are peeled by the travelers themselves, and to avoid ice cubes. These precautions should be maintained even on the way home, because the food and water on the airplane or on other transportation may be prepared locally. Travelers also should be advised that handheld filtration systems and purification tablets do not always work and should not be considered reliable protection against diarrhea. Experts in travel medicine advise presumptive therapy in the event of diarrhea. The traveler is given a prescription for an antibiotic (usually a quinolone, trimethoprim-sulfamethoxazole, or doxycycline) and is instructed to begin taking the antibiotic together with an antimotility agent if diarrhea develops. This strategy is effective for diarrhea caused by enterotoxigenic E. coli, the most common pathogen responsible for traveler’s diarrhea. In areas of the world where quinolone-resistant Campylobacter is the predominant pathogen in travelers (e.g., Thailand), azithromycin is the preferred agent for therapy for traveler’s diarrhea. Persistent fever or bloody stools should prompt the traveler to seek medical attention. Rifaximin is a luminal agent approved in 2004 for prophylaxis in travelers, and its use is still being evaluated. Use of other antibiotics to prevent diarrhea may be associated with side effects, may contribute to the pool of resistant pathogens worldwide, may put the traveler at increased risk for some pathogens owing to the disturbance of the normal flora, and is generally not recommended. Studies linking traveler’s diarrhea to the subsequent development of irritable bowel syndrome have refocused

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investigators on preventive strategies. Bismuth sulfates (e.g., Pepto-Bismol) work by coating the intestine, preventing bacterial adherence and colonization, and inhibiting production of bacterial toxin. They are effective only if taken at least 4 or 5 times per day, which most travelers find inconvenient.

Chronic Diarrhea A large number of conditions, both infectious and noninfectious, can lead to chronic diarrhea, which is defined as diarrhea that persists for more than 4 weeks. Patients with chronic diarrhea can be subclassified further according to whether or not they have malnutrition and/or blood in their stool. Patients with chronic diarrhea who do not have malnutrition but who do have blood in their stool should be evaluated for a colonic neoplasm or parasite-associated conditions, such as ameboma, whipworm colitis, chronic campylobacteriosis, and schistosomiasis. Inflammatory bowel disease also should be considered. Patients without blood in the stool but with signs or symptoms of malnutrition usually have an underlying malabsorption syndrome, which may stem from various conditions. Among the infectious causes of malabsorption syndromes are tropical sprue; bacterial overgrowth syndrome; and several parasites, including G. lamblia, Strongyloides stercoralis, Capillaria, and Cryptosporidium. Some cases of filariasis and intestinal pseudoobstruction from Chagas disease can cause lymphatic obstruction that can lead to chronic diarrhea. The term tropical enteropathy (or sprue) has been used to describe a syndrome of malabsorption and minor intestinal mucosal abnormalities seen in otherwise healthy individuals from tropical countries. Tropical enteropathy is thought to be an adaptation to frequent enteric infections. The wide variety of noninfectious causes of malabsorption is beyond the scope of this chapter. Chronic diarrhea, malnutrition, and wasting are common manifestations of HIV infection in tropical countries. Referred to as slim disease in many parts of Africa, this syndrome has not been linked to a single specific pathogen. It may be related to exposure to many enteric pathogens or to the involvement of the bowel mucosa by HIV infection. Many enteric pathogens cause diseases of more severe and prolonged course in patients with AIDS (see Chapter 39).

Nosocomial Diarrhea Diarrhea that occurs after 3 days of hospitalization is by definition considered nosocomial diarrhea. Patients with nosocomial diarrhea are unlikely to have the standard enteric pathogens, such as Campylobacter, Salmonella, and Shigella. The yield for ova and parasites is similarly low. In 15% to 20% of these patients, C. difficile toxin may be detected in the stool. Among hospitalized patients, it is recommended that stool cultures be made for the following groups:

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● ●

●

Patients who have diarrhea within 72 hours after admission Patients whose onset of diarrhea occurs more than 72 hours after admission and who are age 65 years or older, have preexisting disease that causes alteration of organ function, have HIV infection, or have a neutropenia of 500 cells/mm3 or less or when an outbreak of nosocomial infection is suspected Patients with a suspected nondiarrheal manifestation of enteric infection, such as erythema nodosum, mesenteric lymphadenitis, polyarthritis, or fever of unknown origin (34)

Additionally, testing for C. difficile toxin is an important part of the work-up for diarrhea (35,36).

Summary In the United States, most cases of gastroenteritis and diarrhea in adults are self-limited. A careful history helps identify patients at risk for complications of bacterial or protozoal infection. Specific antimicrobial therapy is indicated for some pathogens, and a subset of patients may benefit from therapy for bacterial pathogens that cause self-limited disease in normal healthy adults.

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14. Stutman HR. Salmonella, Shigella, and Campylobacter: common bacterial causes of infectious diarrhea. Pediatr Ann. 1994;23:538-43. 14a. McCarthy N, Giesecke J. Incidence of Guillain-Barré syndrome following infection with Campylobacter jejuni. Am J Epidemiol. 2001;153:610-4. 14b. Mishu B, Blaser MJ. Role of infection due to Campylobacter jejuni in the initiation of GuillainBarré syndrome. Clin Infect Dis. 1993;17:104-8. 15. Nataro JP, Kaper JB. Diarrheagenic Escherichia coli. Clin Microbiol Rev. 1998;11:142-201. 16. Slutsker L, Ries AA, Greene KD, Wells JG, Hutwagner L, Griffin PM. Escherichia coli O157:H7 diarrhea in the United States: clinical and epidemiologic features. Ann Intern Med. 1997;126:505-13. 17. Kuruvilla A, Jesudason MV, Mathai D, John L, John TJ. The clinical pattern of diarrhoeal illness caused by the new epidemic variant of non-O1 Vibrio cholerae. Trans R Soc Trop Med Hyg. 1994;88:438. 18. Begue RE, Castellares G, Hayashi KE, Ruiz R, Meza R, English CK, et al. Diarrheal disease in Peru after the introduction of cholera. Am J Trop Med Hyg. 1994;51:585-9. 19. Akeda Y, Nagayama K,Yamamoto K, Honda T. Invasive phenotype of Vibrio parahaemolyticus. J Infect Dis. 1997;176:822-4. 20. Materu SF, Lema OE, Mukunza HM, Adhiambo CG, Carter JY. Antibiotic resistance pattern of Vibrio cholerae and Shigella causing diarrhoea outbreaks in the eastern Africa region: 19941996. East Afr Med J. 1997;74:193-7. 21. Currie B. Yersinia enterocolitica. Pediatr Rev. 1998;19:250; discussion 251. 22. McDonald LC, Killgore GE, Thompson A, Owens RC Jr., Kazakova SV, Sambol SP, et al. An epidemic, toxin gene-variant strain of Clostridium difficile. N Engl J Med. 2005;353:2433-41. 23. Brazier JS. The diagnosis of Clostridium difficile-associated disease. J Antimicrob Chemother. 1998;41 Suppl C:29-40. 24. Wilcox MH. Treatment of Clostridium difficile infection. J Antimicrob Chemother. 1998;41 Suppl C:41-6. 25. Cacciò SM, Thompson RC, McLauchlin J, Smith HV. Unravelling Cryptosporidium and Giardia epidemiology. Trends Parasitol. 2005;21:430-7. 26. Wanke CA, DeGirolami P, Federman M. Enterocytozoon bieneusi infection and diarrheal disease in patients who were not infected with human immunodeficiency virus: case report and review. Clin Infect Dis. 1996;23:816-8. 27. Tzipori S, Griffiths JK. Natural history and biology of Cryptosporidium parvum. Adv Parasitol. 1998;40:5-36. 28. Zulu I, Kelly P, Njobvu L, Sianongo S, Kaonga K, McDonald V, et al. Nitazoxanide for persistent diarrhoea in Zambian acquired immune deficiency syndrome patients: a randomized-controlled trial. Aliment Pharmacol Ther. 2005;21:757-63. 29. Brennan MK, MacPherson DW, Palmer J, Keystone JS. Cyclosporiasis: a new cause of diarrhea. CMAJ. 1996;155:1293-6. 30. Connor BA. Cyclospora infection: a review. Ann Acad Med Singapore. 1997;26:632-6. 31. Humphrey T. Food- and milk-borne zoonotic infections. J Med Microbiol. 1997;46:28-33. 32. Hogue A,White P, Guard-Petter J, Schlosser W, Gast R, Ebel E, et al. Epidemiology and control of egg-associated Salmonella enteritidis in the United States of America. Rev Sci Tech. 1997;16:542-53. 33. Steffen R,Tornieporth N, Clemens SA, Chatterjee S, Cavalcanti AM, Collard F, et al. Epidemiology of travelers’ diarrhea: details of a global survey. J Travel Med. 2004;11:231-7. 34. Wood M. When stool cultures from adult inpatients are appropriate. Lancet. 2001;357:901-2. 35. Guerrant RL,Van Gilder T, Steiner TS, et al. Practice guidelines for the management of infectious diarrhea. Clin Infect Dis. 2001;32:331-50. 36. Wilson M. Diarrhea in nontravelers: Risk and etiology. Clin Infect Dis. 2005;41:S541-6.

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Chapter 9

Biliary Tract Infections LAVINIA F. SMULTEA, DO CURTIS J. DONSKEY, MD

Key Learning Points 1. The development of biliary tract infection generally requires obstruction of bile ducts, and the most common cause of this obstruction is gallstones. Obstruction of the cystic duct results in acute cholecystitis, whereas obstruction of the common bile duct may result in cholangitis. 2. The differential diagnosis of right upper quadrant (RUQ) pain and fever includes acute cholecystitis, cholangitis, appendicitis, acute pancreatitis, liver abscess, renal colic or acute pyelonephritis, and pulmonary embolism. 3. Ultrasonography is the most useful imaging study in the initial evaluation of patients who present with acute RUQ pain and fever. 4. Acute acalculous cholecystitis refers to acute inflammation of the gallbladder in the absence of gallstones. The clinical presentation is often subtle, owing to the preponderant occurrence of the disease in elderly and postoperative or critically ill patients. 5. The classic clinical presentation of cholangitis includes Charcot’s triad of fever and chills, jaundice, and RUQ pain; however, the complete triad is seen in only 70% to 85% of patients. 6. ERCP is the “gold standard” procedure for the diagnosis of common bile duct stones, and this technique allows therapeutic drainage at the time of diagnosis.

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New Developments in Biliary Infections • A recent study observed a fivefold increase of postoperative complications in patients with culture-positive bile at the time of surgery for obstructive jaundice • Percutaneous tube cholecystotomy can be an appropriate temporizing measure in patients with severe concurrent medical conditions that significantly increase the risk of surgery.

B

iliary tract infections are common causes of illness and death throughout the world. Although most of these infections are complications of gallstone disease, biliary infections in the absence of gallstones are increasingly recognized in immunocompromised and critically ill patients and as complications of biliary tract instrumentation. The clinician must distinguish infection of the biliary system from other illnesses that can have a similar presentation. Additionally, clinicians must determine whether urgent surgical or endoscopic drainage of such infections is indicated. New imaging, endoscopic, and surgical drainage techniques have improved the diagnosis and management of biliary tract infections; however, they have also increased the complexity of decision making with regard to these conditions. The biliary system includes the gallbladder and bile ducts. In the healthy biliary system, bile is sterile. In the presence of biliary tract pathology, however, bactibilia (the presence of bacteria in the biliary system) is common. Bacteria can reach the biliary tract from the portal circulation or by ascending from the small intestine through the ampulla of Vater. Bactibilia was demonstrated in 12% of patients who underwent elective cholecystectomy for gallstones (i.e., chronic cholecystitis) (1) in approximately one fourth to one third of patients with common bile duct (CBD) obstruction caused by malignancy, and in up to 80% of patients with CBD stones or strictures (2). Additional factors associated with bactibilia include diabetes mellitus, jaundice, advanced age, and instrumentation of the biliary tree. Bactibilia most often represents colonization rather than infection. The development of biliary tract infection generally requires obstruction of bile ducts, and the most common cause of this obstruction is gallstones. Culture-positive bile at the time of surgery for obstructive jaundice is associated with a fivefold increase in the incidence of postoperative infection and with higher incidence of septic complications (3). Cholelithiasis (gallstone disease) is present in 10% to 15% of adults in the Western industrialized countries and in approximately 25 million adults in the United States (4). Cholelithiasis increases in frequency with age and is approximately two times more common in women than in men. By 75 years of age, approximately 35% of women and 20% of men in the United States have developed gallstones. Seventy-five percent of these stones are cholesterol stones, and 25% are black (more common) or brown pigment

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stones. Risk factors for cholesterol gallstones include female gender, genetic predisposition, obesity, pregnancy, rapid weight loss, total parenteral nutrition, and certain medications (e.g., estrogens, clofibrate). Risk factors for black pigment stones include chronic hemolysis, cirrhosis, and pancreatitis. The clinical manifestations of gallstones are illustrated in Figure 9-1. Seventy-five percent of individuals with gallstones remain asymptomatic. The most common presenting symptom of cholelithiasis is biliary pain or colic, a visceral pain caused by transient or partial obstruction of the bile ducts that is not associated with inflammation or secondary infection. In the classic study by Gracie and Ransohoff of people with asymptomatic gallstones, the annual risk of new biliary pain was 2% within the first 5 years after gallstone diagnosis, falling to approximately 0.5% annually thereafter.

Asymptomatic stone (75%)

Long-standing cholelithiasis, resulting in gallbladder carcinoma (20 mg /dL the scan requires use of DISIDA Remains the gold standard for diagnosis of stones in CBD with sensitivity and specificity of ~95% Ability to extract stones/drain infected bile, emergently decompress the biliary tree in severely ill patients, thus reducing the necessity for invasive CBD exploration Not indicated in the management of most cases of ACC; mainly useful in detection of complications (gallbladder perforation, abscess formation, pancreatitis) and to exclude other intraabdominal pathology of diagnosis in doubt; sensitivity for detection of CBD stones is ~75% superior in detection of obstructing malignancy; MRCP is a safe procedure most useful for excluding CBD stones in those with low pretest probability of disease

Abbreviations: ACC, acute calculous cholecystitis; CBD, common bile duct; CT, computed tomography; DISIDA, diisopropyl iminodiacetic acid; ERCP, endoscopic retrograde cholangiopancreatography; EUS, endoscopic ultrasonography; HIDA, hepatoiminodiacetic acid; MRCP, magnetic resonance cholangiopancreatography; US, ultrasonography.

Treatment The management of acute calculous cholecystitis requires a combined medical and surgical approach. Initial medical management of all patients should include administration of intravenous fluids and parenteral analgesics. Nasogastric suctioning can be used if persistent vomiting occurs. Early surgical consultation is recommended.

Antibiotic Therapy Antibiotic therapy is recommended in complicated or severe cases of acute cholecystitis and for perioperative prophylaxis of all patients (Table 9-3). The role of antibiotics in the initial management of uncomplicated acute cholecystitis is not clear. One retrospective study of a series of patients with acute cholecystitis suggested that preoperative administration of antibiotics did not affect the incidence of local complications (e.g., pericholecystic abscess, empyema) but did decrease the incidence of postoperative wound infections and sepsis in elderly, debilitated patients and in those with local septic complications (11). The inability of antibiotics to reach significant

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Table 9-3 Common Bacterial Pathogens Isolated from Biliary Tract Infections and Recommended Empirical Antimicrobial Therapy* Infections

Cholecystitis Cholangitis Bacterial Isolates

Enterobacteriaceae (50%) Enterococci (30%) Anaerobes (15%) Polymicrobial (70%) Suggested Regimens

Mild-moderatea Ampicillin 2g IV q 8 h Cefazolin 1-2 g q 8 h Cefoxitin 2g q 6-8 h Cefotaxime 1-2 g q 8 h Ceftriaxone 2 g q 24 h Ampicillin–sulbactam 3 g IV q 6 h Piperacillin–tazobactam 3.375 g IV q 6 h Ampicillin 2 g IV q 4-6 h + gentamicin Ciprofloxacin 200-400 mg IV q 12 h +/− metronidazole 500 mg IV q 8 h Severeb Ampicilin 5 mg/kg IV q 24 h + metronidazole Piperacillin–tazobactam 3.375 g IV q 6 h Imipenem 0.5-1.0 g IV q 8 h Complex nosocomialc Piperacillin + aminoglycoside + metronidazole or clindamycin 600 mg q 6-8 h Imipenem + aminoglycoside * All empirical antimicrobial regimens should provide coverage for Enterobacteriaceae. For severely ill patients with cholecystitis or cholangitis, the initial antimicrobial regimen includes coverage of anaerobes (including Bacteroides fragilis) and enterococci. The antimicrobial regimen should be adjusted appropriately based on information gained from cultures of blood and bile. The dosages listed are for healthy adults and can require adjustment for patients with abnormal renal or hepatic function. The recommended duration of antimicrobial therapy for uncomplicated cases of cholangitis is 7-14 days. a Elderly patients, patients with chronic conditions, patients without chronic conditions but with fever, leukocytosis, tachycardia, and those who fail to improve after 12 hours of conservative management. b Critically ill and those with infectious complications such as perforation. c Prior common bile duct or complex biliary procedures. Abbreviations: IV, intravenous; q, every.

concentrations within the gallbladder when the cystic duct is obstructed can explain the lack of effect of antibiotics on the incidence of local complications. The favorable results of antibiotic treatment in decreasing septic complications, however, seems to depend on adequate serum concentration rather than tissue concentration. Table 9-3 describes our position and practice vis-à-vis the empiric therapy for ACC. Bacterial cultures should be obtained at the time of surgery, and antimicrobial therapy can be adjusted on the basis of the results. In patients undergoing early uncomplicated cholecystectomy, prolonging the antibiotic therapy more than 1 day beyond

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the surgery has not been shown to be beneficial (4), but treatment for 3 to 5 days after surgery for uncomplicated cholecystitis remains an acceptable practice.

Surgical Therapy Cholecystectomy is the definitive therapy for acute cholecystitis. In cases of severe and complicated disease, cholecystectomy should be performed at an early point if possible. The timing of cholecystectomy in cases of uncomplicated disease is controversial. Randomly assigned controlled trials done before and after the advent of laparoscopic cholecystectomy (LC) of early (within days following presentation) compared with delayed (>6-8 weeks) cholecystectomy for acute cholecystitis have shown that early operation is preferred in most cases because it reduces illness and total hospitalization time and costs (4,12-14). These studies did not show that the death or complication rates are different for early versus delayed surgery (4). LC is a safe and feasible alternative to open surgery in patients with chronic cholecystitis undergoing elective surgery and in most patients with uncomplicated acute cholecystitis (4). Findings from several recent trials seem to favor LC within 48 to 72 hours of onset of symptoms over surgery after 3 to 5 days of conservative management (interval surgery) or surgery delayed 6 to 12 weeks (delayed surgery) (4). In patients with severe concurrent medical conditions that significantly increase the risks of illness and death of surgery, percutaneous tube cholecystotomy can be an appropriate temporizing measure (15).

Acute Acalculous Cholecystitis Acute acalculous cholecystitis refers to acute inflammation of the gallbladder in the absence of gallstones and accounts for 2% to 15% of all cases of acute cholecystitis (1) and 5% to 10% of all cholecystectomies done in the United States. In Western industrialized countries, most cases of acalculous cholecystitis are seen in critically ill patients and after any surgery. Acalculous cholecystitis can also occur in children, outpatients (especially elderly with underlying vascular disease), bone marrow transplant patients, patients with vasculitis syndromes, as well as AIDS patients (16). Additionally, patients with AIDS can develop acalculous cholecystitis as a result of infection with many organisms, including cytomegalovirus, Cryptosporidium species, and microsporidia (17). As a group, patients with acalculous cholecystitis tend to be older men (c.f. acute calculous cholecystitis).

Pathogenesis and Bacteriology In most cases of acalculous cholecystitis, the gallbladder mucosa is injured by ischemia in combination with bile stasis. A disturbed microcirculation

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plays a critical role and is caused by hypoperfusion in critically ill patients or by vascular insufficiency in patients with vasculitis or atherosclerosis. Bile stasis occurs in fasting patients because the gallbladder does not receive a cholecystokinin stimulus to empty itself. As in calculous cholecystitis, inflammatory mediators such as prostaglandins and Hageman factor promote further injury in acalculous cholecystitis. The bacteria that secondarily infect the gallbladder in this condition are similar to those seen in calculous cholecystitis, but anaerobic flora are more commonly seen. As noted previously, Candida species have been associated with occasional cases of acalculous cholecystitis (7). Rare cases of acalculous cholecystitis have been associated with various illnesses, including typhoid fever and leptospirosis.

Clinical Manifestations Although acute acalculous cholecystitis can have a presentation similar to that of calculous cholecystitis, the presentation is more often subtle, owing to the preponderant occurrence of the disease in elderly and postoperative or critically ill patients. RUQ tenderness is initially absent in three fourths of cases. Acalculous cholecystitis should always be considered when unexplained fever, leukocytosis, or hyperamylasemia occurs in a critically ill or postoperative patient. Delays in diagnosis contribute to the much higher rates of gangrene and perforation seen in acalculous cholecystitis compared with calculous cholecystitis; death rates are also higher in the former disease (10%-50% vs. 1%).

Diagnosis The fulminant course of the disease and its high death rate make an early diagnosis crucial, thus a high index of suspicion for this illness is needed in patients at risk for it. Mildly increased amylase, alkaline phosphatase, or aminotransferase activities can be seen but are nonspecific. Ultrasonographic findings are similar to those in calculous cholecystitis (i.e., a gallbladder wall thickened to >4 mm in the absence of ascites or hypoalbuminemia, pericholecystic fluid collection, and a sonographic Murphy sign). The sensitivity of ultrasonography for detection of acute acalculous cholecystitis ranges from 67% to 92%, and its specificity is greater than 90% (18). CT scanning is also useful for detecting acalculous cholecystitis. Radionuclide scintigraphy is of limited use in most cases owing to the high incidence of false-positive tests caused by viscous bile in fasting, critically ill patients.

Management Antibiotic coverage for patients with acalculous cholecystitis should include aerobic gram-negative organisms and anaerobes. Urgent surgical intervention is needed because of the high risk of progression to gangrene or perforation.

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Open cholecystectomy is the preferred procedure in most cases. Surgical or percutaneous cholecystotomy coupled with antibiotics have been used successfully as definitive therapy in patients at high surgical risk and it has been shown to obviate the need for cholecystectomy. For those who cannot tolerate the percutaneous approach, a novel technique of transpapillary endoscopic cholecystectomy can be considered.

Prevention In patients who receive total parenteral nutrition, the use of intravenous cholecystokinin to promote gallbladder contraction has been shown to reduce the formation of gallbladder sludge, which is a risk factor for acalculous cholecystitis (19). Daily cholecystokinin administration in critically ill patients has been proposed as a means of preventing acalculous cholecystitis. The effectiveness of this measure has not been established.

Cholangitis The term cholangitis refers to inflammation of the biliary ducts, which can be caused by infection, induced iatrogenically, or mediated immunologically (e.g., primary sclerosing cholangitis). A wide variety of infectious agents have been associated with cholangitis, including bacteria, parasites, viruses, and fungi. This chapter focuses primarily on acute bacterial cholangitis.

Pathogenesis and Bacteriology The central event in the pathogenesis of acute cholangitis is biliary obstruction and stasis caused by calculi or benign strictures. Cholangitis occurs much more commonly in patients with biliary obstruction from gallstones or strictures than in patients with malignant obstruction. In 80% to 90% of cases, a gallstone obstructs the CBD (4). In most of the remaining cases, obstruction of the CBD is caused by malignancy, biliary strictures, or instrumentation. Rare cases are caused by congenital abnormalities of the bile ducts, parasites, or sclerosing cholangitis. Chronic obstruction results in increased bile stasis, which promotes growth of the bacteria that colonize the bile ducts, and raises the intraluminal pressure, which promotes entry of these organisms into the bloodstream. Bacteria invade the biliary tract by ascension from the duodenum and only rarely by means of the hepatic portal venous blood. The mechanisms of entry are complex and involve breakdown of several host defense mechanisms (hepatic tight junctions, Kupffer cells, bile flow, IgA production). Culture of bile, stones, or biliary tract stents are positive in more than 90% of patients, yielding a mixed growth of gram-positive and gramnegative bacteria. Most commonly isolated are bacteria of colonic origin that

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mirror those associated with bacterial colonization of the biliary tree and that seen with acute cholecystitis: E. Coli (25%-50%), Klebsiella (15%-20%), and Enterobacter species (5%-10%). The most common gram-positive are Enterococcus species (10%-20%) (2). Anaerobic bacteria (Bacteroides and Clostridia) are cultured from bile in up to 40% of cases of cholangitis, usually as part of a polymicrobial infection. Infections are often polymicrobial. Positive blood cultures are seen in approximately 50% of cases of cholangitis; in most such cases, gram-negative rods are isolated. In hospitalized patients or in those who have undergone instrumentation of the biliary tract, infection with more resistant organisms is common, as is the recovery of anaerobes. Ascending cholangitis is also the most common infectious complication of endoscopic retrograde cholangiopancreatography (ERCP) and frequently seen because of occluded stents. This intervention can introduce intestinal flora into the biliary tract and promote the dissemination of bile bacteria through the blood (20). Postprocedural biliary tract sepses in this setting are caused by incomplete drainage of an infected biliary system. The most frequent organisms responsible for cholangitis/sepsis are enteric bacteria; blood cultures usually yield single organisms. Nosocomial infections with Pseudomonas aeruginosa seen in the past caused by ERCP equipment contamination are now rare.

Clinical Manifestations Acute cholangitis has a wide range of clinical presentations, from a mild illness that can be self-limiting to a fulminant illness with septic shock (4,21). The classic clinical presentation of cholangitis includes Charcot triad of fever and chills, jaundice, and RUQ pain; however, the complete triad is seen in only 70% to 85% of patients. Fever occurs in more than 90% of cases. Jaundice is seen in 60% to 80% of cases. Abdominal pain is described by approximately 70% of patients but can be mild and is not always localized to the RUQ. Elderly or debilitated patients can present only with fever or altered mental status as an indication of illness. In contrast with acute cholecystitis, cholangitis is seen as often in men as in women.

Differential Diagnosis The differential diagnosis of cholangitis includes the same previously discussed entities in the differential diagnosis of cholecystitis (see Table 9-1) as well as other illnesses associated with fever and jaundice. The abdominal pain associated with cholangitis is often less severe than that of acute cholecystitis, whereas fever and other signs of systemic illness are often more pronounced. Liver abscess must be considered in the differential diagnosis of cholangitis but also can occur concurrently as a complication of cholangitis. Jaundice associated with sepsis caused by gram-negative or gram-positive bacteria (i.e., the hepatopathy of sepsis or hyperbilirubinemia of sepsis) also

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must be considered in the differential diagnosis. In cholangitis, systemic infection results in increased serum levels of conjugated bilirubin caused by a defect in the excretion of conjugated bilirubin from hepatocytes (22). Other infectious diseases associated with fever and jaundice (e.g., viral hepatitis, malaria, babesiosis, leptospirosis, typhoid fever) must be considered if relevant risk factors are present.

Diagnosis Routine testing typically reveals leukocytosis with left shift and a cholestatic pattern of liver function tests with elevation of alkaline phosphatase, gammaglutamyl transferase, and bilirubin. Aminotransferase levels approaching 1000 IU/L suggest liver microabscess formation and necrosis of hepatocytes. The bilirubin level is increased in more than 80% of patients. A bilirubin level above 4 mg/dL suggests cholangitis rather than cholecystitis as a cause of fever and RUQ pain. In cholangitis, the sensitivity of ultrasonography for the detection of CBD stones is 50%, whereas it is 75% for the detection of dilated CBDs (4). The bile ducts may not be significantly dilated early in the illness and may never become dilated in patients with chronic inflammation related to sclerosing cholangitis or recurrent infection. Ultrasound should always be followed by ERCP. ERCP is the gold-standard procedure for the diagnosis of CBD stones, with both sensitivity and specificity of 95% (4). Additionally, this technique allows therapeutic drainage at the time of diagnosis. If the Charcot triad is present, the ERCP should not be delayed. Percutaneous transhepatic cholangiography is an alternative diagnostic technique to ERCP if the latter is unavailable or cannot be performed but is contraindicated in those with suppurative cholecystitis, because it can lead to sepsis. Recently, magnetic resonance imaging cholangiography has been shown to be as accurate in detecting CBD stones larger than 1 cm as ERCP. Its overall sensitivity exceeds 90% (23).

Treatment The management of acute cholangitis usually includes both decompression of the obstructed CBD and antibiotic therapy. Eighty percent of the patients with acute cholangitis respond to supportive measures and antibiotic therapy, allowing a delay of definitive surgical or radiologic procedures to relieve the obstruction until the acute illness is resolved. However, in 15% to 20% of the cases cholangitis does not alleviate after 12 to 24 hours of antibiotic therapy alone, thus requiring emergent decompression of the CBD. Indications for urgent biliary tract decompression include persistent abdominal pain, hypotension, confusion, and fever greater than 39ºC (102.2ºF). In recent years, endoscopic drainage techniques have become the initial procedure of choice in managing acute cholangitis. In a prospec-

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tive randomly assigned trial, initial endoscopic drainage for severe cholangitis caused by choledocholithiasis was associated with significantly lower illness (34% vs. 66%) and death (10% vs. 32%) than was initial surgical decompression (24). If emergent surgery is necessary in acute cholangitis, then a choledochotomy with T-tube placement is preferred over cholecystectomy with CBD exploration because it carries a lower death rate. When cholangitis is suspected, antibiotic therapy should be started promptly after blood specimens are drawn for culture. Initial antibiotic therapy should include an agent that is active against aerobic gram-negative rods, including E. coli and Klebsiella species. It is unclear whether antimicrobial activity directed against Enterococcus species and anaerobes is necessary in the initial management of patients with cholangitis. Anaerobes are unlikely in those without previous instrumentation of the biliary tract. Antibiotic agents with little or no activity against these organisms (e.g., ciprofloxacin) have been shown to be as effective in managing cholangitis as a ceftazidime/ampicillin/metronidazole regimen. No studies have shown that a particular antibiotic regimen is superior to others in the management of cholangitis (2). Our practice is to include coverage for Enterococcus species and anaerobes for most patients with moderate to severe illness. Preferred antibiotic choices for covering these organisms, in addition to gram-negative rods that include piperacillin–tazobactam, imipenem, ampicillin–sulbactam, are preferred over ampicillin in combination with metronidazole and an aminoglycoside or quinolone owing to their low potential for nephrotoxicity. Antibiotic therapy usually can be directed at specific organisms when the results of blood and biliary cultures are available. Antibiotic therapy for 7 to 14 days is usually recommended, but the duration of therapy is measured on the basis of the patient’s clinical course, adequacy of drainage, and the presence of bacteremia. REFERENCES 1. Chetlin SH, Elliott DW. Biliary bacteremia. Arch Surg. 1971;102:303-7. 2. van den Hazel SJ, Speelman P,Tytgat GN, Dankert J, van Leeuwen DJ. Role of antibiotics in the treatment and prevention of acute and recurrent cholangitis. Clin Infect Dis. 1994;19:279-86. 3. Namias N, Demoya M, Sleeman D, Reever CM, Raskin JB, Ginzburg E, et al. Risk of postoperative infection in patients with bactibilia undergoing surgery for obstructive jaundice. Surg Infect (Larchmt). 2005;6:323-8. 4. Bilhartz LE, Horton JD. Gallstone disease and its complications. In: Feldman M, Scharschmidt BF, Sleisenger MH, eds. Sleisenger and Fordtran’s gastrointestinal and liver disease, 7th ed. Philadelphia: WB Saunders; 2002:1019-1040. 5. Claesson BE, Holmlund DE, Mätzsch TW. Microflora of the gallbladder related to duration of acute cholecystitis. Surg Gynecol Obstet. 1986;162:531-5. 6. Morris AB, Sands ML, Shiraki M, Brown RB, Ryczak M. Gallbladder and biliary tract candidiasis: nine cases and review. Rev Infect Dis. 1990;12:483-9. 7. Diebel LN, Raafat AM, Dulchavsky SA, Brown WJ. Gallbladder and biliary tract candidiasis. Surgery. 1996;120:760-4; discussion 764-5. 8. Morrow DJ, Thompson J, Wilson SE. Acute cholecystitis in the elderly: a surgical emergency. Arch Surg. 1978;113:1149-52. 9. Mentzer RM, Golden CT, Chandler JG, et al. A comparative appraisal of emphysematous cholecystitis. Am J Surg. 1975;125:10-5. 10. Saini S. Imaging of the hepatobiliary tract. N Engl J Med. 1997;336:1889-94. 11. Kune GA, Burdon JG. Are antibiotics necessary in acute cholecystitis? Med J Aust. 1975;2:627-30.

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12. van der Linden W, Sunzel H. Early versus delayed operation for acute cholecystitis. A controlled clinical trial. Am J Surg. 1970;120:7-13. 13. McArthur P, Cuschieri A, Sells RA, Shields R. Controlled clinical trial comparing early with interval cholecystectomy for acute cholecystitis. Br J Surg. 1975;62:850-2. 14. Järvinen HJ, Hästbacka J. Early cholecystectomy for acute cholecystitis: a prospective randomized study. Ann Surg. 1980;191:501-5. 15. Yusoff IF, Barkun JS, Barkun AN. Diagnosis and management of cholecystitis and cholangitis. Gastroenterol Clin North Am. 2003;32:1145-68. 16. Savoca PE, Longo WE, Zucker KA, McMillen MM, Modlin IM. The increasing prevalence of acalculous cholecystitis in outpatients. Results of a 7-year study. Ann Surg. 1990;211: 433-7. 17. French AL, Beaudet LM, Benator DA, Levy CS, Kass M, Orenstein JM. Cholecystectomy in patients with AIDS: clinicopathologic correlations in 107 cases. Clin Infect Dis. 1995;21: 852-8. 18. Mirvis SE, Vainright JR, Nelson AW, Johnston GS, Shorr R, Rodriguez A, et al. The diagnosis of acute acalculous cholecystitis: a comparison of sonography, scintigraphy, and CT. AJR Am J Roentgenol. 1986;147:1171-5. 19. Sitzmann JV, Pitt HA, Steinborn PA, Pasha ZR, Sanders RC. Cholecystokinin prevents parenteral nutrition induced biliary sludge in humans. Surg Gynecol Obstet. 1990;170:25-31. 20. Westphal JF, Brogard JM. Biliary tract infections: a guide to drug treatment. Drugs. 1999;57:81-91. 21. Hanau LH, Steigbigel NH. Cholangitis: Pathogenesis, diagnosis, and treatment. Curr Clin Trop Infect Dis. 1995;25:153-78. 22. Miller DJ, Keeton DG,Webber BL, Pathol FF, Saunders SJ. Jaundice in severe bacterial infection. Gastroenterology. 1976;71:94-7. 23. Lee MG, Lee HJ, Kim MH, Kang EM, Kim YH, Lee SG, et al. Extrahepatic biliary diseases: 3D MR cholangiopancreatography compared with endoscopic retrograde cholangiopancreatography. Radiology. 1997;202:663-9. 24. Lai EC, Mok FP,Tan ES, Lo CM, Fan ST,You KT, et al. Endoscopic biliary drainage for severe acute cholangitis. N Engl J Med. 1992;326:1582-6.

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Chapter 10

Viral Hepatitis HECTOR BONILLA, MD ARJUN VENKATARAMANI, MD, MPH

Key Learning Points 1. Hepatitis A is the commonest hepatitis infection in the US. 2. Hepatitis B can progress to malignancy in the absence of cirrhosis. 3. Hepatitis C infection rates are especially high in prison and HIV populations. 4. Hepatitis D infection cannot occur in the absence of chronic Hepatitis B infection. 5. Hepatitis E can be responsible for fulminant hepatitis in pregnant women.

T

he most common viruses associated with hepatitis are A, B, C, D, and E. In addition, other viruses such as Epstein-Barr virus, Cytomegalovirus, yellow fever, dengue fever, Lassa virus, Marburg virus, Ebola virus, and Rift Valley fever virus, are associated with hepatitis (1). This chapter discusses the various syndromes associated with the heterogeneous alphabetized group of viruses A through E. The virology, epidemiology, transmission, and treatment of hepatitis A through E viruses covered in this chapter are summarized in Table 10-1. According to the Centers for Disease Control (CDC), in 2003 there were an estimated 130,000 cases of infection with hepatitis A, B, and C in the United States. Most of the cases were caused by hepatitis A virus (HAV) infection (2). Chronic viral liver disease, reported only with the B, C, and D viruses, is now the leading cause of cirrhosis, hepatocellular carcinoma (HCC), and liver transplantation. More than 4 million Americans are infected with the hepatitis C virus (HCV), and more than a million are chronically infected with the hepatitis B virus (HBV). 185

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New Developments in the Management of Viral Hepatitis ●

●

Newer nucleoside analogs hold promise for suppression and possible eventual clearance of hepatitis B infections. Specification of genotypes will be increasingly important in predicting the clinical course and response to therapy in hepatitis C infections.

Table 10-1 Hepatitis Virology, Epidemiology, and Treatment for A-E Viruses Incubation (days) Transmission

Virus

Type

A

Picornavirus ssNA (+)

B

Hepadnavirus 30-180 dsDNA

C

Flavivirus ssRNA (+)

15-150

D

Deltaviridae ssRNA (−)

Few weeks

E

Caliciviridae ssRNA (+)

15-45

Contaminated food Raw fish, green onions (fecal-oral) IDU, blood/ blood products Needlestick, sex, etc. IDU, blood/ blood products, needlestick IDU, blood/ blood products Contaminated water (fecaloral)

History

Chronic Treatment Infection of Infection

Childcare, No Supportive household care exposure, travel to endemic areas Promiscuous, 5%-10% INF, PEGMSM INF, lamivudine adefovir, entecavir Promiscuous, 70%-90% INF, PEGMSM INF/ Ribavirin Promiscuous, 50% MSM

INF

Travel to endemic area

Supportive care

No

Abbreviations: IDU, intravenous drug use; INF, interferon; MSM, men who have sex with men; PEG-INF, pegylated interferon; PEG-INF.

Hepatitis A The hepatitis A virus (HAV) is a single (+) stranded nonenveloped RNA virus, genus Herpetovirus and belonging to the Picornaviridae family. Seven genotypes have been identified, but only one serotype has been associated with human disease (3-5). Certain nucleotide changes in the HAV genome have been associated with more severe disease (6).

Epidemiology Hepatitis A is the major cause of hepatitis in the United States. In 2003, the CDC estimated approximately 61,000 new cases of HAV infection in the United States. Approximately 6% of these cases are caused by travel to

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developing countries. Almost 40% of Americans have antibody evidence of past HAV infection. Historically, Native Americans, Alaskan natives, and Hispanics are the ethnic groups with the highest incidence of HAV infection (2). Approximately 100 deaths from fulminant HAV infection occur annually. The risk of death increases with age and with coexistent liver disease. The route of transmission is predominantly fecal-oral (food or water contamination) with an incubation period of 30 days (range of 15-60 days). After oral ingestion, HAV crosses the gastrointestinal mucosa and replicates in liver cells. It is excreted through bile into the gastrointestinal tract (7). Its lack of an envelope can make HAV more stable in bile. It can be excreted in feces 2 weeks before any clinical illness becomes apparent and for another 2 weeks after the onset of jaundice (8). Therefore, the peak of infectivity of HAV occurs 2 weeks before the onset of jaundice or elevation of the aminotransferases. HAV can survive and remain infectious for 3 to 10 months in water. The course of disease is shown in Figure 10-1.

Clinical Manifestations The spectrum of the disease varies from severe acute illness to asymptomatic disease (9). Most children younger than 5 years of age have asymptomatic infection. Characteristically HAV has an abrupt onset of symptoms that include fever, malaise, anorexia, abdominal discomfort, dark urine, and jaundice. The severity of the symptoms increases with increasing age (jaundice occurs in 10% of children younger than 6 years of age, 40% to 50% in older children, and 70% to 80% in adults) (10).

Clinical illness

Infection

ALT

Response

IgM

IgG

Viremia

HAV in stool

0

1

2

3

4

5

6 Week

7

Figure 10-1 Clinical course of hepatitis A infection.

8

9

10

11

12

13

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HAV can present as a fulminant hepatitis in less than 0.1% of the cases, with a fatality rate greater than 50%, as a cholestatic hepatitis with the persistent high levels of bilirubin, or as a relapsing hepatitis manifested by elevation in the aminotransferases that can occur weeks or months after recovery (10).

Diagnosis and Treatment HAV presents with a rapid elevation in the serum aminotransferases during the prodromal phase followed by elevation in bilirubin levels. Serologic tests are diagnostic. A HAV-positive IgM is almost always found at clinical presentation and can remain positive for several months. Development of the antibody leads to abatement of the clinical illness and infectivity (Table 10-2). The presence of the antibody leads to lifelong protection against reinfection. HAV-specific IgG can be used to test for past exposure, need for vaccination, and ongoing protection against the virus. There is no specific treatment of HAV; supportive care only is indicated.

Prevention Proper food handling and good agricultural and food processing practices are recommended by the Food and Drug Administration (FDA), and the adherence to the current CDC guidelines for viral hepatitis should be universally implemented to prevent outbreaks of hepatitis A (11). Prevention is also possible through passive or active immunization. Prophylaxis with a single dose of immunoglobulin (IG) at 0.02 mg/kg is recommended after exposure to HAV from close personal or household contacts of index cases. The use of IG is 80% to 90% effective in preventing acute clinical hepatitis. Vaccination is recommended for preexposure protection against HAV in trav-

Table 10-2 Antibodies in Viral Hepatitis (A-E) Stage of Infection Virus Type

Acute

Chronic

Resolved

A B

Anti-HA IgM + Anti-HBc IgM +

C

Anti-HCV +*

D

HBsAg + Anti-HD IgM + HD RNA + Anti-HE IgM +

– HB DNA + Anti-c IgG Persistent HCV RNA Persistent HD RNA +** HBsAg –

Anti-HA IgG + HB DNA − Anti-c IgG + HCV RNA − Anti-HCV + HD RNA −

E

Anti-HE IgG +

* Could be negative during acute infection. RNA viral is positive 1 to 2 weeks after exposure and antiHCV is positive 7 weeks after exposure. ** Both HDV IgG and IgM can be present Abbreviations: anti, antibody; HA, hepatitis A; HBc, hepatitis B core antigen; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; HD, hepatitis D; HE, hepatitis E; IgM, immunoglobulin M.

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Table 10-3 Vaccines and Dosing Schedules Vaccine

Hepatitis A vaccine Havrix Vaqta Hepatitis B vaccine Engerix-B Recombivax HB Hepatitis A/B vaccine Twinrix

Dose

Dosing Schedule

1,440 ELISA units 50 U

2 doses 6 to 12 months apart 2 doses 6 to 12 months apart

20 Ug 10 Ug

3 doses at 0, 1, and 6 months 3 doses at 0, 1, and 6 months

720 ELISA U/20 Ug

3 doses at 0, 1, and 6 months

Abbreviation: ELISA, enzyme-linked immunoabsorbent assay.

elers to endemic areas that include Mexico, Central and South America, Africa, and southern parts of Asia and Greenland; in the United States the highest incidence of hepatitis A has been reported on the West Coast. Also vaccination has been recommended in sexually active homosexual men, injection drug users, persons with preexisting liver disease, and health care workers. Infants should also be universally vaccinated. Two inactivated (formalin-killed) vaccines (Havrix or Vaqta) are available (Table 10-3). These two vaccines are highly immunogenic. Approximately 100% of the vaccines develop protective antibodies within 1 month after the first dose, and protective levels can persist for at least 20 years. Therefore postvaccination testing is not recommended. In 2001 the FDA approved the combined hepatitis A and hepatitis B vaccine (Twinrix) for persons older than 18 years of age who need both vaccines. The vaccination schedule is 0, 1, and 6 months with a similar immunogenicity of the single hepatitis vaccine (A or B) (10).

Hepatitis B The hepatitis B virus (HBV) is a member of the Hepadnaviridae family. These viruses are double-stranded DNA viruses with lipid envelope (12). Viral replication in hepatocytes is not cytopathic. In contrast, the specific T-cell host response to the many viral proteins causes hepatocellular damage. Eight different genotypes have been identified (A-H). The most prevalent genotypes in the United States are A and G (13-15). Preliminary data suggests that genotype B is associated with spontaneous seroconversion. Genotypes A and B respond better to interferon (INF) therapy, and genotype C is associated with hepatocellular carcinoma. However, the role of genotypes in the pathogenesis and response to therapy needs further study (16-19). HBV serologies are based on the detection of antigens and antibodies to specific parts of the virus including the surface, envelope, and core. Two strains of HBV have been identified; one that produces hepatitis B early antigen (HBeAg) and the other that does not produce HBeAg, also

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called the core-mutant strain. This hepatitis B virus mutant is associated with either progressive or fulminant cases of HBV (20).

Epidemiology Worldwide, approximately 2 billion people have been infected with HBV; 350 million people experience chronic infection, and 500,000 to 1.2 million cases result in death each year. The problem is especially acute in sub-Saharan Africa, East Asia, and China (21). The CDC reports approximately 1.2 million people in the United States have chronic HBV infection. Approximately 73,000 acute cases were identified in 2003 (22). The highest incidence is in the South, and the lowest is in the Midwest. The incidence of HBV has declined by 67% since the 1980s, presumably because of routine vaccination in children and adolescents. The risk factors for transmission include injection drug use (IDU), sexual contact (especially multiple sex partners or men who have sex with men [MSM]), vertical transmission (from mother to child), and unvaccinated health workers. Blood transfusions and repeated use of hypodermic needles continue to be another source of infection in some developing nations The chronically infected individual with HBV has a 100 times greater risk for HCC (23),especially when both hepatitis B surface antigen (HBsAg) and HBeAg are positive (24). Therefore, it is very important these individuals be screened for evidence of HCC by doing imaging studies of the liver and measuring the alpha-fetoprotein (tumor marker) twice a year (25). Also, HBV coinfection with HCV or hepatitis delta virus (HDV) leads to a greater incidence of cirrhosis and HCC (26).

Clinical Manifestations HBV can cause both an acute and a chronic infection. The acute illness can be asymptomatic. The classic features of malaise, fatigue, anorexia, and nausea followed by jaundice, dark urine, and pale stools occurs after an incubation period of 45 to 160 days. A serum sickness–like illness (maculopapular rash, arthralgias, and fever) precedes clinical hepatitis in a minority of patients. Findings on examination include jaundice, tender hepatomegaly, splenomegaly, and lymphadenopathy. The clinical illness typically lasts 1 to 2 months but can last longer. Children usually have asymptomatic infection or a mild illness. Occasionally, the acute hepatitis can be prolonged or can take a relapsing course. Rarely, a fulminant fatal hepatitis occurs (12). Chronic infection occurs in 1% to 20% of cases after an acute infection. Infection early in life or in the context of an immunosuppressed state is a clear risk factor for chronic infection. In chronically infected adults, serious complications such as cirrhosis and HCC can develop. Extrahepatic manifestations of chronic HBV infection include membranous glomerulonephritis, vasculitis, and polyarteritis nodosa (27).

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Diagnosis Acute HBV infection is characterized by elevated aminotransferases and bilirubin, a positive HBsAg, IgM against the HBV core (HBcIgM), HBeAg, and active viremia measured by commercially available HBV-DNA assays (Figure 10-2). The hepatitis B infection is a dynamic process that can proceed as follows (28), shown in Table 10-4. Serology in chronic HBV is illustrated by Figure 10-3.

Treatment The goal of therapy is to prevent progression of liver disease to cirrhosis and HCC by suppressing the virus to the lowest possible level. Before making a decision to initiate therapy for hepatitis B, the following three variables need to be considered: 1. Alanine aminotransferase (ALT) levels 2. HBV-DNA copies/mL 3. The HBeAg status Therapy is indicated for patients with positive HBeAg, elevated ALT, and HBV-DNA viral loads greater than 105 copies/mL and for patients with negative HBeAg with elevated ALT and HBV-DNA viral load greater than 104 copies/mL (29). In the cases where ALT is normal a liver biopsy needs to be considered before initiation of HBV therapy (28). Decompensated cirrhosis is not a contraindication to therapy with nucleoside analogs and is almost an urgent indication for institution of therapy.

Symptoms HBeAg

anti-HBe

Titer

Total anti-HBc

0

4

anti-HBs

IgM anti-HBc

HBsAg

8

12 16 20 24 28 32 36

52

100

Weeks after Exposure Figure 10-2 Typical serologic course of acute hepatitis B infection with recovery.

+ + − −

+

+ +

+

I. Immune-Tolerance

II. Immune-Active III. Inactive-Carrier

IV. Reactivation

+

− +

−

Anti-HBe

>105 Copies (fluctuating) Nondetected low levels + (fluctuating)

>10

5 Copies

HB-DNA

50-200 U/L

50-200 U/L Normal

Normal

ALT

Chronic hepatitis Mild/moderate hepatitis-fibrosis Active hepatitis

Normal

Biopsy

Vertical transmission, low risk HCC and cirrhosis Higher risk HCC and cirrhosis May persist inactive indefinitely Occur after inactive-carrier

Comment

Source: Yim HJ, Lok ASF. Natural history of chronic hepatitis B virus infection: What we knew in 1981 and what we know in 2005. Hepatology. 2006;43S(1):S173-81. Abbreviations: ALT, alanine aminotransferase; HB, hepatitis B; HBe, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HCC, hepatocellular carcinoma.

HBe Ag

HBs Ag

Phase

192

Table 10-4 Clinical Phases of Chronic Hepatitis B

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Acute (6 months)

193

Chronic (Years) HBeAg

anti-HBe HBsAg

Titer

Total anti-HBc

IgM anti-HBc

0 4 8 12 16 20 24 28 32 36

52

Years

Weeks after Exposure Figure 10-3 Typical serologic course of hepatitis B infection in progression from acute to chronic infection.

Pegylated interferon alfa, and nucleoside analogs such as lamivudine (Epivir), adefovir (Hepsera), and entecavir (Baraclude) are all currently FDAapproved drugs for initial therapy for HBV. Lamivudine therapy is ideal for initiation because of the lack of side effects, availability, and lower cost. However, the high rate of development of resistance (YMDD mutant) with prolonged use of lamivudine has led to recommendations for the use of adefovir or entecavir for at least 48 weeks. The doses of these last two nucleoside analogs must be adjusted according to the individual’s renal function. Therapy with pegylated INF is limited by the many physical, psychological, and hematological side effects. It is likely that combination therapy (nucleoside analogs with INF) will be the mainstay in the future treatment of HBV infection, but this remains to be confirmed by extensive studies (28,30). Decompensated cirrhotic patients who do not respond to nucleoside analogs need to be considered for liver transplantation. Post-transplant immunoprophylaxis with HBV-specific immunoglobulin (HBIG) is necessary. Results of therapy with nucleoside analogs in this population are very encouraging.

Prevention The best form of prophylaxis against HBV is immunization. Candidates for vaccination include all infants and children younger than 19 years of age, adults in high-risk groups that include multiple sex partners or sexually transmitted diseases (STDs), MSM, IDU, incarcerated persons, sexual contact with someone with chronic hepatitis B, health care workers with blood exposure in the workplace, hemodialysis patients (31), and patients with

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other chronic liver diseases. However there has been a trend toward universal HBV vaccination. A routine course of three injections of recombinant hepatitis B vaccine, Engerix-B or Recombivax, (scheduled at 0, 1, and 6 months) provides immunity in 90% to 95% of cases (see Table 10-3). Postvaccination testing of people at high risk for HBV infection is worthwhile to determine appropriate prophylaxis if an exposure occurs. For those nonresponders to a primary vaccination a new series of the vaccine in the deltoid area is recommended. Booster doses of HBV vaccine have not been recommended for healthy adults or children with normal immune status, but recommended for hemodialysis patients. The need for a booster dose in these individuals should be considered when the antibody level declines below 10 mIU/mL (10). Decreased exposure to a known risk factor for HBV is also crucial in preventing the disease. HbsAg-positive health care workers (HCWs) need to adopt universal precautions; actively viremic HCWs should not be allowed to do invasive procedures. The two most commonly encountered clinical situations in which passive immunization against HBV are indicated are vertical transmission and needlestick injury. In the case of vertical transmission, the combination of active and passive immunization provides approximately 95% protection. HBIG in a dose of 0.5 mL should be given to the neonate in the delivery room, and active vaccination should begin within a week of delivery. In cases of known nosocomial exposure of unimmunized or nonimmune people, the recommended dose of HBIG is 0.06 mL/kg within 48 hours of exposure; again, active immunization should be given concurrently (30,32).

Hepatitis C HCV is an enveloped single-stranded RNA virus of the Flaviviridae family. There are six major genotypes and many subtypes of HCV. Genotype 1 is the most common in the United States. Additionally, variants referred to as quasispecies develop in individual patients. It is hypothesized that the development of quasispecies are associated with chronic infection and resistance to therapy (32).

Epidemiology The estimated prevalence of HCV infection in the world is 2% to 3%. Approximately 123 million people are infected with HCV (33). According to the CDC, the prevalence in the United States is approximately 1.8% of the population representing 3.9 million cases. Sixty-five percent of the afflicted individuals are between the ages of 30 to 49 years (34). More than 80% of patients infected with HCV develop chronic infection, which can lead to cirrhosis in 20% and HCC in 1% overall (35).

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In 2003 the CDC estimated 4900 cases of clinical symptomatic acute hepatitis C and 30,000 new infected cases (2). The genotype 1 was present in 73.7% of the infected population. The strongest risk factors associated with HCV infection were illegal drug use and high-risk sexual behavior. However, other methods of transmission include tattoos, body piercing, and needlestick injury. Breast-feeding does not seem to be a risk factor. The risk of sexual transmission of HCV is estimated at 5% over a 10- to 20-year period. The risk of vertical transmission is slightly lower. However, in approximately 30% of patients, a convincing risk factor is not identified (34,35). In the U.S. correctional system it has been estimated that 39% of its population has HCV infection. In the human immunodeficiency virus (HIV) population, the prevalence of coinfection HIV/HCV is on average 35% (36). Worldwide, contaminated equipment and syringes seem to be the major risk factor for HCV infection (33).

Clinical Manifestations After acute HCV infection, clinical manifestations can appear after 7 to 8 weeks of exposure with either mild symptoms (malaise, nausea, or vomiting) or no symptoms at all and in very rare cases fulminant hepatitis (23). Transition to chronic hepatitis is the usual pattern. Chronic hepatitis is usually asymptomatic or associated with nonspecific symptoms. Besides the clinical manifestations associated with liver disease (cirrhosis or HCC), HCV can present with several extrahepatic manifestations that include cryoglobulinemia (37), membranoproliferative glomerulonephritis, cognitive dysfunction, non-Hodgkin lymphoma, sicca syndrome, porphyria cutanea tarda, and lichen planus (38-44). Approximately 15% to 20% of the chronic infected cases develop hepatitis and some degree of fibrosis and cirrhosis, HCC, and death (31,32). The median time of progression to cirrhosis in untreated HCV infection is 30 years (13 years for men and 42 years for women after infection). Factors that increase the rate of progression of fibrosis are age older than 40 years, alcohol use (greater than 50 g/day), male gender, and coinfection with HBV or HIV infection (45).

Diagnosis The diagnosis of hepatitis C is based on detection of antibodies by enzyme immunoassay against viral antigens (46). These serologies do not distinguish acute from chronic or active from resolved disease and must be interpreted in the context of the overall clinical picture. Consequently, the determination of the HCV RNA, either qualitatively or quantitatively by polymerase chain reaction (PCR) confirms the diagnosis of HCV infection (47). However, the magnitude of the viral load does not correlate with progression of HCV but does correlate with the response to therapy (48).

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Newer generation PCR tests have reduced the lower limit of detection to well below 100 copies per mL (47,48). The value of serum ALT is limited by the fact that it can be normal in up to 60% of infected patients (49). The HCV genotype is an integral part of the workup that should be done before instituting therapy because the genotype can predict the response and duration of therapy. For example, genotypes 2 and 3 have a higher likelihood of response and require a shorter course of IFN/ribavirin therapy (6 months vs. 12 months for the other genotypes) (50). Liver biopsy is considered the gold standard in evaluation of the activity (inflammation) and stage (fibrosis) of the liver disease (51). Because of complications associated with biopsy and sampling error (52), alternatives to liver biopsy have been proposed such as the use of biochemical markers for fibrosis and necrosis (alpha-2 macroglobulin, haptoglobulin, gamma-glutamyl transpeptidase [GGT], total bilirubin, apolipoprotein A and ALT) also called the Fibrospect II test (fibrosis marker) and Acti test (necrosis marker). The accuracy of these markers needs to be validated in different study populations (53,54).

Treatment The treatment of choice for chronic HCV infection is the combination of weekly subcutaneous pegylated IFN and daily oral ribavirin. Studies have shown sustained response (defined as absence of virus 6 months after cessation of a standard course of therapy) to be 42% to 46% for genotype 1infected patients and 76% to 82% in cases involving genotypes 2 and 3 (50). For genotype 1-infected patients, the duration of therapy is 48 weeks. The HCV-RNA PCR is quantitatively measured before and 12 weeks into therapy. If the patient does not demonstrate early virologic response (defined as undetectable viral load or at least a two-log decrease in the viral load), therapy is usually discontinued at this point. The daily dose of ribavirin is weight based (1200 mg in patients weighing more than 75 kg [165 lb], 1000 mg in patients between 70-75 kg [154-165 lb], and 800 mg or less in patients weighing less than 70 kg [154 lb]). In genotypes 2 or 3, the duration of therapy is only 24 weeks. Unfortunately, therapy is fraught with physical, psychological, and hematological side effects that can lead to dose reduction or adjunctive therapy with hematologic growth factors. Therapy is unsafe in patients with decompensated cirrhosis and should be offered only through research protocols. HCV-related cirrhosis is the most common reason for liver transplantation in the United States. Unfortunately, recurrence is universal (50). As noted, the genotype predicts the response and duration of HCV therapy (response rate is higher and shorter for genotypes 2 and 3). However, all genotypes can be associated with cirrhosis and HCC (50). Studies done in African American populations treated with IFN and ribavirin have shown lower rates of response to treatment when compared to

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non-Hispanic white patients, a difference that cannot be explained by the genotype distribution alone (55).

Prevention The principles of prophylaxis for HCV infection are similar to those for HBV infection. The sheer number of subtypes and quasispecies complicates development of vaccines. To date there is no effective vaccine or postexposure prophylaxis available. Therefore, primary prevention to decrease the risk of contracting the infection to reduce liver disease should be advised (needle-exchange programs, HAV and HBV vaccination where indicated, reduced alcohol use, etc.). Secondary prevention (counseling patients about their infectivity) is mandatory and should include advice about sharing toothbrushes, razors, nail clippers, and hypodermic needles (30). Protected sexual intercourse is not necessary in the context of a monogamous relationship (10,56). In acute hepatitis C infection, the use of IFN has been shown to be effective by clearing the infection in 98% of the cases (57).

Hepatitis D HDV is a defective small-RNA virus belonging to the delta family. HDV is a chimera that contains RNA and enveloped proteins consisting of HDV antigen and HBsAg. Three different genotypes have been identified with a geographic distribution; genotype 1a is the predominant strain in the United States. The HDV infection can occur as a superinfection (HBV infection predates HDV) or as a coinfection of both viruses. There is no evidence of replication of HDV outside the liver (58).

Epidemiology Geographical distribution of this virus is broad and includes southern Italy; Okinawa, Japan; Northern India; China; Albania; the Sahara; European Russia; and parts of South America (59,60). In the United States, more than 10,000 new infections occur annually, and a few acute infections are fatal. Additionally, approximately 1000 people die annually in the United States from chronic HDV infection. The parenteral route, which is the most efficient way of transmission of HDV, leads to a high incidence rate in injection drug users and hemophiliacs. Sexual transmission has been documented (58,61,62).

Clinical Manifestations The clinical manifestations of acute HDV infection are similar to other types of hepatitis ranging from subclinical to fulminant hepatitis. Acute HDV

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infection can occur as a coinfection (HBV/HDV) that resolves in 95% of the cases or as a superinfection (after HBV infection) that often has a more severe course leading to a chronicity in 70% of the cases. The chronic HDV infection is defined by the presence of IgG anti-HDV antibody, the increase of IgM anti-HDV titer and persistent HDV RNA in blood samples. These chronically infected HDV patients have a faster progression to cirrhosis than those with HBV infection alone eventually requiring liver transplantation. HCC is another complication of chronic HDV infection, and the rate is approximately 40%, which is similar to patients with cirrhosis and chronic HBV infection (58).

Diagnosis During the acute HDV infection, serological markers such as HDV-RNA levels and HDV antigen can be detected (36). During the primary HDV infection, there are increased titers of the IgM antibody that declines in a few weeks followed by an IgG antibody response. The diagnosis of coinfection (HBV/HDV) is made by detection of IgM antibody against HBcAg, HBeAg, and anti-HBe antibody and IgM anti-HDV (Figure 10-4). In contrast, superinfection is diagnosed by the presence of chronic hepatitis B [HBsAg (+), IgG anti-HBc antibody and anti-HBe antibody], superimposed by acute HDV infection (anti-HDV IgM and HDV RNA) (58). The HDV test should be considered in patients who present with acute hepatitis, excluding acute viral hepatitis A, B, and C, such as HAV IgM (−), HBc IgM (−), HCV antibody (Ab) (−), and HBsAg (+).

Symptoms

Titer

ALT Elevated Anti-HBs IgM anti-HDV

HDV RNA HBsAg

Total anti-HDV

Time after Exposure

Figure 10-4 Typical serologic course in HBV-HDV coinfection.

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Treatment Therapy for HBV should be effective in the sense that it eliminates the infection that is essential for HDV to survive and replicate. IFN is the only licensed drug for treatment of chronic HDV infection. In patients with liver failure, liver transplantation is an option with excellent survival rates (62,63).

Prevention The principles of prophylaxis for HDV infection are similar to those for HBV infection. HBV and HDV can be prevented by pre- and postexposure prophylaxis for hepatitis B and education to reduce the risk factors for superinfection (IDU and sexual contact) (10,30).

Hepatitis E The hepatitis E virus (HEV) is a single-stranded, nonenveloped, RNA virus that belongs to the Calciviridae family. HEV has been classified in four major genotypes (1, 2, 3, and 4) (59,64).

Epidemiology HEV spreads by means of the fecal-oral route. Outbreaks of hepatitis E have been associated with contaminated water. Several genotypes are identified with geographical distribution: genotype 1 in Asia and Africa; genotype 2 in Mexico, Nigeria, and Chad; genotype 3 in Asia, Europe, Oceania, North and South America; and genotype 4 exclusive from Asia (59). During the recent conflicts in Sudan and Iraq, several suspected cases of hepatitis E have been reported (65).

Clinical Manifestations The incubation period of HEV ranges from 15 to 60 days. The symptoms are similar to those of HAV and include fever, abdominal discomfort, jaundice, dark urine, and pale stools. Less commonly, diarrhea, arthralgias, and an urticarial rash develop. The disease is self-limited, but fulminant cases of HEV have developed in 10% of the women, especially during the third trimester of pregnancy (66). HEV is not associated with chronic hepatitis although preexisting chronic liver disease can be associated with more severe HEV disease.

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Symptoms IgG anti-HFV

ALT

Titer

IgM anti-HFV

Virus in stool 0

1

2

3

4

5

6

7

8

9

10 11 12 13

Time after Exposure Figure 10-5 Typical serologic course in hepatitis E infection.

Diagnosis and Treatment The diagnosis is made by serology (IgM antibodies), stool antigen detection, or by HEV genome amplification by PCR techniques (10,60). The serologic course of HEV is shown in Figure 10-5. No specific therapy has shown to be of benefit for HEV.

Prevention The prevention of HEV depends on the provision of clean water supplies. Individuals should avoid drinking water (also beverages with ice) of unknown purity, raw shellfish, and raw fruit and vegetables not peeled or prepared by traveler (10, 30). Research on vaccines for HEV is evolving.

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7. Mathiesen LR, Møller AM, Purcell RH, London WT, Feinstone SM. Hepatitis A virus in the liver and intestine of marmosets after oral inoculation. Infect Immun. 1980;28:45-8. 8. Menon KV, Zein NN. What do we need to know about non-A-to-E viral hepatitis? Curr Gastroenterol Rep. 2000;2:33-9. 9. Lednar WM, Lemon SM, Kirkpatrick JW, Redfield RR, Fields ML, Kelley PW. Frequency of illness associated with epidemic hepatitis A virus infections in adults. Am J Epidemiol. 1985;122: 226-33. 10. Centers for Disease Control. Hepatitis A-E, report of the division of viral hepatitis. Available at: www.cdc.gov/ncidod/diseases/hepatitis/slideset/slide_.htm. Accessed May 16, 2003. 11. Centers for Disease Control. Prevention of hepatitis A through active or passive immunization practices (AICIP). MMWR. 1999;48(RR12):1-37. 12. Robinson WS, Lutwick LI. The virus of hepatitis, type B (first of two parts). N Engl J Med. 1976;295:1168-75. 13. Summers J, O’Connell A, Millman I. Genome of hepatitis B virus: restriction enzyme cleavage and structure of DNA extracted from Dane particles. Proc Natl Acad Sci U S A. 1975;72:4597-601. 14. Kao JH. Hepatitis B viral genotypes: clinical relevance and molecular characteristics. J Gastroenterol Hepatol. 2002;17:643-50. 15. Kidd-Ljunggren K, Miyakawa Y, Kidd AH. Genetic variability in hepatitis B viruses. J Gen Virol. 2002;83:1267-80. 16. Chu CJ, Lok AS. Clinical significance of hepatitis B virus genotypes [Editorial]. Hepatology. 2002;35:1274-6. 17. Chu CJ, Hussain M, Lok AS. Hepatitis B virus genotype B is associated with earlier seroconversion compares with compare with hepatitis B virus genotype C. Gastroenterology. 2002;120: 1756-62. 18. Kao JH,Wu NH, Chen PJ, et al. Hepatitis B genotypes and the response to interferon therapy. J. Hepatology. 2000;33:998-1002. 19. Fujie H, Moriya K, Shintani Y, Yotsuyanagi H, Iino S, Koike K. Hepatitis B virus genotypes and hepatocellular carcinoma in Japan [Letter]. Gastroenterology. 2001;120:1564-5. 20. Liu CJ, Kao JH, Lai MY, Chen PJ, Chen DS. Precore/core promoter mutations and genotypes of hepatitis B virus in chronic hepatitis B patients with fulminant or subfulminant hepatitis. J Med Virol. 2004;72:545-50. 21. Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J Viral Hepat. 2004;11:97-107. 22. Centers for Disease Control. Incidence of acute hepatitis B—United States, 1990-2002. MMWR. 2004;52:1252-4. 23. Farci P,Alter HJ, Shimoda A, Govindarajan S, Cheung LC, Melpolder JC, et al. Hepatitis C virus-associated fulminant hepatic failure. N Engl J Med. 1996;335:631-4. 24. Beasley RP. Hepatitis B virus. The major etiology of hepatocellular carcinoma. Cancer. 1988;61:1942-56. 25. Practice Guidelines Committee, American Association for the Study of Liver Diseases. Chronic hepatitis B. Hepatology. 2001;34:1225-41. 26. Liaw YF, Chen YC, Sheen IS, Chien RN,Yeh CT, Chu CM. Impact of acute hepatitis C virus superinfection in patients with chronic hepatitis B virus infection. Gastroenterology. 2004;126:1024-9. 27. French Vasculitis Study Group. Hepatitis B virus-associated polyarteritis nodosa: clinical characteristics, outcome, and impact of treatment in 115 patients. Medicine (Baltimore). 2005;84: 313-22. 28. Keeffe EB, Dieterich DT, Han SH, Jacobson IM, Martin P, Schiff ER, et al. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States. Clin Gastroenterol Hepatol. 2004;2:87-106. 29. Chen G, Lin W, Shen FM, et al. Viral load as a predictor of liver disease in chronic hepatitis B infection. Hepatology. 2004;40:594 (abstract 996). 30. Centers for Disease Control. Guidelines for viral hepatitis surveillance and case management. Available at: www.cdc.gov. Accessed January, 2005. 31. Centers for Disease Control. Update: Recommendations to prevent hepatitis B virus transmission—United States. JAMA. 1999;281:790. 32. Centers for Disease Control. Hepatitis B virus: A comprehensive strategy for eliminating transmission in the United States through universal childhood vaccination: Recommendations of the immunization practices advisory committee (AICP). MMWR. 1991;40(RR-13):1-19. 33. Shepard CW, Finelli L,Alter MJ. Global epidemiology of hepatitis C virus infection. Lancet Infect Dis. 2005;5:558-67.

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34. Alter MJ, Kruszon-Moran D, Nainan OV, McQuillan GM, Gao F, Moyer LA, et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med. 1999;341:556-62. 35. Seeff LB. Natural history of hepatitis C. Am J Med. 1999;107:10-15. 36. Verucchi G, Calza L, Manfredi R, Chiodo F. Human immunodeficiency virus and hepatitis C virus coinfection: epidemiology, natural history, therapeutic options and clinical management. Infection. 2004;32:33-46. 37. Horcajada JP, García-Bengoechea M, Cilla G, Etxaniz P, Cuadrado E,Arenas JI. Mixed cryoglobulinaemia in patients with chronic hepatitis C infection: prevalence, significance and relationship with different viral genotypes. Ann Med. 1999;31:352-8. 38. Tsukazaki N,Watanabe M, Irifune H. Porphyria cutanea tarda and hepatitis C virus infection. Br J Dermatol. 1998;138:1015-7. 39. Ramos-Casals M, Font J. Extrahepatic manifestations in patients with chronic hepatitis C virus infection. Curr Opin Rheumatol. 2005;17:447-55. 40. Gisbert JP, García-Buey L, Pajares JM, Moreno-Otero R. Systematic review: regression of lymphoproliferative disorders after treatment for hepatitis C infection. Aliment Pharmacol Ther. 2005;21:653-62. 41. Silvestri F, Pipan C, Barillari G, Zaja F, Fanin R, Infanti L, et al. Prevalence of hepatitis C virus infection in patients with lymphoproliferative disorders. Blood. 1996;87:4296-301. 42. Zuckerman E,Zuckerman T,Levine AM,Douer D,Gutekunst K,Mizokami M,et al. Hepatitis C virus infection in patients with B-cell non-Hodgkin lymphoma. Ann Intern Med. 1997;127:423-8. 43. Fargion S, Piperno A, Cappellini MD, Sampietro M, Fracanzani AL, Romano R, et al. Hepatitis C virus and porphyria cutanea tarda: evidence of a strong association. Hepatology. 1992;16:1322-6. 44. Haddad J, Deny P, Munz-Gotheil C, Ambrosini JC, Trinchet JC, Pateron D, et al. Lymphocytic sialadenitis of Sjögren’s syndrome associated with chronic hepatitis C virus liver disease. Lancet. 1992;339:321-3. 45. Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet. 1997;349:825-32. 46. Vrielink H, Reesink HW, van den Burg PJ, Zaaijer HL, Cuypers HT, Lelie PN, et al. Performance of three generations of anti-hepatitis C virus enzyme-linked immunosorbent assays in donors and patients. Transfusion. 1997;37:845-9. 47. Beld M, Habibuw MR, Rebers SP, Boom R, Reesink HW. Evaluation of automated RNA-extraction technology and a qualitative HCV assay for sensitivity and detection of HCV RNA in poolscreening systems. Transfusion. 2000;40:575-9. 48. McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med. 1998;339:1485-92. 49. Esteban JI, López-Talavera JC, Genescà J, Madoz P,Viladomiu L, Muñiz E, et al. High rate of infectivity and liver disease in blood donors with antibodies to hepatitis C virus. Ann Intern Med. 1991;115:443-9. 50. American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C. Hepatology. 2004;39:1147-71. 51. Bedossa P, Poynard T. An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group. Hepatology. 1996;24:289-93. 52. Regev A, Berho M, Jeffers LJ, Milikowski C, Molina EG, Pyrsopoulos NT, et al. Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection. Am J Gastroenterol. 2002;97:2614-8. 53. Poynard T, Imbert-Bismut F, Munteanu M, et al. Overview of the diagnostic value of biochemical markers of liver fibrosis (Fibro Test, HCV FibroSure) and necrosis (ActiTest) in patients with chronic hepatitis C. Comp Hepatol. 2004;23:3-8. 54. Lackner C, Struber G, Liegl B, Leibl S, Ofner P, Bankuti C, et al. Comparison and validation of simple noninvasive tests for prediction of fibrosis in chronic hepatitis C. Hepatology. 2005;41:1376-82. 55. Atlantic Coast Hepatitis Treatment Group. Peginterferon alfa-2b and ribavirin for the treatment of chronic hepatitis C in blacks and non-Hispanic whites. N Engl J Med. 2004;350:2265-71. 56. Wejstål R. Sexual transmission of hepatitis C virus. J Hepatol. 1999;31 Suppl 1:92-5. 57. German Acute Hepatitis C Therapy Group. Treatment of acute hepatitis C with interferon alfa2b. N Engl J Med. 2001;345:1452-7.

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58. Smedile A, Ciancio A, Rizzetto. Hepatitis D virus. In: Richman DD, Whitley RJ, Hayden FG, eds. Clinical virology. 2nd ed. Herndon, VA: ASM Press; 2002:1227-40. 59. Lu L, Li C, Hagedorn CH. Phylogenetic analysis of global hepatitis E virus sequences: Genetic diversity, subtypes and zoonosis. Rev Med Virol. September 21, 2005. 60. Anderson DA, Shrestha. Chapter 48. In: Richman DD, Whitley RJ, Hayden FG, eds. Clinical virology. 2nd ed. Herndon, VA: ASM Press; 2002:1061-74. 61. Ponzetto A, Forzani B, Parravicini PP, Hele C, Zanetti A, Rizzetto M. Epidemiology of hepatitis delta virus (HDV) infection. Eur J Epidemiol. 1985;1:257-63. 62. Ciancio A, Ottobrelli A, Marzano A, et al. A long-term follow-up in patients treated with orthotopic liver transplantation (OLT) for hepatitis delta virus (HDV). J Hepatol. 2001;34:28. 63. Rosina F, Pintus C, Meschievitz C, Rizzetto M. A randomized controlled trial of a 12-month course of recombinant human interferon-alpha in chronic delta (type D) hepatitis: a multicenter Italian study. Hepatology. 1991;13:1052-6. 64. Tam AW, Smith MM, Guerra ME, Huang CC, Bradley DW, Fry KE, et al. Hepatitis E virus (HEV): molecular cloning and sequencing of the full-length viral genome. Virology. 1991;185:120-31. 65. Emerson SU, Purcell RH. Running like water—the omnipresence of hepatitis E. N Engl J Med. 2004;351:2367-8. 66. Khuroo MS,Teli MR, Skidmore S, Sofi MA, Khuroo MI. Incidence and severity of viral hepatitis in pregnancy. Am J Med. 1981;70:252-5.

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Chapter 11

Peritonitis JENNIFER A. HANRAHAN, DO ROBERT A. BONOMO, MD

Key Learning Points 1. Spontaneous bacterial peritonitis (SBP) is the most common type of primary peritonitis, and usually occurs in the setting of liver cirrhosis. 2. SBP should be considered in any patient with ascites who experiences a clinical deterioration, and diagnostic paracentesis should be performed as soon as possible. 3. An ascitic fluid neutrophil count greater than 250 is considered indicative of infection even in the absence of positive cultures. 4. SBP and secondary peritonitis can be difficult to distinguish by history and physical exam, and management differs. 5. Initial antimicrobial therapy for SBP should be directed at enteric organisms. 6. Secondary peritonitis can be treated with a short course of antibiotics once adequate source control is obtained, unless there is persistent evidence of infection. 7. Peritonitis in the setting of peritoneal dialysis usually presents with cloudy dialysate fluid, and any change in the appearance of the fluid should be investigated.

P

eritonitis is the condition of acute or chronic inflammation of the abdominal cavity from any cause. It can result from diffuse or localized infection, chemical irritation, or malignancy and can be associated with an intra-abdominal infection such as an abscess. The cause of peritonitis differs depending on whether the infection is acquired in the health care setting or in the community, and by route of infection. Generally, peritonitis 204

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New Developments in the Management of Peritonitis • Prophylaxis for SBP is recommended for all cirrhotics with gastrointestinal

hemorrhage. The recommended antibiotic is norfloxacin 400 mg every 12 hours for at least 7 days. • Prophylaxis for SBP is also recommended for individuals with cirrhosis and a prior history of SBP. • Individuals with cirrhosis and ascites who have not had an episode of SBP are at high risk for developing peritonitis. However, those most likely to benefit from prophylaxis have not been clearly identified, and no consensus exists on whom should be offered prophylaxis in the absence of prior SBP. • Oral moxifloxcin 400 mg orally daily can be prescribed to those individuals with SBP who are not severely ill and can be managed as outpatients, provided that they have not had quinolone prophylaxis. This should be done after paracentesis is performed. • Ertapenem is a newer antibiotic that can be considered for community-acquired intra-abdominal infections.

can be divided into the three main categories of primary, secondary, and tertiary peritonitis. Primary peritonitis is a diffuse bacterial peritonitis that occurs in the absence of disruption of hollow viscera. An apparent source of infection is not evident in primary peritonitis. Examples of primary peritonitis include spontaneous bacterial peritonitis (SBP) in patients with liver disease, spontaneous peritonitis in children, and tuberculous peritonitis (TBP). In contrast, secondary peritonitis results from intra-abdominal infection, usually as a result of rupture of hollow viscera. Secondary peritonitis can be localized with abscess formation, or it can be diffuse. This type of peritonitis can result from many conditions, including a ruptured appendix, perforated gastric ulcer, intestinal ischemia, ruptured diverticula, perinephric abscess, anastomotic leak, and trauma. Tertiary peritonitis is a term used to describe peritonitis that occurs after secondary peritonitis, in the setting of chronic illness or prolonged hospitalization and can involve fungi or highly resistant nosocomial pathogens.

Primary Peritonitis Primary peritonitis is a diffuse infection in the peritoneal cavity that occurs in the absence of another source of infection. Examples of primary peritonitis include primary peritonitis in children, fungal peritonitis, TBP, and SBP. SBP is currently the most common type of primary peritonitis and involves the infection of ascitic fluid in patients with ascites. This condition most commonly occurs with ascites from liver disease but also can occur with ascites caused by many other diseases, including nephrotic syndrome, congestive heart failure (especially chronic constrictive pericarditis), systemic lupus

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erythematosus, rheumatoid arthritis, and Budd-Chiari syndrome. SBP also has been described in patients with chronic active hepatitis, acute viral hepatitis, and lymphedema (1).

Epidemiology Primary peritonitis is rare other than SBP in individuals with underlying liver disease. The incidence of primary peritonitis in children has decreased after the introduction of antibiotics, and TBP peritonitis is an unusual manifestation of tuberculosis. SBP in individuals with ascites is the most common type of primary peritonitis seen today. It is unusual to find SBP in asymptomatic outpatients, however, the prevalence in patients hospitalized with ascites ranges from 10% to 30% (2,3). The 2-year death rate after SBP is high and ranges from 44% to 95% (4-6). Risk factors for development of SBP in individuals with ascites include an elevated serum bilirubin concentration, ascitic fluid protein content of 1 g/dL, and a previous episode of SBP (2,3,7,8). In addition, cirrhotics with gastrointestinal bleeding are at increased risk of peritonitis, whether or not ascites is present (3). Patients who developed SBP in one series were found to have a 69% recurrence rate at 1 year and a 1-year survival probability of only 38% (5). Patients who survive an initial episode of SBP, often go on to die of liver failure and complications of portal hypertension.

Pathogenesis Various mechanisms have been proposed for the pathogenesis of SBP. When SBP was initially described, the infection was presumed to result from transient enteric bacteremia followed by sepsis (6). More recently, it has been demonstrated in an animal model that a combination of intestinal bacterial overgrowth and increased bowel-wall permeability lead to translocation of bacteria to the lymphatic system (9), which can lead to bacteremia. Direct translocation of bacteria from the gut is thought to be less likely given that SBP is usually monomicrobial. If direct translocation from the gut were responsible, polymicrobial infection would be expected to occur, and anaerobes would be expected to play a greater role in SBP. Another likely factor in the development of SBP is delayed clearance of bacteria from the hepatic reticuloendothelial system in individuals with portal hypertension.

Etiology Organisms usually recovered in SBP include normal enteric flora. As noted previously, SBP is generally a monomicrobial infection. Aerobic gramnegative bacilli are responsible for most cases, with Escherichia coli and Klebsiella pneumoniae causing more than 70% of cases (Table 11-1) (4,10).

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Table 11-1 Classification and Microbiology of Peritonitis Classification

Primary Peritonitis Diffuse bacterial peritonitis with no disruption of hollow viscera Examples: SBP TB peritonitis Fungal peritonitis ● ● ●

Secondary Peritonitis Localized (abscess) or diffuse peritonitis from rupture of hollow viscus Examples: Ruptured appendix Ischemic bowel Perforated gastric ulcer ● ● ●

Tertiary Peritonitis Persistent peritonitis not responding to therapy or peritonitis in patients with multiple organ failure Examples: Peritonitis with lowgrade pathogens Fungal peritonitis ●

●

Microbiology ●

●

● ●

SBP: Escherichia coli, E. coli and anaerobes Klebsiella pneumoniae, including: streptococci, enterococci, Bacteroides species anaerobes and Streptococci Staphylococcus aureus rare Clostridium species TB: Mycobacterium tuberculosis Fungal: blastomycosis Coccidioidomycosis, histoplasmosis ●

●

● ●

●

●

●

Staphylococcus epidermidis Candida species Enterococci including VRE Pseudomonas aeruginosa Stenotrophomonas maltophilia Aspergillus

Abbreviations: SBP, spontaneous bacterial peritonitis; TB, tuberculosis; VRE, vancomycin-resistant Enterococcus.

Gram-positive organisms (e.g., enterococci, streptococci [including pneumococcus]) account for an additional 25% of cases of SBP. Anaerobes are rare and account for less than 5% of cases. Additionally, polymicrobial infection is unusual, and secondary peritonitis should be considered when this is found. Staphylococcus aureus is rarely isolated from patients with SBP, accounting for only 2% to 4% of all cases (4), and has been found in patients with erosion of an umbilical hernia. Other sites of infection should be sought when this organism is recovered.

Clinical Manifestations The diagnosis of SBP should be considered in any patient with ascites who exhibits clinical deterioration, and diagnostic paracentesis should be done in such cases. The clinical findings in SBP can be quite subtle. Up to one third of patients with SBP can be asymptomatic. Furthermore, although all patients with SBP have ascites, it is not evident on physical examination. If a small amount of ascites is present, ultrasonography can be helpful in localizing fluid for paracentesis. Approximately 50% to 75% of patients with SBP have fever (2), and approximately half have abdominal pain. Hypotension and hypothermia can occur but are uncommon. Hepatic encephalopathy is often present, and worsening encephalopathy can occur in the absence of other signs.

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Diagnosis A diagnostic paracentesis confirms the diagnosis of SBP. This procedure is safe, even in the presence of thrombocytopenia and prolonged prothrombin time (11). Most patients do not require correction of the coagulopathy before paracentesis (12). The neutrophil count is the single best predictor of infection, and one greater than 250 to 500 cells/mm3 is indicative of infection, even in the absence of positive cultures. It is recommended that antibiotic therapy be started when the ascitic fluid neutrophil count is greater than or equal to 250 cells/mm3 (3). Although a Gram stain is usually negative, it is a simple and useful diagnostic test and can help guide empirical antibiotic administration and identify bowel perforation. Cultures should be obtained by directly inoculating from 10 to 15 mL of ascites fluid into blood culture bottles. Runyon and coworkers (13) found that the diagnostic yield for positive cultures increased from 42% to 91% when blood culture bottles were inoculated at the bedside as opposed to using conventional plating methods. The pH of ascitic fluid is also helpful in making the diagnosis; however, this generally reflects the neutrophil count. The ascitic fluid albumin and total protein concentrations should be obtained, because they help establish both the diagnosis of portal hypertension and the risk of recurrence of SBP. Although peritoneal fluid cytology is rarely diagnostic of SBP, it can be done in a search for tumor cells. The amylase concentration can help establish the diagnosis of pancreatic ascites and bowel perforation. Other optional tests that should be done when TBP is suspected include smears for acid-fast bacilli and mycobacterial cultures. Studies to be performed on ascitic fluid are listed in Table 11-2. Blood culture can be positive in one third to one half of cases of SBP and can be particularly helpful in patients whose ascitic fluid cultures are negative. Urine culture is not usually helpful in the diagnosis of SBP because culture results rarely coincide with ascites fluid culture.

Differentiating Spontaneous Bacterial Peritonitis from Secondary Peritonitis Although most patients who present with infected ascitic fluid are found to have primary peritonitis, approximately 15% have secondary peritonitis (14). Because the management of primary peritonitis differs from that of secondary peritonitis, it is important to distinguish the two. A history and physical examination are insufficient for differentiating primary from secondary peritonitis. Secondary peritonitis can be present when patients do not respond to antibiotic therapy for SBP, polymicrobial Gram stain or culture is present, or if the following ascitic fluid characteristics are present: 1. Total protein concentration is greater than 1 g/dL, 2. Glucose concentration is less than 50 mg/dL, and/or

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Table 11-2 Evaluation of Ascites Fluid Recommended Tests

Optional Tests

Cell count and differential Albumin (serum and ascites fluid) Total protein Gram stain Bacterial culture

Glucose Amylase Lactate dehydrogenase pH Ziehl-Neelsen stain Mycobacterial and fungal culture Cytology Bilirubin (ascites fluid and serum)

3. Ascitic-fluid lactate dehydrogenase concentration is greater than the upper limit of normal (2). Additionally, if the ascitic fluid is deeply bile stained with a bilirubin concentration greater than 6 mg/dL and if the ascitic fluid-to-serum bilirubin ratio is greater than 1, then biliary perforation should be suspected. Patients who meet these criteria should undergo evaluation to rule out perforation of a hollow viscus. Plain radiographs of the abdomen can be obtained to look for free air under the diaphragm. If these are unrevealing, a contrastenhanced computed tomography (CT) scan of the abdomen should be done on patients with suspected secondary peritonitis. Secondary peritonitis also can have other causes than those previously named, which are not as readily distinguishable. Repeat paracentesis is helpful in these situations. Akriviadis and Runyon (14) found that all patients with the disease had a decrease in their peritoneal fluid neutrophil count at 48 hours. Furthermore, all patients who had positive ascitic fluid cultures with organisms susceptible to the initial antibiotic regimen had negative cultures at 48 hours. All patients who were found to have secondary peritonitis had persistently positive ascitic fluid cultures at 48 and 96 hours despite antibiotic therapy, and more than half had multiple organisms. It is recommended that repeat paracentesis be done at least once after 48 hours of therapy in patients being treated for SBP (3). If the neutrophil count fails to decline or if the ascitic fluid culture remains positive, further evaluation is indicated, and antibiotic therapy can be changed.

Treatment Initial treatment of SBP should include the administration of antibiotics with activity against enteric flora. After the infecting organism has been identified by culture and susceptibility testing, treatment should be

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pinpointed to the specific pathogen. Cefotaxime has been the most extensively studied drug for treatment of SBP, and should be considered for empirical treatment (Table 11-3) (3,8). Other cephalosporins have also been found to be effective for treatment of SBP and can be considered along with ampicillin-sulbactam, piperacillin-tazobactam, and quinolones for individuals who have beta-lactam hypersensitivity. Oral antibiotic therapy with moxifloxacin 400 mg orally every 24 hours can be considered for individuals who are not severely ill and who have not had prophylaxis with a quinolone (3). Most patients with SBP have sterile ascitic fluid soon after beginning antibiotic therapy. Often, the ascitic fluid becomes sterile after the initial dose of an antibiotic agent (14). In an evaluation of 90 patients with SBP and culture-negative neutrocytic ascites (CNNA), who were randomly assigned to receiving either 5 or 10 days of intravenous cefotaxime, no difference between the two groups was found in the death rate, bacteriologic cure, or recurrence of infection (15). Although antibiotic therapy is often continued for 10 to 14 days, a shorter course of therapy is acceptable and more cost-effective. Currently, 5 to 7 days of therapy is considered standard, as long as repeat paracentesis at 48 hours demonstrates improvement. If ascitic fluid neutrophil counts remain high or if resistant organisms are found on culture, then a longer course of therapy can be necessary.

Prophylaxis The risk of recurrence of SBP within 1 year is 40% to 70% (3), and the death rate is high. Both primary and secondary prevention strategies have been used with nonabsorbable antibiotics to selectively decontaminate the gut. Norfloxacin at 400 mg/day has been used for prophylaxis; however, although this has been shown to be effective in reducing the occurrence of SBP, it can select for quinolone resistance (16). Trimethoprim-sulfamethoxazole has also been demonstrated to be effective at preventing SBP (17). Studies of both primary and secondary prophylaxis have shown a substantial decrease in the incidence of SBP, but whether death rates are affected is less clear (2,4,17, 18). Oral ciprofloxacin at 500 mg twice daily has been demonstrated to decrease the risk of bacterial infection in individuals with acute upper gastrointestinal bleeding when administered for 7 days (19). Although individuals with cirrhosis and ascites are at high risk for development of SBP, in those with no previous episodes of SBP, those most likely to benefit from prophylaxis have not been clearly identified, and no consensus exists on whom should be offered prophylaxis (18). The current recommendation is that individuals with upper gastrointestinal bleeding receive antibiotic prophylaxis, independent of presence of ascites (3), and that individuals with a previous episode of SBP receive prophylaxis with norfloxacin or trimethoprim-sulfamethoxazole (2,3).

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Culture-Negative Neutrocytic Ascites and Bacterascites In 1984, Runyon and Hoefs (20) originally described a variant of SBP, that is CNNA. This entity was described as existing when a neutrophil count of more than 500 cells/mm3 is present in the absence of positive ascitic fluid cultures. Negative ascitic fluid cultures were found in up to 35% of suspected cases of SBP that were otherwise clinically indistinguishable from diagnosed SBP. The diagnosis of CNNA should be made only when patients have not received antibiotics in the recent past and when no alternate explanation exists for an increased neutrophil count. The clinical presentation, laboratory findings, death rate, and response to treatment are similar in patients with SBP and CNNA. Despite the negative cultures, CNNA is thought to be caused by bacterial infection, and can be a precursor to SBP. Repeat paracentesis usually shows improvement after initiation of antibiotic therapy. It is possible that the number of organisms present in CNNA is below the threshold of detection for culture. Although the original case series defined CNNA in patients with a neutrophil count of more than 500 cells/mm3, a neutrophil count of more than 250 cells/mm3 is used as a cutoff (4,21). Patients occasionally have positive ascites fluid culture, but a neutrophil count less than 250 cells/mm3. This clinical situation is called bacterascites, and can be caused by colonization of ascitic fluid either because of extraperitoneal infection or as precursor to SBP, or perforation of the intestine with the paracentesis needle. When perforation of the intestine during paracentesis occurs, the culture will generally be polymicrobial. Although CNNA should be treated with antibiotics, bacterial agglutination (BA) may not require treatment (4). In the setting of bacterascites, symptoms of peritonitis correlate with progression to SBP, whereas asymptomatic patients often do not experience this progression (10). If culture of ascitic fluid is positive, then repeat paracentesis is recommended at the time the culture result is obtained to determine whether evidence of peritonitis exists, and whether antibiotic therapy is indicated (3).

Secondary Peritonitis Pathogenesis Secondary peritonitis is a distinct clinical entity that results from the rupture or spillage of an abdominal viscus into the normally sterile abdominal cavity. Predisposing factors include abdominal trauma, perforation, or intraperitoneal spread from an infected abdominal organ or abscess. Perforation of a gastric or duodenal ulcer, cholecystitis, rupture of diverticula, rupture of the appendix, and penetrating abdominal wounds are all common causes. Subsequent infection can either be localized, as with an abscess, or consist of generalized peritonitis. Chemical peritonitis also can occur, especially after rupture of the stomach.

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Etiology The number and types of bacteria increases progressively as one proceeds distally in the gastrointestinal tract. Therefore, the bacteria involved in secondary peritonitis depend on the level at which the rupture takes place. Proximally, there are sparse aerobes and oral anaerobes, whereas the colon contains the largest concentration of bacteria. The stomach in the fasting state contains relatively few microorganisms; however, many organisms are found after colonic perforation. If an organ ruptures below the ligament of Treitz, anaerobes constitute 99% of the organisms isolated. Bacteroides fragilis is the predominant anaerobe isolated from culture, and E. coli is the predominant facultative aerobe in gastrointestinal perforation (1). B. fragilis is present in approximately 75% of postoperative infections but accounts for less than 5% of fecal flora (22). Meleney and coworkers (23) recognized early on that microbial synergy plays an important role in establishing infection within the peritoneum. It was noted that the clinical course of illness was much more severe if two or more organisms were found. Because synergy plays an important role in infection, it is usually not necessary to treat all the organisms that are isolated from a culture.

Clinical Manifestations The signs and symptoms of secondary peritonitis are generally more pronounced than those of SBP. Most patients present with pain, either over a localized area (as can be seen with appendicitis) or as generally within the abdomen. Usually, the area of pain tends to extend as the inflammation progresses. Examination reveals tenderness over the involved area. Vomiting can be present at an early stage or can develop later if ileus or bowel obstruction develops. Fever and diarrhea also can be present, and abdominal rigidity, guarding, or rebound tenderness can be present. Immunocompromised or elderly patients can have more subtle symptoms. Peritonitis can be more difficult to diagnose in patients who are paralyzed and in those undergoing mechanical ventilation.

Diagnosis Patients who present with abdominal pain should have the usual laboratory tests to aid in establishing a diagnosis, including a complete blood count, electrolyte measurements, and plain radiography of the abdomen. Blood cultures are not useful in patients with community-acquired intraabdominal infection, and are not recommended (24). Although laboratory tests can be helpful in raising the index of suspicion for peritonitis, the definitive diagnosis can be made only surgically. Therefore, any patient suspected of having secondary peritonitis should undergo evaluation by a surgeon.

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Patients should have aerobic and anaerobic cultures sent from intraabdominal infection at the time of surgery. Gram stain is not useful in patients with community-acquired infection, but can be useful in those with health care-associated infections to help guide antibiotic therapy (24).

Treatment Secondary peritonitis is usually a surgical disease. The most important aspect of its treatment is the evacuation of pus and fecal contamination from the abdominal cavity. The principles of therapy involve supportive measures, followed by operative intervention. The surgical approach involves controlling the source of infection, evacuating contaminated material, decompressing the abdomen, and preventing or treating persistent infection. Antimicrobial therapy is recommended in established infections, but is not recommended to exceed 24 hours in the following situations (24,25): 1. There is bowel perforation, either traumatic or iatrogenic when the operation is done within 12 hours. 2. There is acute perforation of the stomach and duodenum in the absence of antacid therapy. 3. There is acute appendicitis and cholecystitis without perforation, abscess, or peritonitis. Patients with the previously listed clinical situations should be given prophylactic antibiotics only, not extended courses of therapy. If infection is suspected with cholecystitis, antibiotic therapy aimed at Enterobacteriaceae should be administered, and surgical consultation should be obtained (24). In individuals with established intra-abdominal infection for whom adequate source control is achieved at the time of operation, antibiotics can be administered until the resolution of signs and symptoms of infection. The duration of therapy can be limited to 5 to 7 days unless there is evidence of persistent infection (24,25). If persistent signs of infection occur, diagnostic investigation should take place. Antibiotic therapy should be aimed at potential organisms. For patients with community-acquired infections that are mild-to-moderate in severity, options include ampicillin/sulbactam, ticarcillin/clavulanic acid, ertapenem, cefazolin or cefuroxime plus metronidazole, or a quinolones plus metronidazole (24). For patients who are severely ill or are immunocompromised, broad-spectrum antibiotics are recommended including the following: piperacillin/tazobactam, imipenem/cilastatin, meropenem, a third or fourth-generation cephalosporin plus metronidazole, or aztreonam plus metronidazole (24). Aminoglycosides are not recommended for communityacquired infections because less toxic agents are now available. Postoperative infections are more likely to involve resistant pathogens including resistant gram-negative and gram-positive organisms, and Candida species. Antibiotic therapy should be tailored according to local antibiograms (Table 11-3).

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Table 11-3 Empiric Antibiotics for Peritonitis Dosage for Normal Renal Function, Can Require Adjustment for Renal and Hepatic Insufficiency

Primary Peritonitis

Cefotaxime Ampicillin/sulbactam Piperacillin/tazobactam For beta-lactam allergy: Monifloxicin

2.0 g IV q 8 h 3.0 g IV q 6 h 3.375 g IV q 6 h 400 mg PO or IV q 24 h

Secondary Peritonitis: Community-Acquired

Ampicillin/sulbactam Ticarcillin/clavulanic acid Ertapenem For beta-lactam allergy: ciprofloxacin and metronidazole

3.0 g IV q 6 h (ampicillin/sulbactam) 3 g ticarcillin and 100 mg clavulanic acid IV q 4-6 h 1 gram IV q 24 h 400 mg IV q 12 h (ciprofloxacin) and 500 mg IV or PO q 8 (metronidazole)

Secondary Peritonitis: Health Care-Associated

Piperacillin/tazobactam Meropenem Imipenem/cilastatin Cefepime plus metronidazole

3.375 g IV q 6 h 1 g IV q 8 h 500 mg IV q 6 h 2.0 g IV q 8 h plus 500 mg IV or PO q 8 h

Tertiary Peritonitis

Meropenem Imipenem/cilastatin Cefepime and vancomycin Fluconazole Amphotericin

1 g IV q 8 h 500 mg IV q 6 h 2.0 g IV q 8 h and 1 g IV q 12 h 200-400 mg IV q 24 h 0.5-1.0 mg/kg IV q 24 h

Abbreviations: h, hour; IV, intravenous; PO, orally; q, every.

Even though fungi can be recovered from patients with acute gastrointestinal tract perforation, therapy is not necessary unless the patient has recently received immunosuppressive therapy for malignancy or inflammatory disease, has undergone transplantation, or has postoperative or recurrent intra-abdominal infection (24). Likewise, enterococci do not need to be treated in community-acquired infections, but should be treated in health care-associated infections (24).

Tertiary Peritonitis Tertiary peritonitis is a syndrome that occurs in patients who have inadequate host defenses and who often have multiple-organ failure. The term tertiary peritonitis was originally used in the 1980s to describe patients who died of sepsis and multiple-organ failure caused by a delay in management

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or by iatrogenic factors (26). These patients were sometimes found to have peritoneal fluid that was free of microorganisms or that contained low-grade pathogens at the time of surgery. The term tertiary peritonitis has been used largely to describe a situation that presents as sepsis late in the postoperative phase, but also can describe patients with complicated peritonitis associated with continuous ambulatory peritoneal dialysis (CAPD). Persistent peritonitis with systemic inflammation ensues after what usually would be an adequate course of antimicrobial therapy.

Pathogenesis Microorganisms can gain access to the abdominal cavity by translocation of intestinal flora, which can result from malnutrition, alteration of the intestinal wall from CAPD, intestinal ischemia, or growth of resistant bowel flora through antibiotic selection pressure. Additionally, selection among the initial polymicrobial peritoneal inoculum can occur through antibiotic therapy, direct contamination during surgery, or direct access along peritoneal catheter devices. Patients develop a sepsis syndrome with hypotension, fever, low systemic vascular resistance, high cardiac output, and multiorgan failure. The death rate for patients with nonlocalized postoperative intra-abdominal sepsis approaches 100% when medical therapy alone is given (27). This death rate can be reduced somewhat by repeated laparotomy. The microorganisms involved in tertiary peritonitis are often highly resistant nosocomial pathogens, and include resistant gram-negative and gram-positive organisms and Candida species. As previously discussed, peritoneal fluid culture also can be negative.

Diagnosis Patients with tertiary peritonitis will usually have signs and symptoms of sepsis, and many will have obvious clinical signs of peritonitis. In contrast to secondary peritonitis, blood cultures can be positive in more than 30% of patients with tertiary peritonitis (28). An abdominal CT scan is useful to determine whether an intra-abdominal abscess is present.

Treatment Tertiary peritonitis is a health care-associated infection, and involves highly resistant organisms. Empiric therapy should be based on local resistance data, and can require several antibiotics. Broad-spectrum antibiotic therapy should be started and should be tailored according to culture results from blood and infected peritoneal fluid. Patients can also require surgical intervention or CT-guided drainage if a localized intra-abdominal abscess is present.

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Peritonitis in Patients Undergoing Continuous Ambulatory Peritoneal Dialysis Epidemiology Peritonitis in patients who are undergoing CAPD is a distinct clinical entity and is the main complication of CAPD. The incidence has decreased from 1.0 to 1.3 episodes per patient per year (14,15,24) to 1 episode per 20 to 30 patient-months (29). The incidence is lower in centers with more experience and higher in those with less. Peritonitis is a major complication in CAPD and is the main reason for loss of the dialysis catheter and for changing to hemodialysis. Unlike with SBP, the recurrence of which is common, CAPD is estimated to recur in only approximately 25% of cases (30).

Pathogenesis The main factor in the development of CAPD peritonitis is usually a violation of sterile technique during the four or five daily fluid exchanges that occur in CAPD. The pathogenesis of this infection is similar to that of infections that result from intravascular devices, when organisms migrate along the catheter groove, and the catheter serves as an entry point for microorganisms into the normally sterile peritoneal cavity. Other host factors also can play a role. Recurrent CAPD peritonitis is thought to be associated with some type of impairment in host bactericidal activity (31).

Etiology Given that they are consequences of a laxity in sterile technique, most infections are caused by skin flora. Gram-positive organisms account for up to 70% of CAPD peritonitis, gram-negative organisms for 15% to 25%, and fungi for 2% to 3% (29). Anaerobes rarely cause CAPD peritonitis, and the infection is generally monomicrobial. Similar to SBP, when polymicrobial infection is found, or when anaerobes are present, secondary peritonitis from a gastrointestinal perforation should be sought.

Clinical Manifestations Although signs and symptoms of CAPD peritonitis are variable, the onset of the disease is usually noted by the presence of cloudy dialysate fluid. Additionally, most patients have abdominal pain and tenderness on examination. Other signs and symptoms of CAPD peritonitis are much less frequent. Only approximately 35% of patients have fever, and only approximately one quarter of patients have nausea and vomiting (30). CAPD patients are taught that they should be able to read newsprint through the dialysate fluid as a means of ensuring the absence of infection. If turbidity

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is present, it should always be taken seriously; the presence of infection should be assumed until proven otherwise.

Diagnosis The diagnosis of CAPD peritonitis is established by evaluating the dialysate fluid, as discussed in the following section on Laboratory Findings. Laboratory evaluation of the dialysate fluid should be undertaken in any patient who notes a change in the appearance of this fluid. Peritonitis is diagnosed when two or more of the following are present: 1. There is cloudy dialysate fluid with more than 100 leukocytes/ mm3 2. Abdominal pain is present. 3. There is positive culture from dialysate fluid (29). Cloudy dialysate fluid can also result from conditions other than infection, such as malignancy or allergic reaction.

Laboratory Findings The initial evaluation of turbid dialysate fluid includes a leukocyte count with differential. Generally, a leukocyte count of 100 cells/cm3 or more, with more than 50% polymorphonuclear leukocytes, is considered indicative of infection. It is important to obtain a differential count along with the leukocyte count because conditions such as eosinophilic peritonitis, which occurs as an allergic reaction to the dialysis catheter, also can cause cloudiness of the dialysate fluid. A Gram stain is useful in evaluating peritonitis and is positive in 20% to 30% of cases. It is recommended that 10 to 20 mL of effluent be centrifuged for the Gram stain. Although the Gram stain is positive in less than 30% of cases, the procedure is simple and can give an early clue to the presence of fungal peritonitis. Culture of infected peritoneal dialysate fluid is positive in more than 90% of cases (32). Various approaches have been tried for culture. As with SBP, 10 to 15 mL of fluid can be injected directly into blood culture bottles. Alternately, many dialysis centers send the entire bag of effluent to the microbiology laboratory, where the number of organisms can be concentrated either by filtration or by centrifugation. In contrast to other types of peritonitis, blood cultures in CAPD peritonitis are often negative and are not routinely helpful in making a diagnosis. In patients who are hospitalized with fever, blood cultures are indicated to rule out other sources of infection.

Treatment Treatment of CAPD peritonitis can be based on Gram stain results when the Gram stain is positive. Gram-positive organisms should be treated with a

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first-generation cephalosporin, and gram-negative organisms should be treated with a third-generation cephalosporin (29,33). Intraperitoneal therapy is preferred for CAPD peritonitis, although oral therapy has also been successful. For patients whose Gram stains are negative, empiric therapy should include a first- and third-generation cephalosporin or vancomycin and a third-generation cephalosporin (29,33). In patients known to be colonized with methicillin-resistant Staphylococcus aureus (MRSA), it is reasonable to treat empirically with vancomycin until cultures are available. Individuals who have recurrent peritonitis within 4 weeks from the same organism, or who have fungal peritonitis require catheter removal. Catheter salvage can be attempted in those with gram-positive organisms, but should not be considered in those with Pseudomonas or fungi. If recurrent S. aureus peritonitis occurs, an intraabdominal abscess or other occult infection should be looked for. The clinical response of CAPD peritonitis to such therapy is generally rapid, and symptoms alleviate within 48 hours after treatment is begun. If the culture of the dialysate fluid is negative but the patient is responding to empirical therapy, empirical therapy can be continued for the duration of therapy. Most cases of CAPD peritonitis can be treated with 7 to 10 days of intraperitoneal antimicrobial therapy; however, S. aureus and gramnegative organisms should be treated for 10 to 14 days. S. aureus often causes severe peritonitis, and is often present from catheter-related infection. Successful eradication of S. aureus often requires catheter removal (33). Uncomplicated CAPD peritonitis can be treated on an outpatient basis. Hospitalization is indicated when patients exhibit signs of sepsis, when there is suspicion of abscess formation or perforation, or when there is concern about resistant organisms. Tunnel- or exit-site infections usually require the removal of the dialysis catheter and temporary hemodialysis. Certain microorganisms, including P. aeruginosa and fungi, are often associated with tunnel-site infections. Infection with these organisms tends to have a higher illness rate and usually does not resolve without the removal of the dialysis catheter. Aminoglycosides can be given to those individuals whose residual urine output is less than 100 cc/day. Treatment should be given for at least 2 weeks, or until the catheter exit site looks completely normal (29,33). There have been anecdotal reports of successful treatment of fungal peritonitis with maintenance of the CAPD catheter; however, fungal peritonitis is associated with a high illness rate, and it is recommended that the catheter be removed. Fungal peritonitis also carries a high risk of adhesion formation, which can preclude future peritoneal dialysis. In addition to being relatively inefficacious in peritoneal dialysate fluid, amphotericin B is poorly tolerated intraperitoneally and causes severe inflammation in the patient. After catheter removal, patients with fungal peritonitis require a period of systemic antimicrobial therapy.

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Tuberculous Peritonitis The differential diagnosis of peritonitis should include consideration of TBP. This entity is not commonly seen in the United States, but is characterized by an insidious onset, often over a period of more than 1 month. Progressive ascites, fever, and abdominal pain are present. Night sweats, vomiting, chills, and weight loss also can occur. Active pulmonary tuberculosis is associated with TBP in approximately 20% of cases (34). A “doughy” abdomen caused by tuberculous adhesion can sometimes be found on physical examination, and an abdominal mass can be palpable in up to 50% of cases. TBP can present either as a chronic condition (plastic TBP)—in which there tends to be more abdominal pain, little ascites, and adhesions—or as a more acute condition (serous TBP) with ascites of rapid onset and fever (35). Tuberculous peritonitis usually results from the rupture of a caseous necrotic abdominal lymph node with contents that spill into peritoneal fluid. Occasionally, a characteristic calcified abdominal node can be seen on plain radiographs of the abdomen. This entity should be suspected when a predominantly lymphocytic exudate is found on evaluation of ascitic fluid and in conjunction with an increased total protein concentration. The organism is rarely seen on a Ziehl-Neelsen stain but can be cultured in up to 69% of cases. The yield of culture is improved if a large volume of fluid is concentrated for culture. Culture of peritoneal fluid can give positive results in more than 80% of cases if 1 L of fluid is cultured (34). A polymerase chain reaction test probably aids in the diagnosis of TBP but is not currently approved as a diagnostic tool in the disease in the United States. Ascitic adenosine deaminase levels can be useful in the diagnosis of TBP, but false-negative tests can occur (36). Peritoneoscopy and peritoneal biopsy often are used to examine the abdomen for evidence of characteristic pathology. Caseating granulomas, tissue that contains acid-fast bacilli, or granulomas (including epithelioid giant cells) must be found to make a definitive diagnosis histologically. When tubercles are seen studding the peritoneum, the yield on biopsy is approximately 75%. (Other chronic granulomatous diseases can produce an identical studding.) Because fluid cultures are often positive, it is recommended that they be done even when no characteristic features are seen on peritoneoscopy. Death from TBP has declined substantially since the advent of drugs to treat tuberculosis. The treatment of this disease consists of standard antimycobacterial drugs in regimens that resemble those used for treating pulmonary tuberculosis.

Summary Peritonitis is a relatively common condition that results from various underlying problems. The most common type of peritonitis seen in adults is SPB

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in the presence of liver disease with ascites. SBP can present with various signs and symptoms, and thus any clinical deterioration in a patient with liver disease and ascites warrants diagnostic paracentesis. These individuals can also develop secondary peritonitis, and clues are evident from examination of ascitic fluid. Individuals with very low ascitic glucose, high total protein, or polymicrobial Gram stain should be promptly investigated for secondary peritonitis. If secondary peritonitis is suspected, surgical consultation should be considered. Secondary peritonitis occurs most commonly because of a perforated viscus and requires surgical intervention. With adequate control of the source of peritonitis at the time of surgery, antibiotic therapy can be given for a short period of time, unless there is persistent evidence of infection. In both primary and secondary peritonitis, antimicrobial therapy should be aimed at enteric organisms. Both enterococci and candida species usually do not require therapy in community-acquired infections. Tertiary peritonitis represents a less common situation in which individuals with inadequate host defenses go on to develop ongoing sepsis and peritonitis after what would normally be adequate therapy for peritonitis. These cases often involve resistant pathogens including fungi. CAPD peritonitis is an entity that often presents initially with few systemic symptoms, but a change in the appearance of the dialysate is generally noted. This should be promptly investigated, and antibiotic therapy can be given by means of peritoneal dialysis. Finally, TBP is an uncommon disease in the United States, but should be considered in individuals with chronic abdominal pain, ascites, and fever. The diagnosis can be difficult to establish, and it is important to remain vigilant for this entity. Peritonitis is a disease that can be often be managed with appropriate antimicrobial therapy. However, diagnostic tests are necessary to establish the cause of peritonitis as treatment varies based on the underlying cause for peritonitis.

REFERENCES 1. Johnson CC, Baldessarre J, Levison ME. Peritonitis: update on pathophysiology, clinical manifestations, and management. Clin Infect Dis. 1997;24:1035-45; quiz 1046-7. 2. Sheer TA, Runyon BA. Spontaneous bacterial peritonitis. Dig Dis. 2005;23:39-46. 3. Rimola A, García-Tsao G, Navasa M, Piddock LJ, Planas R, Bernard B, et al. Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club. J Hepatol. 2000;32:142-53. 4. Gilbert JA, Kamath PS. Spontaneous bacterial peritonitis: an update. Mayo Clin Proc. 1995;70:365-70. 5. Titó L, Rimola A, Ginès P, Llach J,Arroyo V, Rodés J. Recurrence of spontaneous bacterial peritonitis in cirrhosis: frequency and predictive factors. Hepatology. 1988;8:27-31. 6. Conn HO, Fessel JM. Spontaneous bacterial peritonitis in cirrhosis: variations on a theme. Medicine (Baltimore). 1971;50:161-97. 7. Andreu M, Sola R, Sitges-Serra A,Alia C, Gallen M,Vila MC, et al. Risk factors for spontaneous bacterial peritonitis in cirrhotic patients with ascites. Gastroenterology. 1993; 104:1133-8.

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8. Guarner C, Solà R, Soriano G, Andreu M, Novella MT, Vila MC, et al. Risk of a first communityacquired spontaneous bacterial peritonitis in cirrhotics with low ascitic fluid protein levels. Gastroenterology. 1999;117:414-9. 9. Guarner C, Runyon BA,Young S, Heck M, Sheikh MY. Intestinal bacterial overgrowth and bacterial translocation in cirrhotic rats with ascites. J Hepatol. 1997;26:1372-8. 10. Bhuva M, Ganger D, Jensen D. Spontaneous bacterial peritonitis: an update on evaluation, management, and prevention. Am J Med. 1994;97:169-75. 11. Grabau CM, Crago SF, Hoff LK, Simon JA, Melton CA, Ott BJ, et al. Performance standards for therapeutic abdominal paracentesis. Hepatology. 2004;40:484-8. 12. Runyon BA. Care of patients with ascites. N Engl J Med. 1994;330:337-42. 13. Runyon BA, Umland ET, Merlin T. Inoculation of blood culture bottles with ascitic fluid. Improved detection of spontaneous bacterial peritonitis. Arch Intern Med. 1987;147: 73-5. 14. Akriviadis EA, Runyon BA. Utility of an algorithm in differentiating spontaneous from secondary bacterial peritonitis. Gastroenterology. 1990;98:127-33. 15. Runyon BA, McHutchison JG,Antillon MR,Akriviadis EA, Montano AA. Short-course versus longcourse antibiotic treatment of spontaneous bacterial peritonitis. A randomized controlled study of 100 patients. Gastroenterology. 1991;100:1737-42. 16. Bauer TM, Follo A, Navasa M,Vila J, Planas R, Clemente G, et al. Daily norfloxacin is more effective than weekly rufloxacin in prevention of spontaneous bacterial peritonitis recurrence. Dig Dis Sci. 2002;47:1356-61. 17. Singh N, Gayowski T,Yu VL,Wagener MM. Trimethoprim-sulfamethoxazole for the prevention of spontaneous bacterial peritonitis in cirrhosis: a randomized trial. Ann Intern Med. 1995;122:595-8. 18. Frazee LA, Marinos AE, Rybarczyk AM, Fulton SA. Long-term prophylaxis of spontaneous bacterial peritonitis in patients with cirrhosis. Ann Pharmacother. 2005;39:908-12. 19. Hsieh WJ, Lin HC, Hwang SJ, Hou MC, Lee FY, Chang FY, et al. The effect of ciprofloxacin in the prevention of bacterial infection in patients with cirrhosis after upper gastrointestinal bleeding. Am J Gastroenterol. 1998;93:962-6. 20. Runyon BA, Hoefs JC. Culture-negative neutrocytic ascites: a variant of spontaneous bacterial peritonitis. Hepatology. 1984;4:1209-11. 21. Such J, Runyon BA. Spontaneous bacterial peritonitis. Clin Infect Dis. 1998;27:669-74; quiz 675-6. 22. Wilson SE, Hopkins JA. Clinical correlates of anaerobic bacteriology in peritonitis. Clin Infect Dis. 1995;20 Suppl 2:S251-6. 23. Meleney FL, Harvey HD, Zaytseff-Jern H. Peritonitis: The correlation of the bacteriology of the peritoneal exudates and the clinical course of the disease in one hundred six cases of peritonitis. Arch Surg. 1931;22:1-23. 24. Infectious Diseases Society of America. Guidelines for the selection of anti-infective agents for complicated intra-abdominal infections. Clin Infect Dis. 2003;37:997-1005. 25. Mazuski JE, Sawyer RG, Nathens AB, et al. Therapeutic Agents Committee of the Surgical Infections Society. The surgical infection society guidelines on antimicrobial therapy for intra-abdominal infections: An executive summary. Surg Infect (Larchmt). 2002 Fall;3(3): 161-73. 26. Wittmann DH, Schein M, Condon RE. Management of secondary peritonitis. Ann Surg. 1996;224: 10-8. 27. Munson JL. Management of intra-abdominal sepsis. Surg Clin North Am. 1991;71:1175-85. 28. Malangoni MA. Evaluation and management of tertiary peritonitis. Am Surg. 2000;66: 157-61. 29. Teitelbaum I, Burkart J. Peritoneal dialysis. Am J Kidney Dis. 2003;42:1082-96. 30. Saklayen MG. CAPD peritonitis. Incidence, pathogens, diagnosis, and management. Med Clin North Am. 1990;74:997-1010. 31. Holmes CJ. Peritoneal host defense mechanisms in peritoneal dialysis. Kidney Int. 1994;46(suppl 48):S58-70. 32. Diagnosis and management of peritonitis in continuous ambulatory peritoneal dialysis. Report of a working party of the British Society for Antimicrobial Chemotherapy. Lancet. 1987;1: 845-9. 33. ISPD Ad Hoc Advisory Committee. Peritoneal dialysis-related infections recommendations: 2005 update. Perit Dial Int. 2005;25:107-31. 34. Moreyra E, Rollhauser CA,Tenner SM. Tuberculous peritonitis: clinical manifestations, diagnosis, and treatment. Res Staff Phys. 1994;40:29-32.

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35. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 3-1998. A 31-year-old woman with a pleural effusion, ascites, and persistent fever spikes. N Engl J Med. 1998;338:248-54. 36. Fernandez-Rodriguez CM, Perez-Arguelles BS, Ledo L, Garcia-Vila LM, Pereira S, RodriguezMartinez D. Ascites adenosine deaminase activity is decreased in tuberculous ascites with low protein content. Am J Gastroenterol. 1991;86:1500-3.

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Chapter 12

Intra-Abdominal Abscess FARID F. MUAKKASSA, MD WILLIAM C. PAPOURAS, MD DANIEL P. GUYTON, MD

Key Learning Points 1. Control of infection in intra-abdominal abscesses can be accomplished with either percutaneous drainage or with surgical debridement of devitalized and necrotic tissue. 2. Both monotherapy and combination therapy can be effective in treatment of intra-abdominal abscesses with source control. 3. Empiric antimicrobial therapy should include coverage for aerobic gram positive, aerobic gram negative, and anaerobic organisms. 4. Therapy in general can be discontinued after 5-7 days or after the resolution of clinical signs of sepsis. If no improvement in one week then source is not controlled and further radiologic evaluation or surgical re-exploration may be warranted. 5. Antifungal prophylaxis may be considered in cases of gastrointestinal perforations, anastomotic leaks or severe acute necrotizing pancreatitis with treatment duration of 2-3 weeks for confirmed fungal sepsis.

I

ntra-abdominal abscesses are walled-off collections of pus surrounded by inflammatory adhesions that occur either within or outside the abdominal viscera. In abscesses that occur outside the abdominal viscera, the abscess wall can be surrounded by adhesions, loops of small or large bowel and their mesenteries, or the omentum; sometimes they are retroperitoneal. The formation of a well-defined intra-abdominal abscess may take several days to a week, depending on the cause of the responsible insult. Formation of abscesses in the peritoneal cavity usually follows 1) the resolution of a diffuse peritonitis, of which a remaining small, infected focus becomes walled off by 223

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New Developments • The epidemiology of healthcare associated intra-abdominal abscess is evolving to

include more antimicrobial resistant pathogens. • Intra-abdominal abscesses (especially pyogenic liver abscess) remain important

causes of unexplained fever particularly in the elderly. • Antimicrobial coverage for Enterococcus spp. Is controversial but is more

important in patients with healthcare acquired infection, those with septic shock, those who have received prior cephalosporins and in those with prosthetic heart valves.

the host-defense system; 2) a perforation in a viscus; or 3) a postsurgical anastomotic leak. More than 80% of intra-abdominal abscesses occur after an abdominal operation. Postoperative intra-abdominal abscesses in the upper gastrointestinal tract are largely caused by anastomotic leaks, whereas those in the lower tract are caused by the bacterial load in the colon. In contrast, most visceral abscesses result from hematogenous or lymphatic spread of organisms. Retroperitoneal abscesses can result from perforations of retroperitoneal organs, from the retroperitoneal portion of an organ, or from lymphatic or hematogenous seeding by infectious organisms. The approach to the diagnosis and treatment of intra-abdominal abscesses may vary with the cause of the etiologic disease process and with the involved organs. Although this chapter takes an organ-focused approach to the diagnosis and management of intra-abdominal abscesses, a broader initial perspective sometimes is needed before focusing on a specific organ.

Liver Abscesses Liver abscesses can be divided into 2 major categories—pyogenic and amebic abscesses—and share many clinical manifestations. Although liver abscesses are uncommon, their early diagnosis and management are crucial because of their high rate of death. The incidence of hepatic abscesses is rising, possibly as a result of increased instrumentation of the biliary tree, transplantation and immunosuppression, and improved diagnosis The incidence of pyogenic liver abscess ranges between 8 and 22 cases per 100,000 hospital admissions (1). In the United States, approximately 80% of liver abscesses are pyogenic, 10% are amebic, 10% are caused by superinfections, and less than 10% are caused by fungal and other organisms (2). Liver abscesses are solitary in 50% to 60% of cases and multiple in the remainder. Pyogenic abscesses tend to be multifocal, especially when they originate from sepsis or pyelophlebitis, whereas amebic abscesses are usually solitary. Abscesses are more common in the right lobe of the liver (60%) than in the left lobe (10%-15%) and are bilobar in 20% of cases. Their high prevalence in the right

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lobe may be caused by the laminar drainage of the superior mesenteric vein into this lobe of the liver. Pyogenic liver abscesses affect both sexes and all age groups. Amebic abscesses of the liver occur in 10% of cases of amebic colitis and in a male-to-female ratio that ranges from 9:1 to 10:1.

Etiology The cause of liver abscesses varies worldwide and is changing in some countries as a result of better health care and increased recognition through more advanced diagnostic techniques. Although pyogenic liver abscesses are the type preponderantly seen in most of the United States, amebic liver abscesses are endemic in many areas of the world. Other, less common abscesses involve fungi, infected echinococcal cysts, and other organisms. Bacteria may spread to the liver through the following routes (3): ●

●

●

●

●

● ●

Biliary tree: from cholecystitis, choledocholithiasis, cholangitis, obstructing biliary or pancreatic malignancies, occluded stents, or Ascaris lumbricoides migrating into the biliary tree Portal vein: from appendicitis, pancreatitis, omphalitis, diverticulitis, inflammatory bowel diseases, or pelvic inflammatory diseases Hepatic artery: from hematogenous spread from other foci in the body Adjacent organs: from direct extension from organs such as the gallbladder, kidney, or subhepatic or subdiaphragmatic infections Direct trauma: from penetrating trauma or seeding of bacteria in blunt hepatic hematomas Necrosis of hepatic neoplasms: including embolizations Cryptogenic infection: infection without an identifiable source

The bacteriology of liver abscesses shows that most cases (79%) are polymicrobial, and enteric gram-negative bacilli (usually E. coli and Klebsiella pneumoniae) are the most common pathogen. Other less common gramnegatives are Pseudomonas, Proteus, Enterobacter, Citrobacter, and Serratia. Common gram-positives are Streptococcus (anginosus group also called Streptococcus milleri), Enterococcus species and other viridans streptococci. Less common gram-positives are Staphylococcus aureus and β-hemolytic streptococci. (4). With recent progress in anaerobic culture techniques, the frequency of anaerobe involvement in hepatic abscess has been found to be approximately 50% (5). The involved anaerobes include species of Bacteroides (most common), Fusobacterium, Actinomyces, Peptostreptococcus, Clostridium, Lactobacilli, and Prevotella (4). Fungal liver abscesses, especially those caused by Candida albicans, are usually many; stem from systemic fungemia; and are prevalent in patients with cancer and immune-deficiency syndromes (6). Rare causes of hepatic abscess are Yersinia enterocolitica and tuberculosis.

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Clinical Manifestations Symptoms of pyogenic liver abscesses are variable and, in some cases, entirely absent. Clinical findings include fever, chills, malaise, abdominal pain mostly localized to the right upper quadrant, nausea, anorexia, and weight loss usually of less than 2-weeks’ duration but in some cases lasting several months. Because of the nonspecific symptoms of pyogenic liver abscesses, a significant number of patients with prolonged illness caused by such abscesses may have had a previous diagnosis of fever of unknown origin. Physical findings include right-upper-quadrant tenderness with hepatomegaly in 50% to 70% of patients, pleural dullness on percussion, and jaundice (7). Abscesses located high in the right upper lobe may cause respiratory symptoms, including cough, pleuritic pain that may radiate to the right shoulder, and a pleuritic rub. Patients with amebic abscesses have a presentation similar to that of those with pyogenic abscesses but additionally may have a history of diarrhea and radiographic chest findings and, in some series, have lacked the spiking temperature of the latter group. Rarely, patients with amebic abscesses may present with left-upper-quadrant pain if the abscess involves the left lobe of the liver and extends into the pericardium.

Diagnosis Radiologic evaluation is the key to diagnosing liver abscesses in more than 95% of cases. Ultrasonography is the most helpful screening test for liver abscess because of its high sensitivity (85%-95%), better biliary tree imaging than with computed tomography (CT), and therapeutic applicability to the biopsy or drainage of abscesses. Ultrasonography has its limitations in heterogeneous livers, lesions high in the chest cavity, and obese patients. CT is the most sensitive of all imaging modalities for liver abscess (95%-100%) and can be used for therapeutic intervention. It also can provide information about other abdominal lesions that may have caused a liver abscess. In some cases, CT reveals an enhancing rim around an abscess. Because the Kupffer cells within the abscess and the Kupffer cells that surround the abscess differ in their ability to engulf the technetium-99m–labeled colloid, this scanning technique widely and effectively diagnoses and locates liver abscesses. However, limitations of the technique include the inability to detect lesions smaller than 2 cm, differentiate solid from cystic lesions, and allow planning for therapeutic interventions. Chest and abdominal radiography reveal nonspecific abnormalities in approximately 50% of cases. Although hepatic arteriography also has been used to image hepatic abscesses, it is invasive and does not offer any benefits over CT. Magnetic resonance imaging (MRI), although accurate in detecting liver abscesses, offers no advantage over CT scanning and does not allow percutaneous aspiration for diagnosis or treatment.

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Most patients with liver abscesses have leukocytosis and increased liver enzyme activity, with alkaline phosphatase the enzyme most severely affected. Half of patients with pyogenic abscesses have positive blood cultures. The presence of viridans streptococci, especially S. anginosus group, and increased liver enzyme activities in the absence of endocarditis is an important clue to the diagnosis of pyogenic liver abscesses. Amebiasis and amebic abscesses of the liver may be difficult to diagnose, because amebae may not be recovered from pus and are more often found on the wall of the abscess. CT and ultrasonography can be used to aspirate these lesions for rapid diagnosis. Both aerobic and anaerobic cultures should be obtained. A sterile, brownish aspirate without a foul smell is characteristic of an amebic abscess. However, fluid in amebic abscesses can be yellow or green and secondarily infected, rarely, with other organisms. Finding Entamoeba histolytica trophozoites on direct microscopy or culture is diagnostic of an amebic abscess. The diagnosis of amebic abscess can be confirmed by the finding of increased serum antiamebic antibody titers with an indirect hemagglutination test, for which results are readily available within 24 hours in most major medical centers. The serologic test for amebiasis indicates either past or current exposure to ameba and is positive in 90% of cases of amebic liver abscess. In areas of the world where such disease is endemic, high titers may be found in a high percentage of the population. If the diagnosis is in doubt, a trial or inclusion of amebicidal therapy is helpful in reaching a conclusion.

Treatment Pyogenic Liver Abscess The keystones of treatment of pyogenic liver abscesses are drainage and antibiotic therapy in addition to eliminating the underlying source of the condition if it is known (8). Untreated pyogenic hepatic abscesses carry a 95% to 100% death rate. When a pyogenic hepatic abscess is suspected, the patient should be given broad-spectrum antibiotic therapy directed against gram-negative rods, Streptococcus species, and anaerobes. Appropriate initial antibiotics may include an aminoglycoside, clindamycin or metronidazole for anaerobes, and a penicillin. Antibiotic coverage is then adjusted according to the results of culture of the aspirated or drained abscess. The duration of antibiotic coverage can range from 1 week to 4 months, depending on the response of the patient. Once empirical antibiotic therapy commences, CT or ultrasonography should be done for diagnostic aspiration. If there is no intra-abdominal source of infection but at least 1 large abscess, percutaneous drainage and antibiotic therapy may suffice. In patients with many small abscesses without intra-abdominal pathology, antibiotic therapy alone is a reasonable treatment choice, with surgical drainage reserved for cases of antibiotic failure if the clinical setting

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dictates the need. If on the initial CT scan an intra-abdominal source is found, surgical drainage and surgical treatment of the source is recommended. Simple aspiration is useful as a diagnostic adjunct to antibiotic therapy in healthy young individuals and for draining many small abscesses. Most liver abscesses require continuous catheter drainage, with assessment by CT or ultrasonography once per week (or sooner if there is no response to therapy). In the past, surgical drainage was the only available treatment option for hepatic abscesses. Currently, the indications for surgery include cases of liver abscess with an identifiable abdominal pathology and cases in which percutaneous drainage fails or cannot be done. Recently, alternative approaches have been introduced for the treatment of pyogenic liver abscesses. Laparoscopic techniques have been used to drain hepatic abscesses and to identify and treat underlying abdominal pathology. This approach, in addition to antibiotic therapy, has been used for patients in whom percutaneous drainage has failed, thereby avoiding a laparotomy (9). Radiologic advances have allowed the drainage of pyogenic liver abscesses and the intracavitary instillation of antibiotics without the need for indwelling, percutaneously placed catheters (10). Endoscopic sphincterotomy with local antibiotic lavage by means of endoscopically placed nasobiliary catheters has been shown to be a safe and effective technique for completely resolving pyogenic abscesses of biliary origin, with only 1 of 19 patients requiring salvage surgical drainage (11).

Amebic Liver Abscess The treatment of choice for amebic liver abscesses is an amebicidal agent. Metronidazole 750 mg 3 times daily orally for 7 to 14 days can be effectively used to treat both the hepatic and intestinal phases of most cases of amebiasis. In some cases, however, metronidazole may have to be continued for 4 to 6 weeks. Patients unable to take metronidazole orally, can take it intravenously with similar results. Other agents used include emetine, dehydroemetine, and chloroquine; however, the toxicity of these drugs seldom makes them the primary agents of choice. Aspiration is rarely needed unless the diagnosis is suspect or a secondary bacterial infection is present. Surgical drainage has a role in suspected abscess rupture, adjacent structure perforation, and cases of erosion or poor response to medical therapy. Patients who fail to respond to antiamebic therapy may have a bacterial infection, and their treatment should be adjusted accordingly. In patients with perforated amebic abscesses, needle aspiration in combination with drug therapy is superior to drug therapy alone (12). The prognosis of hepatic amebic abscess is good: Death from uncomplicated amebic abscesses is less than 5%. In cases in which there is erosion into the pericardium or free intraperitoneal rupture, death increases to 30% to 50%.

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Splenic Abscesses Isolated splenic abscesses are rare and potentially lethal, and their diagnosis is often delayed. The incidence of splenic abscesses in autopsy series ranges from 0.14% to 0.70% (13). Immunosuppression by AIDS and for organ transplantation, more aggressive chemotherapy for a wider variety of cancers, and efforts to conserve the spleen after trauma have contributed to the recent increase in splenic abscesses and to the change in pattern and bacteriology of these lesions (14). Splenic abscesses can be seen de novo in patients in intensive care units (ICUs) and carry a high death rate (40%100%), especially after surgery or trauma (15).

Etiology The cause of splenic abscesses can be divided into the following 5 major categories (16): 1. Hematogenous spread from septic foci: probably the most common; distant sources of infection that affect the spleen include endocarditis, pyelonephritis, disseminated tuberculosis, Salmonella bacteremia in AIDS patients, immunosuppression in cancer patients, intravenous drug abuse, intra-abdominal sepsis, chest infections, osteomyelitis, infected vascular access sites, infected ventriculoperitoneal shunts, and tooth extractions. 2. Contiguous infection through direct spread from adjacent viscera: such as in the case of colonic or gastric perforations and pancreatic and subphrenic abscesses. 3. Secondary infection of a splenic infarction: such as those caused by emboli from the heart, lipid embolization in Weber-Christian disease, splenic artery embolization, and infarction caused by splenic vein thrombosis from sickle cell disease or hemoglobinopathies (e.g., thalassemia). 4. Splenic trauma: including procedural or iatrogenic injury. 5. Immunodeficiency: especially when fungi or unusual organisms are involved.

Clinical Manifestations The clinical presentation of splenic abscesses is nonspecific but includes abdominal pain in the left upper quadrant, pleuritic chest pain, fever, and leukocytosis (14). Most patients present with fever (69%-90%) and abdominal pain (56%-70%). Other findings that may suggest splenic abscesses are pain referred to the left shoulder (from diaphragmatic irritation), elevation of the left hemidiaphragm, and left pleural effusion. Splenomegaly is present in 31% to 40% of patients.

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Diagnosis A high degree of clinical suspicion is essential for the early diagnosis of splenic abscesses. Diagnosis usually is delayed, with the duration of symptoms averaging 16 to 22 days (17). Ultrasonography, CT, and MRI have been used successfully for diagnosing splenic abscesses. CT is superior to ultrasonography because it 1) can define the exact location of an abscess, 2) can demonstrate subcapsular or perisplenic pathology, 3) is unhindered by air in the left upper quadrant, and 4) has both a reported sensitivity and specificity of 96% (18). Leukocytosis has been reported in 60% to 100% of patients with splenic abscesses. Positive blood cultures have been found in 48% of patients, with only 24% having organisms similar to those obtained from their abscess pus. Thrombocytosis (mainly caused by splenic infarction) could occur in up to 17% of cases; however, it was present in 8 of 9 patients in an ICU setting. It is worth mentioning that unexplained thrombocytosis in a septic ICU patient with persistent left pleural effusion is suggestive of splenic abscess (15).

Treatment Once the diagnosis of a splenic abscess is made, treatment with broadspectrum antibiotics should be instituted, because 25% of splenic abscesses are polymicrobial with anaerobes (14). Antibiotic therapy should be targeted against streptococci and staphylococci, which are the most common organisms seen in splenic abscesses and reflect the most common causes of abscesses that result from endocarditis or intravenous drug abuse. Gram-negative rods such as Salmonella and E. coli account for 30% of cases of splenic abscess, whereas anaerobes account for 12%; both types of organism should be covered initially. Antibiotic therapy can then be tailored to the results of blood cultures, and surgical drainage can be done (Table 12-1). Fungal splenic abscesses (especially those caused by Can-dida) have been on the increase, principally among patients who receive corticosteroids and those who undergo chemotherapy for cancer; antifungal coverage alone may be adequate for treating these abscesses, particularly because most of those are caused by fungi and are small and multifocal. Antibiotic therapy alone, without drainage of a splenic abscess, carries a high death rate. Up to 90% of patients with unilocular, well-contained bacterial abscesses may be managed with CT-guided percutaneous indwelling catheter drainage in addition to antibiotics with splenectomy reserved for failures (18). Splenectomy remains the treatment of choice for many splenic abscesses and the gold standard for treating most of these lesions (19). Splenotomy with drainage is reserved for the most acutely ill patients, in whom extensive adhesions preclude the performance of a safe splenectomy.

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Table 12-1 Common Causes and Recommended Antimicrobial Therapies for Various Intra-abdominal Abscesses Condition

Liver abscess Pyogenic

Amebic Splenic abscess

Pancreatic abscess

Appendiceal abscess

Diverticular abscess

Common Etiologic Microorganisms

Antimicrobial Therapies*

Actinomyces spp. Bacteroides spp. Clostridium spp. Enterococcus spp. Escherichia coli Fusobacterium spp. Klebsiella pneumoniae Peptostreptococcus spp. Pseudomonas spp. Staphylococcus aureus Viridans-group Streptococcus

Single agents: Imipenem 500 mg IV q6h/meropenem 1 g IV q8h/ertapenem*. 1g IV daily/ tigecycline 100 mg IV initially then 50 mg IV q12h# or Beta-lactam or beta-lactamaseinhibitor combinations† Combination therapy: Ampicillin 1-2 g IV q6h + gentamicin‡ I.5 mg/kg IV q8h + metronidazole 500 mg IV q6-8h or Ceftazidime 2 g IV q12h or cefepime 2 g IV q12h + metronidazole 500 mg IV q6-8h For penicillin-allergic patients: Ciprofloxacin 400 mg IV q12h + metronidazole 500 mg IV q6-8h Metronidazole 750 mg PO tid for 7-14 d Entamoeba Single agents: histolytica Ceftriaxone 2 g IV q24h or Escherichia coli levofloxacin 500 mg IV q24h Salmonella spp. Combination therapy: Staphylococcus Nafcillin or oxacillin 2 g IV q4h + spp. gentamicin‡ I.5 mg/kg IV q8h Streptococcus spp. For penicillin-allergic patients: Vancomycin 1 g q12h* + gentamicin‡ I.5 mg/kg IV q8h or Aztreonam 2 g IV q8h** + clindamycin 600-900 mg IV q8h Bacteroides fragilis Single agents: Enterobacteriaceae As with pyogenic liver abscesses Enterococcus spp. Combination therapy: Escherichia coli Ceftazidime 2 g IV q12h + either Klebsiella pneumoniae metronidazole 500 mg IV q6h§ or Pseudomonas clindamycin 600-900 mg IV q8h aeruginosa For penicillin-allergic patients: Staphylococcus aureus As with pyogenic liver abscesses Bacteroides fragilis Single agents: Escherichia coli As with pyogenic liver abscesses Peptostreptococcus spp. Combination therapy: Pseudomonas As with pyogenic liver abscesses aeruginosa For penicillin-allergic patients: As with pyogenic liver abscesses Bacteroides fragilis Single agents: Escherichia coli As with pyogenic liver abscesses Continued

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Table 12-1 Continued Condition

Common Etiologic Microorganisms

Antimicrobial Therapies*

or Cefotetan 2 g q12h or cefoxitin 2 g q6h IV Combination therapy: Ampicillin 1-2 g IV q6h + gentamicin‡ 1 mg/kg IV q8h + either metronidazole 500 mg IV q6h§ or clindamycin 600-900 mg IV q8h For penicillin-allergic patients: As with pyogenic liver abscesses or Aztreonam 2 g IV q6h + metronidazole 500 mg IV q6h§ * Antibiotic therapy should be directed toward the final culture results. Unless otherwise specified, treatment should last for 5-14 days until the patient is afebrile and has a normal leukocyte count. The antibiotic dosages should be adjusted according to the patient’s renal and hepatic functions, with levels measured as necessary. # No pseudomonal coverage, no data available on viridans strep coverage. † These combinations include piperacillin-tazobactam 4.5 g q8h, ticarcillin—clavulanate 3.1 g q6h (has weak antienterococcal activity), and ampicillin-sulbactam 3 g IV q8h (has no antipseudomonal activity and increasing E. coli resistance reported). ** No reliable pseudomonal activity and no enterococcal activity. ‡ Dosing based on nonobese patients with normal renal function. Also, gentamicin 5-7 mg/kg/once-daily dosing has been used but not supported in critically ill patients. § Has poor antistaphylococcal activity. ¶ In some cases, a duration of up to 4-6 weeks may be necessary. ** This combination does not have good activity against gram-positive cocci such as Staphylococcus and Streptococcus species. Abbreviations: d = d day; h = hour; IV = intravenously; PO = orally; q = every; spp. = species; tid = three times a day.

Pancreatic Abscesses Pancreatic infection is usually a secondary process. The infection is usually bacterial and occurs in previously damaged pancreatic tissue. This damage is typically from acute pancreatitis (usually severe enough to cause necrosis) or trauma. Pancreatic abscess can be defined as a contained, intra-abdominal infection with purulent material close to the pancreas with or without pancreatic necrosis. Infected pancreatic necrosis is defined as a diffuse or focal area of nonviable parenchyma with associated bacterial infection (20). Infected necrosis is an important risk factor for illness and death (21).

Etiology Pancreatic abscesses occur as complications of pancreatitis and trauma. Additionally, endoscopic retrograde cholangiopancreatography is a cause

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Table 12-2 Etiologies of Acute Pancreatitis Biliary tract disease Alcohol Hyperlipidemia Hypercalcemia Familial Trauma

Ischemia Pancreatic duct obstruction Viral infection Scorpion venom Idiopathic Drugs

of pancreatitis and subsequent abscesses. Acute pancreatitis has many causes (Table 12-2). Most cases are related to the biliary tract or to alcohol consumption. Gallstones obstruct the ampulla of Vater, which diverts bile flow into the pancreatic duct, causing injury and subsequent pancreatitis. The exact mechanism of alcohol-induced pancreatitis is unknown. The presence of acute necrotizing pancreatitis increases the likelihood of pancreatic infection and/or abscess. Infection develops in 40% of cases of pancreatic necrosis, usually in the second or third week of the disease (22). Secondary pancreatic infections occur in 2% to 5% of cases of acute pancreatitis and represent serious complications (20). As a result, the pancreas becomes infected, either from the hematogenous spread of pathogens or from their transmural translocation from adjacent inflamed bowel. Organisms cultured from pancreatic abscesses are predominantly gramnegative and polymicrobial. They include E. coli, Klebsiella pneumonia, Enterococcus species, staphylococcus species, and pseudomonal species (23). Fungal pancreatic abscesses are mostly associated with ERCP, parenteral nutrition, and broad spectrum antibiotics. Most common isolates are Candida albicans and Candida glabrata.

Clinical Manifestations The clinical presentation of acute pancreatitis varies. The patient can present with a mild form of the disease or with hypovolemic shock, sepsis, and metabolic abnormalities (20). The pain typically begins in the midepigastrium and is constant. The pain itself is of varying intensity, and the patient may present with generalized peritonitis. The patient may report pain “boring into the back.” Nausea and vomiting may accompany the abdominal pain. Abdominal distention resulting from paralytic ileus may be present. If hemorrhagic pancreatitis is present, Grey Turner sign or Cullen sign (i.e., a bluish discoloration of the flank or umbilicus, respectively) may be present, indicating severe pancreatitis. Jaundice may be present in patients with gallstone-induced pancreatitis. The patient with secondary infection may recover initially from a bout of acute pancreatitis only to deteriorate suddenly, or he or she may simply fail to respond to the initial therapy.

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Diagnosis The diagnosis of acute pancreatitis is based on the clinical presentation of the patient, laboratory variables, and radiologic studies. An increased serum amylase is the laboratory parameter accepted most widely for assisting the diagnosis (24). A persistently increased amylase level beyond the first week usually reflects ongoing inflammation or may signal the development of complications such as a pseudocyst, phlegmon, or abscess (20). Persistent abdominal pain, fever, and leukocytosis also should alert the physician to the possibility of secondary infection. Identifying a pancreatic pseudocyst, phlegmon, or abscess can be made in 80% to 90% of cases through imaging studies with ultrasonography, CT, or radionuclide scanning; however, CT is diagnostically superior to ultrasonography. Plain radiography may reveal a left pleural effusion, elevated hemidiaphragm, or retrogastric or retroperitoneal air. Contrast studies might show displacement of the stomach or duodenum. It can be difficult to distinguish sterile pancreatic necrosis from secondarily infected pancreatic abscesses. A CT scan alone may be beneficial in this regard; but CT-guided aspiration, Gram staining, and culture may be necessary to make the distinction (24). Dynamic CT scanning can provide information about the viability of the pancreas through the uptake of intravenous contrast medium. MRI is not typically beneficial in aiding in the diagnosis of pancreatic abscess (25).

Treatment Prophylactic antibiotic treatment in severe pancreatitis may prevent complications such as an abscess. The choice of antibiotic is critical, because it must penetrate the pancreatic parenchyma. Drugs with poor pancreatic penetration include aminoglycosides, first-generation cephalosporins, cefoxitin, and ampicillin. Imipenem is usually the first choice, with ciprofloxacin or levofloxacin with metronidazole an alternative (21). In case of fungal infections, treatment could be either fluconazole 800 mg IV then 400 mg IV daily or amphotericin B lipid complex 5 mg/kg IV daily. New fungal agents such as echinocandins and voriconazole have been approved. Percutaneous drainage alone seems inadequate in most cases but can be considered as the initial treatment of culture-positive cysts (26). The indications for surgical drainage include demonstration of an infected pancreatic necrosis by bacterial cytology or dynamic CT scan or by a failure of a trial of percutaneous drainage. Several surgical options are available for the management of pancreatic cysts. Each has its proponents, and the surgeon should be familiar with all possible treatments. Reexploration is frequently needed in this group of patients. All necrotic material must be débrided. The pancreatic bed must be irrigated copiously. The pancreatic bed can be packed, and plans can be made

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for reoperation 48 hours later, with the absence or presence of healthy granulation used to determine a plan for subsequent laparotomies. Largebore drains are typically left in place. Another operative plan is to leave several large-bore drains in place after adequate tissue debridement. Subsequently, these drains can be used for continuous postoperative lavage in the ICU. Surgical debridement with closed-suction drainage is another option. With this method it is occasionally difficult to determine clinically when a repeat exploration is necessary. With the other methods described, reexploration is done at 48-hour intervals to assess the viability of the tissue. Recently, laparoscopic assisted drainage of pancreatic abscesses has been successful (27).

Appendiceal Abscess The natural history of appendicitis includes perforation in 16% of cases (28). When an appendix perforates, a periappendiceal abscess, a phlegmon, or diffuse peritonitis develops. A periappendiceal abscess is a pus-containing periappendiceal mass, which usually lies in the right lower quadrant. A periappendiceal phlegmon is an inflammatory mass that comprises the appendix, adjacent viscera, and the omentum but does not contain purulent material (29). Diffuse peritonitis signifies a surgical emergency. It is best to diagnose and treat appendicitis before perforation occurs to prevent the illness associated with the latter.

Etiology Appendiceal abscesses result from the rupture of an acutely inflamed appendix. From 2% to 6% of cases of acute appendicitis are complicated by periappendiceal masses and/or abscesses (29). Obstruction of the lumen by a fecalith is the most common cause of appendicitis. The obstruction causes distention of the appendiceal lumen, which in turn increases the intraluminal pressure (28). Mucosal secretion and multiplication of bacteria continue, adding to the increased pressure. The intraluminal pressure eventually exceeds venous pressure, whereas arterial inflow continues, resulting in vascular congestion (28). As the distention progresses, the arterial inflow is compromised, causing areas of infarction and necrosis. Ultimately this leads to perforation, usually on the antimesenteric side of the appendix. The bacteriology of appendiceal abscesses, as with most intra-abdominal abscesses, is polymicrobial. Anaerobes, aerobes, and facultative bacteria have been cultured from appendiceal abscesses. Bacteroides fragilis and E. coli are the most common organisms identified (30).

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Clinical Manifestations Abdominal pain is the most common report in appendicitis. The classic pain of appendicitis begins in the periumbilical region and, after a period of several hours, localizes to the right lower quadrant (28). This classic symptomatology is not always present. Anorexia almost always accompanies appendicitis, and vomiting occurs in most patients. If vomiting occurs before the onset of pain, the diagnosis of appendicitis should be questioned (28). The patient usually lies still, occasionally with the hips flexed to help relieve the peritoneal irritation. If the appendix lies anteriorly, right-lower quadrant pain is present in its characteristic fashion. Rebound and guarding are usually present, with maximal pain in the right lower quadrant. Leukocytosis is present. A low-grade fever is present, with the temperature rarely exceeding 38.5°C (28). Appendiceal rupture should be suspected in patients with a temperature more than 39°C and with leukocytosis exceeding 18,000/mm3 (28). Most appendiceal ruptures are contained, and generalized peritonitis is not present. If the rupture cannot be contained, generalized peritonitis occurs. In cases of appendiceal rupture, a mass may be palpable in the right lower quadrant. However, because of abdominal-wall guarding or obesity, the mass may not be palpable until the patient is anesthetized. Patients with an appendiceal mass and/or abscess tend to have longer periods of symptoms (usually lasting 5–7 days) before they present for treatment (29).

Diagnosis Plain radiography of the abdomen in appendicitis patients reveals a nonspecific bowel gas pattern and only rarely reveals a fecalith. Ultrasonography has been used to diagnose acute appendicitis and appendiceal masses and abscesses. The diameter of the appendix is measured together with graded compression. The diagnosis of appendicitis can be made if the appendix is noncompressible and 6 mm in diameter (31). The appendiceal mass can be seen more clearly on CT, which also allows one to assess the feasibility of percutaneous drainage. Contrast-enhanced CT is helpful in differentiating a phlegmon from an abscess.

Treatment Broad-spectrum antibiotics that are targeted at the polymicrobial nature of appendiceal abscesses should be instituted in patients with these lesions. An antibiotic regimen such as ampicillin/sulbactam or piperacillin/tazobactam or combination of an aminoglycoside with either clindamycin or metronidazole is effective (29) (see Table 12-1).

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Appendiceal abscesses can be treated in 2 ways: 1) immediate appendectomy with abscess drainage, or 2) initial nonoperative management with no oral intake, intravenous fluids, and intravenous antibiotics with percutaneous drainage. It has been shown that patients undergoing immediate appendectomy have a longer hospital stay, and a delayed elective operation may be safer (32). Most appendiceal masses resolve promptly with initial nonoperative treatment. If the mass and/or signs of infection persist, the causative abscess or phlegmon should be drained, preferably percutaneously. An interval appendectomy should be done 6 to 8 weeks later. An interval appendectomy is done to prevent recurrent episodes of appendicitis (29). The failure rate of nonoperative management is approximately 5% (33). Failure consisted of progression of disease to peritonitis or simply failure to improve. Most of those patients who had recurrent appendicitis had it within the first 9 weeks after discharge (33). Laparoscopic appendectomy is typically the treatment of choice for appendicitis (31). It permits a more complete examination of the abdomen and is especially useful for ruling out gynecologic diseases (31). Laparoscopically performed interval appendectomy has been proved to be safe (34). Patients 40 to 50 years of age or older who develop perforated appendicitis with a phlegmon or abscess and who initially were treated nonsurgically should have either a double-contrast enema or should undergo colonoscopy to rule out a malignant cecal tumor.

Diverticular Abscesses The terminology for diverticular disease and associated inflammation or abscesses may be confusing. Acute diverticulitis implies an acute inflammatory process that results from an inflamed diverticulum. The inflammation is limited to the involved bowel wall and surrounding structures (most commonly the attached mesentery), and there is no confined collection of pus. In contrast, a diverticular abscess is a collection of pus usually associated with a perforated diverticulum. This abscess may be relatively contained by either the bowel wall mesentery or other structures in close proximity (e.g., lateral or anterior abdominal wall, urinary bladder, loops of small intestine). The perforation may spread freely within the peritoneal cavity, leading to generalized peritonitis, which is a surgical emergency.

Etiology Diverticular abscesses arise from a diverticular perforation that may occur anywhere along the gastrointestinal tract. Diverticula are either congenital or acquired. Small bowel and cecum diverticula are congenital and may

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perforate, leading to many abscesses within a particular loop. The sigmoid colon is by far the most frequent point of origin of acquired diverticula, arising from a point of vascular egress within the hypertrophied muscular wall of the sigmoid colon. The following discussion focuses on abscesses associated with sigmoid diverticula (35).

Clinical Manifestations and Diagnosis Patients who present with a diverticular abscess usually have concomitant fever, leukocytosis, and abdominal pain. The temperature may reach 39°C or higher, and a marked left shift is usually noted in the complete blood count. Findings on physical examination are highly variable and range from a dull but persistent abdominal pain to signs of frank peritonitis. The pain may be localized to the suprapubic region in the midline if the abscess is confined to the mesentery. In this situation, the sigmoid colon is pushed medially and anteriorly. The pain may be restricted to the left lateral abdominal wall if the abscess or inflammation is located between the colon and the lateral abdominal wall. Bowel movements may reflect either constipation or diarrhea; but the passage of formed, regular stool is the exception. In some patients who present with acute diverticulitis, intensive antibiotic therapy may fail to resolve the inflammation and an abscess may develop. The clinical course of such patients is often characterized by unremitting fever, rising leukocytosis, and worsening abdominal pain. Scanning with CT has proved an invaluable radiographic method both for the diagnosis of diverticular abscess and as a guide to its treatment. Pus or abscess formation may be readily distinguished from the more common mesenteric inflammation. Importantly, CT permits the evaluation of other diseases, such as perforated cancer of the colon and appendicitis, which often mimics the clinical presentation of diverticulitis with associated abscess. In patients with diverticular abscesses, it is important to remember that, as with all intra-abdominal abscesses, occult hypoxemia may be present. Thus, routine monitoring of oxygenation becomes important. Additionally, the overall nutritional status of the patient should be assessed at the time of hospital admission.

Treatment Once diagnosed, a diverticular abscess is an indication for drainage. Diverticular abscesses do not resolve with antibiotic therapy alone. CT and CT-guided percutaneous drainage represent a huge step forward in the management of difficult, often elderly and frail, patients in whom many diverticular abscesses occur. A loculated abscess may be approached percutaneously, and effective drainage may be achieved. Usually, once defervescence and signs of systemic toxicity resolve, repeat CT is done at 5 to 7 days, along with a sinogram to ensure closure of the diverticulum and

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the absence of any persisting fistulous tract. A repeat CT scan is also done if the patient has not improved by 24 to 48 hours after drainage. This is used to assess any residual or ongoing abscesses. If at this point CT-guided drainage has been unsuccessful, surgical drainage by means of laparotomy should be instituted promptly. Broad-spectrum antibiotic coverage commences, with the regimen usually consisting of ampicillin and sulbactam, piperacillin and tazobactam or a combination of an aminoglycoside and an agent effective against anaerobes (e.g., clindamycin, metronidazole). Aminoglycosides should be administered with caution in the elderly, particularly those with underlying renal dysfunction. Alternatively, initial therapy may begin as monotherapy with a broad-spectrum cephalosporin (see Table 12-1). Once control of the abscess is achieved by nonoperative means, consideration should be given to elective colon resection with a primary anastomosis and a 1-stage operation (36).

Special Considerations Coverage of Enterococcus in intra-abdominal sepsis is controversial. Although coverage is not indicated in community-acquired intra-abdominal infections, coverage is recommended in complicated intra-abdominal infections in patients in septic shock, patients previously receiving prolonged treatment with cephalosporins, immunosuppressed patients with high risk for bacteremias, and patients with prosthetic heart valves and recurrent intra-abdominal infections (37). Isolation of fungi from intra-abdominal fluid after a viscous perforation is common because fungi are part of the normal intestinal flora. There is no consensus on prophylactic treatment of fungal isolates in all cases of intra-abdominal sepsis. Use of antifungal agents is recommended in patients with severe acute necrotizing pancreatitis, with recurrent gastrointestinal perforations or anastomotic leaks, with positive yeast blood cultures or yeast cultured from intra-abdominal abscesses (in the absence of other organisms), and who are profoundly immunocompromised (37,38). Antifungal therapy in the form of fluconazole or amphotericin B should always be continued for 2 to 3 weeks.

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5. Perera MR, Kirk A, Noone P. Presentation, diagnosis and management of liver abscess. Lancet. 1980;2:629-32. 6. Thaler M, Pastakia B, Shawker TH, O’Leary T, Pizzo PA. Hepatic candidiasis in cancer patients: the evolving picture of the syndrome. Ann Intern Med. 1988;108:88-100. 7. Barbour GL, Juniper K Jr. A clinical comparison of amebic and pyogenic abscess of the liver in sixty-six patients. Am J Med. 1972;53:323-34. 8. Gerzof SG, Johnson WC, Robbins AH, Nabseth DC. Intrahepatic pyogenic abscesses: treatment by percutaneous drainage. Am J Surg. 1985;149:487-94. 9. Tay KH, Ravintharan T, Hoe MN, See AC, Chng HC. Laparoscopic drainage of liver abscesses. Br J Surg. 1998;85:330-2. 10. Miller FJ,Ahola DT, Bretzman PA, Fillmore DJ. Percutaneous management of hepatic abscess: a perspective by interventional radiologists. J Vasc Interv Radiol. 1997;8:241-7. 11. Dull JS, Topa L, Balgha V, Pap A. Non-surgical treatment of biliary liver abscesses: efficacy of endoscopic drainage and local antibiotic lavage with nasobiliary catheter. Gastrointest Endosc. 2000;51:55-9. 12. Meng XY, Wu JX. Perforated amebic abscess: Clinical analysis of 110 cases. South Med J. 1994;87:988-90. 13. Chun CH, Raff MJ, Contreras L, Varghese R, Waterman N, Daffner R, et al. Splenic abscess. Medicine (Baltimore). 1980;59:50-65. 14. Nelken N, Ignatius J, Skinner M, Christensen N. Changing clinical spectrum of splenic abscess. A multicenter study and review of the literature. Am J Surg. 1987;154:27-34. 15. Ho HS,Wisner DH. Splenic abscess in the intensive care unit. Arch Surg. 1993;128:842-6; discussion 846-8. 16. Madoff LC. Splenic abscess. In Mandell GL, et al, eds. Principals and Practices of Infectious Diseases. 6th ed. Philadelphia, Pa: Churchill Livingstone; 2005:967-8. 17. Phillips GS, Radosevich MD, Lipsett PA. Splenic abscess: another look at an old disease. Arch Surg. 1997;132:1331-5; discussion 1335-6. 18. Gleich S,Wolin DA, Herbsman H. A review of percutaneous drainage in splenic abscess. Surg Gynecol Obstet. 1988;167:211-6. 19. Sarr MG, Zuidema GD. Splenic abscess—presentation, diagnosis, and treatment. Surgery. 1982;92:480-5. 20. Yeo CJ, Cameron J. Acute pancreatitis. In Zuidema G, ed. Shackelford’s Surgery of the Alimentary Tract. 4th ed. Philadelphia, Pa: WB Saunders; 1996:18-37. 21. Hartwig W, Werner J, Uhl W, Büchler MW. Management of infection in acute pancreatitis. J Hepatobiliary Pancreat Surg. 2002;9:423-8. 22. Stiles GM, Berne TV,Thommen VD, Molgaard CP, Boswell WD. Fine needle aspiration of pancreatic fluid collections. Am Surg. 1990;56:764-8. 23. Shi EC,Yeo BW, Ham JM. Pancreatic abscesses. Br J Surg. 1984;71:689-91. 24. Reber H. Pancreas. In Schwartz S, ed. Principles of Surgery. 7th ed. New York, NY: McGrawHill; 1999:1467-99. 25. Paushter DM, Modic MT, Borkowski GP, Weinstein MA, Zeman RK. Magnetic resonance. Principles and applications. Med Clin North Am. 1984;68:1393-421. 26. Baril NB, Ralls PW,Wren SM, Selby RR, Radin R, Parekh D, et al. Does an infected peripancreatic fluid collection or abscess mandate operation? Ann Surg. 2000;231:361-7. 27. Horvath KD, Kao LS, Wherry KL, Pellegrini CA, Sinanan MN. A technique for laparoscopicassisted percutaneous drainage of infected pancreatic necrosis and pancreatic abscess. Surg Endosc. 2001;15:1221-5. 28. Kozar R, Roslyn J. The appendix. In Schwartz S, ed. Principles of Surgery. 7th ed. New York, NY: McGraw-Hill; 1999:1383-94. 29. Nitecki S,Assalia A, Schein M. Contemporary management of the appendiceal mass. Br J Surg. 1993;80:18-20. 30. Thadepalli H, Mandal AK, Chuah SK, Lou MA. Bacteriology of the appendix and the ileum in health and in appendicitis. Am Surg. 1991;57:317-22. 31. Pegoli W. Acute appendicitis. In Cameron J. Current Surgical Therapy. 6th ed. St. Louis, Mo: Mosby; 1995:263-6. 32. Brown CV,Abrishami M, Muller M,Velmahos GC. Appendiceal abscess: immediate operation or percutaneous drainage? Am Surg. 2003;69:829-32. 33. Oliak D,Yamini D, Udani VM, Lewis RJ,Vargas H,Arnell T, et al. Nonoperative management of perforated appendicitis without periappendiceal mass. Am J Surg. 2000;179:177-81.

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34. Vargas HI,Averbook A, Stamos MJ. Appendiceal mass: conservative therapy followed by interval laparoscopic appendectomy. Am Surg. 1994;60:753-8. 35. Saini S, Kellum JM, O’Leary MP, O’Donnell TF,Tally FP, Carter B, et al. Improved localization and survival in patients with intraabdominal abscesses. Am J Surg. 1983;145:136-42. 36. Pruett TL, Rotstein OD, Crass J, Frick MP, Flohr A, Simmons RL. Percutaneous aspiration and drainage for suspected abdominal infection. Surgery. 1984;96:731-7. 37. Blot S, De Waele JJ. Critical issues in the clinical management of complicated intra-abdominal infections. Drugs. 2005;65:1612-20. 38. Infectious Diseases Society of America. Guidelines for treatment of candidiasis. Clin Infect Dis. 2004;38:161-89.

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Part V

Genitourinary Infections

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Chapter 13

Urinary Tract Infections in Adults ALLEN R. RONALD, OC, MD

Key Learning Points 1. Acute bacterial cystitis episodes in women are very common, often related to sexual intercourse, best managed with a three day course of an anti-infective usually with minimal investigation, and prevented by intermittent or continuous prophylactic regimens. 2. Acute pyelonephritis is a relative medical emergency, should be diagnosed by urine culture, stratified by severity of illness and comorbidities, and imaging performed if indicated with effective, often parenteral, initial anti-infective treatment. 3. Asymptomatic bacteriuria regardless of pyuria, should in nonpregnant women and in men only be treated if an indication for treatment is present.

A

urinary tract infection (UTI) is the presence of microbes anywhere in the urinary tract, including the proximal urethra, bladder, prostate gland, ureters, and kidneys. UTIs are common in all populations, and their global annual incidence probably exceeds 250 million. The infection may be limited to asymptomatic superficial colonization of the epithelial lining of the urinary tract, or it may progress to invasive inflammatory injury to the renal parenchyma or suppuration of renal tissue, occasionally spreading through the renal capsule and creating a perinephric abscess. UTIs are categorized as uncomplicated if there is no known functional or anatomic abnormality of the urinary tract and no underlying host abnormalities. Approximately 80% of UTIs are uncomplicated. UTIs are termed complicated whenever any of the entities listed in Table 13-1 is present (1). Although many infections categorized as complicated can be readily cured, 245

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New Developments in the Diagnosis and Management of Urinary Tract Infections ●

●

●

Trimethoprim-sulfonamide resistance continues to increase and in most areas of the world, including the United States, can no longer be used as empiric therapy for community-acquired urinary infection if the patient is moderately or seriously ill. Clonal Escherichia coli with invasive uropathogenic genes are spread widely in food and can be acquired from pets. Asymptomatic urinary infection in patients with diabetes mellitus and in patients with indwelling catheters should not be treated regardless of pyuria.

Table 13-1 Classification of Causes of Complicated Urinary Tract Infections Structural Abnormalities

Obstruction Vesicouretal reflux Neurogenic bladder Calculi Renal abscess(es) Fistula to intestine or other sites Urinary diversion procedures Infected cysts Urinary catheters Metabolic or Hormonal Abnormalities

Diabetes mellitus Pregnancy Renal impairment Impaired Host Response

Post-transplantation Neutropenia HIV/AIDS Unusual Pathogens Pseudomonas aeruginosa and other multiresistant organisms Calculi-associated bacteria Yeasts, fungi, mycobacteria AIDS = acquired immune deficiency syndrome; HIV = human immunodeficiency virus.

a proportion of complicated UTIs will be persistent, difficult-to-treat infections with frequent recurrences. As a result, the categorization of a UTI as complicated is important for patient management.

Epidemiology Approximately 150,000 individuals, or 1 per 1000 adults per year, are estimated to be admitted to hospitals with acute pyelonephritis in the United States (2,3). UTIs are the most common nosocomial-acquired infection,

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and their acquisition increases health care costs substantially. Although pyelonephritis is identified as the cause of death in only approximately 1000 individuals in the United States (3,4) septicemia, which arises from the urinary tract in at least 25% of instances, is responsible for more than 20,000 deaths each year (2). The epidemiology of urinary infection varies with age, gender, and underlying risk factors (5). During the first year of life, the cumulative prevalence of UTI in men is approximately 0.2%. These infections are frequently symptomatic, and require urologic investigation because of the possibility of underlying congenital anomalies. Urinary infections are subsequently rare in male children, with a cumulative incidence by the age of 10 years of less than 1%. The presence of a foreskin increases by at least 5-fold the probability of urinary infection during childhood (6). Among girls, the cumulative incidence of UTI during the first 10 years of age is 3%. UTIs in infancy and early childhood can be associated with symptomatic pyelonephritis, persisting renal infection with failure of renal growth, and extensive renal scarring. As a result, urinary infections in early childhood are investigated and managed more aggressively. Treatment is usually prescribed, and follow-up cultures should be done to ensure cure. However, asymptomatic bacteriuria in a normal urinary tract in girls older than age 6 years is usually benign, and aggressive investigation and management only warranted with recurrences. Acute cystitis is by far the most common clinical presentation of urinary infection in adults. Urinary infections are extremely common in sexually active women, with at least one third of women having had an episode of symptomatic UTI within 10 years of the initiation of sexual activity. In a prospective study of sexually active women in a health management organization, 50 of every 100 women, had acute cystitis each year (7). Extrapolating from these data would suggest that at least 25 million episodes of acute cystitis occur annually in the United States. Studies have shown that sexual intercourse and the use of spermicides, with or without a diaphragm, are predisposing factors for UTIs among sexually active women (8). Condoms coated with nonoxyl-9 also increase the risk of cystitis. Many other factors have been studied and seem not to be significant in predisposing to acute cystitis. These include voiding habits, bathing, intake of fluid, voiding after intercourse, the direction of wiping after defecation, douching habits, types of menstrual protection, or perineal hygiene (7). However, recent antecedent antimicrobial use, and in particular the use of beta-lactam antibiotics, alters normal vaginal flora and predisposes women to cystitis (9). Factors that predispose women to an initial episode of acute cystitis also predispose to recurring bouts. Approximately 5% of women are UTI-prone and experience many, closely spaced episodes of infection (7). Many of these women have a genetic trait and potentially invasive strains of Escherichia coli adhere more readily to their uroepithelial cells (10). No other functional

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abnormalities or defects in host response have been identified in these infection-prone women, and urologic investigation or treatment has no proven role in their management. A proportion of patients who present with acute cystitis have renal involvement. Table 13-2 identifies factors shown to increase the probability of upper tract infection in patients with symptoms confined to the bladder. Both acute and recurrent cystitis are common in postmenopausal women. The risk factors for such cystitis are not well understood, but at least 1 study suggests it may occasionally be caused by estrogen deficiency (11). Additionally, older women with recurring UTIs may often have increased residual urine or other functional abnormalities of the urinary tract. Acute pyelonephritis tends to occur among patients who are susceptible to acute cystitis. Pregnancy, diabetes, immunosuppression, and obstruction predispose both men and women to acute pyelonephritis. Among patients with diabetes, the incidence of acute hospitalization for pyelonephritis is almost 10 times that for controls without diabetes for both men and women (4). The epidemiology of complicated UTIs has not been well studied. In a survey of nosocomial UTI, the incidence was 4.3/1000 patient days, and 88% of these infections were catheter related (12). However, UTIs are common in a wide range of patients with abnormalities of the urinary tract. All patients with chronic indwelling catheters have bacteriuria, but most remain asymptomatic unless obstruction occurs. However, over decades of urinary drainage with a catheter, patients with cord injuries often experience complications caused by urinary stones or abscess formation, and a few progress to having end-stage renal disease. Complications are at least 3 times more common in chronically catheterized men than in chronically catheterized women. UTIs in pregnancy cause preterm labor and low birth weight (13). Also, almost half of patients with asymptomatic infections, if untreated, will develop pyelonephritis during pregnancy. Presumably, this is caused by physiologic and anatomic changes in the urinary tract during pregnancy. Screening for and treating asymptomatic bacteriuria in all pregnant patients during the first trimester will prevent approximately 80% of episodes of acute pyelonephritis during pregnancy, and this intervention has been shown in

Table 13-2 Factors that Predict Renal Involvement in Patients Presenting with Cystitis or Asymptomatic Bacteriuria Vesicouretal reflux Pregnancy Upper tract pathology (known or unknown) Diabetes Relapse (rapid recurrence with identical pathogen) Unusual or resistant pathogen Older age Nosocomially acquired infection

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prospective studies to decrease the overall incidence of prematurity by 10% to 20% (13). Asymptomatic UTIs are common, and their prevalence is increased among patients who are prone to symptomatic infections (5,14). The prevalence of asymptomatic bacteriuria has been studied in many populations, and relevant data are summarized in Table 13-3. Asymptomatic bacteriuria has been a controversial diagnosis. Is it a benign happening or is it a disease burden with links to other illness or consequences? Studies throughout the past decade have determined that, with the exception of its occurrence during pregnancy, asymptomatic UTI in the healthy adult urinary tract has limited significance for the patient’s ongoing health and rarely ever alters renal function or overall illness (15). As a result, asymptomatic UTI should not be routinely sought and treated. In particular, asymptomatic bacteriuria is extremely common among the elderly, and its treatment is usually futile and unnecessary (16). The known factors predisposing to asymptomatic infection are similar to those for symptomatic urinary infection and include diabetes, residual urine, urinary instrumentation, and in females sexual intercourse (5,15).

Etiology Most UTIs are caused by rapidly growing pathogens, with a predominance of E. coli, often of a restricted number of O:K:H serotypes. Table 13-4 compares the prevalence of organisms in community-acquired infections, most of which are uncomplicated, and in hospital-acquired infections, many of which are complicated. The E. coli strains that cause most communityacquired infections originate from colonic flora. E. coli strains that have uropathogenic genes can be acquired from sources in the environment including food and water and colonize the colon (17). Women with increased susceptibility to infections are more often colonized on the perineum with E. coli, which brings the potential pathogen into close proximity with the urethra (10). Bacterial multiplication in the urinary tract results in cytokine generation by mucosal cells, with the production of interleukins (ILs) IL-6 and IL-8 (18,19). IL-6 activates acute-phase reactants

Table 13-3 Prevalence of Asymptomatic Bacteriuria Population Screened

Males 1–12 years old Females 1–12 years old Females 20–40 years old (including pregnant women) Males 20–40 years old Elderly ambulatory patients (men and women) Elderly bedridden patients (men and women) Chronically catheterized patients (men and women)

0.1% 1% 3–6% 0.1% 5–15% 10–50% 100%

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Table 13-4 Microbiology of Urinary Infection Uncomplicated

Escherichia coli Klebsiella spp. Enterobacter spp. Proteus spp. Pseudomonas spp. Staphylococcus saprophyticus Staphylococcus epidermidis Enterococci Group B streptococci Staphylococcus aureus Candida spp.

80–85% 1–3% 1–3% 1–3% 4.5 • Positive amine test • Clue cells

Trichomonads present on wet mount?

−

+

Consider: • Allergy • Hypersensitivity • Chemical/irritant

Treat for vulvovaginal candidiasis

No

Yes

Treat for Trichomonads trichomoniasis culture positive?

No

Yes

Possibilities include postcoital, post-douche, or atrophic vaginitis

Treat for bacterial vaginosis

No

Yes

Consider desquamative inflammatory vaginitis, erosive lichen planus, foreign body

Treat for trichomoniasis

Figure 17-2 Algorithm for the management of the patient with vulvovaginal symptoms. Abbreviations: KOH = potassium hydroxide; PMNs = polymorphonuclear leukocytes.

flora, specifically overgrowth of anaerobes in causing cervical inflammation, has been proposed. More specifically, bacterial vaginosis has recently been associated with cervical inflammation, both macroscopic and subclinical inflammation, identified on Pap smears (34). Rare causes of cervicitis include Mycobac-terium tuberculosis and Actinomyces israeli, the latter almost invariably in the presence of intrauterine devices. Although the most important and prevalent infection of the cervix is undoubtedly human papillomavirus (HPV), this virus does not cause cervicitis.

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Pap smear report of inflammation

Speculum examination

Appearance of cervix

Normal

Ectopy

Screen for Chlamydia trachomatis and Neisseria gonorrhoeae in women with high-risk characteristics‡

Mucopurulent cervicitis*

"Inflammatory" cervicitis

Confirm by Gramstain wet mount†

Exclude bacterial vaginosis (pH, microscopy)

Positive Positive in patient unlikely to follow-up Consider PID

Absent

Positive in Negative reliable patient

Test for C. trachomatis and N. gonorrhoeae

Consider colposcopy; refer to Ob-Gyn

Present Positive

Culture probe, DNA probe, or LCR urine test

Test for C. trachomatis or N. gonorrhoeae cervicitis

Treat PID

Positive

Negative

Observe

Trace and notify contacts

∗ Mucopurulent cervicitis is recognized by purulent endocervical discharge and friability. † Positive Gram stain is considered >30 PMNL/high-power field. ‡ High-risk characteristics include age 30 years ● A test for cure at 6 months after treatment of CIN 8. Treatment options for condyloma acumanata include: ● No treatment ● Patient-applied therapy ● Provider-applied therapies ● Surgical treatment 9. No prospective randomized trials have clearly shown that any one treatment for condyloma acumanata is superior. 10. HPV vaccine offers the best promise of effective HPV prevention. 352

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New Developments in the Management of Human Papillomavirus ●

●

The use of HPV testing for high-risk HPV: for follow-up of screening PAP of ASC, in addition to a screening PAP in women older than age 30 years; test for cure 6 months after treatment of CIN The development of HPV vaccines for the prevention of HPV associated intraepithelial neoplasia and cancer

Abbreviations: ASC = atypical squamous cells; CIN = cervical intraepithelial neoplasia; HPV = human papillomavirus.

H

uman papillomaviruses (HPVs) are DNA viruses associated with genital warts (condyloma acuminata), intraepithelial neoplasia and cancer of the female external genital tract (cervix, vagina and vulva), and the male external genital tract (penis and anus). Approximately 40 of the greater than 100 human papillomaviruses affect the external genital tract; the 4 most common are HPV 6, 11, 16, and 18 (1,2). More than 80% of highgrade intraepithelial neoplasia and cancers of the external genital tract are caused by HPV 16 or 18 (1,2). Most genital warts (condyloma acuminata) are caused by HPV 6 or 11 (1,2). Most HPV infections are transient with most men and women clearing their infection in 6 to 8 months (1,3,4).

Pathogenesis The ability of HPV infections to progress to intraepithelial neoplasia and cancer is caused by the incorporation of HPV DNA genes E6 and E7 into the human genome. HPV E6 and E7 interfere with tumor suppressor genes p53 and RB resulting in unregulated cell growth, intraepithelial neoplasia, and cancer (1,2). Histologically, the first sign of HPV infection is koilocytosis, which is described as perinuclear halos. Intraepithelial neoplasia develops as the HPV neoplastic process progresses. This is seen as abnormal maturation and atypia confined to the epithelium. Ultimately, intraepithelial neoplasia can progress to cancer with invasion through the epithelial basement membrane into the underlying stroma.

Epidemiology HPV is 1 of the most common sexually transmitted infections. Greater than 15% of the population or approximately 20 million people are infected with HPV (1,5). Maximum prevalence occurs between ages 15 and 25 years followed by a decrease until plateauing at age 35 years (1,5). At least 90% of young women and at least 50% of men who have intercourse will acquire

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HPV. The prevalence of HPV in men who have sex with men (MSM) is almost 100% (6). Genito-oral transmission is rare and neonatal transmission is infrequent (1). Although HPV infection is rampant, most infections are subclinical and transient with resolution in 6 to 8 months without treatment. Fewer than 1% of women with HPV infections will develop genital warts and 4% will develop cervical intraepithelial neoplasia (7). The lifetime risk of developing cervical cancer in the United States is less than 1% (7). Risks of vaginal and vulvar intraepithelial lesions and cancers are even lower. The incidence of anal intraepithelial neoplasia (AIN) and anal cancer has increased 2 to 3 times in the last 30 years. The main risk factors for progression of HPV infections into intraepithelial neoplasia or cancer are early age of first intercourse, multiple sexual partners, smoking, immunosuppression (HIV), and MSM. During puberty, the cervix undergoes metaplasia from a glandular to a squamous epithelium, and during this time the cervix is vulnerable to HPV. Early age of intercourse before age 15 years increases the relative risk of cervical cancer by 2.9 (8). An increased number of sexual partners increases a woman’s exposure to HPV and increases the odds of infection by an HPV to which she is not immunocompetent. Intercourse with 6 or more lifetime sexual partners increases the chance of developing cervical cancer by a relative risk of 2.1 (8). Smoking exposes the cervix to carcinogens, is immunosuppressive, and increases the relative risk of cervical cancer by 3.4 (9). Immunosuppression, such as in HIV or after transplantations, significantly increases the risk for HPV leading to intraepithelial neoplasia and cancer. HIV-seropositive women with CD4 counts less than 500/µL have an increased chance of developing cervical intraepithelial neoplasia (CIN) by a relative risk of 2.9 (10). HIV-seropositive MSM have a 95% prevalence of HPV infection and a 52% prevalence of high-grade AIN (6). HIV-seronegative MSM have a 5% prevalence of high-grade AIN (11).

Clinical Manifestations Condyloma Acuminata Condyloma acuminata appears most commonly on the vulvar and perianal area but may also infect the vagina and cervix. In men, condyloma acuminata appear most commonly on the penile shaft but may affect the glands, scrotum, or urethral meatus. Typical condyloma acuminata present as many wellcircumscribed exophytic cauliflower-like lesions (Table 18-1). Condylomas are usually approximately 5 mm in diameter but may be any size and in some instances may be so numerous that they form a confluent patch. Rather than the typical cauliflower-like lesions, condylomas may also be flat and sessile. The main presenting symptom of condyloma acuminata is pruritus.

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Table 18-1 Clinical Manifestations Condyloma Acuminata

Symptoms

Intraepithelial Neoplasia: VIN AIN CIN, VAIN

Pruritus Pruritus and bleeding Asymptomatic

Cancer: Vulvar

Cervical, vaginal

Anal

Physical Exam Multiple exophytic lesions

Brown, red, white raised lesion Brown, red, white raised lesion Needs colposcopy for visualization Postmenopausal pruritus ● Red, raised and exophytic or ulcerative ● Red, raised and exophytic or ulcerative ● Postcoital bleeding ● Postmenopausal bleeding ● Vaginal discharge ● Urological or intestinal symptoms ● Bleeding Red, raised and exophytic or ● Pruritus ulcerative ● Pain

Abbreviations: CIN = cervical intraepithelial neoplasia; VAIN = vaginal intraepithelial neoplasia; VIN = vulvar intraepithelial neoplasia.

Intraepithelial Neoplasia Vulvar intraepithelial neoplasia (VIN) can present anywhere on the vulva. These lesions can be any color but are usually brown in premenopausal women and red or white in postmenopausal women. Typically the lesions are well circumscribed and raised. The most common presenting symptom of VIN is persistent, vulvar pruritus. CIN and vaginal intraepithelial neoplasia (VAIN) are routinely invisible to the naked eye. They can be visualized by the use of a colposcope after the application of acidic acid. During colposcopy, VAIN typically appears as a thickened, white, discrete lesion; and CIN appears as a thickened, white, discrete area, which may also have red blood vessels giving a punctation or mosaic tile–like appearance. Routinely, CIN and VAIN are asymptomatic and are picked up during PAP screening. Similar to VIN, anal intraepithelial neoplasia (AIN) can be any color but usually are red, well circumcised, and raised. The most common presenting symptoms of AIN are pruritus or bleeding.

Cancer The main symptoms of vulvar cancer are persistent, postmenopausal pruritus; bleeding; and pain. The lesions tend to be raised and exophytic or

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ulcerative. The lesions may be any color but are typically red. Cervical cancer typically presents with postcoital bleeding. Other symptoms may include postmenopausal bleeding or vaginal discharge. As cervical cancer progresses, it may cause pressure on the bladder or rectum resulting in urologic or intestinal symptoms. The terrible triad of advanced cervical cancer includes sciatic back pain, hydroureter, and leg swelling. Cervical cancers tend to be red and exophytic or ulcerative. Vaginal cancer typically presents with postmenopausal bleeding or postcoital bleeding. Symptoms caused by pressure on the bladder or rectum appear sooner than in cervical cancer. Vaginal cancers tend to be red and exophytic or ulcerative. The main symptoms of anal cancer are bleeding, pruritus, and pain. The lesions tend to be raised, exophytic, or ulcerative and are usually red.

Diagnosis Condyloma Acuminata Visual inspection is usually sufficient for diagnosis of genital warts. Biopsy is usually unnecessary unless the wart has an unusual appearance or grows despite adequate treatment. Unusual appearances of warts that may necessitate biopsy include atypical size or shape, unusual pigmentation, or a fixed or ulcerative lesion. To differentiate condyloma acuminata from a verrucous type of squamous cancer, the biopsy must be taken at the base of the lesion.

Intraepithelial Neoplasia The diagnosis of VIN and AIN is made by full thickness biopsy usually obtained using a dermal Keyes punch after local anesthesia is administered. Application of silver nitrate along with 5 to 10 minutes of direct pressure is usually sufficient to prevent hemorrhage. The diagnosis of CIN and VAIN is usually first suggested after PAP screening. PAP screen follow-up is shown in Table 18-2. A screening PAP result of squamous intraepithelial lesion, high grade, requires colposcopic examination for definitive diagnosis. Biopsy is required at colposcopy unless an excisional procedure (loop electrosurgical excision procedure [LEEP] or conization) is done for treatment. Colposcopic biopsy should not occur during pregnancy unless it is needed to rule out invasive cancer. Because a screening PAP result of squamous intraepithelial lesion— low-grade or ASC is rarely associated with a high-grade CIN (15% and 5%, respectively), colposcopy is not always required (12,13). A screening PAP result of squamous intraepithelial lesion, low grade, or ASC can be followed by repeat PAP in 3 to 6 months or colposcopic examination. Alternatively,

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Table 18-2 Pap Screening Follow-Up Pap

Normal ASC

Follow-Up

Repeat 1 year Repeat Pap in 6 months, or ● Colposcopy, or ● HPV testing for high risk HPV ●

ASC-H LGSIL

Colposcopy

HGSIL

Colposcopy

Comment

If HPV high risk positive: perform colposcopy ● If HPV high risk negative: repeat Pap in 1 year ● Alternate to colposcopy would repeat Pap in 6 months, especially in adolescence ● Do not perform HPV testing Do not perform HPV testing ●

Abbreviations: ASC = atypical squamous cells; HPV = human papillomavirus; HGSIL = high-grade squamous intraepithelial lesion; LGSIL = low-grade squamous intraepithelial lesion.

a screening PAP of ASC can be triaged by HPV testing for high-risk HPV types. If HPV testing is positive for high-risk HPV types (HPV 16 or 18), colposcopy should be done. If HPV testing is negative for high-risk HPV types, repeat PAP can be done in 1 year. HPV testing is not indicated for triage of a screening PAP of squamous intraepithelial lesion, low or high grade, because HPV testing is routinely positive in these cases. Other indications for HPV testing for high-risk HPV, besides its use in the management of ASC, are described in Table 18-3. Women older than 30 years can have HPV testing in addition to routine PAP screening; and if both are negative, screening can be repeated in 3 years rather than annually (12,14,15). Also, HPV testing can be used as a test of cure at 6 months after treatment of CIN2-3 (12,16).

Cancer Any tumor of the vulva, vagina, cervix, or anus suspicious for cancer should be biopsied.

Table 18-3 Indications for Human Papillomavirus Testing for High-Risk Human Papillomavirus ●

●

●

Triage of screening PAP of ASC; do not do HPV testing for triage of ASC-H, LGSIL, or HGSIL because HPV testing is routinely positive in these situations. Screening PAP with HPV testing in women older than age 30 years. If both tests are negative, screening PAP can be repeated in 3 years instead of annually. A test for cure 6 months after treatment of CIN with LEEP, laser cone, etc.

Abbreviations: ASC = atypical squamous cells; CIN = cervical intraepithelial neoplasia; HPV = human papillomavirus; HGSIL = high-grade squamous intraepithelial lesion; LEEP = loop electrosurgical excision procedure; LGSIL = low-grade squamous intraepithelial lesion.

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Treatment Condyloma Acuminata Treatment options for condyloma acuminata include no treatment, patientapplied therapy, provider-applied therapies, and surgical treatment (Table 184). Prospective studies have shown that up to 30% of warts will spontaneously resolve in 3 months; and therefore, no treatment with repeat evaluations is an option (17). There are no prospective randomly assigned trials, which have clearly shown that any 1 treatment is superior. The 2 most common patientapplied therapies are podofilox (0.5% solution or gel) and imiquimod (5% cream). These therapies have approximately a 70% cure rate with a 30% recurrence rate (17-19). Neither podofilox or imiquimod should be used during pregnancy. The most common physician-administered local therapies are podofilox resin (10%-25%) and trichloroacetic acid (80%-90%). The cure rates and recurrence rates are similar to patient-applied therapy (17-19). Surgical treatment includes cryotherapy, surgical excision, and laser ablation. Surgical treatment tends to have a slightly higher cure rate (approaching 90%) with similar recurrence rates compared to patient or physician applied therapies (17). A small percentage of patients treated with laser ablation develop postlaser severe pain, which can last for up to a month.

Intraepithelial Neoplasia Moderate to severe VIN should be treated with surgical excision (20). If microinvasive cancer can be ruled out, laser ablation is also appropriate. Lowgrade VIN can be treated with excision, laser ablation or close follow-up. Moderate to severe CIN can be treated with LEEP, knife conization, laser ablation, or cryotherapy. Prospective studies have shown similar cure rates with all modalities except for slightly inferior results with cryotherapy when treating large, high-grade lesions (21). An advantage of LEEP is that it is an office procedure and also obtains a pathologic specimen to rule out invasive cancer.

Table 18-4 Treatment of Genital Warts Treatment

Notes

Observation Patient-applied therapies ● Podofilox ● Imiquimod Physician-applied therapies ● Podofilox resin ● Trichloroacetic acid Surgical excision

30% regression rate ● ●

Podofilox: bid × 3 dqwk, total area 10 cm2 Imiquimod: qHS × 3 dqwk, total area 20 cm2

Abbreviations: bid = twice daily; d = day; HS = at bedtime; q = every; wk = week.

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Moderate to severe VAIN can be treated with surgical excision or laser ablation. Technically, excision of VAIN is more difficult than the excision of CIN (22). Low-grade CIN, VAIN, and VIN can be treated expectantly with close follow-up because up to 70% of these lesions will resolve spontaneously without treatment. Treatment of AIN is challenging. Surgical excision is the mainstay of treatment, but recurrence in HIV seropositive men is common (23).

Cancer Vulvar, vaginal, and cervical cancers should be treated using the modified Halsted philosophy of cancer surgery, which involves removing the tumor en bloc, with an adequate margin (usually 2 cm) and regional lymph nodes. For vulvar cancer this entails a modified radical vulvectomy with inguinal lymphadenectomy. For cervical cancer this requires a radical hysterectomy with pelvic lymphadenectomy. For vaginal cancer this requires a modified radical vaginectomy with pelvic lymphadenectomy. Advanced-stage cervical and vaginal cancers are treated with chemoradiation. Chemoradiation has replaced radical surgery (abdominoperineal resection with colostomy) as the initial treatment of anal cancer. 5-Fluoracil and mitomycin C or 5-fluorouracil and cisplatinum is administered concomitantly with external beam radiation (24).

Prevention Presently, the best HPV prevention measures are through sexual abstinence. Because this is not necessarily practical, an alternate strategy is emphasis on patient education about decreasing the risk factors for progression of HPV infections into intraepithelial neoplasias or cancers (Table 18-5). This includes delaying the onset of sexual debut; limiting the number of sexual partners, preferably remaining in a monogamous relationship; and avoiding cigarettes. Using condoms provides some protection against HPV transmission. HPV vaccine offers the best promise of effective HPV prevention if administered in preadolescence before their sexual debut. Presently, 2 large studies have been done, and early data indicated that the vaccines are highly effective in preventing persistent infection and CIN. In a study of more than 2000 women receiving an HPV 16 vaccine, no patients in the vaccine group developed persistent HPV infection versus 4% in the placebo group (25). Even more importantly, at 4-year follow-up, no patient in the vaccine group developed high-grade CIN versus 2% in the placebo group (26). In a study using a HPV 16 or 18 vaccine in more than 1000 women, 0.1% of patients who received the vaccine developed persistent infections versus 4% in the placebo group (27).

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Table 18-5 Patient Education on Human Papillomavirus Infection ●

● ●

● ●

● ● ●

● ●

HPV infection is very common. Almost all sexually active men and women are infected with HPV sometime in their lives. Most HPV infections are asymptomatic and resolve spontaneously. Reduce risk of developing HPV-related diseases by delaying sexual debut, limiting the number of sexual partners, not smoking, and using condoms. If both partners remain monogamous, rarely can partners reinfect each other. If a patient is in a monogamous relationship and develops HPV, it does not mean the partner cheated. The Pap test is an excellent screen for cervical cancer. Annual Pap screening decreases chances of dying from cervical cancer by 95%. Patients with persistent vulva or anal pruritus, a vulvar mass, anal bleeding, or postcoital bleeding should seek medical attention. Genital warts cannot be spread to other parts of the body. Genital warts in pregnancy rarely cause complications, rarely will the child be infected, and caesarean delivery is not useful in preventing HPV transmission to the baby.

Abbreviation: HPV = human papillomavirus.

REFERENCES 1. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin. Clinical Management Guidelines for Obstetrician-Gynecologists. Number 61, April 2005. Human papillomavirus. Obstet Gynecol. 2005;105:905-18. 2. International Agency for Research on Cancer Multicenter Cervical Cancer Study Group. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med. 2003;348:518-27. 3. Franco EL,Villa LL, Sobrinho JP, Prado JM, Rousseau MC, Désy M, et al. Epidemiology of acquisition and clearance of cervical human papillomavirus infection in women from a high-risk area for cervical cancer. J Infect Dis. 1999;180:1415-23. 4. Ho GY, Bierman R, Beardsley L, Chang CJ, Burk RD. Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med. 1998;338:423-8. 5. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines 2002. MMWR Recomm Rep. 2002;51(RR-6):1-78. 6. Palefsky JM, Holly EA, Efirdc JT, Da Costa M, Jay N, Berry JM, et al. Anal intraepithelial neoplasia in the highly active antiretroviral therapy era among HIV-positive men who have sex with men. AIDS. 2005;19:1407-14. 7. Lawson HW, Lee NC, Thames SF, Henson R, Miller DS. Cervical cancer screening among lowincome women: results of a national screening program, 1991-1995. Obstet Gynecol. 1998;92:745-52. 8. Herrero R, Brinton LA, Reeves WC, Brenes MM,Tenorio F, de Britton RC, et al. Sexual behavior, venereal diseases, hygiene practices, and invasive cervical cancer in a high-risk population. Cancer. 1990;65:380-6. 9. Slattery ML, Robison LM, Schuman KL, French TK, Abbott TM, Overall JC Jr., et al. Cigarette smoking and exposure to passive smoke are risk factors for cervical cancer. JAMA. 1989;261:1593-8. 10. Harris TG, Burk RD, Palefsky JM, Massad LS, Bang JY,Anastos K, et al. Incidence of cervical squamous intraepithelial lesions associated with HIV serostatus, CD4 cell counts, and human papillomavirus test results. JAMA. 2005;293:1471-6. 11. Chin-Hong PV,Vittinghoff E, Cranston RD, Browne L, Buchbinder S, Colfax G, et al. Age-related prevalence of anal cancer precursors in homosexual men: the EXPLORE study. J Natl Cancer Inst. 2005;97:896-905. 12. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin number 66, September 2005. Management of abnormal cervical cytology and histology. Obstet Gynecol. 2005;106:645-64.

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13. ASCUS-LSIL Triage Study (ALTS) Group. A randomized trial on the management of low-grade squamous intraepithelial lesion cytology interpretations. Am J Obstet Gynecol. 2003;188:1393-400. 14. Sherman ME, Lorincz AT, Scott DR, Wacholder S, Castle PE, Glass AG, et al. Baseline cytology, human papillomavirus testing, and risk for cervical neoplasia: a 10-year cohort analysis. J Natl Cancer Inst. 2003;95:46-52. 15. Bory JP, Cucherousset J, Lorenzato M, Gabriel R, Quereux C, Birembaut P, et al. Recurrent human papillomavirus infection detected with the hybrid capture II assay selects women with normal cervical smears at risk for developing high grade cervical lesions: a longitudinal study of 3,091 women. Int J Cancer. 2002;102:519-25. 16. Wright TC Jr., Schiffman M, Solomon D, Cox JT, Garcia F, Goldie S, et al. Interim guidance for the use of human papillomavirus DNA testing as an adjunct to cervical cytology for screening. Obstet Gynecol. 2004;103:304-9. 17. Beutner KR, Reitano MV, Richwald GA,Wiley DJ. External genital warts: report of the American Medical Association Consensus Conference. AMA Expert Panel on External Genital Warts. Clin Infect Dis. 1998;27:796-806. 18. Gunter J. Genital and perianal warts: new treatment opportunities for human papillomavirus infection. Am J Obstet Gynecol. 2003;189:S3-11. 19. Wiley DJ, Douglas J, Beutner K, Cox T, Fife K, Moscicki AB, et al. External genital warts: diagnosis, treatment, and prevention. Clin Infect Dis. 2002;35:S210-24. 20. Modesitt SC, Waters AB, Walton L, Fowler WC Jr., Van Le L. Vulvar intraepithelial neoplasia III: occult cancer and the impact of margin status on recurrence. Obstet Gynecol. 1998;92:962-6. 21. Mitchell MF,Tortolero-Luna G, Cook E,Whittaker L, Rhodes-Morris H, Silva E. A randomized clinical trial of cryotherapy, laser vaporization, and loop electrosurgical excision for treatment of squamous intraepithelial lesions of the cervix. Am J Obstet Gynecol. 1998;92, S737-44. 22. Fanning J, Manahan KJ, McLean SA. Loop electrosurgical excision procedure for partial upper vaginectomy. Am J Obstet Gynecol. 1999;181:1382-5. 23. Chang GJ, Berry JM, Jay N, Palefsky JM,Welton ML. Surgical treatment of high-grade anal squamous intraepithelial lesions: a prospective study. Dis Colon Rectum. 2002;45:453-8. 24. Sato H, Koh PK, Bartolo DC. Management of anal canal cancer. Dis Colon Rectum. 2005;48:1301-15. 25. Proof of Principle Study Investigators. A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med. 2002;347:1645-51. 26. Mao C, Koutsky LA,Ault KA,Wheeler CM, Brown DR,Wiley DJ, et al. Efficacy of human papillomavirus-16 vaccine to prevent cervical intraepithelial neoplasia: a randomized controlled trial. Obstet Gynecol. 2006;107:18-27. 27. GlaxoSmithKline HPV Vaccine Study Group. Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomised controlled trial. Lancet. 2004;364:1757-65.

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Part VI

Respiratory Tract Infections

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Chapter 19

Pharyngotonsillitis, Peritonsillar, Retropharyngeal, and Parapharyngeal Abscesses, and Epiglottitis ITZHAK BROOK, MD, MSC

Key learning points 1. Antimicrobials should be administered only to treat pharyngotonsillitis caused by Group A streptococci, documented by rapid test or culture. 2. Antimicrobials other than penicillins (e.g. cephalosporins, clindamycin) may be more efficacious in eradicating Group A streptococci. However, presently penicillin remains the recommended treatment for Group A streptococcal pharyngitis. 3. Most peritonsillar, retropharyngeal, and lateral pharyngeal abscesses are caused by polymicrobial aerobic-anaerobic flora. 4. The treatment of choice for oral cavity abscess is surgical drainage combined with the administration of parenteral antimicrobial therapy directed at the polymicrobial flora. 5. Complete airway obstruction is the major risk in acute epiglottitis. 6. The H. influenzae vaccine has decreased but not eliminated the number of epiglotittis due to infection with this organism.

Pharyngotonsillitis Pharyngotonsillitis (PT) is characterized by the presence of increased redness and an exudate or ulceration in the pharynx or tonsil or a membrane that covers the tonsils. Because the pharynx is served by lymphoid tissues of Waldeyer ring, an infection can spread to include various parts of the ring, such as the nasopharynx, uvula, soft palate, tonsils, adenoids, and 365

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Box 19-1 New Developments in the Management Streptococcal Infection ● ● ● ●

Group A streptococci resistance to the macrolides is growing. Penicillin failure rate in eradicating group A streptococci may reach up to 35%. Toothbrushes may serve as a source of reinoculation of group A streptococci. Anaerobic bacteria may be involved in nonstreptococcal tonsillitis.

cervical lymph glands (1,2). Based on its extent, the infection can be called pharyngitis, tonsillitis, tonsillopharyngitis, or nasopharyngitis. Furthermore, any of these illnesses can be acute, subacute, or recurrent.

Etiology The finding of PT generally requires the consideration of infection with group A β-hemolytic streptococci (GABHS); however, many other bacteria, viruses, other infectious agents, and noninfectious causes should be considered sources of PT (1). Recognizing the causative agent(s) and choosing appropriate therapy are of the utmost importance in ensuring a rapid recovery and for preventing complications. The different agents that cause PT and the characteristic clinical features they produce are shown in Table 19-1. The occurrence of a particular etiologic agent depends on numerous variables, including environmental conditions (e.g., season, geographic location, exposure) and individual variables (e.g., age, host resistance, immunity). The most prevalent agents responsible for PT are GABHS, adenoviruses, influenza and parainfluenza viruses, Epstein-Barr virus, and enteroviruses. However, the precise cause is generally not measured, and the role of some potential pathogens is uncertain. Recent studies have suggested that interactions between various organisms, including GABHS, other aerobic and anaerobic bacteria, and viruses, may occur during PT. Some interactions may be synergistic (e.g., the relationship between Epstein-Barr virus and anaerobic bacteria) (3), thus enhancing the virulence of some pathogens. Others may be antagonistic (e.g., the relationship between GABHS and certain interfering β-hemolytic streptococci) (4). Furthermore, β-lactamase–producing bacteria (BLPB) can protect themselves and other bacteria from β-lactam antibiotics (5).

Aerobic Bacteria Infection with GABHS is the most common bacterial cause of PT. It is an endemic infection, peaks in late winter and early spring, is rare in children younger than 2 years of age, and generally occurs in children 5 to 11 years of age. However, people of all ages are susceptible. Non-GABHS organ-

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Table 19-1 Infectious Agents of Pharyngotonsillitis Organism

Bacteria Aerobic Groups A, B, C, and G streptococci Streptococcus pneumoniae Staphylococcus aureus Neisseria gonorrhoeae Neisseria meningitidis Corynebacterium diphtheriae Corynebacterium haemolyticum Arcanobacterium haemolyticum Bordetella pertussis Haemophilus influenzae Haemophilus parainfluenzae Salmonella typhi Francisella tularensis Yersinia pseudotuberculosis Treponema pallidum Mycobacterium spp. Anaerobic Peptostreptococcus spp. Actinomyces spp. Pigmented Prevotella and Porphyromonas spp. Bacteroides spp. Mycoplasma Mycoplasma pneumoniae Mycoplasma hominis Viruses and Chlamydia Adenovirus Enteroviruses (e.g., poliovirus, echovirus, coxsackie virus) Parainfluenza virus types 1–4 Epstein–Barr virus Herpesvirus hominis Respiratory syncytial virus Influenza virus A and B Cytomegalovirus Rheovirus Measles virus Rubella virus Rhinovirus Chlamydia trachomatis and C. pneumoniae Fungi Candida spp. Parasites Toxoplasma gondii Rickettsia Coxiella burnetii

Clinical Lesions

Clinical Frequency

Er, E Er, Er, Er, Er, Er, Er, Er, Er, Er, Er Er, Er Er, Er

Ex, F, P

A C C C C C C C C C C C C C C C

Er, Er, Er, Er,

E U Ex, U Ex, U

C C C C

Er, Ex, F Er, Ex

B C

Er, Ex, F Er, Ex, U

A A

Er Er, Ex, F Er, Ex, U Er Er Er Er Er, P P Er Er

A B C C A C C C C C C

Er, Ex

B

Er

C

Er

C

Ex, F Ex Ex Ex Ex Ex Ex Ex Ex Ex F

A = most frequent (>66% of cases); B = frequent (33%–66% of cases); C = uncommon (5 mm in adults) are indicative of infection as established by sinus aspiration in 75% of cases, whereas a normal radiograph correlates with a negative aspirate in 80% of cases (1). Radiology is less useful in cases of chronic sinusitis, because of persistent abnormalities, and in infants younger than 12 months of age, because of redundant sinus mucosa and asymmetry of sinus development. Limited-view computed tomography (CT), a very sensitive means of diagnosing sinus abnormalities, is recommended more than plain sinus radiography because of similar cost. CT scanning has a role in chronic sinusitis in helping to differentiate bacterial from fungal disease, with bone destruction sometimes seen in the latter. The predominant bacterial pathogens are Streptococcus pneumoniae and Haemophilus influenzae, which together are responsible for more than 50% of cases of acute maxillary sinusitis in both children and adults. In children, Moraxella catarrhalis is another common pathogen. Recovery of anaerobes in acute sinusitis should prompt an investigation for an odontogenic source of infection. Anaerobes are also more commonly encountered in cases of chronic sinusitis. Staphylococcus aureus, although a common nasal colonist, is an uncommon cause of community-acquired maxillary sinusitis. However, S. aureus and streptococci are major pathogens in sphenoid sinusitis. The sinuses also have been reported to serve as reservoirs of S. aureus in cases of toxic shock syndrome. Viruses can be isolated in approximately 15% of cases of sinusitis. The most common viral isolate is rhinovirus. Viruses are thought to be the major

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agents predisposing to bacterial sinusitis, but the temporal delay between URI and bacterial sinusitis may account for the low viral culture rate seen at the time of presentation with sinusitis. Nosocomial sinusitis is commonly polymicrobial and caused by gramnegative bacilli or S. aureus, and less frequently by anaerobes. Predisposing factors include the presence of nasopharyngeal or nasogastric tubes, nasal packing, nasal cranial fractures, previous antibiotic use, corticosteroid therapy, and mechanical ventilation. Fungal sinusitis is rare among cases of community-acquired disease. It is usually seen in debilitated patients. Aspergillus is the most common fungal pathogen, and it can infect in a noninvasive or invasive manner. The noninvasive infection, more often seen in immunocompetent individuals, includes allergic aspergillosis and rarely mycetoma. Invasive Aspergillus occurs primarily in immunocompromised or HIV-infected patients. Rhinocerebral mucormycosis is a fulminant fungal infection occurring in debilitated and immunocompromised patients. It is often seen in individuals with uncontrolled diabetes with ketoacidosis, profoundly dehydrated children, and persistently neutropenic patients (especially those with lymphoreticular malignancy). Mucormycosis begins in the nose and can rapidly spread by way of the sinuses to the orbits or central nervous system (CNS). The diagnosis is suspected in acutely febrile patients with a blackened nasal discharge and eschar on the palate and nasal mucosa, cranial nerve findings, or altered mental status. Certain patients are predisposed to sinus infection with specific organisms. Patients with cystic fibrosis, for example, are predisposed to sinus infection with Pseudomonas aeruginosa and S. aureus. Immunocompromised patients with nosocomial sinusitis have a higher rate of polymicrobial infection with gram-negative bacteria such as Escherichia coli, Pseudomonas species, and Serratia species.

Treatment The goals of therapy for sinus infection are to eradicate infection, restore or alleviate sinus function, provide symptomatic relief, and prevent suppurative complications. Empiric treatment of sinus infection should target the most common infections in the patient’s age and cultural/environmental group, while also taking into consideration the duration of the infection. The specific bacterial resistance patterns in each community and hospital should also be taken into account. Until recently, amoxicillin was the mainstay of treatment of sinus infection. With the increase in beta-lactamase–producing strains of Haemophilus and Moraxella, other agents can be considered. Increasing emergence of resistant S. pneumoniae is also of concern. Antibiotics to consider include amoxicillin–clavulanate, cefuroxime axetil, new macrolides (telithromycin, azithromycin, or clarithromycin), and fluoroquinolones that have enhanced pneumococcal activity (levofloxacin and

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Table 20-2 Treatment of Acute Sinusitis or Otitis Media Penicillins

High-dose Amoxicillin Amoxicillin/ Clavulanate-ER

Adult

Pediatrics

1000 mg tid

90 mg/kg/d div q8 or q12h extra strength 90 mg/kg/d div q8 or q12h

2000 mg bid

Cephalosporins

Cefuroxime axetil Cefpodoxime

250 mg bid 200 mg bid

Cefixime Cefdinir Cefprozil

500 mg qd 600 mg qd 250-500 mg qd

30 mg/kg/d div q12h 10 mg/kg/d qd (max 400 mg) 8 mg/kg/d 14 mg/kg/d 30 mg/kg/d div q12h

250-500 mg bid 500 mg once, then 250 mg qd×4d

15 mg/kg/d div q12h 10 mg/kg once, then 5 mg/kg qd×4d

750 mg qd 400 mg qd

do not use do not use

1 DS bid

8-12 mg TMP kg/d/ 40-60 mg SMX kg/d div q12

Macrolides

Clarithromycin Azithromycin Fluoroquinolones

Levofloxacin Moxifloxacin Sulfa

TMP-SMX

* All treatments listed by mouth. Abbreviations: bid = twice a day; d = day; div = divide; DS = double strength; max = maximum; q = every; tid = three times a day; TMP-SMX = trimethoprim-sulfamethoxazole.

moxifloxacin) (Table 20-2). The local incidence of resistant S. pneumoniae should be taken into consideration when selecting a first-line antimicrobial agent for treating sinus infection. The recommended duration of initial treatment is for a 7- to 10-day course of antibiotics. A general treatment algorithm for primary management of acute sinusitis is given in Figure 20-1 (2-4). In general, bacterial sinusitis should be considered when symptoms have been present or worsened over at least 7 days. At this point an antibiotic can be given. If there is not significant resolution in 3 to 5 days or a relapse, resistant flora might be present; and a switch in antibiotics to a more broad spectrum agent is indicated. If there is no resolution of the symptoms after a switch of antibiotics, the primary care physician should consider referral for otolaryngology consultation. The patient should also be carefully questioned to assess for development of extension of disease or more serious complications. Complications include local extension causing sinus osteomyelitis, orbital cellulitis, or infection to the CNS including meningitis, brain abscess, or infection of the intracranial venous sinuses. Fortunately, these complications are rare with treatment. If

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Signs and symptoms of URI

Symptoms for 10-14 d ● New macrolide ● Fluoroquinolone Chronic bronchitis Increased cough and sputum ● Haemophilus ● Ketolides (respiratory) without risk factors volume, sputum purulence, influenzae ● Haemophilus spp ● 2nd or 3rd generation ● Beta-lactam/beta(simple) and increased dyspnea ● No comorbid illness ● Moraxella cephalosporin lactamase inhibitor ● 3 months after transplant)

Sickle cell disease HIV infection and CD4 cell count of 37ºC (98.6ºF) Crackles Rhonchi Confusion Consolidation

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the following: respiratory rate more than 30 breaths per minute, diastolic blood pressure less than 60 mm Hg, or blood urea nitrogen greater than or equal to 7 mmol/L (41). Patients with two or more of the preceding findings had a death rate 16 times higher than those who did not have such findings (42). Another variation of the preceding scoring system is the CURB-65 rule wherein age older than 65 years is added to the features just given (43). In this system, one point is given for the presence of any of these findings. For a score of 0 or 1 the death rate is 1.5%, although for 2 it is 9%, and for 3 or more it is 22%. The authors suggested that patients with a CURB-G5 score of 0-1 be treated as outpatients, those with a score of 2 be admitted to the ward, and those with a score of ≥ 3 often require ICU care. A more complex severity of illness scoring system was described by Fine and coworkers (44). Using this method, points are assigned for 20 different items (Table 23-7). These points are then totaled, and a patient is placed into one of five risk strata for death. Patients in risk classes I to III (131 points) has a 27% death rate. This scoring system has been used to help with the admission decision. Patients in classes I and II can be treated on an ambulatory basis; those in classes IV and V should be admitted. Patients in class III can require a period of observation in the emergency room before a decision is made about admission or discharge. Those who are improving can be sent home. With further study it has become apparent that the Fine scoring system is a guide only to the point-of-care decision, as are all the other systems designed to predict death. A physician’s judgement is crucial in the admission decision. Many factors including psychosocial ones also influence the admission decision. Functional status in the week before admission predicts in-hospital death (45). For those who were walking without assistance there was a 3.5% in hospital death rate, although for those who required assistance to walk the death rate was 5.6%, and for those who were wheelchair and bed bound the rates were 20% and 25% respectively. Both hypo- and hypercapnia at the time of admission are associated with excess death rates. In a study of 2171 patients, those with a partial pressure of carbon dioxide (PCO2) of less than 32 mm Hg had a 1.8 times higher death rate than those who had a normal value, although those with a PCO2 of greater than 45 had a 2.6 times higher death rate (46). All patients with pneumonia who are discharged from the emergency room should be given printed material clearly stating what indicates worsening of the pneumonia with instructions to return if any of these occur. It is not uncommon that patients who are sent home from the emergency room with CAP will have a positive blood culture reported later. All of these patients should be recalled for assessment. If they are doing well there is no need for admission except for patients with S. aureus bacteremia, in which case rightsided endocarditis must be ruled out. In patients with bacteremia and pleuritic chest pain, a careful assessment for empyema must be carried out.

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Table 23-7 Community-Acquired Pneumonia Severity-of-Illness Scoring System: How to Assign Points* (44) Patient Characteristics

Number of Points

Demographic Factors

Age Men Women Nursing home resident

Age in years Age in years minus 10 10

Coexisting Illnesses

Neoplastic disease1 Liver disease2 Congestive heart failure3 Cerebrovascular disease4 Renal disease5

30 20 10 10 10

Physical Examination Findings

Altered mental status6 Respiratory rate >30/min Systolic blood pressure 125/min

20 20 20 15 10

Laboratory and Radiographic Findings

Arterial pH 30 mg/dL (11 mmol/L) Sodium 250 mg/dL (14 mmol/L) Hematocrit 103 CFU/mL for PSB) after 72 hours of antimicrobial therapy suggests that the treatment regimen is ineffectual. Studies differ on the utility of invasive versus noninvasive diagnostic management strategies for HAP, particularly VAP. A study from France evaluated whether an invasive diagnostic approach using PSB or BAL was superior to clinical criteria in 413 ICU patients with a clinical suspicion of VAP (9). Patients managed with the invasive strategy had a significantly lower 14 day death (16% versus 26%); this advantage persisted at day 28 and was also associated with significantly more antibiotic-free days and a lower mean number of antibiotics administered. However, other studies have not shown that these invasive techniques affect patient outcome. As an example, 1 study of 132 patients with VAP who had bronchoscopy demonstrated no improvement in mortality when

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bronchoscopy successfully defined the pathogen, which occurred in approximately 50% of the patients (10). The adequacy of initial, empiric antibiotics seemed to be a more important factor in determining death. Recently, the American College of Chest Physicians assembled a panel of scientific experts to develop recommendations for assessing diagnostic tests for VAP based on a rigorous review of the literature (6). The panel concluded there is insufficient high-level evidence to indicate that quantitative testing procedures produce better clinical outcomes than empiric therapy. However, 1 benefit of quantitative culture is reduced use of antibiotics. Antibiotics can be safely stopped in patients with negative quantitative cultures, with no adverse effect on mortality (2). This strategy should reduce the selective potential for antimicrobial resistance, adverse effects, and costs, which are associated with overuse of broad spectrum antimicrobials. In the new ATS/IDSA guidelines, the emphasis was to tie diagnostic approaches to management, and it was acceptable to use either a clinical or bacteriologic strategy, provided that there was an effort to use the culture data to achieve appropriate therapy with the least exposure to antibiotics possible. Thus, it is always necessary to obtain a lower respiratory tract sample before initiating or changing therapy and to use the results, along with serial evaluations of the clinical course, to modify therapy. In the new guidelines, the emphasis on antibiotic control is not at the time of diagnosis, but rather on day 2 to 3, when more data are available, and it is possible to use this information to modify therapy (see the following text). In summary, the diagnosis of HAP, VAP, and HCAP is imprecise when using clinical data alone, but the use of bronchoscopic methods to obtain respiratory specimens for microbiologic diagnosis remains controversial. Thus, the most important intervention is to obtain a lower respiratory tract sample for culture, if available, from all patients suspected with HAP before antimicrobial therapy. However, the collection of a sample for culture should not hold up the initiation of therapy, because delay of antimicrobial therapy is associated with poor outcomes.

Treatment Available information suggests that the outcome of NP is improved when effective antimicrobial agents are given initially (2). The importance of providing early effective antimicrobial therapy for NP patients has been demonstrated in several recent investigations of VAP patients. These studies have shown that the death attributable to VAP was significantly greater among patients who received inappropriate initial antimicrobial therapy (during the first 24 hours) than it was among patients who received appropriate initial therapy. In the new guidelines, the term appropriate was used to refer to a therapy that was active, in vitro, against the etiologic pathogen. The term adequate referred to not only using appropriate therapy, but

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using it in a timely manner, by the right route, having it penetrate to the site of infection, and having it administered in the correct dosage. Antimicrobial management of NP can be divided into empirical and pathogen-directed therapy. Certainly, once a pathogen is isolated from an appropriate lower respiratory tract specimen, therapy can be given on the basis of in vitro-susceptibility test results and other characteristics of the antimicrobial agent and host. However, most patients initially are treated empirically, and the choice of antimicrobial agent(s) should be based on local susceptibility patterns and the most likely pathogens. Clinicians should be aware of the most common bacterial pathogens in NP and their susceptibility patterns associated in the hospitals where they practice. A summary of management strategies is represented in Figure 24-1. Antimicrobial selection for each patient should be based on risk factors for MDR pathogens (Figure 24-2). The choice of antibiotic should be influenced by the patient’s recent antibiotic therapy (if any), the resident flora in the hospital or ICU, the presence of underlying diseases, and available culture data (interpreted with care). For patients with risk factors for MDR pathogens, empiric broad spectrum, multidrug therapy is recommended to provide the

HAP, VAP or HCAP Suspected

Obtain Lower Respiratory Tract (LRT) Sample for Culture (Quantitative or Semi-quantitative) & Microscopy Unless There Is Both A Low Clinical Suspicion for Pneumonia & Negative Microscopy of LRT Samply, Begin Empiric Antimicrobial Therapy Using Algorithm in Figure 2 & Local Microbiologic Data Days 2 & 3: Check Cultures & Assess Clinical Response: (Temperature, WBC, Chest X-ray, Oxygenation, Purulent Sputum, Hemodynamic Changes & Organ Function)

Clinical Improvement at 48-72 Hours

YES

NO Cultures −

Search for Other Pathogens, Complications, Other Diagnoses or Other Sites of Infection

Cultures + Adjust Antibiotic Therapy, Search for Other Pathogens, Complications, Other Diagnoses or Other Sites of Infection

Cultures −

Consider Stopping Antibiotics

Cultures +

De-escalate Antibiotics, if Possible. Treat Selected Patients for 7-8 Days & Reassess

Figure 24-1 Summary of management strategies for nosocomial pneumonia. Republished with permission from: Niederman MS, Craven DE, Bonten MJ, et al. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005;171:388-416.

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Empiric Antibiotic Therapy for HAP HAP, VAP or HCAP Suspected (All Disease Severity)

HAP, VAP or HCAP Suspected Late Onset ( >5 days) or Risk Factors for Multi-drug Resistant (MDR) Pathogens (Table 2) No

Limited Spectrum Antibiotic Therapy (Table 1)

Yes Broad Spectrum Antibiotic Therapy For MDR Pathogens (Table 2)

Figure 24-2 Decision for initiating empiric therapy for nosocomial pneumonia. Republished with permission from Niederman MS, Craven DE, Bonten MJ, et al. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005;171:388-416.

best chance of effective therapy. Recommendations for antimicrobial regimens for initial empiric therapy are listed in Tables 24-1 and 24-2. Once the results of initial cultures are available, therapy should be narrowed based on the susceptibility pattern of the pathogens identified. If there is no laboratory or epidemiologic evidence of coinfection, treatment regimens should be simplified and directed to that pathogen, with specific agents being dictated by the results of susceptibility testing. It is crucial to avoid broad-spectrum therapy once a pathogen has been identified (2). Patients who are improving clinically, hemodynamically stable, and able to take oral medications can be switched to oral therapy. If the pathogen has been identified, the choice of antibiotic for oral therapy is based on the susceptibility profile for that organism. If a pathogen is not identified, the choice of antibiotic for oral therapy is either the same antibiotic as the intravenous antibiotic, or an agent in the same drug class. Treatment of pneumonia caused by gram-negative enteric bacilli should be based on the susceptibility profile for that organism.

Duration of Therapy The duration of therapy should be based on the clinical response. The standard duration of therapy in the past was 14 to 21 days in part because of a concern for difficult to treat pathogens (e.g., Pseudomonas spp). However,

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Table 24-1 Initial Empiric Therapy for Hospital-Acquired Pneumonia or VentilatorAssociated Pneumonia in Patients with Early Onset or No Known Risk Factors for Multidrug-Resistant Pathogens Potential Pathogen

Recommended Antibiotic*

Streptococcus pneumoniae

Ceftriaxone 1-2 g qd or Levofloxacin 750 mg qd, Moxifloxacin 400 mg q12h, Ciprofloxacin 400 mg q8-12h (levofloxacin or moxifloxacin preferred for S. pneumoniae) or Ampicillin/sulbactam 3 g q6h or Ertapenem 1 g qd

Haemophilus influenzae Methicillin-susceptible Staphylococcus aureus

Antibiotic-susceptible enteric gram-negative bacilli (e.g., Escherichia coli, Klebsiella pneumoniae, Enterobacter species)

* Doses are based on normal renal and hepatic function. Republished with permission from: Niederman MS, Craven DE, Bonten MJ, et al. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005;171:388-416. Abbreviations: d = day; h = hour; q = every.

Table 24-2 Empiric Therapy for Hospital-Acquired Pneumonia,Ventilator-Associated Pneumonia, or Healthcare-Associated Pneumonia in Patients with Late Onset or Known Risk Factors for Multidrug-Resistant Pathogens Potential Pathogens

Antimicrobial Therapy*

Pathogens listed in Table 24-1 and MDR pathogens Pseudomonas aeruginosa Klebsiella pneumoniae (ESBL**+)

Antipseudomonal cephalosporin (Cefepime 1-2 g q8-12h, Ceftazidime 2 g q8h) or Antipseudomonal carbapenem (imipenem 500 mg q6h or 1 g q8h or meropenem 1 g q8h) or Beta-lactam/beta-lactamase inhibitor (piperacillin-tazobactam 4.5 g q6h) plus Antipseudomonal fluoroquinolone (ciprofloxacin 400 mg q8h or levofloxacin 750 mg qd; these are preferred if Legionella possible) or Aminoglycoside (gentamicin or tobramycin 7 mg/kg per d, amikacin 20 mg/kg per d) plus Linezolid 600 mg q12h or vancomycin 15/kg mg q12h*** (if MRSA a concern)

Acinetobacter species MRSA Legionella pneumophila

* Doses are based on normal renal and hepatic function. ** Extended spectrum beta-lactamase producing strain (a carbapenem is preferred). *** Trough levels should be 15-20 µg/mL. Republished with permission from: Niederman MS, Craven DE, Bonten MJ, et al. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005;171:388-416. Abbreviations: d = day; ESBL = extended-spectrum beta-lactamase; h = hour; MRSA = methicillin-resistant Staphylococcus aureus; q = every.

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a shorter course could significantly reduce the amount of antimicrobials used in hospitals where the emergence of resistant pathogens is a concern. Recent studies have suggested that short-course treatment is effective. This is illustrated by the following: ●

●

●

A prospective, randomly assigned, multicenter trial of 401 patients with VAP compared outcomes after 8 versus 15 days of treatment (11). All patients had bronchoscopy for quantitative cultures and were empirically treated with either a combination of an antipseudomonal beta-lactam plus an aminoglycoside or a fluoroquinolone. If initial therapy was appropriate, patients were randomly assigned to either 8 or 15 days of therapy. There was no significant difference between patients treated for 8 days compared to 15 in such outcomes as 28-day mortality or recurrent infection; as expected, patients treated for 8 days had more antibiotic-free days. Among patients who developed recurrent infections, MDR pathogens were isolated less frequently in those treated for 8 days (42% versus 62% for those treated 15 days). However, patients with VAP caused by nonfermenting gramnegative bacilli (e.g., Pseudomonas species) had a higher pulmonary infection recurrence rate when treated for 8 versus 15 days (41% versus 25% with 15 days of treatment), but the death rate was not different. An ICU study evaluated clinical outcomes, including duration of treatment, following implementation of a clinical guideline for the treatment of VAP compared to historical controls (patients with VAP treated before implementation of the guideline) (12). The clinical guideline recommended empiric treatment with vancomycin, imipenem, and ciprofloxacin with modification of the antibiotic regimen after 24 to 48 hours based on the patient’s clinical course and culture results. Duration of therapy in the clinical guideline group was 7 days unless the patient had persistent signs and symptoms of active infection or had not alleviated. The duration of antibiotic treatment was significantly less in the clinical study group (8.6 versus 14.8 days in the historical controls). A prospective study evaluated the ability of the CPIS (summarized in Table 24-3) to determine the duration of therapy for ICU patients with new pulmonary infiltrates (13). Patients were included in the study if they had new-onset pulmonary infiltrates and a CPIS less than 6 (low likelihood of having pneumonia). The patients were randomly assigned to either a control group (current standard therapy; e.g., number, choice and duration of antibiotics measured by the care providers) or to the experimental group (intravenous ciprofloxacin 400 mg every 8 hours for 3 days). The CPIS was reevaluated at 3 days and in patients with a CPIS less than 6,

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Table 24-3 Clinical Pulmonary Infection Score (CPIS) Scoring Sheet Assess on entry and on day 3:

_____Temperature: ≥36.5˚C or ≤38.4˚C (afebrile) = 0 point; ≥38.5˚C or ≤38.9˚C = 1 point; ≥39˚C or ≤36.5˚C = 2 points _____Blood leukocytes, mm3: ≥4000 or ≤11,000 = 0 points; 11,000 = 1 point; + band forms ≥50% = add 1 point _____Tracheal secretions: absence of tracheal secretions = 0 point; presence of nonpurulent tracheal secretions = 1 point; presence of purulent tracheal secretions = 2 points _____Oxygenation: PaO2/FiO2, mm Hg >240 or ARDS (ARDS defined as PaO2/FiO2 ≤200, pulmonary arterial wedge pressure ≤18 mm Hg and acute bilateral infiltrates) = 0 points; ≤240, no ARDS = 2 points _____Pulmonary radiography: no infiltrate = 0 point; diffuse (patchy) infiltrate = 1 point; localized infiltrate = 2 points Assess only on day 3:

_____Progression of pulmonary infiltrate: no radiographic progression = 0 point; radiographic progression (after CHF and ARDS excluded) = 2 points _____Culture of tracheal aspirate: pathogenic bacteria cultured in rare or light quantity or no growth = 0 point; pathogenic bacteria cultured in moderate or heavy quantity = 1 point; same pathogenic bacteria seen on Gram stain = 1 point _____Total Using this approach, pneumonia is more likely in those with a CPIS of at least 6, compared to those with a lower score. Modified with permission from: Pugin J, Auckenthaler R, Mili N, et al. Diagnosis of ventilator-associated pneumonia by bacteriologic analysis of bronchoscopic and nonbronchoscopic “blind” bronchoalveolar lavage fluid. Am Rev Respir Dis. 1991;143:1121. Abbreviations: ARDS = adult respiratory distress syndrome; CHF = congestive heart failure.

antibiotics were discontinued in the experimental group. If the CPIS was more than 6 at day 3, the ciprofloxacin was continued or antibiotics were changed based on the microbiologic results. Significantly more patients in the control group received antibiotics beyond 3 days compared to those in the experimental group (90% compared to 28% in the experimental group). In addition to reduced antibiotic use, the experimental group was less likely to have colonization/infection with resistant organisms (15% compared to 35% of patients in the control group) and had a trend toward lower death.

Recommendations Based on these data, we recommend that all patients with HAP, VAP, and HCAP be evaluated after 72 hours of initial empiric antimicrobial therapy. At 72 hours, we recommend assessment of both the CPIS and the results of microbiologic tests. If the initial CPIS was less than 6 and remains so at 72 hours, we would discontinue antimicrobial therapy, especially if

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there is no microbiologic documentation of a pathogen in significant quantity. If the initial CPIS was greater than 6, the patient has alleviated after 72 hours, and a pathogen is isolated, antimicrobial therapy should be changed to a pathogen-directed regimen based on the susceptibility pattern. Therapy should be continued to complete a total course of 7 to 8 days; we would treat up to 15 days if P. aeruginosa were the etiologic agent. If no pathogen were identified, we would narrow the regimen, discontinuing therapy for Pseudomonas species and MRSA. If the patient is not improving at 72 hours and a resistant pathogen is identified, therapy can be changed to pathogen-directed treatment based on the susceptibility pattern. In addition, failure to alleviate at 72 hours should prompt a search for infectious complications, other diagnoses, or other sites of infection (Figure 24-1).

Prevention The pathogenesis of NP usually requires 2 major processes: microbial colonization of upper airway secretions and aspiration of these secretions into the lung. Therefore, strategies aimed at reducing the incidence of NP focus on reducing the amount of bacterial colonization or reducing the incidence of aspiration (14). The most effective methods that are supported by controlled studies include adequate hand washing between patient contacts, maintaining semirecumbent patient positioning, avoiding gastric over distention, continuous subglottic suctioning for patients on mechanical ventilation, limiting stress-ulcer prophylaxis, and using chlorhexidine oral rinses. Importantly, the use of aerosolized antibiotic prophylaxis and routine use of antimicrobial agents for selective digestive decontamination have not been found to be beneficial. Isolating patients with resistant organisms (e.g., MRSA) can decrease the likelihood of transferring these pathogens between patients. REFERENCES 1. Craven DE, Palladino R, McQuillen DP. Healthcare-associated pneumonia in adults: management principles to improve outcomes. Infect Dis Clin North Am. 2004;18:939-62. 2. American Thoracic Society. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005;171:388-416. 3. Kollef MH, Shorr A,Tabak YP, et al. Epidemiology and outcomes of healthcare-associated pneumonia: Results from a large US database of culture-positive pneumonia. Chest. 2005. In press. 4. Fagon JY, Chastre J, Vuagnat A, Trouillet JL, Novara A, Gibert C. Nosocomial pneumonia and mortality among patients in intensive care units. JAMA. 1996;275:866-9. 5. El-Solh AA,Pietrantoni C,Bhat A,Aquilina AT,Okada M,Grover V,et al. Microbiology of severe aspiration pneumonia in institutionalized elderly. Am J Respir Crit Care Med. 2003;167:1650-4. 6. Grossman RF, Fein A. Evidence-based assessment of diagnostic tests for ventilator-associated pneumonia: Executive summary of the clinical practice guideline panel. Chest. 2000;117 (suppl 2):177-81S.

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7. Pugin J,Auckenthaler R, Mili N, Janssens JP, Lew PD, Suter PM. Diagnosis of ventilator-associated pneumonia by bacteriologic analysis of bronchoscopic and nonbronchoscopic “blind” bronchoalveolar lavage fluid. Am Rev Respir Dis. 1991;143:1121-9. 8. Fartoukh M, Maitre B, Honoré S, Cerf C, Zahar JR, Brun-Buisson C. Diagnosing pneumonia during mechanical ventilation: the clinical pulmonary infection score revisited. Am J Respir Crit Care Med. 2003;168:173-9. 9. Fagon JY, Chastre J,Wolff M, Gervais C, Parer-Aubas S, Stéphan F, et al. Invasive and noninvasive strategies for management of suspected ventilator-associated pneumonia. A randomized trial. Ann Intern Med. 2000;132:621-30. 10. Ruiz M,Torres A, Ewig S, Marcos MA,Alcón A, Lledó R, et al. Noninvasive versus invasive microbial investigation in ventilator-associated pneumonia: evaluation of outcome. Am J Respir Crit Care Med. 2000;162:119-25. 11. PneumA Trial Group. Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized trial. JAMA. 2003;290:2588-98. 12. Ibrahim EH,Ward S, Sherman G, Schaiff R, Fraser VJ, Kollef MH. Experience with a clinical guideline for the treatment of ventilator-associated pneumonia. Crit Care Med. 2001; 29:1109-15. 13. Singh N, Rogers P,Atwood CW,Wagener MM,Yu VL. Short-course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit. A proposed solution for indiscriminate antibiotic prescription. Am J Respir Crit Care Med. 2000;162:505-11. 14. Kollef MH. The prevention of ventilator-associated pneumonia. N Engl J Med. 1999;340:627-34.

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Chapter 25

Tuberculosis SCOTT MAHAN, MD JOHN J. JOHNSON, MD

Key Learning Points 1. One third of the world population is infected with M. tuberculosis. Nine million new cases of TB and 2 million deaths due to TB occur worldwide each year. 2. TB most commonly presents as apical fibrocavitary reactivation pulmonary disease. 3. Patients with advanced HIV/AIDS often present atypically when infected with TB. 4. Standard 6 month short course chemotherapy with two months of isoniazid, rifampin, ethambutol and pyrazinamide followed by 4 months of isoniazid and rifampin is highly effective for the treatment of drug-susceptible TB when fully administered. 5. Directly observed therapy (DOT), where treatment is supervised and facilitated by a health care worker or trained lay supervisor, is the global standard for TB treatment.

T

uberculosis (TB) is a chronic granulomatous disease caused by organisms of the Mycobacterium tuberculosis complex. Most human tuberculous disease is caused by M. tuberculosis, an intracellular pathogen primarily infecting mononuclear phagocytes. Although tuberculosis can affect many organs and cause disseminated disease, the most frequent and important form is pulmonary tuberculosis, which is spread in the community by aerosol droplet transmission. Despite the availability of highly effective treatment, TB remains one of the world’s leading infectious disease killers. In the United States and other industrialized countries, great strides have been made in controlling TB; 495

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New Developments ●

●

●

A whole blood interferon-gamma assay, an in vitro T-cell based assay using specific MTB antigens, has potential benefits for screening and has been recently recommended by the CDC as an acceptable alternative to tuberculin skin testing for contact investigations, screening of immigrants, and for sequential testing of health care workers. Fluoroquinolones such as moxifloxacin are currently being evaluated in clinical trials for their potential role in shortening the required duration of treatment of drug-susceptible TB. New classes of drugs with novel mechanisms of action such as the nitroimidazopyran PA-824 and the diarylquinoline TMC-207 are in preclinical and early clinical testing for TB treatment.

however, the emergence of multidrug resistant (MDR) TB and a high incidence of disease in foreign-born persons, marginalized populations in poor urban areas, and HIV-infected persons are ongoing challenges to TB control. The primary care physician is charged with the vital role of identifying and treating persons with latent TB infection and quickly diagnosing and beginning initial therapy in persons with active TB. Most patients with TB should be referred to an infectious disease specialist or public health clinic with expertise in TB care.

Epidemiology The World Health Organization estimates that up to one third of the world’s population is infected with M. tuberculosis (1). Approximately 9 million new cases of active TB and 2 million deaths caused by TB occur each year. TB is the second leading cause of death worldwide from an identifiable infectious pathogen, exceeded only by HIV/AIDS. Tuberculosis is a major public health problem in developing countries where 95% of all cases and 98% of TB-related deaths occur. Eighty percent of TB cases occur in 22 high burden countries—mainly in sub-Saharan Africa, Asia, and regions of the former Soviet Union. In the United States, TB is primarily a disease of immigrants from high-prevalence countries and the socially and economically disadvantaged. During the early 1980s declining case rates in the United States led to the underfunding and dismantling of public clinics and agencies that provided TB care. This, combined with the HIV pandemic, led to a sharp increase in cases during the late 1980s. With renewed funding, the rebuilding of the public health infrastructure for TB care, the widespread implementation of directly observed therapy (DOT), and improved case management strategies, the TB case rate in the United States has now decreased by approximately 5% annually since 1992.

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Tu b e r c u l o s i s

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TB control remains a public health concern in the United States because of the infectiousness of M. tuberculosis as a respiratory pathogen and persistently high TB case rates among certain groups. In 2004 a total of 14,511 confirmed TB cases (4.9 per 100,000 population) were reported to the U.S. Centers for Disease Control (CDC) (2). In the United States, TB disproportionately affects the poor, the foreign-born, and native-born non-Hispanic blacks. Case rates are 8- to 20-fold greater among Hispanics, African Americans, and Asian Americans than whites. For the first time in 2002, the number of TB cases among foreign-born persons exceeded the number of cases in those born in the United States; most occurred in immigrants from Mexico, the Philippines, Vietnam, India, China, Haiti, and South Korea. Geographic disparities also exist. Some states and large cities have disproportionate numbers of TB cases; California, Florida, Illinois, New York, and Texas are among the states with the highest number of TB cases.

Etiology and Pathogenesis Tuberculosis is caused by the M. tuberculosis complex, which consists of M. tuberculosis (MTB), Mycobacterium bovis, Mycobacterium bovis bacille Calmette-Guérin (BCG), Mycobacterium africanum, Mycobacterium microti, and Mycobacterium canetti. MTB is the main pathogen in humans. MTB is an obligate aerobic, nonmotile bacillus with a lipid rich cell wall that stains acid fast, meaning it maintains a reddish hue after staining with carbol fuchsin followed by washing with acid alcohol. Humans are the only known reservoir for MTB. The primary method of transmission of TB is when an infected person with active pulmonary disease coughs, sneezes, sings, or talks and creates fine aerosolized droplets of tuberculous bacilli, 1 to 5 µm in size, that are inhaled by another person and deposited in the distal respiratory tree (3). Persons who have detectable acid-fast bacillus (AFB) on sputum smear are more likely to transmit TB than persons whose sputum smears are negative. Increased duration of exposure to a smear-positive patient, close contact, and poor ventilation all increase the likelihood of transmission (4). After deposition in the lungs, the tubercle bacilli are ingested by alveolar macrophages that initiate a cascade of immunologic events. The vast majority of persons infected with MTB are asymptomatic or have transient flu-like symptoms. More than 90% of infected persons are able to contain the infection and do not go on to develop active TB. In these persons, the only marker that tuberculous infection has occurred is the conversion of the tuberculin skin test (TST) from negative to positive approximately 4 to 6 weeks after infection. A small percentage of individuals, particularly infants and young children, the elderly, and immunocompromised persons develop progressive primary TB after infection. The risk of progression to active TB is approximately 5% during the first 2 years after tuberculous infection with a subsequent 5%

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additional risk over the person’s lifetime giving an approximate 10% lifetime risk of developing active TB (5).

Clinical Manifestations Most cases of TB are caused by reactivation of latent tuberculosis infection in the following settings: immunosenescence caused by aging; immunosuppression caused by comorbid conditions such as HIV infection, diabetes mellitus, cancer, or end stage renal disease, or immunosuppressive agents such as corticosteroids. The most frequent signs and symptoms of TB are a productive cough for more than 3 weeks, fever, weight loss, night sweats, anorexia, malaise, and chest pain (6). Hemoptysis occurs in only 10% to 20% of smear-positive patients. Chest radiographs in reactivation TB commonly show infiltrates, cavities, and destructive lesions most frequently in the apical and posterior segments of the upper lobes and the superior segments of the lower lobes (7).

Diagnosis The diagnosis of TB is made by demonstrating the presence of the tubercle bacillus, its antigens, or its genomic products in smears, cultures, or tissue samples. The key examination for the diagnosis of pulmonary TB is sputum smear and culture. Sputum smears for AFB are done using hot (Ziehl-Neelsen) or cold (Kinyoun) carbol fuchsin stains, or fluorescent auramine staining methods. Approximately 5000 to 10,000 tubercle bacilli per mL of sputum must be present for consistent detection of a positive sputum smear (8). Sputum smears can be done quickly and facilitate the rapid diagnosis of patients with the most infectious form of TB. Sputum smears are approximately 60% to 70% sensitive for the diagnosis of TB. Fluorescent auramine staining allows more rapid scanning of large numbers of smears under lower magnification and is used by laboratories examining large numbers of specimens. The sensitivity and specificity of carbol fuchsin and fluorescent auramine staining methods are roughly equivalent when done in experienced laboratories. Because of the limited sensitivity of sputum examination, at least three sputum samples should be obtained for acid-fast smear and culture. Collection of early morning sputum specimens, which samples respiratory sections accumulating in the bronchial tree during sleep is best, but spot collections are acceptable. In those unable to produce adequate sputum samples, sputum production can be induced by inhalation of aerosolized 3% (hypertonic) sterile saline solution, or samples can be collected by early morning gastric lavage or by means of bronchoscopy. When bronchoscopy is done, transbronchial biopsy can be done for culture and histologic evaluation. In miliary TB, sputum AFB

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smears and culture are frequently negative. Biopsy of the lung, bone marrow, or liver is frequently required to confirm the diagnosis. Cultures should be done on all sputum and tissue specimens. Cultures have improved sensitivity versus smears (80%-85%) as well as a specificity of approximately 98% (4). Cultures allow species identification and drug susceptibility testing. Historically, culture has been grown on solid media such as the egg-based Lowenstein-Jensen media and the clear oleicalbumin agar based Middlebrook media. Because of the slow growth of MTB (dividing time 12-18 hours), it can take several weeks before growth is evident. Therefore, cultures should be examined weekly until growth is present or for a total of 8 weeks. Organisms from culture can then be speciated to identify them as MTB or atypical mycobacteria by the use of biochemical, morphologic, and genomic methods. Drug susceptibility requires an additional 2 to 4 weeks using traditional methods. The time for detection of growth in culture has been shortened through the use of automated liquid culture systems such as BACTEC and the Mycobacterial Growth Indicator Tube (MGIT). These systems shorten the time for positive cultures by measuring metabolically active mycobacteria, thereby signaling growth more rapidly than the traditional method of waiting for visible growth on solid culture media. By using automated liquid culture systems, the time to detectable growth of mycobacteria has been shortened to roughly 14 days from smear positive sputa and to approximately 21 days in smear negative cases (9). Promising new rapid diagnostic techniques involve the use of nucleic acid amplification to identify MTB. These tests, however, are not a replacement for sputum acid-fast smears and mycobacterial cultures that provide an indication of infectivity and allow for drug susceptibility testing. Several nucleic acid amplification tests that can be done directly from sputum specimens (or from positive cultures) have been approved by the U.S. Food and Drug Administration. These amplified tests detect genetic sequences that are highly conserved among M. tuberculosis species. They have been shown to have a sensitivity of 84% to 92% for smear positive cases, but only 41% to 75% for smear negative cases, with a specificity of 96% to 99% (10). The lower diagnostic yield in sputum-smear–negative patients is likely caused by the lower bacillary load in smear-negative patients and the smaller inoculum of specimen examined compared with culture. Because of their higher costs and limited availability, the current roles of nucleic acid testing methods for TB are for the rapid confirmation of the diagnosis of TB in smear-positive patients and for the evaluation of patients with negative smears where the physician has a high clinical suspicion for TB. Although licensed only for examining sputum and respiratory secretions, nucleic acid amplification methods have been used to evaluate other specimens such as cerebrospinal fluid (CSF) or pleural fluid where their sensitivity has also been reported to be limited. The performance of smears, cultures and nucleic acid based methods is compared in Table 25-1.

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Table 25-1 Microbiologic Tests for the Diagnosis of Tuberculosis Sputum Smear (percentage)

One Culture (percentage)

Three Cultures (percentage)

Sensitivity

60-70

80-85

80-100

Specificity

95

98

98

Nucleic Acid Amplification (PCR) (percentage)

80-100 (95 in smear positive; 60 in smear negative) 98

Abbreviations: PCR, polymerase chain reaction.

Drug susceptibility testing should be done on an initial positive culture, and should be repeated if there is failure to respond clinically and when sputum cultures remain positive after 2 months of treatment. Standard methods of testing that determine drug susceptibility of mycobacteria by observing for inhibition of growth in critical concentrations of drugs, often require 2 to 4 weeks to do after initial culture positivity. The use of radiometric or fluorescent-based detection systems using liquid culture media speeds resistance testing, but still requires several weeks. Rapid molecular methods for identifying resistant isolates to rifampin (RMP) have been developed, based on detection of mutations in a short portion of the mycobacterial RNA polymerase gene. Other rapid susceptibility tests are in development. In addition to sputum microscopy and culture, chest radiography is useful in evaluating patients with suspected TB. Active pulmonary TB classically presents with upper lobe involvement of one or both lungs. The apical and posterior segments of the upper lobes are the most commonly involved areas of the lung. In the right clinical situation, active pulmonary TB is suggested by consolidation, nodular infiltrates, and cavitation. Although highly suggestive of TB, these findings are nonspecific. Other diseases such as histoplasmosis, chronic necrotizing pulmonary aspergillosis, sarcoidosis, and atypical mycobacterial infections can present with very similar findings and must be considered in the differential diagnosis. Approximately 5% of patients with pulmonary TB, such as those with endobronchial TB, can have normal chest radiographs at the time of presentation. Tuberculin skin testing has a limited role in the evaluation of patients with suspected TB. It is important to remember that a positive tuberculin skin test only indicates that a patient has been infected with MTB and does not indicate whether or not a patient has active TB. Tuberculin skin testing is useful, however, when information about previous tuberculous infection is important in narrowing the differential diagnosis and guiding decisions about further testing or empiric treatment in appropriate clinical situations.

Treatment Modern RMP-containing short-course chemotherapy is highly effective for the treatment of TB. When fully administered, cure rates of more than 95% can

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be achieved in patients with drug-susceptible TB. In the United States, four regimens are currently recommended for the treatment of patients with drugsusceptible TB (Table 25-2). Each includes an initial 2-month intensive phase with four drugs followed by a 4 to 7 month continuation phase with two drugs. The intensive phase targets the initial high burden of tubercle bacilli, and the continuation phase targets the remaining slowly dividing organisms. Previously untreated patients without risk factors for drug-resistant TB should initially be treated with INH (INH), RMP, pyrazinamide (PZA), and ethambutol (EMB) for 2 months, followed by INH and RIF for 4 months. Drugsusceptibility testing against standard first-line anti-TB drugs should be done on an initial isolate from all patients whenever possible. If the patient’s isolate is susceptible to INH, RMP, and PZA, EMB can be discontinued. Patients with cavitary disease on chest radiograph whose sputum cultures are still positive after 2 months of treatment, patients who were not treated with PZA during the initial phase of therapy, and patients being treated with once-weekly INH and rifapentine whose sputum cultures are positive after 2 months of treatment should be treated for 7 months during the continuation phase (11). Baseline evaluation before beginning treatment should include HIV testing, testing for viral hepatitis in at-risk individuals, serum liver function tests, serum creatinine, and platelet count. Vision testing, including red-green color discrimination testing, should be done if EMB is part of the regimen. The main serious toxicity of anti-TB drugs is hepatotoxicity. Hepatotoxicity can be caused by INH, RMP, and PZA. Drug-induced hepatitis is defined as a serum aspartate aminotransferase (AST) more than three times the upper limit of normal with symptoms, or five times the upper limit without symptoms. The risk of clinical hepatitis with INH-containing regimens is approximately 3% (12). Minor, asymptomatic, self-limited increases in hepatic aminotransferases occur in approximately 20% of patients treated for TB with standard short-course chemotherapy. The risk for clinical hepatitis increases with advancing age, preexisting liver disease, in those with heavy alcohol consumption, and in pregnant and postpartum women. Patients should be instructed about symptoms and signs of hepatotoxicity and told to stop taking their drugs and seek immediate medical attention for persistent nausea, jaundice, anorexia, or abdominal pain. INH, RIF, PZA, and any other potentially hepatotoxic drugs that the patient is taking should be stopped. Evaluation for other causes of hepatitis should be done. Two or more antituberculous medications without hepatotoxicity should be substituted until the AST has returned to less than two times the upper limit of normal, and symptoms have resolved. Then the first-line drugs (Table 25-3) can be reintroduced sequentially (usually starting with RIF, then INH, then PZA) with close monitoring of hepatic function (11). During treatment, sputum should be examined monthly by smear and culture until two consecutive samples are negative on culture. It is also important for patients to have monthly clinical evaluations for evidence of treatment failure, drug side effects, and to assess adherence. Patients on

INH RIF PZA EMB

INH RIF PZA EMB

INH RIF PZA EMB INH RIF EMB

1

2

3

4

Drugs

Regimen

‡

Seven days per week for 56 doses (8 wk) or 5 d/wk for 40 doses (8 wk)¶

Seven days per week for 14 doses (2 wk), then twice weekly for 12 doses (6 wk) or 5 d/wk for 10 doses (2 wk),¶ then twice weekly for 12 doses (6 wk) Three times weekly for 24 doses (8 wk)

Seven days per week for 56 doses (8 wk) or 5 d/wk for 40 doses (8 wk)¶

Interval and doses (minimal duration)

Initial phase

INH/RIF

INH/RIF

4a

4b

INH/RIF

INH/RIF INH/RPT INH/RIF INH/RPT

1b 1c** 2a 2b**

3a

INH/RIF

Drugs

1a

Regimen

Seven days per week for 217 doses (31 wk) or 5 d/wk for 155 doses (31 wk)¶ Twice weekly for 62 doses (31 wk)

Three times weekly for 54 doses (18 wk)

Seven days per week for 126 doses (18 wk) or 5 d/wk for 90 doses (18 wk)¶ Twice weekly for 36 doses (18 wk) Once weekly for 18 doses (18 wk) Twice weekly for 36 doses (18 wk) Once weekly for 18 doses (18 wk)

Interval and doses ‡§ (minimal duration)

Continuation phase

(26 (26 (26 (26

wk) wk) wk) wk)

(I) (I) (II) (I)

B (I)

A B A B

118–102 (39 wk) C (I)

273–195 (39 wk) C (I)

78 (26 wk)

92–76 74–58 62–58 44–40

C (II)

C (II)

B (II)

A (II)# E (I) B (II)# E (I)

A (II)

Rating* (evidence)† HIV − HIV +

182–130 (26 wk) A (I)

Range of total doses (minimal duration)

502

Table 25-2 Drug Regimens for Culture-Positive Pulmonary Tuberculosis Caused by Drug-Susceptible Organisms

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Definition of abbreviations: EMB = Ethambutol; INH = isoniazid; PZA = pyrazinamide; RIF = rifampin; RPT = rifapentine. * Definitions of evidence ratings: A = preferred; B = acceptable alternative; C = offer when A and B cannot be given; E = should never be given. † Definition of evidence ratings: I = randomized clinical trial; II = data from clinical trials that were not randomized or were conducted in other populations; III = expert opinion. ‡ When DOT is used, drugs may be given 5 days/week and the necessary number of doses adjusted accordingly. Although there are no studies that compare five with seven daily doses, extensive experience indicates this would be an effective practice. § Patients with cavitation on initial chest radiograph and positive cultures at completion of 2 months of therapy should receive a 7-month (31 week; either 217 doses [daily] or 62 doses [twice weekly]) continuation phase. ¶ Five-day-a-week administration is always given by DOT. Rating for 5 day/week regimens is AIII. # Not recommended for HIV-infected patients with CD4+ cell counts 70%

>70%

—

>90%

>90%

50,000 cells/mm3

Reevaluate based on clinical response Consider noninfectious causes

Yes Modify antimicrobial therapy as needed Repeat arthrocentresis as needed

Figure 31-2 Algorithm for the management of monoarticular arthritis.

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crobial agent directly into a joint is unnecessary and not recommended because it can lead to excessively high concentrations of antibiotic in the synovial fluid, increasing the inflammatory response. An exception to this is the use of amphotericin B in treating infectious arthritis caused by fungi, in which intraarticular injection of small doses of the drug has proven safe and effective (33). The optimal duration of antimicrobial therapy for septic arthritis is not well established and varies with the causative pathogen, the adequacy of host defenses, and the clinical response (21). Disseminated gonococcal infection with polyarthritis is usually cured with a 7- to 10-day course of antibiotic, whereas acute nongonococcal suppurative arthritis can require a longer duration of therapy. Infections caused by most streptococci and by H. influenzae usually respond to a 2-week course of antimicrobial therapy, whereas S. aureus and gram-negative bacillary infections are treated for 3 to 4 weeks. If staphylococcal bacteremia occurs, the risk of endocarditis or other metastatic infection often necessitates 4 to 6 weeks of parenteral therapy. The antimicrobial agents of choice for common pathogens causing septic arthritis are listed in Table 31-8. The prevalence of community-associated methicillinresistant S. aureus (CA-MRSA) is increasing in many communities. If S. aureus Table 31-8 Antimicrobial Agents of Choice for Common Pathogens That Cause Septic Arthritis Pathogen*

Drug Regimen†

Staphylococcus aureus

Nafcillin 2 g IV q6h

Staphylococcus epidermidis Methicillin-resistant S. aureus Streptococcus groups A, B, C, and G Enterococcus faecalis


Neisseria meningitidis Haemophilus influenzae beta-Lactamase negative beta-Lactamase positive Pseudomonas aeruginosa

Alternative Drugs**

Vancomycin, cefazolin, clindamycin Vancomycin 15 mg/kg IV q12h TMP-SMX Vancomycin 15 mg/kg TMP-SMX, doxycycline, IV q12h linezolid Penicillin G 2 MU IV q4h Vancomycin, cefazolin, erythromycin Penicillin G 2 MU IV q4h Vancomycin with (or ampicillin 2 g q6h) + gentamicin gentamicin 1 mg/kg IM/IV q8h Ceftriaxone 1 g IV q24h Spectinomycin, ciprofloxacin, or other quinolones Penicillin G 2 MU IV q4h Ceftriaxone Ampicillin 2 g IV q6h Ceftriaxone 2 g IV q24h Piperacillin 4 g IV q6h +/tobramycin 5–7 mg/kg IV

Cefuroxime, TMP-SMX TMP-SMX Ceftazidime with aminoglycoside or ciprofloxacin

IM = intramuscularly; IV = intravenously; MU = million units; TMP-SMX = trimethoprim–sulfamethoxazole. * Duration of drug regimen is determined by pathogen: 2 weeks for Streptococcus, Haemophilus, Neisseria, and Enterococcus species, and 3 weeks for Staphylococcus species and gram-negative bacilli. † Dose may vary with body weight and renal function. ** See Appendix for recommended doses in adults.

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is suspected or proven to be the causative agent, vancomycin should be used as initial empirical therapy. Vancomycin-resistant S. aureus occur but are rare and need not be considered. The second facet of treatment of septic arthritis is drainage of pus from the affected joint. Drainage decompresses the joint and removes inflammatory cells, degradative enzymes, and fibrinous debris. In nongonococcal suppurative arthritis, adequate drainage is essential for a satisfactory outcome (2). However, the effusions in septic arthritis caused by N. gonorrhoeae or N. meningitidis, are rarely large enough to require drainage, and these conditions usually respond well with antimicrobial therapy alone. When effusions are present, needle aspiration is almost always adequate and surgical drainage is rarely indicated. The efficacy of repeated needle aspiration compared with surgical arthrotomy in septic arthritis has long been a subject of debate. No prospective controlled studies have compared medical and surgical drainage. An early study by Goldenberg and coworkers indicated a better result with needle aspiration than with surgical drainage, but the difference was not statistically significant (34). However, the study did clearly show the importance of early therapy to good outcome. A subsequent retrospective analysis of several studies showed no significant difference in outcome with medical and surgical therapy but did confirm the importance of early diagnosis and treatment (35). It is very likely that the drainage method used on a joint effusion has little effect on outcome so long as the drainage procedure is effective in removing the effusion. If needle aspiration is selected as the technique for drainage, the affected joint should be aspirated at least daily until fluid no longer accumulates. Repeat cultures and leukocyte counts on the joint fluid are useful in monitoring response to therapy. The fluid should become sterile over 48 to 96 hours, and the leukocyte count should steadily decline. Positive synovial fluid cultures after 7 days of therapy and high synovial fluid leukocyte counts after 5 days are associated with a poor outcome (36). Therefore, if fluid continues to reaccumulate after 2 to 3 days of needle aspiration or there is worsening of systemic sepsis, surgical drainage should be considered. Recent advances in arthroscopic technique have made surgical drainage of infected joints more attractive and in most cases the preferred approach (37). Open surgical drainage usually is reserved for severe infections with loculated debris within the infected joint and for infections involving the shoulder and hip. Hip infections require open surgical arthrotomy to relieve the pressure on the intravascular structures completely and to prevent ischemic destruction of the epiphyseal plate or femoral head (38). In most other cases, arthroscopic drainage is preferable to repeated needle aspiration. Many surgeons insert a closed suction drainage system postoperatively to irrigate an infected joint and to deliver intra-articular antimicrobial agents. This practice has not proven beneficial and is probably unnecessary, because most systemically administered antimicrobials reach adequate

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levels in synovial fluid (32). If used, these irrigation systems should remain in place for no longer than 48 hours. The third facet of treatment of septic arthritis is restoration of normal function of the affected joint. During the initial presentation and early treatment period, any movement of the joint can be very painful. Immobilization during this phase of treatment alleviates pain; however, after adequate decompression and a response to initial treatment, passive motion should be initiated to prevent fibrous adhesions and permanent joint injury (39). Whenever possible, continuous passive motion is preferred to intermittent passive or active motion. When the inflammatory process is controlled, appropriate physical therapy can be required to ensure the return of normal joint function.

Outcome Several factors have been identified as important in influencing the outcome of septic arthritis. These include the causative microorganism, the duration of symptoms before the beginning of appropriate antimicrobial therapy, the adequacy of drainage of the infected joint, the particular joint or joints involved, and host factors of age and underlying disease (3,21,36). Generally gonococcal arthritis has a much better prognosis than does nongonococcal arthritis and rarely requires surgery. Arthritis caused by gramnegative or anaerobic bacteria has been associated with a poor outcome in some series but not in others (2,16,21); however, more important than the microbial cause is the presence of underlying disease, because most deaths of patients with septic arthritis occur in those with serious underlying or chronic disease (3,21). The overall death rate for nongonococcal septic arthritis is approximately 10%, but varies with the preceding factors (3). Delay in instituting appropriate antimicrobial therapy is associated with a poor outcome. The duration of symptoms before therapy is inversely related to outcome (36). The outcome is also related to the time required to sterilize the synovial fluid after therapy is begun. Patients in whom this requires more than 7 days have a poor outcome (36). Synovial fluid leukocyte response can also be used as a prognostic indicator, because those patients with persistently high synovial fluid leukocyte counts on repeated aspirations have a poor outcome (3).

REFERENCES 1. Fink CW. Reactive arthritis. Pediatr Infect Dis J. 1988;7:58-65. 2. Goldenberg DL, Reed JI. Bacterial arthritis. N Engl J Med. 1985;312:764-71. 3. Goldenberg DL, Cohen AS. Acute infectious arthritis. A review of patients with nongonococcal joint infections (with emphasis on therapy and prognosis). Am J Med. 1976;60:369-77. 4. Shirtliff ME, Mader JT. Acute septic arthritis. Clin Microbiol Rev. 2002;15:527-44. 5. Nilsson IM, Lee JC, Bremell T, Rydén C,Tarkowski A. The role of staphylococcal polysaccharide microcapsule expression in septicemia and septic arthritis. Infect Immun. 1997;65:4216-21.

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6. Goldenberg DL. Infectious arthritis complicating rheumatoid arthritis and other chronic rheumatic disorders. Arthritis Rheum. 1989;32:496-502. 7. Sherman OH, Fox JM, Snyder S J. Arthroscopy: No problem surgery. J Bone Joint Surg. 1986;68A: 256-65. 8. Kuipers JG, Köhler L, Zeidler H. Reactive or infectious arthritis. Ann Rheum Dis. 1999;58:661-4. 9. Lundy DW, Kehl DK. Increasing prevalence of Kingella kingae in osteoarticular infections in young children. J Pediatr Orthop. 1998;18:262-7. 10. Rompalo AM, Hook EW 3rd, Roberts PL, Ramsey PG, Handsfield HH, Holmes KK. The acute arthritis-dermatitis syndrome. The changing importance of Neisseria gonorrhoeae and Neisseria meningitidis. Arch Intern Med. 1987;147:281-3. 11. Centers for Disease Control and Prevention. Sexually transmitted disease surveillance 1999. Available at: http://www.cdc.gov/nchstp/dstd/Stats_Trends/1999SurvRpt.htm. 12. Roca RP,Yoshikawa TT. Primary skeletal infections in heroin users: a clinical characterization, diagnosis and therapy. Clin Orthop Relat Res. 1979:238-48. 13. Newman ED, Davis DE, Harrington TM. Septic arthritis due to gram negative bacilli: older patients with good outcome. J Rheumatol. 1988;15:659-62. 14. Ewing R, Fainstein V, Musher DM, Lidsky M, Clarridge J. Articular and skeletal infections caused by Pasteurella multocida. South Med J. 1980;73:1349-52. 15. Bilos Z J, Kucharchuk A, Metzger W. Eikenella corrodens in human bites. Clin Orthop Relat Res. 1978:320-4. 16. Fitzgerald RH Jr., Rosenblatt JE,Tenney JH, Bourgault AM. Anaerobic septic arthritis. Clin Orthop Relat Res. 1982:141-8. 17. Gredlein CM, Silverman ML, Downey MS. Polymicrobial septic arthritis due to Clostridium species: case report and review. Clin Infect Dis. 2000;30:590-4. 18. Gordon SC, Lauter CB. Mumps arthritis: a review of the literature. Rev Infect Dis. 1984;6: 338-44. 19. Woolf AD, Campion GV, Chishick A,Wise S, Cohen BJ, Klouda PT, et al. Clinical manifestations of human parvovirus B19 in adults. Arch Intern Med. 1989;149:1153-6. 20. Rynes RI, Goldenberg DL, DiGiacomo R, Olson R, Hussain M, Veazey J. Acquired immunodeficiency syndrome-associated arthritis. Am J Med. 1988;84:810-6. 21. Rosenthal J, Bole GG, Robinson WD. Acute nongonococcal infectious arthritis. Evaluation of risk factors, therapy, and outcome. Arthritis Rheum. 1980;23:889-97. 22. Gelfand SG, Masi AT, Garcia-Kutzbach A. Spectrum of gonococcal arthritis: evidence for sequential stages and clinical subgroups. J Rheumatol. 1975;2:83-90. 23. McCutchan HJ, Fisher RC. Synovial leukocytosis in infectious arthritis. Clin Orthop Relat Res. 1990;256:226-30. 24. Baer PA,Tenebaum J, Fam AG. Coexistent septic and crystal arthritis. Report of four cases and literature review. J Rheumatol. 1986;13:3. 25. O’Brien JP, Goldenberg DL, Rice PA. Disseminated gonococcal infection: a prospective analysis of 49 patients and a review of pathophysiology and immune mechanisms. Medicine (Baltimore). 1983;62:395-406. 26. Yagupsky P. Diagnosis of Kingella kingae arthritis by polymerase chain reaction analysis [Letter]. Clin Infect Dis. 1999;29:704-5. 27. Stahl HD, Hubner B, Seidl B, Liebert UG, van der Heijden IM,Wilbrink B, et al. Detection of multiple viral DNA species in synovial tissue and fluid of patients with early arthritis. Ann Rheum Dis. 2000;59:342-6. 28. Hendrix RW, Fisher MR. Imaging of septic arthritis. Clin Rheum Dis. 1986;12:459-87. 29. Beltran J, Noto AM, McGhee RB, Freedy RM, McCalla MS. Infections of the musculoskeletal system: high-field-strength MR imaging. Radiology. 1987;164:449-54. 30. Tumeh SS. Scintigraphy in the evaluation of arthropathy. Radiol Clin North Am. 1996;34: 215-31, ix. 31. Johnson CC,Tunkel AL. Viridans streptococci and groups C and G streptococci. In: Mandell GL, Douglas RG, Bennett JE, eds. Principles and Practice of Infectious Diseases. 5th ed. New York: Churchill Livingstone; 2000:2167-83. 32. Nelson JD. Antibiotic concentrations in septic joint effusions. N Engl J Med. 1971; 284:349-53. 33. Downs NJ, Hinthorn DR, Mhatre VR, Liu C. Intra-articular amphotericin B treatment of Sporothrix schenckii arthritis. Arch Intern Med. 1989;149:954-5. 34. Goldenberg DL, Brandt KD, Cohen AS, Cathcart ES. Treatment of septic arthritis: comparison of needle aspiration and surgery as initial modes of joint drainage. Arthritis Rheum. 1975;18: 83-90.

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35. Broy SB, Schmid FR. A comparison of medical drainage (needle aspiration) and surgical drainage (arthrotomy or arthroscopy) in the initial treatment of infected joints. Clin Rheum Dis. 1986;12:501-22. 36. Ho G Jr., Su EY. Therapy for septic arthritis. JAMA. 1982;247:797-800. 37. Jackson RW. The septic knee—arthroscopic treatment. Arthroscopy. 1985;1:194-7. 38. Wilson N, DiPaola M. Acute septic arthritis in infancy and childhood: 10 year experience. J Bone Joint Surg. 1986;68B:584-7. 39. Salter RB. The biologic concept of continuous passive motion of synovial joints. The first 18 years of basic research and its clinical application. Clin Orthop Relat Res. 1989:12-25.

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Chapter 32

Prosthetic Joint Infection ANTHONY R. BERENDT

Key Learning Points 1. Rates of infection vary from 0.5 to 2%. 2. Infections may be caused by virulent pathogens or skin commensals. 3. Clinical features of infection include: “start up pain”, delayed wound healing, and a history that the joint was “never right”. 4. Multiple well-obtained intra-operative samples are recommended for identification of the pathogen. 5. Treatment should be multidisciplinary and includes surgical debridement, potential removal the implant, antibiotic therapy, and rehabilitation. 6. Patients with joint replacements should have prompt treatment of infections elsewhere in the body to reduce risks of bacteremia and spread to the implant.

P

rosthetic joint infections are uncommon. As such they can seem, at face value, to be of little relevance to the primary care physician. However they are devastating conditions for patients to experience, coming as they do as complications of procedures that are usually remarkably effective in relieving pain and enhancing quality of life. It is therefore all the more problematic that when infection does complicate joint replacement, it causes considerable illness and is very difficult to eradicate without combinations of surgery and prolonged antibiotic use. The gap between preoperative expectation and postoperative reality is difficult for many patients and health care workers to adjust to and contributes to the illness of the patients. This

599

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New Developments in the Diagnosis and Treatment of Prosthetic Joint Infection ●

●

New diagnostic tests include use of polymerase chain reaction (PCR) for detection of microbial DNA. Protocols that use initial intravenous (IV) therapy followed by oral therapy (often with fluoroquinolone-rifampin combination) have shown good rates of success in selected patients.

and the high economic costs for health care providers and systems makes it important for all physicians to have a basic understanding of the condition. For the primary care physician specifically, there are important potential roles in raising early suspicions of prosthetic joint infection, in long-term antibiotic prescribing and supervision, and in providing support and advocacy for patients in their journey through often complex and demanding treatment programs.

Epidemiology Infection can arise through operative contamination or by hematogenous spread and can present early or late. Published rates, which vary from 0.5% and 2% but are sometimes higher (1,2), are sensitive to case definition and the duration and carefulness of follow-up (3). Risk factors for infection include the following (1): ●

●

●

●

A history of previous surgery on the joint. This likely reflects the technical difficulties in carrying out revision surgery or primary joint replacement after other procedures. A history of cancer past or present. Probably caused mainly by the immunosuppressive effect of chemotherapy and the locally compromising effect of radiotherapy, but other elements can be relevant. A score greater than 1 in the National Nosocomial Infections Surveillance (NNIS) system, which awards one point for each of prolonged surgery, a poor wound score, or an American Society of Anesthesiology score of over 1. A history of superficial wound infection. Anatomic barriers are disrupted by joint replacement, so that what seems to be superficial infection can easily progress to deep infection. Furthermore some apparently superficial infections are in fact the presentation of deep infection.

Other risk factors include the presence of significant hematoma. Although all joint replacements will have some associated hematoma, persistent drainage from the wound for more than 5 days after surgery is indicative of a deep

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collection and a greatly increased risk of superficial and deeper infection (4). Although many other individual factors have been quoted as important risks, these have not been identified through less rigorous methodology.

Pathophysiology and Etiology Two separate elements come together in the pathogenesis of prosthetic joint infection. First, the implant has effects on local innate immunity that make the implant more liable to infection than would be the case for native structures. These effects include complement depletion in the vicinity of the implant and inhibition of phagocytosis by foreign material. For this reason, the inoculum required to set up infection is greatly reduced, and some organisms not normally considered to be pathogenic become important causes of prosthetic joint infection. Thus prosthetic joint infections are caused not only by virulent pathogens such as Staphylococcus aureus, β-hemolytic Streptococci and Enterobacteriaceae, but also by skin commensals such as coagulase-negative Staphylococci, Corynebacteria, and Propionibacterium (for review see reference 5). Second, prosthetic joint infections are characterized by adherence of organisms to the implant and other biomaterials. The resulting multicellular adherent consortium is known as a biofilm, and it comprises one or more microbial species enmeshed in a polysaccharide glycocalyx (6). Organisms in the adherent state display a phenotype of relative resistance to many antibiotics, although they remain genetically susceptible and identifiable as such on conventional laboratory testing. The impairment of antibioticrelated killing is accompanied by a simultaneous inhibition of host-related killing. The inability of the host to kill the infecting organisms leads to chronic suppuration. Collections of pus and granulation tissue can form next to the implant and eventually track through adjacent tissue planes or surgical scars to produce collections or sinuses. In addition, the inflammatory response activates recruit osteoclastic cells. Bone resorption at the interface between implant and bone leads to loosening and eventual mechanical failure of the prosthesis.

Clinical Manifestations Prosthetic joint infection therefore presents in various ways. Early and late presentations have already been referred to. Another useful distinction is between acute and chronic infection. Acute infection, which is here defined as infection associated with an acute inflammatory response, most commonly occurs in the early postoperative period as a wound infection. It can, however, present late because

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of the bacteremic spread of infection to the joint. The clinical manifestations of acute infection include fever, systemic illness, signs of wound infection if the surgical wound has not yet healed (purulence in the wound or purulent discharge from it, erythema, swelling, and pain), and painful limitation of movement of the joint. Although there is no consensus definition of chronic infection, it is a useful concept as it implies a different level of urgency in treatment, and different treatment protocols. Implants with a history of infection exceeding 2 weeks are likely to behave, from a prognostic point of view, as chronically infected. Any joint replacement with an established sinus, mechanical loosening, or where infection recurred after treatment is unequivocally chronically infected, even if there is an acute flare at the time of presentation. Sinuses usually develop down old drain sites or surgical scars. Rarely, sinus formation occurs into more distant sites, such as the ischiorectal area (7) or pelvis (8). They can produce substantial amounts of purulent or serous drainage, requiring management with dressings or even a stoma bag to collect the drainage. Any or all of the appearance, drainage, excoriation of skin, offensive smell, or the need to modify or restrict activities can be highly distressing for patients. The natural history of loosening is a progressive, painful deterioration in prosthesis function. In early loosening, the joint feels stiff or painful only for a few minutes at a time when first moved after a period of rest or sleep. As loosening progresses, this start-up pain becomes more severe and prolonged. The joint becomes constantly painful and later, irritable even on minor movement. Finally, gross mechanical failure, with migration of one or both components, dislocation, or fracture of the cement mantle, can occur. Chronic infections can have significant effects on the patient’s general health. Fever is rare, but loss of well-being, fatigue, and some weight loss are commonplace. Indeed, it is often not until after the infection has successfully been treated that some patients appreciate the extent of the illness associated with a chronic infection.

Diagnosis There is no single, simple test that identifies infection. Clinical features are start-up pain, a history of delayed wound healing, a history that the joint was “never right,” or more overt signs of infection. Although C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are usually elevated, this finding is neither specific nor sensitive in chronic infections. In very active cases there can be an associated anemia of chronic disease and/or hypoalbuminemia. Plain radiographs can show periprosthetic lucency indicating loosening; fracture of cement or bone; gross migration or dislocation of components; and soft tissue swelling. However these changes do not distinguish septic

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from aseptic cause. The same is true of technetium-99 (99Tc) bone scanning. Other isotope scans (leukocyte or antibody scans) are not reliably reproducible in their performance between different centers. Culture of joint fluid and joint tissues has been widely investigated (9). Aspiration of the joint is more reliable for high burdens of infection, and false-negative results can occur in chronic, low-grade disease. Tissue samples allow improved diagnostic yield on culture, and histological examination of peri-prosthetic tissue. There are good criteria for identifying infection according to the numbers of polymorphs present in the tissues (10). Enhanced diagnostic methods under scrutiny at present include the use of sonication to dislodge biofilms from the surface of the prosthesis (11), and broad-range polymerase chain reaction (PCR) for detection of microbial DNA (12). These methods are gaining increasing currency but are not yet standard, and in some hands, have been inferior to culture (13). They can substantially alter our concept of the apparently noninfective causes of prosthesis loosening (aseptic loosening) if it transpires that many implants can be shown to have associated microbes. At present, it is reasonable to restrict our consideration of infection to those clinically obvious presentations described here, but one additional entity can be included. Many studies have demonstrated that the isolation of organisms from many well-taken intra-operative samples is diagnostic of infection (14), with a high correlation with the characteristic histologic changes (15). These diagnostic results are sometimes obtained from cases undergoing revision surgery with no previous suspicion of infection and with no macroscopic evidence of infection at surgery. Surgeons are therefore encouraged routinely to send many different samples at revision surgery to pick up these clinically inapparent cases, as well as to rule infection in or out confidently when the level of suspicion is higher. For this reason, antibiotics should routinely be withheld from patients for at least 2 weeks before revision surgery, unless with the express agreement of the surgeon.

Treatment Treatment should be multidisciplinary, because for success, many different elements must be encompassed. These include surgical debridement of infected soft tissue, potential removal of the implant and subsequent reconstruction, antibiotic choice and administration, management of medical and psychological illness, and rehabilitation (Table 32-1). The role of the primary care physician as part of a multidisciplinary team is outlined in Table 32-2. Acute infections that arise in the context of a soundly fixed implant can sometimes be treated successfully with debridement and retention of the prosthesis. There has been increasing confidence in this approach since the studies by Zimmerli and colleagues of the use of fluoroquinolone-rifampin

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Table 32-1 Treatment Options for Prosthetic Joint Infection Treatment Option

Usual Indication for Consideration of Option

Do nothing

No reconstructive option; patient unwilling to have surgery; unable to tolerate antibiotics, or already proved to be ineffective in controlling symptoms Acute infection, soundly fixed prosthesis

Debridement and retention Suppress with antibiotics alone Excision arthroplasty One-stage revision Two-stage revision Fusion (knee) Amputation

No reconstructive option; morbidity of excision unacceptable No reconstructive option, but symptoms of infection unacceptable Medically fit patient with sensitive pathogen (consider also if very high anesthetic risk) More resistant or unknown pathogens Complex reconstruction required Patient and surgeon preference; reconstruction impossible or high risk Severe symptoms, reconstruction impossible

Problems

High failure rate No alleviation of symptoms

Long-term antibiotics can be required High failure rate Antibiotic intolerance Inferior functional outcome Greater rate of recurrence Morbidity Cost of two operations Technically difficult; disability from rigid leg Morbidity, disability, and body image

Table 32-2 Roles of the Primary Care Physician in Management of Prosthetic Joint Infection Role

Rationale

Prompt referral if infection suspected Prompt treatment of infection in other body sites Consider prophylaxis for dental treatment and obtain specialist advice if need be Ensure no antibiotics for at least 2 weeks prior to revision surgery Partnership working with specialist hospital team

Prognosis for acute infection adversely affected by delay Reduce risk of bacteremic or local spread

Advocacy and support

Prevention of hematogenous infection, balanced against risk of anaphylaxis Allows most reliable ruling in or out of chronic, sometimes occult, infection Patient can need outpatient parenteral antibiotic therapy, prolonged oral antibiotics, or reevaluation for suspected relapse or recurrence Patient needs expert, often complex, management; psychological illness and disability can be significant

combinations in device-related infections. Initially in an animal model, using subcutaneous Teflon cages infected with staphylococci to mimic a biomedical device-related infection (16,17), this work has shown that the combination of ciprofloxacin and rifampin can be curative for an infected foreign body. This has been extrapolated to the clinical situation in many contexts

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including case series (18,19) and a randomized controlled trial of prosthesis retention comparing ciprofloxacin and rifampin with ciprofloxacin monotherapy (20). The positive results of these studies have led to the proposal of a specific protocol for the retention of implants acutely infected with staphylococci (21). No randomly assigned comparative study of intravenous versus oral antibiotic therapy has been made, so treatment regimens vary substantially about the duration of intravenous therapy. Many units still give 6 weeks of intravenous therapy according to antimicrobial sensitivity patterns, with subsequent oral follow-up. Using protocols of a period of intravenous therapy (can be given as outpatient parenteral therapy) followed by oral follow-up with fluoroquinolone-rifampin combinations, high rates of arrest of infection have been achieved (22,23). However it is important to recognize that in some studies at least, time is of the essence, with a narrow window, for S. aureus in particular, for the delivery of the debridement and the antibiotic therapy after the onset of symptoms (24). Other studies have suggested that the prognosis of infections treated with S. aureus remains particularly poor (25), although this can reflect variations in the antibiotic regimens used, the host status, or inherent differences in the likelihood of success when comparing hip and knee replacement. Given this, the primary care physician needs to be alert to the possibility of infection. Because early hospital discharge after joint replacement is the norm in most health care systems, most acute infections will present in the primary care setting. The temptation to give empiric antibiotics if deep infection is suspected should be resisted until after evaluation by the surgeon. Should a referral to the surgical team result in advice simply to give empiric antibiotics without secondary care review, it is perfectly appropriate for the primary care physician to challenge this and ask for a justification. How can deep infection requiring timely treatment be ruled out, how will the causative organism(s) be identified once empiric therapy has been initiated, and what effect will delay of diagnosis and treatment of deep infection have on the longer term outcome? The orthopedic surgeon should be able to give rational responses to these questions. Chronic infections are yet more complex entities to treat. Although their established nature means that time is no longer of the essence in their management, there is a greater variety of treatment options needing individual tailoring to the needs, expectations, and status of the patient. There is more likely to be a history of previous infection and failed management; mechanical loosening of the implant; and a compromised soft tissue envelope caused by both previous surgeries and sinus-tract formation. Experience also suggests that in most cases, there will be significant levels of anxiety, depression, and/or anger directed at previous or present health care providers, which relate to the uncertainty of the prognosis, fear of future pain and disability, and the iatrogenic nature of the condition. These variations and difficulties make it essential to assess the individual patient’s physical and psychological illness and to set realistic expectations for the future management.

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Removal of the implant, known as excision arthroplasty, can be an end point of treatment in its own right or can be a prelude to reconstruction. In the hip, it is possible to function acceptably, in many cases, through the establishment of a Girdlestone pseudarthrosis. However most other major joints cannot produce pseudarthroses with acceptable levels of comfort and function. In areas such as the knee and ankle, weight bearing after resection would be bone-on-bone, and intolerably painful. In the shoulder and elbow, there are issues of potential gravitational traction on nerves and soft tissues and poor function caused by lack of mechanical stability. If reconstruction is carried out after excision, this can be done in a single stage or two. In a two-stage procedure, all infected and foreign material is removed at the first operation, and a new joint is implanted, using antibiotic-loaded cement, several weeks later. Single-stage exchange has no such interval, with the new joint inserted immediately after the debridement. Elements of the two approaches can be combined; for example, there is increasing interest in the use of articulating antibiotic-loaded spacers, which support the soft tissues, maintain some mobility, and maintain limb length while providing locally high levels of antibiotic. These can be quite complex, and there are anecdotal reports of occasional patients needing no further reconstruction. Single-stage exchange has success rates of approximately 80% to 85% (26,27); two-stage exchange has success rates of more than 90% (28,29). Fusion and amputation represent end-stage procedures. Although fusion preserves the distal part of the limb, this can produce new disability. For example in the knee, fusion leads to leg rigidity, which impedes sitting in cars, trains, buses, airplanes, and theater seats. Even amputation is no panacea, with possible sequelae of a range of stump problems, and a threat to independent living for older patients.

Prevention In response to high-infection rates, Charnley devised the laminar flow enclosure and body exhaust suits. This achieved reductions in rates that are equivalent to those caused by the deployment of antibiotics; in the landmark MRC trial that established this, the effects of ultraclean air and antibiotics were additive (30). The surgeon also takes other measures to reduce the risk of infection, including meticulous attention to technique and the avoidance of unnecessary tissue trauma; elimination of surgical dead spaces; insistence on good theatre discipline; and correction of preoperative comorbidities. Prophylactic antibiotics have been shown to reduce infection rates. Patients with joint replacements should have prompt treatment of infections elsewhere in the body to reduce risks of bacteremia and spread. Prophylaxis for dental work is controversial (31,32), but it is recommended by some expert bodies and should be strongly considered for those with

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new or loose implants, and prompt treatment is advised in all patients with prosthetic joints who develop overt dental infection.

Summary Prosthetic joint infection is a formidable problem. The primary care physician can contribute to its management by acting on clinical suspicion with prompt referral back to the original surgeon, who should possess or have access to appropriate skills; by participating in the long-term management plan; and by ensuring, through advocacy and support, that the needs and wishes of the whole patient are being appropriately considered at all times.

REFERENCES 1. Berbari EF, Hanssen AD, Duffy MC, Steckelberg JM, Ilstrup DM, Harmsen WS, et al. Risk factors for prosthetic joint infection: case-control study. Clin Infect Dis. 1998;27:1247-54. 2. Ridgeway S,Wilson J, Charlet A, Kafatos G, Pearson A, Coello R. Infection of the surgical site after arthroplasty of the hip. J Bone Joint Surg Br. 2005;87:844-50. 3. Reilly J, Noone A, Clift A, Cochrane L, Johnston L, Rowley DI, et al. A study of telephone screening and direct observation of surgical wound infections after discharge from hospital. J Bone Joint Surg Br. 2005;87:997-9. 4. Saleh K, Olson M, Resig S, Bershadsky B, Kuskowski M, Gioe T, et al. Predictors of wound infection in hip and knee joint replacement: results from a 20 year surveillance program. J Orthop Res. 2002;20:506-15. 5. Zimmerli W,Trampuz A, Ochsner PE. Prosthetic-joint infections. N Engl J Med. 2004; 351:164554. 6. Gristina AG, Costerton JW. Bacterial adherence and the glycocalyx and their role in musculoskeletal infection. Orthop Clin North Am. 1984;15:517-35. 7. Briggs RD, McLauchlan J, Davidson AI. Late infection of a total hip prosthesis presenting as an ischiorectal abscess. Br J Surg. 1979;66:291-2. 8. Gasiunas V, Plénier I, Hérent S, May O, Senneville E, Migaud H. [Transabdominal removal of femoral and acetabular components of a severely protruded and infected hip arthroplasty with urinary tract complications]. Rev Chir Orthop Reparatrice Appar Mot. 2005;91:346-50. 9. Barrack RL, Harris WH. The value of aspiration of the hip joint before revision total hip arthroplasty. J Bone Joint Surg Am. 1993;75:66-76. 10. Athanasou NA, Pandey R, de Steiger R, Crook D, Smith PM. Diagnosis of infection by frozen section during revision arthroplasty. J Bone Joint Surg Br. 1995;77:28-33. 11. Tunney MM, Patrick S, Gorman SP, Nixon JR,Anderson N, Davis RI, et al. Improved detection of infection in hip replacements. A currently underestimated problem. J Bone Joint Surg Br. 1998;80:568-72. 12. Tunney MM, Patrick S, Curran MD, Ramage G, Hanna D, Nixon JR, et al. Detection of prosthetic hip infection at revision arthroplasty by immunofluorescence microscopy and PCR amplification of the bacterial 16S rRNA gene. J Clin Microbiol. 1999;37:3281-90. 13. Panousis K, Grigoris P, Butcher I, Rana B, Reilly JH, Hamblen DL. Poor predictive value of broadrange PCR for the detection of arthroplasty infection in 92 cases. Acta Orthop. 2005;76:341-6. 14. Atkins BL, Athanasou N, Deeks JJ, Crook DW, Simpson H, Peto TE, et al. Prospective evaluation of criteria for microbiological diagnosis of prosthetic-joint infection at revision arthroplasty. The OSIRIS Collaborative Study Group. J Clin Microbiol. 1998;36: 2932-9. 15. Pandey R, Drakoulakis E,Athanasou NA. An assessment of the histological criteria used to diagnose infection in hip revision arthroplasty tissues. J Clin Pathol. 1999;52:118-23. 16. Widmer AF, Frei R, Rajacic Z, Zimmerli W. Correlation between in vivo and in vitro efficacy of antimicrobial agents against foreign body infections. J Infect Dis. 1990;162:96-102. 17. Blaser J,Vergères P,Widmer AF, Zimmerli W. In vivo verification of in vitro model of antibiotic treatment of device-related infection. Antimicrob Agents Chemother. 1995; 39:1134-9.

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18. Widmer AF, Gaechter A, Ochsner PE, Zimmerli W. Antimicrobial treatment of orthopedic implantrelated infections with rifampin combinations. Clin Infect Dis. 1992;14:1251-3. 19. Jacquier A, Champsaur P, Vidal V, Stein A, Monnet O, Drancourt M, et al. [CT evaluation of total HIP prosthesis infection]. J Radiol. 2004;85:2005-12. 20. Zimmerli W,Widmer AF, Blatter M, Frei R, Ochsner PE. Role of rifampin for treatment of orthopedic implant-related staphylococcal infections: a randomized controlled trial. Foreign-Body Infection (FBI) Study Group. JAMA. 1998;279:1537-41. 21. Zimmerli W, Ochsner PE. Management of infection associated with prosthetic joints. Infection. 2003;31:99-108. 22. Berdal JE, Skråmm I, Mowinckel P, Gulbrandsen P, Bjørnholt JV. Use of rifampicin and ciprofloxacin combination therapy after surgical debridement in the treatment of early manifestation prosthetic joint infections. Clin Microbiol Infect. 2005;11:843-5. 23. Marculescu CE, Berbari EF, Hanssen AD, Steckelberg JM, Harmsen SW, Mandrekar JN, et al. Outcome of prosthetic joint infections treated with debridement and retention of components. Clin Infect Dis. 2006;42:471-8. 24. Brandt CM, Sistrunk WW, Duffy MC, Hanssen AD, Steckelberg JM, Ilstrup DM, et al. Staphylococcus aureus prosthetic joint infection treated with debridement and prosthesis retention. Clin Infect Dis. 1997;24:914-9. 25. Deirmengian C, Greenbaum J, Lotke PA, Booth RE Jr., Lonner JH. Limited success with open debridement and retention of components in the treatment of acute Staphylococcus aureus infections after total knee arthroplasty. J Arthroplasty. 2003;18: 22-6. 26. Wroblewski BM. One-stage revision of infected cemented total hip arthroplasty. Clin Orthop Relat Res. 1986:103-7. 27. Callaghan JJ, Katz RP, Johnston RC. One-stage revision surgery of the infected hip. A minimum 10-year followup study. Clin Orthop Relat Res. 1999:139-43. 28. Haleem AA, Berry DJ, Hanssen AD. Mid-term to long-term followup of two-stage reimplantation for infected total knee arthroplasty. Clin Orthop Relat Res. 2004:35-9. 29. Kraay MJ, Goldberg VM, Fitzgerald SJ, Salata MJ. Cementless two-staged total hip arthroplasty for deep periprosthetic infection. Clin Orthop Relat Res. 2005;441:243-9. 30. Lidwell OM, Lowbury EJ, Whyte W, et al. Effect of ultraclean air in operating rooms on deep sepsis in the joint after total hip or knee replacement: A randomised study. Br Med J (Clin Res Ed). 1982;285:10-4. 31. American Dental Association. Antibiotic prophylaxis for dental patients with total joint replacements. J Am Dent Assoc. 2003;134:895-9. 32. Jacobson JJ, Schweitzer S, DePorter DJ, Lee JJ. Antibiotic prophylaxis for dental patients with joint prostheses? A decision analysis. Int J Technol Assess Health Care. 1990;6:569-87.

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Chapter 33

Osteomyelitis JASON H. CALHOUN, MD REBECCA A. BRADY, PHD MARK E. SHIRTLIFF, PHD

Key Learning Points 1. Osteomyelitis is progressive and results in the inflammatory destruction of bone, in bone necrosis, and in new bone formation. 2. Osteomyelitis is predominantly of bacterial origin. 3. The most determinate diagnostic tool for osteomyelitis is isolation of the causative pathogen through bone, blood, or joint culture. 4. Radiologic evaluation of osteomyelitis can be used to support or refute clinically suspected disease, but no radiologic technique can confirm or rule out the presence of osteomyelitis. 5. Appropriate treatment of osteomyelitis includes drainage, debridement, obliteration of dead space, wound protection, stabilization if necessary, and specific antimicrobial coverage. 6. Most cases of long-bone osteomyelitis are posttraumatic or postoperative.

O

steomyelitis is commonly characterized by infection of the cortical and/or medullary portions of the bone. The term osteo refers to bone and the term myelo to the marrow cavity, both of which are involved in the disease. Osteomyelitis is progressive and results in the inflammatory destruction of bone, bone necrosis, and new bone formation. Although there are many etiologic microorganisms, osteomyelitis is predominantly of bacterial origin.

609

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New Developments • Magnetic resonance imaging (MRI) is becoming the radiographic test of choice to

detect osteomyelitis. • New treatment options for methicillin-resistant Staphylococcus aureus (MRSA),

such as linezolid, daptomycin, and tigecycline, hold promise for treatment of osteomyelitis. Studies with these agents are ongoing. • Hyperbaric oxygen (HBO) therapy may facilitate healing in patients with vascular insufficiency in areas of borderline-normal cutaneous oxygen tension.

Etiology For the purpose of discussing the cause of osteomyelitis, the Waldvogel staging system (Table 33-1) is used because it is based on the cause of the infection (1-3). His staging system describes 3 categories of osteomyelitis: 1) hematogenous osteomyelitis, 2) osteomyelitis with a contiguous focus, and 3) osteomyelitis associated with a vascular insufficiency. Additionally, each category can be either acute or chronic.

Acute Osteomyelitis Acute Hematogenous Osteomyelitis Hematogenous osteomyelitis occurs primarily in infants and children. In these cases, the disease most often begins in the tibial and femoral metaphyses, because the anatomy and histology of the long-bone metaphyses make them susceptible to infection (4). There are no functionally active phagocytic cells in the lining of the afferent loops of these metaphyseal capillaries, and blood flow through them slows considerably and becomes more turbulent (5). For these reasons, any obstruction of the capillary ends can lead to avascular necrosis. Because children bear the greatest amount of mechanical stress on their epiphyseal growth plates, they are at greater risk than adults or infants for trauma in this area. When minor trauma occurs in an infant, it may cause a small hematoma or bone necrosis, which can be invaded by an infecting pathogen. The targets of infection are the large sinusoids that form from the terminal vessels of the growth plates. At the onset of hematogenous osteomyelitis, the acute infection is focal. Subsequently, many cumulative physiological factors in the host add to the Table 33-1 Osteomyelitis: Waldvogel Classification ● ● ● ● ●

Hematogenous osteomyelitis Osteomyelitis caused by contiguous focus of infection No generalized vascular disease Generalized vascular disease Chronic osteomyelitis (necrotic bone)

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extension of the infection by compromising the medullary circulation. These factors include leukocyte breakdown, increased bone pressure, decreased pH, and decreased oxygen tension. In addition, the coordinated expression of the particular virulence factors of the infecting microbial species also determines the disease progression and severity. As it progresses, the infection swells laterally through haversian and Volkmann canal systems, perforating the bony cortex and lifting the periosteum from the surface of the bone. At this point in the progression of the disease, the periosteal and endosteal circulations are lost, leaving large segments of dead cortical and cancellous bone. In infants, because capillaries extend across the growth plate, infection can spread into the epiphysis and the joint space. In children older than 1 year of age, the capillaries no longer penetrate the growth plate, and therefore the epiphysis and joint space are protected from spreading infection. However, because the growth plate in adults has been resorbed completely, infection can pass into the joint space. A single pathogenic species is most commonly recovered from bone cultures of hematogenous osteomyelitis, and Staphylococcus aureus is the most commonly isolated organism (6). Although normally described as a disease of children, hematogenous osteomyelitis has been reported in older age groups. In adults, hematogenous osteomyelitis usually occurs in the vertebrae or in the bones of the wrist and ankle. It is thought that vertebral osteomyelitis begins with an infected embolus within the vertebral body. The resulting ischemia and infarction lead to bone destruction and the infection’s spread into the contiguous disk space. The lumbar vertebral bodies are the most common sites of infection in vertebral osteomyelitis, followed by (in order of frequency of infection) the thoracic and cervical vertebrae. The infection can spread rapidly in the axial skeleton by means of the abundant venous networks of the spine. Commonly, patients with vertebral osteomyelitis have a history of chronic skin infections, urinary tract infections, and intravenous drug use. The osteomyelitis in such cases is typically monomicrobial, with S. aureus again being the most frequent pathogen (1-3).

Acute Osteomyelitis Secondary to a Contiguous Focus of Infection with Normal Vascularity Contiguous osteomyelitis occurs when bacteria are introduced exogenously into bone by trauma or the extension of an adjacent soft tissue infection. The most common factors that contribute to contiguous osteomyelitis are open fractures, joint infections, and soft tissue infections. Traumatic injury often deprives the bone and surrounding tissues of blood flow, providing a good environment for the survival of bacteria. Another important source of contiguous osteomyelitis is an infection that originates from surgical contamination, including that of hardware and joint prosthetic devices. The most common site of contiguous osteomyelitis is the tibia, and the most common cause is trauma (6). This is because the midportion of the tibia lacks

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dense vascularity and has little surrounding soft tissue, which limits its degree of protection and recovery from injury. Bone necrosis, soft tissue damage, and loss of bone stability often result from contiguous osteomyelitis. Unlike hematogenous osteomyelitis, many species of organisms are often isolated from the infected bone in contiguous osteomyelitis, with S. aureus and Staphylococcus epidermidis the most prevalent pathogens. Also isolated are gram-negative bacilli and anaerobic microorganisms.

Acute Osteomyelitis Secondary to a Contiguous Focus of Infection with Generalized Vascular Insufficiency Neuropathy, ischemia, and immunopathy are the 3 pathophysiologic factors responsible for infection in the diabetic foot (7, 8). Neuropathy and vascular compromise make the feet of diabetic individuals more susceptible to minor trauma (e.g., skin ulceration, tissue breakdown) and, along with immunopathy, set the stage for infection (8). One third of diabetic foot infections that require hospitalization are accompanied by osteomyelitis; in such cases, the small bones of the feet are the most common sites of infection. A delayed inflammatory response, stemming from poor tissue perfusion, predisposes the bone to infection in these patients. The disease begins in a claudicated area of traumatized skin. Most often, the infection gains entry through a cutaneous portal (e.g., a diabetic foot ulcer), which leads to cellulitis. Although it is only a local infection, the cellulitis can spread contiguously to tendons, a joint capsule, or bone. However, only when the infection penetrates the medullary cavity can the resulting condition be diagnosed as osteomyelitis. Osteomyelitis is present if a diabetic foot ulcer extends to the bone. Many aerobic organisms are isolated from the infected bone in such cases. Additionally, because of the ischemic environment, anaerobic organisms are often isolated from the infected bone as well. Chronic Osteomyelitis Although the pathogenesis of acute and chronic osteomyelitis are similar, some characteristics that are unique to each of these 2 states of infection distinguish them from one another. Pathologic features of chronic osteomyelitis are the presence of necrotic bone, the formation of new bone, and the exudation of polymorphonuclear leukocytes joined by large numbers of lymphocyte histiocytes, and occasionally plasma cells. The hallmark of chronic osteomyelitis is infected dead bone within a compromised soft tissue envelope. The cause of the infection is variable: Pathogenic organisms can reach the bone through hematogenous seeding, open trauma, or contiguous spread. Once the infection is established, an involucrum of fibrous tissue and chronic inflammatory cells forms around the granulations and dead bone. After the infection is contained, there is a decrease in vascularization of the infection site, and the metabolic demands of an effective inflammatory response cannot be satisfied. The revascularization and resorption of the dead bone and scar tissue are similarly affected. The process of resorption eventually subsides, and the haversian

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canals are sealed by scar tissue. The bacteria responsible for the infection are enclosed in a biofilm. A biofilm may be defined as a microbe-derived sessile community characterized by cells that are attached to a substratum, interface, or each other, are embedded in a matrix of extracellular polymeric substance, and exhibit an altered phenotype with respect to growth, gene expression, and protein production (9). Once in this state, the bacteria have a greatly reduced metabolic activity, and the host immune system and antimicrobial agents are incapable of clearing the infection. The coexistence of infected, nonviable tissues and an ineffective host response leads to chronicity of the infection. The nidus of persistent contamination must be removed before the infection can regress. New bone formation is another characteristic of chronic osteomyelitis. New bone develops from the surviving fragments of periosteum, endosteum, and cortex in the region of the infection and is produced by a vascular reaction to the infection. The newly forming bone may extend outward from the periosteum and along the intact periosteal and endosteal surfaces, thereby surrounding the dead bone and forming an involucrum. This involucrum is irregularly shaped and contains openings through which pus may permeate into the surrounding soft tissues, forming a sinus tract that allows pus to travel from the involucrum to the skin surface. The involucrum may increase in density gradually and form part or all of a new bone shaft. Depending on the size of the affected bone and the duration of the infection, the amount and density of the new bone may increase progressively for weeks or months. New endosteal bone may proliferate and obstruct the medullary canal. Once the sequestrum has been removed surgically, the remaining cavity may be filled with new bone, especially in children. In adults, however, the cavity may persist or may be filled with fibrous tissue that connects with the skin surface through a sinus tract.

Clinical Manifestations Local findings that lead to the diagnosis of osteomyelitis are often absent in neonates (10). When present, these local findings include edema and decreased motion of a limb. A joint effusion adjacent to the site of bone infection is present in 60% to 70% of cases of osteomyelitis. In contrast with infants, children with hematogenous osteomyelitis have fever of abrupt onset, irritability, lethargy, and local signs of inflammation that are typically present for 3 weeks or fewer from the time that the bone infection began. Although there may be a minimal increase in temperature, systemic toxicity is absent in 50% of children with hematogenous osteomyelitis. Children with the disease have reports referable to the involved bone, such as pain for 1 to 3 months’ duration in the affected limb. Infants with hematogenous osteomyelitis usually have normal soft tissue that envelops the infected bone and are capable of an efficient immune response to the infection.

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In hematogenous vertebral osteomyelitis in adults, the clinical signs of soft tissue extension often dominate the findings at presentation and may lead to misdiagnosis and improper treatment, unless the possibility of osteomyelitis is considered. Patients with hematogenous vertebral osteomyelitis present with vague symptoms and signs that include dull, constant back pain, spasms of the paravertebral muscles, point tenderness over the involved vertebral body, and no (or only a low-grade) fever. There is localized pain and tenderness of the involved bone segments in at least 90% of cases (11). The pain, usually of insidious onset, progresses slowly over a period from 3 weeks to 3 months. An acute clinical presentation of chills, swelling, and erythema over the involved bone is seen occasionally. The clinical features of osteomyelitis with a contiguous force and normal vascularity include low-grade fever, local pain, draining sinuses, tenderness, and erythema over the involved bone. The infection usually manifests within 1 month after the inoculation of one or more organisms by means of trauma, surgery, or soft tissue infection. The patient is often afebrile and frequently has loss of bone stability, bone structure, and soft tissue damage. In patients who have vascular disease, the clinical features are more subtle and are usually associated with foot ulcers, which render this form of bone infection difficult to diagnose. Patients can present with an apparently localized process that includes an ingrown toenail, a perforating foot ulcer, cellulitis, or a deep-space infection. Furthermore, concurrent peripheral neuropathy often blunts the patient’s perception of pain. Fever and toxicity are frequently absent. There are no exact criteria for defining the transition from acute to chronic osteomyelitis. The hallmark of chronic osteomyelitis is the presence of dead bone as exemplified by the presence of sequestrum (1-3). Involucrum, local bone loss, persistent drainage, and/or sinus tracts are the common features of chronic osteomyelitis. Patients with chronic osteomyelitis present with chronic pain and drainage. Fever is usually of a low grade or absent. The erythrocyte sedimentation rate (ESR) is often increased, reflecting chronic inflammation; however, the leukocyte count is usually normal. Squamous cell carcinoma and amyloidosis are complications of chronic osteomyelitis that take many years to develop.

Classification Osteomyelitis can be classified by duration, pathogenesis, location, extent, and host status. Osteomyelitis is currently classified according to the Waldvogel (Table 33-1) or the Cierny-Mader (Table 33-2) system (1-3,12). Although the Waldvogel system remains the most popular classification system, it is limited to the cause of the infection and does not lend itself well to the identification of different clinical features of the disease for diagnosis and treatment. For this reason, the Cierny-Mader classification system is used

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Table 33-2 Cierny-Mader Staging System Anatomic Type ● ● ● ●

Stage Stage Stage Stage

1: 2: 3: 4:

Medullary osteomyelitis Superficial osteomyelitis Localized osteomyelitis Diffuse osteomyelitis

Physiologic Class ● ●

●

A Host: Normal host B Host: Systemic compromise (Bs)* ● Local compromise (Bl)* ● Systemic & local compromise (Bls)* C Host: Treatment worse than the disease

* See Table 33-3 for a list of systemic or local factors that affect immune surveillance, metabolism, and local vascularity.

in this chapter as a model for discussion of the diagnosis and treatment of osteomyelitis. It is based on the anatomy of the bone infection and the physiology of the host and allows the staging of long-bone osteomyelitis and the development of comprehensive treatment guidelines for each stage of the disease. The Cierny-Mader classification is based on the status of the disease process, regardless of cause, localization, or chronicity. The anatomical categories of osteomyelitis in the Cierny-Mader system are medullary, superficial, localized, and diffuse. Stage 1, or medullary osteomyelitis, denotes an infection that is confined to the intramedullary surfaces of the bone (e.g., hematogenous osteomyelitis, infection of intramedullary rods). Stage 2, or superficial osteomyelitis (a true contiguous-focus infection of bone), occurs when an exposed, infected, or necrotic surface of bone lies at the base of a soft tissue wound. Stage 3 or localized osteomyelitis is usually characterized by a full-thickness cortical sequestration that can be removed surgically without compromising bone stability. Stage 4, or diffuse osteomyelitis, is a process that involves all structural components of the bone; its arrest usually requires an intercalary resection of the bone. Diffuse osteomyelitis includes infections in which there is loss of bone stability, either before or after débridement. According to the Cierny-Mader system, the patient is classified as an A, B, or C host (Tables 33-2 and 33-3): An A host represents a patient with normal physiologic, metabolic, and immunologic capabilities; a B host is either systemically compromised, locally compromised, or both; and a C host is a patient in whom the illness of treatment is worse than that of the disease itself. The terms acute and chronic osteomyelitis are not used in this staging system, because areas of macronecrosis must be removed regardless of the acuity or chronicity of an uncontrolled infection. The stages of osteomyelitis in the Cierny-Mader system are dynamic and may be altered by treatment or by changes in the host.

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Table 33-3 Systemic or Local Factors that Affect Immune Surveillance, Metabolism, and Local Vascularity Systemic (Bs)

Local (Bl)

Malnutrition Renal, hepatic failure Diabetes mellitus Chronic hypoxia Immune disease Malignancy Extremes of age Immunosuppression or neuropathy Immune deficiency

Chronic lymphedema Venous stasis Major vessel compromise Arteritis Extensive scarring Radiation fibrosis Small vessel disease Complete loss of sensation Tobacco abuse

Diagnosis It is important that the physician recognize the clinical signs of osteomyelitis in its earliest stages. Most presentations of osteomyelitis, such as radiographic features or draining sinus tracts, are late complications of the disease. Osteomyelitis crosses from the more easily treated acute form to the difficult-to-treat chronic form when the bone dies, which usually occurs 10 days into the infection. When osteomyelitis is first discovered through radiographic manifestations, the diagnosis is already late and the treatment is more costly and difficult. Making the diagnosis at an early stage gives the patient the best opportunity for full recovery.

Culture and Microbiology The most determinate diagnostic tool for osteomyelitis is isolation of the causative pathogen through bone, blood, or joint culture (13-15). With stage 1 hematogenous osteomyelitis, a blood or joint culture can eliminate the need for a bone biopsy when radiographs and nucleotide scans show evidence of osteomyelitis. It should be noted that only 50% of patients with hematogenous osteomyelitis have positive blood cultures; however, for all other stages of the disease, it is necessary to obtain a bone culture from débridement surgery or deep bone biopsy to make a diagnosis. Sinus tract culture should not be used as a diagnostic technique because it has proven a poor indicator of gram-negative infection (16). Antimicrobial treatment of osteomyelitis should be based on susceptibility tests of culture isolates. If possible, the cultures should be made before any antibiotic is given and after the patient has ceased receiving antibiotic therapy for 24 to 48 hours. Furthermore, both fungi and mycobacteria should be considered pathogens in immunocompromised patients. In osteomyelitis that occurs after a footpuncture wound, Pseudo-monas aeruginosa is the most commonly found organism.

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Hematologic Findings In acute osteomyelitis, there is leukergy (the clumping of leukocytes that accompanies some inflammations and infections), increased ESR, and increased C-reactive protein (CRP) level and leukocyte count before treatment is begun (17-19). In cases of chronic disease, the leukocyte count rarely exceeds 15,000 cells/mm3 and is most often normal. The ESR, CRP level, and leukocyte count may decrease with appropriate treatment; but they often increase after débridement surgery. Return of the ESR and CRP to normal during the course of therapy is a favorable prognostic sign.

Imaging Studies Radiologic evaluation of osteomyelitis can be used to support or refute clinically suspected disease; no radiologic technique can confirm or rule out the presence of osteomyelitis absolutely. Because the radiologic approaches and techniques used for investigating osteomyelitis are numerous and diverse, there is confusion about which is most effective. It is difficult to interpret changes on plain radiography in early stage 1 osteomyelitis. In particular, radiographic changes often lag behind the evolution of infection by at least 2 weeks because 30% to 50% loss in bone density is often required to reach a level of bony destruction that can be visualized (20). The first radiographic changes to occur are soft tissue swelling, periosteal thickening, and focal osteopenia; however, these findings are subtle and often missed. The most diagnostic changes are delayed and occur in association with an indolent infection of several months’ duration. It should be remembered that at the beginning of antibiotic therapy, the patient shows clinical improvement before radiographic improvement is evident. In stage 2 osteomyelitis, the outer cortex of the bone is involved. In these cases there is evidence of periosteal thickening and/or sclerosis. Osteomyelitis of stages 3 and 4 may be more evident than the disease in its earlier stages; soft tissue swelling, osteopenia, lytic changes, and sclerosis are all characteristic findings. Small and large sequestra also may be present. Because of the degree of sclerosis and nonspecific radiographic changes, it is often difficult to estimate the scope of the infection by visualization on films. Therefore, the physician must carefully evaluate the disease clinically and possibly surgically as well. Sensitivity and specificity are only 70% and 50%, respectively, making this technique often unreliable (8-9). Although it is the least sensitive diagnostic technique, plain radiography is the most informative technique when there is a clinical suspicion of osteomyelitis. Ultrasound is another option, but it is only able to diagnose soft tissue infection surrounding the bone making this imaging technique of limited use. Radionuclide scans, computed tomography (CT), and magnetic resonance imaging (MRI) are often used to diagnose osteomyelitis in cases in which it is ambiguous and to determine the extent of bone and soft tissue

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infection. In most cases, these diagnostic tests are not required for osteomyelitis of the long bones. Radionuclide scans are widely used, and these help to identify areas of inflammation better than radiography alone. This method also has the benefit of being useful for suspected implant infections as well, because there are no issues with metallic scatter like MRI or CT. The technetium-99m (99mTc) methydiphosphonate scan demonstrates increased isotope accumulation in areas of osteoblastic activity and increased vascularity (21). Sensitivity and specificity of osteomyelitis detection for this method range from 69% to 100% and 38% to 94%, respectively. However, any event leading to bone injury leads to a positive scan, causing false diagnoses. Falsepositive rates have been reported from 0% to 64% in reported series (22) and high rates can be attributed to cases of new bone formation, fracture healing, heterotopic ossification, arthritis, and local minor trauma (23). A second class of radiopharmaceuticals used for the evaluation of osteomyelitis includes gallium-67 (67Ga) citrate and indium-111 chloride; both become bound to transferrin, which leaks from the blood into areas of inflammation. These scans also show increased isotope uptake in malignant tumors and in areas in which polymorphonuclear leukocytes or macrophages are concentrated. Because they do not show bone detail well, these scans do not readily distinguish between bone and soft tissue inflammation. Three-phase 99m Tc methydiphosphonate scans help resolve this problem. Another radionuclide technique exploits indium-111 (111In) labeled leukocytes, in which patient leukocytes are isolated, labeled with 111In, and injected back into the patient. These radiolabeled leukocytes will accumulate in regions of acute infection, causing it to be a sensitive method (except in most cases of chronic osteomyelitis) and the radionuclide technique of choice for diagnosing and localizing acute osteomyelitis in the limbs (22-25). Although its sensitivity is 86%, its specificity is only 12% (26). Also, these scans are positive in approximately 40% of patients with acute osteomyelitis and in 60% of patients with septic arthritis. Chronic osteomyelitis, bony metastases, and degenerative arthritis often yield negative scans. However, this method works well in cases of suspected prosthetic implant infection when combined with bone marrow imaging with 99mTc sulfur colloid marrow scintigraphy because leukocyte uptake around prostheses may be caused by surgery. When an accumulation of leukocytes is seen, coupled with noncongruent bone marrow patterns and absent marrow uptake, an infection is likely. 99mTc hexamethylpropylene amine oxime leukocytes ( 99mTc HMPAO WBCs) are also used to overcome the problems with 111In leukocytes, such as the 24-hour delay required for imaging, high levels of radiation in the spleen, and limited injection dose. The combination of these 2 scans leads to a sensitivity of 100% and a specificity of 94% (26). CT may be useful in the diagnosis of osteomyelitis by measuring the increased marrow density that occurs early in the infection (27). CT is also useful in identifying areas of devitalized bone and reveals the involvement of

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surrounding soft tissues, particularly in cases of vertebral osteomyelitis. In a difficult infection, the CT scan may assist in selecting the most appropriate surgical approach (28). MRI has become the most useful diagnostic tool for identifying and determining the extent of musculoskeletal sepsis (29-30). The spatial resolution of MRI makes it useful in differentiating bone from soft tissue infections. MRI displays greater anatomic detail than does radionuclide scanning and has greater specificity for abnormalities than do either CT or radiography. Moreover, MRI does not expose patients to ionizing radiation. The sensitivity and specificity to detect cases of osteomyelitis are between 68% to 100% and 50% to 100%, respectively (31-32). In cases of vertebral osteomyelitis, MRI is particularly valuable and has a sensitivity and specificity of 96% and 92%, respectively (33). The main disadvantage of MRI is its poor resolution of the cortex, which could yield many false-negative results in cases of isolated cortical infection (34). Initial MRI screening usually consists of both T1- and T2-weighted spin echo pulse sequences. In a T1-weighted study, edema and fluid are dark, whereas fat (including the fatty marrow of bone) is bright. In a T2-weighted study, the reverse is true. The typical appearance of osteomyelitis is of a localized area of abnormal marrow with a decreased signal intensity (darker appearance) on T1-weighted images and increased signal intensity on T2weighted images. Occasionally, however, there also may be a decreased signal intensity on T2-weighted images. Cellulitis is seen as a diffuse area of intermediate signal intensity on T1-weighted images of soft tissue and as an increased signal intensity on T2-weighted images of the same tissue. Because it may be difficult to differentiate infection from neoplasm on the basis of MRI alone, further clinical and radiographic confirmation may be necessary.

Osteomyelitis with Vascular Insufficiency For patients with vascular disease, the diagnosis of osteomyelitis can become a challenge because of coexisting clinical effects. It is essential, however, that the physician recognizes osteomyelitis in its early stages to arrest the infection and prevent amputation caused by complications of peripheral vascular disease. Clinical evaluation is the most important step in diagnosing osteomyelitis in patients with vascular disease. Any ulcer or skin laceration near a bony area of the foot that has persisted for more than 1 to 2 weeks should be considered a risk factor for underlying osteomyelitis. When the bone can be visualized, treatment of osteomyelitis can begin immediately and be adjusted when culture results are known. In all other cases, radiographic evidence is necessary to confirm the existence of the disease. Patients with both osteomyelitis and vascular disease often have radiographs that show patchy bone destruction, a periosteal reaction, and illdefined bone margins. CT scans, although more sensitive, are less useful than radiographs for identifying infections of the foot bones because of the

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small amount of bone and adjacent soft tissue in the extremities. Radionuclide scans yield positive findings in cases of both soft tissue and bone inflammation. Consequently, a positive scan may indicate only a soft tissue infection. In studies of patients with osteomyelitis with complicating soft tissue infections of the foot, MRI proved to be diagnostically better than plain radiography, bone scanning, 67Ga scanning, and leukocyte scanning (35). MRI is also useful in distinguishing areas of neuropathy, which are identified by a low signal intensity on all pulse sequences within bony structures and soft tissue. This contrasts with osteomyelitis, in which marrow gives a high signal intensity on all pulse sequences except for T1weighted sequences. Because of their high cost, MRI studies should be reserved for patients who have a questionable diagnosis of osteomyelitis.

Vertebral Osteomyelitis The most common radiographic feature of vertebral osteomyelitis is faint lucency at the edge of the affected vertebral body, with loss of clear demarcation of the cortical margin. MRI is the simplest and most effective method for determining osteomyelitis of the spine. Involvement of the vertebral bodies, discs, and paravertebral region is detected easily. Disease-induced changes in MRI scans include increased enhancement on T1-weighted images and increased intensity on T2-weighted images. Consistently, infection has been associated with an early decreased intensity of the vertebral marrow on T1-weighted images and an enhanced intensity of the same area with gadolinium-enhanced contrast studies. Significant changes on T2weighted images also have been shown to be early signs of infection.

Treatment Many factors must be considered in determining the appropriate course of treatment of the patient with osteomyelitis and especially the effect that treatment will have on the patient. If curative measures will adversely affect the patient’s quality of life, simple suppression of the disease with oral antibiotic therapy may be preferred. If the patient is a good surgical candidate, foreign material and sequestra must be removed. Appropriate treatment of osteomyelitis includes adequate drainage, thorough débridement, obliteration of dead space, wound protection, stabilization if necessary, and specific antimicrobial coverage. If the patient is a compromised host, an effort should be made to correct or alleviate the host’s defect(s).

Medical Management After cultures are obtained from a patient with osteomyelitis, a parenteral antimicrobial regimen is begun to eliminate the clinically suspected pathogens (Table 33-4). Once the causative pathogen has been identified,

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the specific classes of antimicrobial drugs for its eradication can be selected through appropriate methods of sensitivity testing (36). Most experts prefer bacteriocidal over bacteriostatic therapy (with the exception of clindamycin); and, with the exception of acute osteomyelitis, antimicrobial therapy by itself is rarely curative. Cure usually requires surgery, and most experts use parenteral therapy in adults and with chronic osteomyelitis to ensure high concentrations of drug at the infected site. Stage 1, or hematogenous osteomyelitis, in children usually can be treated with antimicrobial drugs alone (37). Antibiotic therapy without surgery is possible because children’s bones are very vascular and children have an effective immune response to infection. It is recommended that children with osteomyelitis initially receive 2 weeks of parenteral antibiotic therapy followed by an oral antibiotic regimen. Oral therapy should be given for 4 to 6 weeks. Because the quinolone class of antimicrobial drugs has been shown to cause articular damage in young animals, this class of drugs should not be used in pediatric patients. Stage 1 osteomyelitis is more refractory to therapy in adults than in children and is usually treated with antimicrobial drugs and surgery. The patient is given 4 weeks of appropriate parenteral antimicrobial therapy, dating from the initiation of therapy or after the last major débridement surgery. For methicillin-susceptible S. aureus (MSSA) and Streptococcus species, the antimicrobial agent initially chosen should be clindamycin, nafcillin, or cefazolin. Clindamycin may the drug of first choice for sequential intravenous or oral therapy because of its excellent bone penetration and bioavailability. If the initial medical management fails and the patient is clinically compromised by a recurrent infection, medullary and/or soft tissue débridement is necessary in conjunction with another 4-week course of antibiotic therapy. As noted earlier, an infected intramedullary rod can cause stage 1 osteomyelitis. If the bone is stable, the rod can be removed. The patient is given a 4-week course of antibiotic therapy beginning at the time of rod removal. If the bone is unstable, the patient is given suppressive oral antibiotic therapy until bone stability is achieved. Once stability is achieved, the rod is removed and the patient is given a 4-week course of antibiotic therapy, again beginning at the time of rod removal. Stage 2, or superficial osteomyelitis, occurs when an exposed infected, necrotic surface of bone lies at the base of a soft tissue wound. After superficial bone débridement and soft tissue treatment, the patient is given 2-week parenteral antimicrobial therapy beginning after the last major débridement surgery. Without adequate débridement, most antibiotic regimens fail no matter the duration the therapy. Even when all necrotic tissues have been débrided adequately, the remaining bed of tissue must be considered contaminated with the causative pathogen(s). Consequently, it is important to give the patient at least 4 weeks of antibiotic treatment. The arrest rate for stages 3 and 4 osteomyelitis with such treatment is approximately 90% (10).

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Table 33-4 Initial Choice of Antibiotics for Therapy of Osteomyelitis* Organism

Antibiotics of First Choice

Alternative Antibiotics

MSSA

Nafcillin or oxacillin 2 g IV q4h for 4-6 wk

●

Cefazolin 2 g IV q8h for 4-6 wk ● Penicillin-intolerant patient: ● Vancomycin 15 mg/kg IV q12h for 4-6 wk ● Clindamycin 900 mg q8h for 4-6 wk ● Linezolid 600 mg IV or PO MRSA and MRSE Vancomycin 15 mg/kg IV q12h for 4-6 wk for 6 wk (platelet count should be checked weekly if this drug is given over 14 days ● TMP/SMX DS (if tested susceptible) 2 tablets q12h for 4-6 wk ● Levofloxacin (if tested susceptible) 500-750 mg PO/IV q24h with or without rifampin 600 mg/day for 4-6 wk ● Cefazolin 2 g q8h IV or Streptococcus Penicillin G 2 million units IV (Groups A, B, q4h or ampicillin 2 g IV q4h Ceftriaxone 1-2 g IV q24h for and viridans for 4-6 wk 4-6 wk ● Penicillin intolerant patient: streptococci) ● Vancomycin 15 mg/kg IV q12h for 4-6 wk ● Clindamycin 900 mg q8h for 4-6 wk** Enterococcus Ampicillin 2 g IV q4h for Vancomycin 15 mg/kg IV q12h and streptococ4-6 wk plus gentamicin for 4-6 wk plus (optional) cus with MIC 1 mg/kg IM q8h for 1-2 wk gentamicin 1 mg/kg IM q8h > 0.5 µg/mL for 1-2 wk ● Ciprofloxacin 750 mg PO Enteric bacteria Ceftriaxone 1-2 g IV q24h for 4-6 wk (if tested susceptible) q12h for 4-6 wk ● Levofloxacin 750 mg PO (if tested susceptible) q24h for 4-6 wk ● Based on susceptibility ESBL-producing Imipenem/cilastatin 500 mg IV enteric bacteria q6h or Meropenem 1 g IV q8h results for 4-6 wk ● Piperacillin 4 g IV q6h or Pseudomonas Cefepime 2 g IV q12h ● Imipenem/cilastatin 500 mg aeruginosa IV q6h or Meropenem 1 g IV q8h for 4-6 wk ● Ciprofloxacin 750 mg PO q12h for 4-6 wk * Adult doses. ** Clindamycin resistant group B streptococci has been increasingly found in certain geographic areas Abbreviations: h = hour; ESBL = extended-spectrum beta-lactamase; IM = intramuscular; IV = intravenous; MIC = minimum inhibitory concentration; MRSA = methicillin-resistant Staphylococcus aureus; MRSE = methicillin-resistant Staphylococcus epidermidis; MSSA = methicillin-susceptible Staphylococcus aureus; PO = by mouth; q = every; TMP/SMX DS = trimethoprim/sulfamethoxazole double-strength; wk = week.

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Hospital lengths of stay for osteomyelitis have been decreased in recent years by the development of outpatient catheters and oral antibiotic therapy. Intravenous therapy can be given on an outpatient basis with longterm intravenous access catheters, such as Hickman or Groshong catheters (38,39). In addition to outpatient intravenous therapy, oral therapy with quinolones for gram-negative organisms is used for adult patients with osteomyelitis (40,41). The second-generation quinolones (e.g., ciprofloxacin, ofloxacin) have poor activity against Streptococcus, Enterococcus, and anaerobic bacteria. The third-generation quinolones (e.g., levofloxacin, gatifloxacin) have excellent activity against Streptococcus but provide minimal coverage of anaerobic organisms. None of the quinolones provides reliable coverage of Enterococcus. The currently available quinolones provide variable coverage of S. aureus and S. epidermidis, and resistance to the secondgeneration quinolones is increasing. MSSA should be covered with another oral antimicrobial agent, such as clindamycin or amoxicillin-clavulanate. Before being moved to an oral antimicrobial regimen, the patient should be given 2 weeks of parenteral antibiotic therapy; it is important to ascertain whether the organisms isolated from the patient’s infection are sensitive to the oral regimen. The patient must be compliant with treatment and have close outpatient follow-up. A combination of parenteral and oral antibiotic therapy has been used in some situations. Osteomyelitis caused by MSSA has been treated successfully with the combination of a semisynthetic penicillin and rifampin, and osteomyelitis caused by methicillin-resistant S. aureus (MRSA) has been treated successfully with a combination of vancomycin and rifampin. New treatment options for MRSA include linezolid, daptomycin, and tigecycline. Studies in osteomylitis treatment with these agents are ongoing.

Surgical Management Surgical management of osteomyelitis can be very challenging. The principles of surgically treating any infection are equally applicable to the treatment of infection in bone. These include adequate drainage, extensive débridement of all necrotic tissue, obliteration of dead spaces, adequate soft tissue coverage of the treated bone, restoration of an effective blood supply, and stabilization of the patient. The goal of débridement in osteomyelitis is to leave healthy, viable bone tissue and conditions that can lead to the rapid formation of new bone. However, even when all necrotic tissue has been débrided adequately, the remaining bed of tissue must be considered to be contaminated with the etiologic pathogen. The challenge in treating osteomyelitis compared with that of an infection of soft tissue alone is the need for bone débridement. In cases of chronic osteomyelitis, débridement is essential for cure. Adequate débridement may leave the large-bone defect known as a dead space. To arrest the disease and maintain the integrity of the bone, appropriate management of

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any dead space created by débridement surgery is mandatory. The goal of dead-space management is to replace dead bone and scar tissue with durable, vascularized bone tissue. Allowing the bone to become revascularized is the best way to ensure the arrest of the infection in osteomyelitis. Complete wound closure should be attained whenever possible. Cancellous bone grafts allow the filling of the dead space that remains after débridement surgery with tissue that allows revascularization (42). These grafts also can be placed beneath local or transferred tissues where soft tissue reconstruction is necessary. Careful preoperative planning is critical to conserving the patient’s limited cancellous bone reserves. Open cancellous grafts are useful when a free tissue transfer is not a treatment option and when local tissue flaps are inadequate. Antibiotic-impregnated acrylic beads may be used to sterilize and to maintain dead space temporarily (43,44). The beads are usually removed within 2 to 4 weeks and then replaced with a cancellous bone graft. The antibiotics most commonly used in impregnated beads are vancomycin, tobramycin, and gentamicin. Local delivery of antibiotics (e.g., amikacin, clindamycin) into dead space has been accomplished with an implantable pump. If pathologic movement of bone is present at the site of infection, measures must be taken to achieve permanent stability of the affected skeletal unit. Stability may be achieved with plates, screws, and rods, and/or an external fixator. External is preferred to internal fixation because of the tendency of medullary rods to become secondarily infected and thereby extend the original bone infection. An Ilizarov external fixator allows bone reconstruction of segmental defects and difficult infected nonunions (45,46). This external fixation method is based on the theory of distraction histogenesis, whereby bone is fractured in the metaphyseal region and slowly lengthened. The growth of new bone in the metaphyseal region pushes a segment of healthy bone into the defect left by surgery. The Ilizarov method also may be used to compress nonunions and to correct malunions. Infected pseudoarthroses with segmental osseous defects also may be treated by débridement and microvascular bone transfers. Vascularized bone transfer is a useful procedure for treating infected segmental osseous defects of long bones of more than 3 cm length. Vascularized bone transfers can be performed 1 month or more after the successful treatment of a bone infection. Adequate soft tissue coverage of the bone is necessary to arrest osteomyelitis. Small soft tissue defects may be covered with a split-thickness skin graft. Local tissue flaps or free flaps may be used to fill dead space (47,48). Although local muscle flaps are useful because of their ease of placement, they are often of limited use because of the locality of the bone infection in osteomyelitis. For areas such as the distal tibia, microsurgical implantation of a muscle flap is necessary. In the presence of a large soft tissue defect or with an inadequate soft tissue envelope, local muscle flaps and free vascularized muscle flaps may be placed in a 1- or 2-stage procedure.

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Local and free muscle flaps, when combined with antibiotic therapy and surgical débridement of all nonviable osseous and soft tissue, have a success rate of from 66% to 100% in chronic osteomyelitis (49). Local muscle flaps and free vascularized muscle transfers alleviate the local biological environment by bringing in a blood supply important to host-defense mechanisms, antibiotic delivery, and osseous and soft tissue healing.

Special Treatments Osteomyelitis with Vascular Insufficiency Determination of the vascular status of the tissue at the infection site is crucial in the evaluation of patients in whom osteomyelitis is accompanied by vascular insufficiency. Although several methods can be used to determine the vascular status of such patients, measuring cutaneous oxygen tension and pulse pressure is the most commonly used method. Cutaneous oxygen tensions are measured with a modified Clark electrode that is applied to the skin surface. The results provide guidelines for determining the location of adequately perfused tissue. The tensions recorded in this manner are also helpful for predicting the benefit of local débridement surgery and in selecting surgical margins at which healing can be expected to occur. Revascularization, if possible, or hyperbaric oxygen therapy facilitates healing in areas where oxygen tensions are of borderline normality. Historically, treatment pressures of both 2.0 and 2.4 atmosphere absolute (ATA) have been used, with treatment times varying from 2 hours at the lower pressure to 90 minutes at 2.4 ATA. Treatment pressure and duration are the same for monoplace and multiplace chambers. Now the higher pressure of 2.4 ATA is almost universally used. Because experimental evidence suggests that twice-per-day hyperbaric oxygen (HBO) treatments interfere with bone healing (50-52), if used HBO treatment should be provided on a once-per-day basis for the treatment of osteomyelitis. The patient who has osteomyelitis with vascular insufficiency may be managed with suppressive antibiotic therapy, local débridement surgery, or ablative surgery. The choice of treatment is based on tissue oxygen perfusion at the infection site, extent of the osteomyelitis, and patient preference. The patient can be offered long-term suppressive antibiotic therapy when a definitive surgical procedure might lead to unacceptable illness or disability or in cases in which the patient refuses local débridement or ablative surgery. However, even with suppressive antibiotic therapy, amputation of the involved bone may ultimately be necessary. Local débridement surgery and a 4-week course of antibiotic therapy may be used for the patient who has osteomyelitis in bone that is amenable to débridement. Unless good tissue oxygen tensions are present, the wound fails to heal and ultimately requires an ablative procedure. As noted earlier, hyperbaric oxygen therapy facilitates healing in areas of borderline-normal oxygen tension.

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The patient with extensive osteomyelitis and poor tissue oxygen perfusion usually requires some type of ablative surgery. Digital and ray resections; transmetatarsal amputations; midfoot disarticulations; and Chopart, Lisfranc, and Syme amputations (amputation of the foot with retention of the heel pad) permit the patient to ambulate without a prosthesis. The level of amputation is measured by the vascularity and potential viability of the tissues proximal to the site of infection. Hyperbaric oxygen therapy facilitates healing if surgery is done in or through areas of low oxygen tension as measured cutaneously. When infected bone is transected surgically, the patient is given 4 weeks of antibiotic therapy. Two weeks of antibiotic therapy are given when the infected bone is excised completely, but some residual soft tissue infection remains. When amputation is done proximal to a site of bone and soft tissue infection, the patient should be given from 1 to 3 days of antibiotic therapy.

Vertebral Osteomyelitis Biopsy and débridement cultures dictate the choice of antibiotic(s) to be used in treating vertebral osteomyelitis. Antibiotic therapy is given for 4 to 6 weeks and is dated from the initiation of therapy or from the last major débridement surgery. Open surgical treatment is usually necessary only in cases in which the patient develops an extension of an original infection (e.g., paravertebral or epidural abscess, when medical management fails, when bone instability is likely to occur). The neurological status of the patient must be monitored closely in such cases. Surgical fusion of the involved vertebrae is usually not required, because bone fusion occurs spontaneously within 1 to 12 months after appropriate antibiotic therapy. The frequency of a successful outcome for patients treated with bed rest alone is not substantially different from that for ambulatory patients stabilized with a cast, corset, or brace.

Prevention Most cases of long-bone osteomyelitis are posttraumatic or postoperative. With the increasing number of accidents and orthopaedic procedures done, it is unlikely that infection rate will decrease. Patients with diabetes mellitus can prevent osteomyelitis by minimizing foot trauma and preventing foot ulcers (8) (see Diabetic Foot Infection chapter). This includes education about proper foot care, including daily inspection of the feet. Daily foot washing and use of moisturizing creams are necessary to avoid breaking the skin. Furthermore, patients should avoid activities that might cause unnecessary trauma to vasculitic neuropathic feet. This includes walking barefoot or wearing improperly fitted shoes. The only way to reduce the frequency of contiguous-focus osteomyelitis in diabetic patients is to prevent the development of diabetic foot ulcers or aggressively prevent diabetic foot ulcers from involving bone through treatment of the infection, wound care, and the off-loading of pressure points.

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Acknowledgments The authors thank Gordon Christensen, MD, and M. M. Manring, PhD, for their help in the preparation of this manuscript.

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27. Kuhn JP, Berger PE. Computed tomographic diagnosis of osteomyelitis. Radiology. 1979;130:503-6. 28. Seltzer SE. Value of computed tomography in planning medical and surgical treatment of chronic osteomyelitis. J Comput Assist Tomogr. 1984;8:482-7. 29. Tehranzadeh J,Wang F, Mesgarzadeh M. Magnetic resonance imaging of osteomyelitis. Crit Rev Diagn Imaging. 1992;33:495-534. 30. Modic MT, Pflanze W, Feiglin DH, Belhobek G. Magnetic resonance imaging of musculoskeletal infections. Radial Clin North Am. 1986;24:247-58. 31. Kothari NA, Pelchovitz DJ, Meyer JS. Imaging of musculoskeletal infections. Radiol Clin North Am. 2001;39:653-71. 32. Tehranzadeh J,Wong E,Wang F, Sadighpour M. Imaging of osteomyelitis in the mature skeleton. Radiol Clin North Am. 2001;39:223-50. 33. Modic MT, Feiglin DH, Piraino DW, Boumphrey F, Weinstein MA, Duchesneau PM, et al. Vertebral osteomyelitis: assessment using MR. Radiology. 1985;157:157-66. 34. Erdman WA,Tamburro F, Jayson HT, Weatherall PT, Ferry KB, Peshock RM. Osteomyelitis: characteristics and pitfalls of diagnosis with MR imaging. Radiology. 1991;180:533-9. 35. McAndrew PT, Clark C. MRI is best technique for imaging acute osteomyelitis [Letter]. BMJ. 1998;316:147. 36. Ericsson HM, Sherris JC. Antibiotic sensitivity testing: Report of an international collaborative study. Acta Pathol Microbiol Scand [B]. 1971;217:1. 37. Tetzlaff TR, McCracken GH Jr., Nelson JD. Oral antibiotic therapy for skeletal infections of children. II. Therapy of osteomyelitis and suppurative arthritis. J Pediatr. 1978;92:485-90. 38. Couch L, Cierny G, Mader JT. Inpatient and outpatient use of the Hickman catheter for adults with osteomyelitis. Clin Orthop Relat Res. 1987:226-35. 39. Hickman RO, Buckner CD, Clift RA, Sanders JE, Stewart P, Thomas ED. A modified right atrial catheter for access to the venous system in marrow transplant recipients. Surg Gynecol Obstet. 1979;148:871-5. 40. Mader JT. Fluoroquinolones in bone and joint infections. In: Sanders WE Jr., Sanders CC, eds. Fluoroquinolones in the Treatment of Infectious Diseases. Chicago, IL: Physicians Scientists; 1990:71-86. 41. Mader JT, Cantrell JS, Calhoun J. Oral ciprofloxacin compared with standard parenteral antibiotic therapy for chronic osteomyelitis in adults. J Bone Joint Surg Am. 1990;72:104-10. 42. Minami A, Kaneda K, Itoga H. Treatment of infected segmental defect of long bone with vascularized bone transfer. J Reconstr Microsurg. 1992;8:75-82. 43. Henry SL, Seligson D, Mangino P, Popham GJ. Antibiotic-impregnated beads. Part I: Bead implantation versus systemic therapy. Orthop Rev. 1991;20:242-7. 44. Calhoun JH, Mader JT. Antibiotic beads in the management of surgical infections. Am J Surg. 1989;157:443-9. 45. Calhoun JH, Anger DM, Mader J, Ledbetter BR. The Ilizarov technique in the treatment of osteomyelitis. Tex Med. 1991;87:56-9. 46. Green SA. Osteomyelitis. The Ilizarov perspective. Orthop Clin North Am. 1991;22:515-21. 47. May JW Jr., Jupiter JB, Gallico GG 3rd, Rothkopf DM, Zingarelli P. Treatment of chronic traumatic bone wounds. Microvascular free tissue transfer: a 13-year experience in 96 patients. Ann Surg. 1991;214:241-50; discussion 250-2. 48. Anthony JP, Mathes SJ, Alpert BS. The muscle flap in the treatment of chronic lower extremity osteomyelitis: results in patients over 5 years after treatment. Plast Reconstr Surg. 1991;88:311-8. 49. Gayle LB, Lineaweaver WC, Oliva A, Siko PP, Alpert BS, Buncke GM, et al. Treatment of chronic osteomyelitis of the lower extremities with debridement and microvascular muscle transfer. Clin Plast Surg. 1992;19:895-903. 50. Wray JB, Rogers LS. Effect of hyperbaric oxygenation upon fracture healing in the rat. J Surg Res. 1968;8:373-8. 51. Yablon IG, Cruess RL. The effect of hyperbaric oxygen on fracture healing in rats. J Trauma. 1968;8:186-202. 52. Goldhaber P. The effect of hyperoxia on bone resorption in tissue culture. AMA Archives Path. 1958;66:635-41.

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Chapter 34

Superficial Skin Infections (Pyodermas) THOMAS M. FILE, JR, MD, MS DENNIS L. STEVENS, MD, PHD

Key Learning Points 1. Superficial skin infections (Pyodermas) include infections such as folliculitis, furunculosis, carbuncles, erysipelas, cellulitis, impetigo 2. These infections are usually due to S. aureus or β-hemolytic streptococcus, but other organisms may be the cause based on certain underlying conditions (e.g., Pseudomonas folliculitis associated with hot tub usage; mixed infection with hidradenitis suppurativa) 3. Therapy includes local compresses and drainage, topical antimicrobials or oral antimicrobials

B

acterial skin infections range from mild pyodermas to life-threatening necrotizing infections (1-4). The manifestations of bacterial skin infections result from the interaction of bacterial virulence factors with the immune status and underlying conditions of the host. The skin represents an effective physical barrier against invasion by microorganisms. The normal skin of healthy individuals is resistant to invasion by bacteria that can reside on the skin surface. Infection of the skin usually occurs when there is a defect in the integrity of the epidermis, allowing microorganisms that have colonized the skin to invade the underlying tissues and cause clinical effects. Such defects can result from surgery or trauma or can follow relatively innocuous events, such as an insect bite or abrasion. Skin lesions also can result from the hematogenous spread of bacteria or bacterial toxins from distant sites of infections. This chapter reviews the clinical aspects of superficial bacterial skin infections, which are often referred to as primary pyodermas. 629

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New Developments in the Management of Superficial Skin Infections ●

●

The prevalence of skin infections caused by community-associated methicillinresistant Staphylococcus aureus (CA-MRSA) continues to increase. New guidelines for management of skin and soft-tissue infections.

Pathogenesis and Predisposing Factors Most bacteria decrease in number when applied to the surface of the keratinized layers of normal skin. Various physical characteristics of the skin act to reduce bacterial multiplication: ● ●

● ●

The skin environment has relatively low pH (~5.5). Natural antibacterial substances are present in the secretions of the sebaceous glands. Normal skin is relatively dry. Bacterial interference occurs in the suppressive effect of normal flora on the growth of pathogens.

Normal skin is colonized with various microorganisms that are classified as resident flora, including Propionibacterium species, coagulase-negative staphylococci, and Corynebacterium species. For the most part, these organisms are not pathogenic. When a foreign body (e.g., intravenous catheter) is present, such resident organisms can cause localized infection and bacteremia. The skin can be colonized transiently by Staphylococcus aureus and betahemolytic streptococci, which are more likely to cause invasive disease. Additionally, members of the Enterobacteriaceae family, Pseudomonas species, Enterococcus species, and various anaerobes from fecal sources are particularly prone to colonizing the lower extremities. Colonization of normal skin with pathogenic organisms usually precedes clinical infection. Subsequently, minimal trauma can cause an epidermal defect that allows organisms on the skin surface to cross the keratinized layers that normally protect against infection and cause disease. Although the causative pathogens that are associated with many of the pyodermas are fairly predictable (usually S. aureus or betahemolytic Streptococcus species), other organisms (e.g., Pseudomonas in whirlpool-bath folliculitis, anaerobes and Enterobacteriaceae in chronic hidradenitis suppurativa) can be involved. S. aureus often colonizes patients both in and out of the hospital setting. Common sites for colonization include the anterior nares or perineum. Approximately 50% of patients can be found to carry S. aureus transiently at any given time. Individuals who are prone to colonization include health care workers, patients with diabetes, patients who undergo chronic hemodialysis, and users of illicit intravenous drugs. Most patients with staphylococcal folliculitis or furunculosis experience a selflimiting infection. Certain patients, however, are especially prone to recurrent

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infections, including those who have hypogammaglobulinemia, diabetes mellitus, cancer or organ transplants (who are also receiving immunosuppressive drugs), chronic granulomatous disease of childhood, and Job syndrome. Additionally, poor hygiene, obesity, folliculosis, chronic dermatitis, seborrhea, psoriasis, malnutrition, and occupational trauma all can predispose the patient to recurrent S. aureus pyoderma. The pathogenicity of specific microorganisms is measured in part by virulence factors (5). Local invasiveness is an important element in group A streptococcal infection (e.g., Streptococcus pyogenes), which depends on the antiphagocytic M protein of the bacterial cell envelope (6). Several extracellular products associated with S. pyogenes can contribute to the manifestations of skin infection. These include hyaluronidase, proteinase, deoxyribonuclease, and streptokinase, all of which cause liquefaction of pus and enhance the spread of infection throughout tissue planes. Toxins and enzymes seem to play a role in the ability of S. aureus to produce disease. Alpha- and deltatoxins can contribute to disease manifestations by damaging tissue membranes. Exfoliative toxin, which is produced by certain strains of S. aureus, causes separation between the epidermis and the dermis, resulting in the scalded-skin syndrome. Both S. aureus and S. pyogenes can produce pyogenic toxins associated with a toxic shock syndrome. The staphylococcal toxic shock syndrome characterized by hypotension, rash, and multisystem involvement is caused by strains of S. aureus that produce an exotoxin, toxic shock syndrome toxin 1 (7). More recently, serious skin infections caused by S. pyogenes and characterized by necrotizing fasciitis have been described in association with group A streptococcal toxic shock syndrome (see Chapter 31). The pathogenesis of skin infections associated with gram-negative bacilli (e.g., exotoxins produced by Pseudomonas aeruginosa) and anaerobes can be caused by elaboration of various extracellular toxins. In the case of Clostridium perfringens, the elaboration of collagenases, specific toxins, and proteases seems to play an important role in producing the spreading necrotizing infection that can be associated with this organism. Several host factors contribute to the predisposition to skin infections, including a reduced vascular supply, compromised immune system, disruption of lymphatic or venous drainage, the presence of underlying conditions (e.g., dermatitis), and the presence of a foreign body (e.g., intravenous catheter, suture).

Clinical Manifestations and Natural History Primary superficial skin infections, or pyodermas, usually occur on relatively normal skin and are most often caused by beta-hemolytic streptococci (most commonly group A streptococci) or S. aureus (Table 34-1). Such infections are often mild, and most do not require parenteral antibiotic therapy or hospitalization. They often occur in patients who do not exhibit any significant under-

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Table 34-1 Common Microbial Etiology and Antimicrobial Therapy for Superficial Soft-Tissue Infections Infection

Microorganisms

Therapy and Comments*

Impetigo

Streptococcus pyogenes, Staphylococcus aureus (almost all bullous impetigo is S. aureus)

Cellulitis/ Erysipelas

S. aureus; S. pyogenes (Erysipelas usually S. pyogenes and other β-hemolytic streptococci); See Table 34-2 for other causes

Folliculitis, furuncles, carbuncles

S. aureus (MSSA or MRSA)

Topical: mupirocin, bacitracin Oral: antistaphylococcal Pen†, first gen Ceph‡, macrolides§ (some beta-hemolytic streptococci are resistant), clindamycin (300 mg TID); penicillin VK (250-500 mg BID-QID) if only Group A streptococcus documented The following if concern for CA-MRSA: trimethoprim/sulfamethoxazole (1 DS BID, does not cover beta-hemolytic streptococci), minocycline (100 mg BID), doxycycline (100 mg BID) Oral: penicillin VK; if concern for S. aureus: antistaphylococcal Pen, first gen Ceph‡, macrolides§, clindamycin (300 mg TID); levofloxacin (500-750 mg QD), moxifloxacin (400 mg QD) For CA-MRSA-see impetigo IV: antistaphylococcal Pen, first gen Ceph‡, clindamycin (600-900 mg q 8 h); For MRSA: vancomycin (15 mg/kg q12h), linezolid (600 mg q12h), daptomycin (4 mg/kg q24h) Warm saline compresses with or without topical antimicrobials often sufficient for folliculitis Incision and drainage with or without topical antimicrobials often suffices for furuncles Oral: antistaphylococcal Pen, first gen Ceph‡, clindamycin (300 mg q8h), levofloxacin (500-750 mg QD), moxifloxacin (400 mg QD) For CA-MRSA, see impetigo IV: antistaphylococcal Pen, first gen Ceph‡, clindamycin (600-900 mg q8h) For MRSA: vancomycin (15 mg/kg q12h), linezolid (600 mg q12h), daptomycin (4 mg/kg q24h) If nasal culture positive, nasal mupirocin Oral: antistaphylococcal Pen, first gen Ceph‡, clindamycin (300 mg q8h); or therapy for MRSA (see impetigo) plus rifampin (300 mg BID) Self-limiting, treatment not necessary

Recurrent Check for nasal or furunculosis perianal carrier of S. aureus

Whirlpool folliculitis

Pseudomonas aeruginosa

Continued

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Table 34-1 Continued Infection

Hidradenitis suppurativa

Microorganisms

Acute: S. aureus Chronic: S. aureus, Enterobacteriaceae, Pseudomonas spp., anaerobes

Therapy and Comments*

Antistaphylococcal agents for MSSA or MRSA based on susceptibility Empirical: beta-lactam/beta-lactamase inhibitor⎪⎪, cefoxitin (1-2 g q6h), cefotetan (0.5-1 g q12h), carbapenem; clindamycin (600-900 mg TID) plus fluoroquinolone††

* Doses are based on normal renal and hepatic function. Duration of therapy of most superficial skin infections is 7 to 10 days. One recent study of cellulites in immunocompetent hosts found 5 days was effective for uncomplicated infection. † Oral antistaphylococcal penicillins include cloxacillin (250-500 mg q6h) and dicloxacillin (250-500 mg q6h); parenteral antistaphylococcal penicillins include oxacillin (0.5-2 g q4-6h), nafcillin (0.5-2 g q4-6h). ‡ Oral first-generation cephalosporins include cephalexin (250-500 mg q6h) and cefadroxil (250-500 mg q12h); parenteral first-generation cephalosporins include cephalothin (0.5-2 g q4-6h), cefazolin (0.5-1 g q8h). § Erythromycin (250-500 mg q6h), azithromycin (500 mg on day 1 followed by 25 mg QD), clarithromycin (500 mg q12h or 1 g XL QD). ⎪⎪ Oral beta-lactam/beta-lactamase inhibitors include amoxicillin/clavulanate (875/125 mg q12h), parenteral beta-lactam/beta-lactamase inhibitors include ampicillin/sulbactam (1.5-3.0 g q6h), ticarcillin/ clavulanate (3.1 q4-6h), piperacillin/tazobactam (3.375-4.5 q6h). Abbreviations: BID, twice daily; CA-MRSA, community-acquired methicillin-resistant Staphylococcus aureus; Ceph, cephalosporin; DS, dilute strength; gen, general; h, hour; MRSA, methicillin-resistant S. aureus; MSSA, methicillin-susceptible S. aureus; Pen, penicillin; q, every; QD, daily; QID, four times daily; TID, three times daily; XL, extended release.

lying condition. The infections include folliculitis, furunculosis, carbunculosis, impetigo, cellulitis, erysipelas, and hidradenitis suppurativa.

Folliculitis Folliculitis originates in the hair follicle and is defined by its anatomical features. Clinically, the lesions present as 2- to 5-mm erythematous papules that surround the hair follicle and often exhibit central pustulation. Systemic manifestations are rare. Sycosis barbae is a distinctive form of deep folliculitis that is often chronic and seen in bearded areas. Folliculitis is most commonly caused by S. aureus; however, in immunocompromised patients the causative agent can be gram-negative bacilli or Candida species. A specific form of Pseudomonas folliculitis has been described in association with whirlpool bathing or use of a hot tub. An outbreak of pustular dermatitis was described among mud-wrestling college students; organisms isolated from the pustules included Enterobacter cloacae and Citrobacter species (8). The pathogenesis of this condition can resemble that of pseudomonal folliculitis, with organisms from mud possibly entering the skin through hair follicles or through breaks in the skin that occurred during the wrestling. Patients with whirlpool-bath folliculitis develop generalized, fine, papular pustules from which P. aeruginosa can be isolated (9). The modified apocrine glands of the external canal of the ear and the areolae of the breasts are structures that are particularly susceptible to this infection. The most common sign

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of this syndrome is a generalized rash accompanied by otitis externa, mastitis, malaise, and fever. The average incubation period is approximately 2 days. Pseudomonas infection can follow immersion in swimming pools, Jacuzzis, or whirlpool baths in which the organism can reside in higher numbers if the chlorination or the pH of the system is not adjusted properly. The disease is usually self-limited. Systemic antibiotic therapy is not indicated for treating whirlpool-bath folliculitis unless cellulitis develops.

Furuncle and Carbuncle Folliculitis that extends beyond the hair follicle and into the subcutaneous tissues can give rise to a furuncle or carbuncle. A furuncle is a deeper inflammatory nodule that often follows folliculitis. Furuncles usually measure less than 5 mm in diameter. A carbuncle is a larger, deeper lesion and often occurs as a confluent infection that comprises many furuncles. S. aureus is the organism most often associated with furunculosis and carbunculosis. Clinically, a furuncle begins as an erythematous, firm, tender, nodular lesion that progresses to a fluctuant mass that can drain pus spontaneously. They occur in skin areas that are subject to friction and perspiration and that contain hair follicles (e.g., the neck, face, axillae, buttocks). Predisposing factors include obesity, corticosteroid use, defects in neutrophil function, and probably diabetes mellitus. Some individuals have repeated attacks of furunculosis; see further discussion in the Prevention section. Carbuncles are larger and frequently comprised of many furuncles that have coalesced and are more serious lesions that often are located at the back of the neck, on the back, or in the region of the thigh. Fever and malaise are frequent accompaniments of a carbuncle, and sepsis can occur. Blood stream infection also can occur with carbuncles (less so with furuncles) and can result in metastatic foci of infection (e.g., endocarditis, osteomyelitis). Furuncles on the upper lip and nose can be associated with the spread of infection by means of emissary veins to the cavernous sinus.

Impetigo Impetigo is a vesicular (initially), crusted (later), superficial, intraepithelial infection of the skin that is associated with S. aureus and beta-hemolytic streptococci (alone or in combination). Mixtures of group A streptococci and S. aureus are isolated from approximately half of patients with nonbullous impetigo. Mixed flora of anaerobic streptococci with Prevotella or Fusobacterium species can be found in infections of the head and neck, whereas enteric gram-negative bacilli (often mixed with Bacteroides fragilis) can be isolated from infections of the buttock (3). A relatively specific form of impetigo (bullous impetigo) has been identified as a primarily staphylococcal disease. Non–group A streptococci (i.e., groups B, C, and G) can be responsible for isolated cases of nonbullous impetigo. Because impetigo is a very superficial infection, vesiculopustules develop just beneath the stratum

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corneum, and it is generally not associated with any systemic manifestations of infection. The disease begins with vesicular lesions that rapidly become pustular and crusted. A honey-colored crust over slightly erythematous areas of inflammation is characteristic (10). Regional lymphadenopathy without systemic symptoms is common. The early vesicular lesions of impetigo can resemble the initial lesions of varicella or herpes simplex; however, the crusts that form in these viral infections are usually harder. Impetigo appears primarily in young children during warm, humid months. Predisposing conditions include minor trauma, insect bites, crowding, poor hygiene, and preexisting skin disease. Spread of the disease within families is common through direct contact with infectious material. Bullous impetigo is more often associated with S. aureus than is the nonbullous form of the disease. As in the nonbullous form, the lesions initially appear as vesicles but progress to flaccid bullous lesions filled with yellow fluid. When these lesions rupture, light brown crusts form. These crusts and the bullous lesions are characteristic of the condition. Regional lymphadenopathy is found less commonly in the bullous form of impetigo. Fever and constitutional symptoms are uncommon in both the bullous and nonbullous forms of the disease. Post-streptococcal glomerulonephritis can follow group A streptococcal impetigo caused by nephrogenic strains such as M-49, although currently in the United States this is a rare occurrence.

Cellulitis Cellulitis is a diffuse, spreading, and nonsuppurative infection of the skin and subcutaneous tissues that presents with localized redness, warmth, swelling, and tenderness of the skin. Both S. aureus and beta-hemolytic streptococci are associated with cellulitis. The lesion in cellulitis is often very red, hot, and swollen, but the borders of the lesion are usually not clearly demarcated. Previous trauma (laceration, abrasion) can precede the development of cellulitis. Within days of the trauma, local tenderness, pain, and erythema develop. Fever, chills, malaise, and regional lymphadenitis commonly accompany the infection. If the condition is untreated, local abscesses can develop, and areas of overlying skin also can become necrotic. Because of this, cellulitis can be mistaken for many other clinical disorders, including deep venous thrombosis, erythema nodosum, allergic reactions, reactions to insect bites, and reactions to chemical irritants. The predominant pathogens are S. pyogenes and S. aureus. The microbiology of cellulitis and its correlation with the site of infection were investigated with more than 200 swab- and 64 needle-aspirate specimens (11). The greatest recovery of anaerobic bacteria (predominantly Peptostreptococcus, B. fragilis, Prevotella, and Clostridium) was from the neck, trunk, groin, external genitalia, and leg area. Aerobes (predominantly S. aureus, group A streptococci, and Escherichia coli) outnumbered anaerobes in the arm and hand areas. Many other pathogens can produce cellulites (Table 34-2). Certain clinical findings correlated with the following pathogens: swelling and tenderness

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Table 34-2 Causes of Cellulitis Based on Specific Predisposing Conditions Condition

Anatomical Location

Likely Pathogen/Antimicrobial Therapy

Body piercing

Ear, nose, umbilicus

Post-mastectomy or CABG Cat/Dog bites

Ipsilateral extremity

Staphylococcus aureus; Streptococcus pyogenes (see Table 34-1) Non-group A streptococcus/penicillin

Hand

Human bites

Hand

Fresh water injury

Extremities mostly

Salt water injury

Extremities mostly

Meat-packer Cat scratch Periorbital in children

Hand mostly Bartonella Periorbital

Pasteurella multocida; Capnocytophaga (in immunocompromised)/ Amoxicillin/clavulanate (doxycycline, fluoroquinolone + clindamycin) Mixed flora/hand-surgery consult; antibiotics as for cat bites Aeromonas/fluoroquinolone, broadspectrum beta-lactam Vibrio vulnificus/fluoroquinolone; ceftazidime Erysipelothrix/Penicillin Azithromycin Haemophilus influenzae/ampicillin/ sulbactam or third-generation cephalosporin

Abbreviation: CABG, coronary artery bypass grafting.

with Clostridium species, S. aureus, and group A streptococci; regional adenopathy with B. fragilis; gangrene and necrosis with anaerobes and Enterobacteriaceae; and a foul odor or gas in tissues containing anaerobes. A frustrating problem for some patients is recurrent cellulitis at sites of previous surgery. This problem has been associated particularly with saphenous venectomy for coronary bypass surgery, stripping of varicose veins, and procedures that affect lymphatic drainage (e.g., neoplasia, radiation therapy, surgery) (12,13). Recurrent cellulitis also has been seen after radical mastectomy. Patients with recurrent cellulitis after surgery can experience acute pain, fever, and erythema of acute onset at the site of the surgical scar. Tinea pedis is often an associated finding; however, Hook and colleagues recently reported an instance of underlying psoriasis (14). Although pathogens are often not isolated from sites of recurrent cellulitis, an underlying skin disorder (e.g., tinea pedis) can predispose to invasion of Streptococcus species. Cellulitis often recurs if the underlying skin disorder is not controlled.

Erysipelas Erysipelas is a distinctive form of cellulitis that involves the superficial epidermis. It differs from cellulitis because the lesion is indurated and red, with a well-demarcated border. Additionally, it is usually painful, and the condition is often complicated by lymphangitis. Erysipelas is more common in children and in older adults. The face and lower extremities are the most frequent sites of involvement. It is almost always caused by beta-hemolytic

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streptococci (usually group A), but similar lesions can be caused by streptococcus serogroups C or G. Rarely group B streptococcus or S. aureus can be involved. Because erysipelas tends to produce lymphatic obstruction, it can recur in an originally affected area of the skin. Occasionally, the infection extends more deeply, producing cellulitis, subcutaneous abscess, and necrosis. Fever and systemic symptoms are found in most cases; bacteremia is found in approximately 5% of patients (4). Patients who have venous or lymphatic insufficiency (e.g., recurrent cellulitis after venectomy or radical mastectomy) have been reported to have a high relapse rate for cellulitis. The lesions of cellulitis should be differentiated from those of erythema nodosum, shingles, erysipeloid, and the skin lesions of Lyme disease.

Hidradenitis Suppurativa Hidradenitis suppurativa is a suppurative disease that affects the apocrine glands in the axillary, genital, or perianal areas. The disease rarely has systemic manifestations. Acute infection usually results from obstruction to drainage of the apocrine gland. The lesion seems to result from plugging of the apocrine gland ducts, causing dilation and eventual rupture of the glands and inflammation of the surrounding tissue. Acute infection is often caused by S. aureus. Chronic hidradenitis suppurativa is characterized by recurrent disease. The initial step in the disease is the formation of nodules that slowly become fluctuant and drain. Eventually, with repeated crops of lesions, sinus tracts form and cause intermittent drainage and cicatricial scarring. In some patients, infection is associated with cellulitis of the scalp (acne conglobata); such patients can experience a distinctive spondyloarthropathy. The lesions in this condition are usually bilateral and vary from a few to many, with widespread involvement. A culture of aspirate from the lesions frequently yields a mixture of aerobic and anaerobic organisms.

Diagnosis The diagnosis of pyodermas usually is made clinically on the basis of the manifestations described in the preceding sections of this chapter. Although the skin is easily accessible for culture, isolation of an infecting organism in cases of pyoderma has not been consistent, usually because of the presence of contaminated normal skin flora. Additionally, because bacterial products or toxins, rather than the bacteria themselves, are the sources of certain skin lesions, the number of bacteria at the site of the pathology can be too small to allow consistent culture of pathogens. Therefore, the etiologic diagnosis and management of bacterial skin infections, especially in the office setting, often is based on the clinical presentation and less commonly on microbiologic techniques. In patients who have skin and soft tissue infections that

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require hospitalization, a more aggressive approach is needed to identify the causative agent because outpatient therapy has failed for some reason (e.g., misdiagnosis, wrong therapy choice, noncompliance). A culture of lesions in folliculitis, furunculosis, carbunculosis, impetigo, and hidradenitis suppurativa usually yields the etiologic agent. Although Staphylococcus is often found, certain special circumstances suggest the presence of other organisms (Table 34-2). An emphasis to obtain a culture from such infections, even if clinically mild, has been increased because of the emergence of community-acquired methicillin-resistant S. aureus (CA-MRSA) infections (see Treatment). Exposure to hot tubs should alert the physician to the possible role of P. aeruginosa; patients who have Candida folliculitis can have systemic Candida infection. Culture in impetigo can be achieved by removing the superficial crust of a lesion with sterile saline and by culturing the surface of the lesion. Blood culture is usually not helpful in cases of pyoderma; however, patients who present with systemic manifestations of disease and who have carbuncles can have bacteremia, for which blood culture is appropriate. The diagnosis of cellulitis is usually made clinically, because generally the condition is a closed-skin infection and is not associated with drainage that can be submitted for culture. Ascertaining a specific bacteriologic cause for cellulitis is difficult. Usually, as with cellulitis, the diagnosis of erysipelas is also made clinically. Leukocytosis is a common occurrence in both conditions. In patients who have erysipelas, culture of the pharynx frequently yields S. pyogenes. Several studies have evaluated the use of intradermal needle aspiration in the bacteriologic diagnosis of cellulitis, but the value of the technique remains controversial (15). Studies have reported rates of isolation of pathogenic organisms that range from 5% to 36% (14,16,17). The most common pathogens isolated in studies of needle aspirates are staphylococci and streptococci. A similar method of needle aspiration was used in most of these studies. Briefly, it involves cleansing the site of aspiration with povidone-iodine solution and, without anesthesia, puncturing the skin over the area with a 22-gauge needle attached to a disposable plastic syringe. The contents of the syringe, consisting of 1 mL of sterile isotonic saline, are injected subcutaneously, and the resulting fluid is then aspirated with the needle kept in the subcutaneous tissue. The aspirated material is promptly taken to the microbiology laboratory and immediately inoculated into culture medium. Generally, needle aspiration is not recommended for the diagnosis of superficial skin infections but can be appropriate in selected circumstances (e.g., treatment failure, immunosuppression).

Treatment When a patient presents with a skin or soft tissue infection, an initial consideration for treatment is whether the clinical illness is severe enough

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to warrant hospital admission. Most superficial pyodermas are without systemic symptoms and can be managed in the outpatient setting with oral antimicrobial agents. Previous classified schemes and algorithms have been proposed to guide clinicians with the decision of hospitalization, but there are no well-documented criteria for choice of a site of care (i.e., outpatient vs. inpatient). (18) Consideration of hospitalization should be based on illness severity (i.e., the extent of abnormality of vital signs and of soft tissue involvement), patient age, presence of comorbid conditions that can be affected by an acute infection (e.g., diabetes, congestive heart failure), and the need for close observation or surgical management. (4) Abnormal laboratory tests (hemogram with differential, creatinine, bicarbonate, creatine phosphokinase, and C-reactive protein levels) can be helpful. In patients with hypotension and/or an elevated creatinine level, low serum bicarbonate and elevated creatine phosphokinase levels (two to three times the upper limit of normal), marked left shift, or a C-reactive protein level greater than 13 mg/L, hospitalization should be considered, and a definitive etiologic diagnosis pursued by means of procedures such as Gram stain and culture of needle aspiration or punch-biopsy specimens, as well as requests for a surgical consultation. Additionally, timely surgical intervention should be considered for deep infections (see Chapter 31). For impetigo or uncomplicated folliculitis and furunculosis, local measures (e.g., warm compresses, topical antimicrobial agents such as Bactroban and bacitracin) are usually sufficient. For other pyodermas, oral agents that have a spectrum of activity against the common infecting organisms (e.g., Staphylococcus, Streptococcus) are preferred for outpatients. For hospitalized patients, empirical antimicrobial therapy is initiated to combat or prevent life-threatening infections. Table 34-1 lists our recommendations for initial therapy for common pyodermas based on the most likely pathogens. In the presence of specific epidemiological conditions, other therapy should be considered (Table 34-2). Of increasing concern is the emergence of antimicrobial resistance among isolates of community-acquired S. aureus that are associated with skin infection In the past MRSA was usually limited to patients who were in the hospital or resided in a long-term care facility. Recently, outbreaks of skin infections caused by CA-MRSA have occurred among prison and jail inmates, injection drug users, gay men, participants in contact sports, and children. However, there are now enough cases in patients without these risk factors that CA-MRSA needs to be considered in all patients with skin infections. This has increased the importance of obtaining cultures of even mild skin infections. CA-MRSA strains are distinct from hospital-acquired strains from an epidemiological, genotypic, and phenotypic perspective (19-21). They tend to be less resistant to non–beta-lactam antimicrobials than hospital-acquired MRSA strains and almost always contain a novel type IV staphylococcus cassette chromosome mec (SCCmec) gene. In addition, many of these strains have been found to contain the gene for Panton-Valentine leukocidin (PVL),

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a toxin that has been associated with clinical features of serious disease. In general CA-MRSA strains are usually susceptible in vitro to trimethoprim/sulfamethoxazole and minocycline or doxycycline, and often susceptible to the fluoroquinolones, although pockets of fluoroquinolone-resistant strains exist. In addition, they are often susceptible to clindamycin, but the emergence of resistance during therapy has been reported—especially in erythromycin-resistant strains; thusly, an erythromycin-induction test (D-test) should be done on such isolates to determine the presence of in-vitro inducible resistance. Persistent pustular skin infections that do not respond to oral betalactam therapy are increasingly likely to be caused by MRSA. Such lesions should be cultured, and antibiotic susceptibilities measured. Fluctuant lesions should be drained. An agent to which the isolate is susceptible should be used. For mild infections, oral agents, such as trimethoprim/sulfamethoxazole, doxycycline, or clindamycin can be considered. One caveat about trimethoprim/sulfamethoxazole, however, is that it does not adequately cover for S. pyogenes; thusly, if S. pyogenes is also likely, an alternative agent or combination with penicillin is recommended. At the present time among patients with infections that are presumed to be caused by S. aureus, the clinician must consider the risk factors for MRSA, the prevalence of MRSA in the community, and the seriousness of the infection in deciding what antibiotics are to be used. For those requiring hospitalization, vancomycin, linezolid, tigecycline, or daptomycin are effective first-line agents for MRSA soft tissue infections. Surgical intervention is usually not required for superficial bacterial infections; however, the role of surgery cannot be overestimated in deeper or necrotizing skin infections (see Chapter 31). However, surgical drainage is indicated for furuncles, carbuncles, and hidradenitis suppurativa with large and fluctuant lesions. Antibiotic treatment of furuncles and carbuncles that are surgically drained is recommended if the lesion is greater than 4.5 cm or if the patient has fever or leukocytosis, and it should be continued until evidence of acute inflammation has subsided. Treatment of hidradenitis suppurativa is difficult, particularly when the disease process is chronic, because of deep-seated abscesses and scar tissue that are inaccessible to antimicrobial agents. Antimicrobial therapy accompanied by the local application of moist heat is often helpful in the initial phases of infection. Surgical drainage is required in the management of abscesses. Radical excision of tissue with subsequent skin grafting is often necessary for severe cases that exhibit extensive scarring. With the exception of hidradenitis suppurativa, the duration of antimicrobial therapy for superficial skin infections is usually 7 to 10 days. However, one recent study found that 5 days of antibiotic treatment was as effective as a 10-day course for uncomplicated cellulitis (22). Duration of therapy for hidradenitis suppurativa will depend on the clinical response.

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Prevention The management of patients with recurrent furunculosis presents a troublesome problem because most patients do not have definable underlying defects. Such patients often have S. aureus present in the anterior nares, or occasionally, elsewhere, such as the perineum. The prevalence of nasal staphylococcal colonization in the general population is 20% to 40%, but why some carriers develop recurrent skin infections and others do not is usually unclear. Higher rates of colonization with S. aureus has been seen in subgroups of patients (e.g., diabetic patients, dialysis patients). Therefore, because even small scratches or blisters can be colonized more rapidly and infected at an early stage, the use of topical antibiotics (e.g., mupirocin, bacitracin, neomycin) is recommended for the early treatment of abrasions in such patients. In one comparative study of the efficacy of topical mupirocin (2%) cream with oral cephalexin in treating secondarily infected traumatic skin lesions (e.g., lacerations), pathogen-eradication rates in the patients who could be evaluated were 100% for both treatment groups (23). Preventive management of recurrent furunculosis involves the following measures: ●

●

Institute a regimen of meticulous skin care with antibacterial soaps (e.g., PHisoDerm) and frequent washing: Because infections (particularly impetigo) can be spread among family members, a separate towel and washcloth (carefully washed in hot water before use) should be reserved for each patient. Chlorhexidine solution or hexachlorophene also can be used to reduce staphylococcal skin colonization. Measures aimed at preventing a carrier state can be considered if infection continues to recur: Nasal application of 2% mupirocin ointment in a soft, white paraffin base for 5 days can eliminate colonization of S. aureus in otherwise healthy patients. This regimen reduces recurrences by approximately 50%. Oral antibiotics (e.g., rifampin with another antimicrobial agent to prevent resistance) can be used in an attempt to eradicate a carrier state. In one very limited study, prophylaxis of oral clindamycin (150 mg four times daily for 3 months), without an accompanying intranasal antimicrobial agent, reduced the frequency of recurrent staphylococcal skin infections (24).

The likelihood of recurrent cellulitis at sites of previous surgery (e.g., after coronary artery bypass surgery or mastectomy) also can be reduced by reducing skin colonization with antibacterial soaps and by controlling tinea pedis in the case of recurrent cellulitis of the lower extremities after coronary artery bypass surgery. Prolonged antimicrobial prophylaxis with erythromycin has been shown to be effective and safe for preventing subsequent recurrent episodes of soft tissue infections in such patients (25). However, it is our

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recommendation that, in the case of recurrent cellulitis of the lower extremities, systemic antibiotic therapy should be reserved only for patients who do not respond to antibacterial soaps and control of tinea pedis. REFERENCES 1. File TM Jr.,Tan JS. Treatment of bacterial skin and soft tissue infections. Surg Gynecol Obstet. 1991;S172:17-24. 2. Infectious Diseases Society of America. Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis. 2005;41:1373-406. 3. Brook I. Cellulitis and fasciitis. Curr Treat Op Infect Dis. 2000;2:127-46. 4. Swartz MN. Cellulitis and subcutaneous tissue infections. In Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 6th ed. New York: Churchill Livingstone; 2005:1037-57. 5. Schlüter B, König W. Microbial pathogenicity and host defense mechanisms—crucial parameters of posttraumatic infections. Thorac Cardiovasc Surg. 1990;38:339-47. 6. Bisno AL, Stevens DL. Streptococcal infections of skin and soft tissues. N Engl J Med. 1996;334:240-5. 7. File TM Jr.,Tan JS, DiPersio JR. Group A streptococcal necrotizing fasciitis. Diagnosing and treating the “flesh-eating bacteria syndrome”. Cleve Clin J Med. 1998;65:241-9. 8. Adler AI,Altman J. An outbreak of mud-wrestling-induced pustular dermatitis in college students. Dermatitis palaestrae limosae. JAMA. 1993;269:502-4. 9. Jacobson JA. Pool-associated Pseudomonas aeruginosa dermatitis and other bathing-associated infections. Infect Control Hosp Epidemiol. 1985;6:398-401. 10. Hirshman JV. Impetigo: Etiology and therapy. Curr Clin Top Infect Dis. 2002;22L:42-51. 11. Brook I, Frazier EH. Clinical features and aerobic and anaerobic microbiological characteristics of cellulitis. Arch Surg. 1995;130:786-92. 12. Baddour LM, Bisno AL. Recurrent cellulitis after saphenous venectomy for coronary bypass surgery. Ann Intern Med. 1982;97:493-6. 13. File TM Jr.,Tan JS, Maseelall EA, Snyder RO. Recurrent cellulitis after bypass surgery associated with psoriasis [Letter]. JAMA. 1984;252:1681. 14. Hook EW 3rd, Hooton TM, Horton CA, Coyle MB, Ramsey PG,Turck M. Microbiologic evaluation of cutaneous cellulitis in adults. Arch Intern Med. 1986;146:295-7. 15. Newell PM, Norden CW. Value of needle aspiration in bacteriologic diagnosis of cellulitis in adults. J Clin Microbiol. 1988;26:401-4. 16. Lebre C, Girard-Pipau F, Roujeau JC, Revuz J, Saiag P, Chosidow O. Value of fine-needle aspiration in infectious cellulitis [Letter]. Arch Dermatol. 1996;132:842-3. 17. Sachs MK. The optimum use of needle aspiration in the bacteriologic diagnosis of cellulitis in adults. Arch Intern Med. 1990;150:1907-12. 18. Wong CH, Khin LW, Heng KS, Tan KC, Low CO. The LRINEC (Laboratory Risk Indicator for Necrotizing Fasciitis) score: a tool for distinguishing necrotizing fasciitis from other soft tissue infections. Crit Care Med. 2004;32:1535-41. 19. Lina G, Piémont Y, Godail-Gamot F, Bes M, Peter MO, Gauduchon V, et al. Involvement of PantonValentine leukocidin-producing Staphylococcus aureus in primary skin infections and pneumonia. Clin Infect Dis. 1999;29:1128-32. 20. Herold BC, Immergluck LC, Maranan MC, Lauderdale DS, Gaskin RE, Boyle-Vavra S, et al. Community-acquired methicillin-resistant Staphylococcus aureus in children with no identified predisposing risk. JAMA. 1998;279:593-8. 21. Centers for Disease Control and Prevention. Outbreaks of community-associated methicillinresistant Staphylococcus aureus skin infections—Los Angeles County, California, 2002-2003. MMWR Morb Mortal Wkly Rep. 2003;52:88. 22. Hepburn MJ, Dooley DP, Skidmore PJ, et al. Comparison of short-course (5 days) and standard (10 days) treatment for uncomplicated cellulites. Arch Intern Med. 2004;164:1669-74. 23. Henkel TJ, Bottonfield G, Drehobl M, et al. Comparison of mupirocin calcium cream with oral cephalexin in the treatment of secondarily infected traumatic lesions. 20th International Congress of Chemotherapy. 1997, Sydney, Australia, Abstract No. 5308. 24. Klempner MS, Styrt B. Prevention of recurrent staphylococcal skin infections with low-dose oral clindamycin therapy. JAMA. 1988;260:2682-5. 25. Kremer M, Zuckerman R,Avraham Z, Raz R. Long-term antimicrobial therapy in the prevention of recurrent soft-tissue infections. J Infect. 1991;22:37-40.

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Chapter 35

Necrotizing Soft Tissue Infections THOMAS M. FILE, JR, MD, MS DENNIS L. STEVENS, MD, PHD

Key Learning Points 1. Necrotizing soft tissue infection share a clinical picture which is characterized by necrosis of skin and associated tissues 2. Although these infections can be classified into specific entities (e.g., necrotizing fasciitis, clostridial myonecrosis), the initial clinical manifestations may be similar 3. These infections may be monomicrobial (e.g., group A streptococcal necrotizing fasciitis) or polymicrobial. The latter often follow surgery or in patients with peripheral vascular disease, diabetes, or decubitus ulcers. 4. Management of these infections requires expeditious evaluation and often early surgical intervention 5. A variety of antimicrobials against aerobic gram positive and gram-negative bacteria, as well as anaerobes, may be used in mixed anaerobic infections. For empirical therapy of serious mixed anaerobic infections, a broad spectrum beta-lactam (e.g., piperacillin/tazobactam, ticarcillin/clavulanate, imipenem or meropenem) plus clindamycin is recommended 6. For severe group A streptococcal infection parenteral clindamycin and a penicillin agent is recommended

N

ecrotizing soft tissue infections include infections of the skin and skin structures that share a clinical picture that is characterized by necrosis of the skin and associated tissues (e.g., subcutaneous tissue, fascia, muscle) (1-5). These infections occur less frequently than do pyoderma and differ from the milder, superficial skin infection by clinical presentation, 643

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New Developments in the Management of Necrotizing Soft Tissue Infections ●

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Community-associated methicillin-resistant Staphylococcus aureus has recently been reported as a cause of necrotizing fasciitis and myositis. New guidelines for management of skin and soft tissue infections, including necrotizing infections, have been recently published.

systemic manifestations, and treatment strategies (2). They often progress rapidly and dramatically and can require urgent, aggressive surgical excision of tissue. Additionally, these infections are often deep and devastating because they can cause major destruction of tissue and can have a fatal outcome. Generally, necrotizing soft tissue infections are classified into specific entities (e.g., necrotizing fasciitis [NF], clostridial myonecrosis, synergistic necrotizing cellulitis) according to selected characteristics (Table 35-1) (1-4). However, the initial clinical manifestations of such infections are not distinct. The classification of these infections into precise categories is often difficult and is not significant to the initial management of the patient (6).

Etiology and Pathophysiology Necrotizing soft tissue infections can be classified etiologically as either polymicrobial (involving mixed aerobes and anaerobes) or monomicrobial infectious processes.

Polymicrobial Infectious Processes Polymicrobial infections are commonly found in the perineal area and lower extremities. In such cases, the fecal flora contribute to other skin pathogens. Gram-positive organisms (e.g., Staphylococcus, Streptococcus, Enterococcus species), gram-negative enteric bacilli, and anaerobes are often isolated from such infections. In combination, these bacteria can induce the formation of abscesses as well as severe necrotizing infections. Clinical medicine has many examples of mixed bacterial infections. The polymicrobial nature of peritonitis and intra-abdominal abscess formation is well known to surgeons. Aspiration of oropharyngeal secretions can lead to necrotizing mixed aerobic/anaerobic pneumonitis, which is often more serious than pneumonia that is caused by a single organism. Polymicrobial causes of skin and soft issue infections can be found in surgical-site infections, bite-wound infections, pressure-ulcer infections, and diabetic foot infections. The evaluating physician must be aware of the possibility of a synergistic polymicrobial infection in such cases so that appropriate early therapy can be initiated.

3-14 d Mixed aerobes, anaerobes

Moderate to severe

Acute Moderate to severe

>3 d Clostridia, others

Minimal

Gradual Minimal

Incubation Etiology

Systemic Toxicity Course Wounds/ Findings Local pain Skin Appearance

Gas Abundant Muscle No Involvement

Variable Variable

Swollen, Erythematous or minimal gangrenous discoloration

Diabetes, prior local lesions, perirectal lesions

Trauma

Synergistic Necrotizing Cellulitis

Predisposing Condition

Anaerobic Gas-Forming Cellulitis

Tense and blanched, yellow-bronze, necrotic with hemorrhagic bullae Usually present Myonecrosis

Acute Severe

Severe

1-4 d Clostridia, especially Clostridium. perfringens

Trauma or surgical wound

Clostridial Myonecrosis (Gas Gangrene)

Table 35-1 Characteristics of Severe, Necrotizing Soft Tissue Infections

Variable Myonecrosis

Erythematous or yellowbronze

Infected Vascular Gangrene

Necrotizing Soft Tissue Infections

Continued

Blanched, Erythematous or erythematous, necrotic necrotic with hemorrhagic bullae Variable Variable No Myonecrosis limited to area of vascular insufficiency

Subacute Variable

Diabetes, trauma, Arterial surgery, perineal insufficiency infection 1-4 d >5 d Type I Mixed aerobes, Polymicrobial anaerobes (aerobic-anaerobic) Type II Streptococcus pyogenes Moderate to severe Minimal

Necrotizing Fasciitis

Minimal until late in course Subacute Acute to subacute Late only Minimal to moderate

3-4 d Anaerobic streptococci

Trauma, surgery

Streptococcal Myonecrosis

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Thin, dark, Dark pus or dishwater, sweetish or putrid foul odor PMNs, gram- PMNs, mixed flora positive bacilli Débridement Wide filleting incisions

Synergistic Necrotizing Cellulitis

Extensive excision, amputation

PMNs, gramPMNs, mixed flora; positive bacilli gram-positive cocci Excision of Wide filleting necrotic incisions muscle

Sparse PMNs, grampositive bacilli

Seropurulent or dishwater, putrid

Necrotizing Fasciitis

Seropurulent

Streptococcal Myonecrosis

Serosanguineous, sweet or foul odor

Clostridial Myonecrosis (Gas Gangrene)

Amputation

PMNs, mixed flora

Minimal

Infected Vascular Gangrene

Data from File TM Jr. Necrotizing soft tissue infections. Clin Infect Dis Rep. 2003;5:407-15; Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis. 2005;41:1373-406; Gorbach SL. IDCP Guidelines: Necrotizing skin and soft tissue infections. Part I: Necrotizing fasciitis. Infect Dis Clin Pract. 1996;5:406-11; Gorbach SL. IDCP Guidelines: Necrotizing skin and soft tissue infections. Part II: Myositis, Meleney’s gangrene, pyomyositis, necrotizing cellulitis, nonclostridial cellulitis, and Fournier’s gangrene. Infect Dis Clin Pract. 1996;5:463-72. Abbreviations: PMN, polymorphonuclear leukocyte.

Surgical Therapy

Gram Stain

Discharge

Anaerobic Gas-Forming Cellulitis

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Table 35-1 Continued

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The pathogenic role of mixed aerobic/anaerobic infections has been well demonstrated in many anatomical models of infection (7). Weinstein and coworkers first published results of a rat model of peritonitis/intra-abdominal abscess that demonstrated a biphasic process of infection (8). The first phase manifested itself by peritonitis that was caused by facultative aerobes, whereas anaerobes were predominant in the second phase. Using an animal model that more closely resembles skin and soft tissue infections, Brook evaluated the effect of subcutaneously inoculating various combinations of aerobes and anaerobes into mice (9). The mice were then challenged with either a single organism or a mixture of Bacteroides species and facultative aerobic organisms. The bacterial strains tested included Bacteroides fragilis, Escherichia coli, B. melaninogenicus, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus pyogenes, and Enterococcus faecalis, all of which are organisms commonly found in the mixed aerobic/anaerobic skin and soft tissue infections of humans. Infection caused by individual isolates was relatively innocuous, but combinations of facultative organisms and aerobes showed a synergistic effect, as manifested by the formation of abscesses and by a significant animal death rate. This synergistic effect was demonstrated for Bacteroides species in conjunction with all of the facultative aerobic organisms tested. The effect also was seen among most Peptostreptococcus, P. aeruginosa, and S. aureus. Brook electively treated inoculated animals with various antibiotics that were chosen specifically to cover aerobes, anaerobes, or both of these components of mixed infections (9). Antimicrobial agents that were directed at one component of a mixed infection did not eliminate the infection or the untreated organisms completely; therefore, the abscesses persisted. Treatment aimed at both components was required to achieve significant reductions in the numbers of both contributing agents. Using another model of soft tissue infection, Kelly demonstrated synergy between E. coli and B. fragilis when these organisms were injected subcutaneously into guinea pigs (10). A certain threshold count or number of organisms was required for this synergistic effect to occur. When the size of the E. coli or B. fragilis inoculum was below a critical threshold (104B. fragilis or 103E. coli), there was no abscess or necrosis, whereas when bacterial numbers were above the threshold, significant bacterial growth, abscess formation, and necrosis were present. These animal studies and others tend to confirm the observation that mixed aerobic/anaerobic infections are often more virulent than monomicrobial infections caused by the same organisms. Mackowiak proposed the following four principles by which microorganisms can interact to produce a synergistic infection (11): 1. There is an effect on host defenses (most commonly inhibition of phagocytosis). 2. Vital nutrients are supplemented.

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3. Environmental conditions are provided that are favorable for growth. 4. The infecting organisms exhibit increased virulence.

Monomicrobial Infectious Processes Several individual pathogens can cause necrotizing soft tissue infections. The most clinically significant of these infections are caused by Clostridium species and S. pyogenes. Clostridia can play a role in various infections of skin, subcutaneous tissue, and muscle that include crepitant cellulitis, pyomyositis, and clostridial myonecrosis (gas gangrene). Clostridium perfringens is the major causative species of such infections and accounts for approximately 80% of cases. Other species that cause such infections include C. septicum, C. novyi, C. sordellii, C. histolyticum, and C. bifermentans. Clostridial species that have been implicated in necrotizing soft tissue infections produce various exotoxins that contribute to the pathophysiology of such infections. Clostridia are anaerobic and therefore require an anaerobic environment for multiplication and production of these necrotizing toxins. The clostridial organisms that cause necrotizing soft tissue infections can be of either endogenous or exogenous origin, in that they can be present in the patient’s normal gastrointestinal flora or can come from soil contamination in wounds caused by, for example, motorcycle or lawn-mower accidents. The past decades have seen an increasing number of reports of NF caused by the group A streptococcus (GAS) S. pyogenes (12,13). Such infections can appear suddenly, sometimes in previously healthy patients with no history of a wound or injury, and can progress within hours to necrosis of an entire limb, often culminating in amputation or death. The lay media quickly named this disease the flesh-eating bacteria syndrome. GAS produce many surface components and extracellular products that are believed to play important roles in the pathogenesis of necrotizing soft tissue infections. Such components include M proteins, hyaluronic acid capsules, and pyrogenic exotoxins (streptococcal pyrogenic exotoxins A, B, and C). Streptococcal pyrogenic exotoxins belong to a group of proteins called super antigens, which in some individuals can activate a much larger proportion of T cells than do conventional peptide antigens and can cause various cytokines to be produced. These cytokines, in turn, are thought to be responsible for the manifestations of streptococcal toxic shock syndrome (TSS) and NF (14). Norrby-Teglund and colleagues studied the host-pathogen interactions of patents with severe invasive group A streptococcus soft-tissue infections and compared findings from biopsy samples from such patients to those without inflamed tissue (15). There was increased expression of interleukin-1 and tumor necrosis factor (TNF) in samples from the infected tissue. The cytokine profile at the local site mimicked that of a typical superantigen cytokine response. These findings support the role of super-

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antigens as crucial players in the pathogenesis of NF associated with group A streptococcus. Other single pathogens associated with necrotizing soft tissue infections include group B streptococci, Staphylococcus species, Vibrio vulnificus (in cases of salt-water injury), Aeromonas hydrophila (in cases of fresh-water injury), Enterobacteriaceae, P. aeruginosa, and Yersinia enterocolitica (1).

Predisposing Conditions Necrotizing soft tissue infections frequently occur in association with previous trauma, surgery, or other forms of tissue damage. The portal of entry is varied, and the entrance of bacteria can occur from any break in the skin including preexisting skin conditions, such as psoriasis, pressure ulcers, or dermatitis. Immunosuppression caused by various conditions, such as diabetes, AIDS, or complement deficiency can be a predisposing condition although the degree to which it contributes is not well defined (16). Soft tissue infections associated with preexisting ulcers (i.e., diabetic foot ulcer or decubitus ulcers) can progress to necrotizing infections. Various underlying conditions or medications have been described as predisposing factors for necrotizing infections. These infections have been increasingly reported as a complication of illicit drug injection (17). In addition, although group A streptococcus is a well-recognized complication of varicella in children, NF caused by S. pyogenes or S. aureus has also recently been described in adults with herpes zoster infection (18). Infliximab, an inhibitor of tumor necrosis factor-alpha (TNFα), which has been linked with many infections caused by its effects on lymphocytes and cytokines, has been associated with necrotizing fascitis (19). Several reports have implicated nonsteroidal anti-inflammatory drugs (NSAIDs) with severe presentations of invasive group A streptococcus soft-tissue infections (20-22). NSAIDs are known to have several actions which can lessen the immunological response to bacterial infection: impairment of granulocyte function (adherence, phagocytosis, and cidal activity); augmentation of inflammatory cytokine release; and inhibition of renal prostaglandin synthesis. In addition, NSAIDs can confound the progression of disease by suppressing fever and pain, thus attenuating some of the cardinal manifestations of inflammation in patients with serious streptococcal infection. However, experimental data in at least one animal model refutes this, suggesting that the administration of diclofenac after infection protected rabbits from NF caused by group A streptococcus instead of potentiating tissue damage (23).

Clinical Manifestations Clinical features that suggest necrotizing soft tissue infections include the following (2):

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● ● ● ●

● ● ●

The patient experiences severe, constant pain. There are bullous lesions. There is skin necrosis or ecchymosis that precedes skin necrosis. Gas in soft tissues is detected by palpation, radiography, or scanning; the gas is produced by metabolic activity of the infecting aerobic and/or anaerobic bacteria; when anaerobes are present, there is often a distinctive putrid odor. Edema extends beyond the margin of erythema. Systemic toxicity manifests by fever and occasionally by delirium. There is a tendency toward the rapid spread of infection centrally along fascial planes.

The inflammatory reaction in tissues with necrotizing soft tissue infections is often much different from that seen in pyodermas caused by staphylococci because there is often an associated serous, putrid, dish-watery discharge in the former compared with the purulent discharge associated with abscess formation in the latter. Infections associated with preexisting ulcers (e.g., foot ulcers, decubitus ulcers) can progress to necrotizing infections. Tissue necrosis is characteristic and can occur by any of the following means: pressure necrosis in infected areas of the fascia or skin; vascular thrombosis caused by anaerobic organisms by means of heparinase production or by direct acceleration of coagulation; and extracellular toxins produced by bacteria (e.g., the necrotoxins of C. perfringens). The clinical characteristics of the more common necrotizing soft tissue infections are given in Table 35-1. Many of these conditions are differentiated from one another on the basis of anatomic extent of disease, which often can be measured only at the time of surgical intervention. The following paragraphs discuss further salient clinical features of necrotizing soft tissue syndromes:

Necrotizing Fasciitis NF is the most common of the severe necrotizing soft tissue infections and refers to deep tissue infection involving the fascial cleft between the subcutaneous tissue and underlying muscle. NF can be classified into two types: Type I associated with polymicrobial (mixed aerobic and anaerobic) infection and type II with Streptococci pyogenes (or other single pathogens) as the microbial cause (24). Examples of polymicrobial infection (Type I) include: diabetic foot infections, decubitus ulcer infection, postoperative infection, and infection associated with trauma and bite wounds. The initial presentation of NF is often that of cellulitis, which can advance rapidly. As it progresses, there is systemic toxicity with fever. The local site shows the following features: cellulitis (90% of cases), edema (80%), and skin discoloration or gangrene (70%) (2). A distinguishing clinical feature of NF is the wooden-hard feel of the subcutaneous tissues. In

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cellulitis the subcutaneous tissues are softer, but in fasciitis, the underlying tissues are firm, and the fascial planes cannot be discerned by palpation. If there is an open wound, probing the edges with a blunt instrument permits ready dissection of the superficial fascial planes well beyond the wound margins (2). Childers and coworkers reviewed 163 consecutive patients with NF treated at a university teaching hospital or a large general hospital from 1984 through 1997 (25). The most commonly involved areas were the lower extremities (32%), upper extremities (24%), perineum (16%), trunk (16%), and head and neck (10%). Most patients (83%) had a preceding injury; 24% and 14% were associated with intravenous injection or operative site respectively. Other injuries included insect bites, skin ulcers, tooth abscesses, abrasions, gunshot wounds, and blunt trauma. Of the 145 patients with positive wound cultures 29% had only one bacterial species. The remaining 71% had polymicrobial flora with up to six organisms and infection. Beta-hemolytic streptococcus and S. aureus were found in 32% and 23% of cases respectively. The death rate was 28%. Predictors of death included: age younger than 1 year or older than 60 years; comorbid conditions (cancer, renal insufficiency, CHF); and prolonged time to diagnosis and treatment (although the authors do not indicate specific times evaluated).

Fournier Gangrene Fournier gangrene is a form of NF that involves the fascial planes of the perineum and abdominal wall along with the scrotum and penis in men and the vulva in women. Various pathogens (usually polymicrobial, mixed aerobic/anaerobic flora) have been isolated from infected tissue. Treatment usually includes wide surgical excision of devitalized tissue with the administration of broad-spectrum antibiotics. In a recent review of Fournier gangrene from a single center, Kilic and colleagues reviewed the clinical characteristics of 23 patients (all but one were men) who were treated between 1990 and 1999 (26). Seventy-four percent of patients had a preceding infection (colorectal in 39% and genitourinary tract in 35%). The most commonly isolated pathogens were E. coli (57%), S. aureus (25%), and anaerobic Streptococcus species (13%). Wide scrotal, penile, perineal, and inguinal debridement was done in 10 patients. The remaining 13 patients had limited debridement. Nineteen patients (82.6%) survived.

Group A Streptococcal Necrotizing Fasciitis NF caused by GAS usually follows a rapid course: Diffuse erythema and swelling, exquisite tenderness, and pain are the usual first signs of symptoms; lymphangitis and lymphadenitis are infrequently seen initially. Bullae filled with clear liquid follow next (commonly these bullous lesions rapidly

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become maroon or violaceous). Frank cutaneous gangrene then often evolves rapidly and extends along fascial planes. In some patients necrosis proceeds less quickly; For example, Kaul and coworkers described a subset of patients with diabetes or peripheral vascular disease or both, in whom ischemia and necrosis progressed less rapidly (27). Overlying skin anesthesia provides a clue that a soft-tissue infection is NF and not simple cellulitis. As tissue necrosis progresses, the pain can disappear as thrombosis of small blood vessels leads to destruction of the superficial nerves located in the underlying subcutaneous tissues. TSS is linked to NF in approximately 50% of cases. In the largest population surveillance study of GAS-NF (a prospective, population-based study conducted in Ontario, Canada, from 1992 through 1996), the incidence increased from 0.08 cases per 100,000 population in 1992 to 0.49 cases per 100,000 in 1995 (28). The authors defined patients with either NF or other “soft tissue infection.” Factors which were significantly associated with NF included the presence of diabetes, hypotension at presentation, and the use of NSAIDs after onset of symptoms. Of interest was that patients with cancer and soft-tissue infections were less likely to develop NF. The authors offered possible explanations of this observation: It is possible that the natural progression of NF depends on a certain level of immune status that can be altered with malignancy or its treatment; many of these infections were nosocomial and because the patients were hospitalized they can have had earlier treatment, which can have reduced the risk for NF. The present study did observe that taking NSAIDs after the onset of illness was a risk factor for developing NF. However, because the NSAIDs were used for pain and fever management, it was not possible to determine whether NSAIDs caused more severe infection or were taken for more severe symptoms. In addition, in the multivariate analysis the use of NSAIDs is no longer held as an independent risk factor of NF. Sixty percent of all patients had bacteremia and 78% of NF cases had infection caused by one of six serotypes: M1, M12, M3, M28, M6, and M4. Risk factors for death for all patients with invasive GAS soft-tissue infection included age older than 65 years, hypotension at presentation, any underlying condition and the presence of NF (29). Dahl and colleagues reported the experience of seven patients with GAS-NF seen at the Mayo Clinic or Mayo Clinic Jacksonville between 1992 and 1995 (29). The average age of the patients was 47 years. NF occurred on an extremity (four upper extremities) in all cases. Five patients had associated TSS, and all died. The first symptom in all patients was severe pain in the affected area that was disproportionate to objective findings. In four patients, the pain developed simultaneously with ill-defined violaceous, edematous areas of the skin. GAS NF tends to be sporadic in occurrence. Secondary cases are rare but have been reported among family members and with intimate contact and also among medical personnel caring for patients (30,31).

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Necrotizing Fasciitis Caused by Community-Acquired Methicillin-Resistant Staphylococcus Aureus In the past S. aureus has been an uncommon cause of NF. However, recent reports of NF and necrotizing myositis have been published. Miller and coworkers identified 14 cases of necrotizing infection caused by methicillinresistant S. aureus (MRSA) from January 2003 through April 2004 (32). The median age was 46 years with 71% of patients being men. Coexisting conditions included injection-drug use, diabetes, chronic hepatic C, cancer, and HIV infections. All patients received combined medical and surgical therapy; although none died, they had serious complications, including the need for reconstructive surgery and prolonged intensive care unit (ICU) stays. All the MRSA-isolated recovered belonged to the same USA300 type (USA300 carries the type IV staphylococcus cassette chromosome methicillin-resistance gene [SCCmec IV]) and carried the Panton-Valentine leukocidin.

Necrotizing Fasciitis Associated with Other Monomicrobial Etiology Other single pathogens associated with necrotizing soft tissue infections include: Group B Streptococcus, Staphylococcus species, V. vulnificus (salt water injury), A. hydrophilia (fresh water injury), Enterobacteriaceae, P. aeruginosa, and Y. enterocolitica (1). There are several recent reports of NF caused by S. pneumoniae (1). Most of the patients described in these reports were immunocompromised because of various conditions including drug abuse, diabetes chronic renal failure, and systemic lupus erythematosus (SLE). In several cases, NF seemed to be associated with the use of NSAIDS or steroids.

Other Necrotizing Soft-Tissue Syndromes Synergistic necrotizing cellulitis is similar to Type I NF as both are caused by a mixed aerobic-anaerobic infection; however with necrotizing cellulitis there is often extension beneath the fascia involving muscle. Just as in clostridial myonecrosis, amputation is required when there is muscle involvement of an extremity (1-5). Progressive bacterial synergistic gangrene (often referred to as Meleney gangrene) is an indolent process characterized by poor healing often after a previous surgical operation. The presentation can be one of a slowly progressive (often over several weeks) expanding necrosis. Local pain and tenderness are nearly always present, however fever and systemic toxicity are not as associated as with the other syndromes. Pyomyositis is a discreet abscess within individual muscle groups caused primarily by S. aureus but occasionally by other gram-positive organisms or gram-negative enteric rods. Because of its geographic distribution, this

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condition is often referred to as tropical pyomyositis, but cases are increasingly recognized in temperate climates, especially in patients with human immunodeficiency virus or diabetes. Presenting findings are localized pain in a single muscular group, muscle spasm, and fever. The disease most often occurs in an extremity, but any muscle group can be involved. Additionally it may not be possible to palpate a discreet abscess because the infection is localized deep within the muscle, but the area has a firm, woody feel on palpation, along with pain and tenderness. A recent review of pyomyositis from an urban hospital in the United States was recently reported by Hossain and colleagues (33). The authors reviewed hospital records for the diagnosis of “pyomyositis” from 1988 through 1998 and identified eight patients who fulfilled the criteria for primary pyomyositis. S. aureus was isolated from four cases and betahemolytic streptococcus from three cases (one case had no identified pathogen isolated). The authors found that magnetic resonance imaging (MRI) or computed tomography (CT) seemed to be the most useful tests in identifying pyomyositis. Half of the patients had drainage of the infected muscle; the remaining were treated with antimicrobial agents alone. All the patients recovered.

Clostridial Necrotizing Infections The clinical picture of clostridial myonecrosis, or classic gas gangrene, is well described (1-5). Clostridial myonecrosis can occur within hours of an initiating insult or surgery, and is often associated with sudden pain that increases in severity and extends beyond the wound. Systemic toxicity indicated by tachycardia and mental confusion is common. A thin watery discharge is often noted early in the process; large hemorrhagic bullae can appear in the vicinity of the wound. Microscopic examination of the discharge often reveals gram-positive rods and a paucity of polymorphonuclear leukocytes (PMNs). The lack of PMNs is, in part, attributable to clostridial toxins that cause lysis of cell membranes and cause subsequent cell death. The characteristic finding of clostridial myonecrosis is the appearance of necrotic infected muscle. As the disease progresses, the muscle loses viability and becomes black. Early diagnosis is essential so that complete resection (amputation) of the devitalized tissue can be accomplished. It should be stressed that although classic gangrene implies infection by Clostridium species, the isolation of Clostridium species (i.e., C. perfringens) does not necessarily indicate clinical disease. This is because Clostridium species (including C. perfringens) not uncommonly colonizes or contaminates wounds (either postsurgical or posttraumatic) without causing tissue invasion. In addition, C. perfringens can cause only cellulitis (anaerobic cellulitis) without deep tissue involvement. In such cases there can be an abundance of gas formation, but severe pain and systemic toxicity are absent.

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Diagnosis Although the diagnosis of NF and other necrotizing soft tissue infections can be clear-cut at the later stage of disease (extensive necrosis), it is often difficult to differentiate from primary cellulitis early in presentation. Because cellulitis can be treated with antimicrobial agents without surgical management, whereas deep necrotizing soft tissue infections require timely surgical debridement and excision of tissue in addition to the use of antimicrobial agents, their distinction is important. In cellulitis or erysipelas, the subcutaneous tissues can be palpated and are usually yielding. But in fasciitis, the underlying tissues tend to be firm, and the fascial planes and muscle groups cannot be discernible by palpation. It is often possible to observe a broader erythematous track of the skin along the route of the fascial plane as the infection advances. If there is an open wound, probing the edges with a blunt instrument permits ready dissection of the superficial fascial planes well beyond the wound margins. Remarkably little pain can be associated with this procedure because of anesthesia which occurs secondary to necrosis of nerve endings. Infection of the fascial cleft can spread rapidly; however, on occasion it can be indolent. In more indolent cases, biopsy has been useful. Majeski and coworkers reported a series of cases in which an early, accurate diagnosis of NF was established by a frozensection tissue biopsy obtained at the bedside (34). Of 43 patients evaluated, 12 were found to have NF. These patients were then treated with immediate surgical debridement of all necrotic tissue, broad spectrum antibiotics, and adequate nutritional support. All patients survived. One pitfall from this approach is sampling error. When in doubt, it is better for a surgeon to visualize the tissue to obtain tissue. A blind percutaneous sampling can provide false-negative results. Bullae are often seen with necrotizing soft tissue infections but can also be seen in cellulitis without fasciitis or deep involvement. Bullae can also be associated with toxins (e.g., brown recluse spider bites), and primarily dermatologic conditions (such as pyoderma gangrenosum). Fever with unexplained severe musculoskeletal pain is an important clue to the possibility of necrotizing infection. Other conditions that can mimic the early manifestations of necrotizing soft tissue infections include trauma with hematoma (although fever and leukocytosis is usually absent), phlebitis, bursitis, and arthritis. Leukocytosis is usually present in most deep necrotizing soft tissue infections. Wall and colleagues compared clinical characteristics on hospital admission of 21 cases of NF (most of whom were injection-drug users) with matched non-necrotizing soft tissue infection controls (35). A leukocyte count of more than 15.4 × 106 cells/mL and/or a serum sodium level of less than 135 had a sensitivity of 90% and specificity of 76% for NF. An elevated serum creatine phosphokinase level is often a clue to the presence of NF or myositis. Simonat and coworkers compared data from 17 patients with GAS-NF with data from 145 patients hospitalized for cellulitis (36).

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Admission variables for C-reactive protein and creatine phosphokinase were significantly higher ( p < .001) for patients with NF. The most definitive diagnostic test is therapeutic surgical exploration to define the extent of infection in the involved tissues (i.e., subcutaneous, fascia, muscle). Whenever necrotizing skin infection is considered in the differential diagnosis, an immediate surgical evaluation is imperative. Diagnostic studies before surgical incision and drainage can include radiography, which can demonstrate soft tissue swelling or the presence of gas, and a CT scan or ultrasound to detect fluid or abscesses, for which needle aspiration or biopsy can be directed. Different radiologic methods have been evaluated for the detection of NF. A CT scan can detect subcutaneous and fascial edema, gas formation, and abscesses. However, magnetic resonance (MR) has the highest sensitivity for detecting NF and is better for differentiating between NF and cellulitis. Schmid and colleagues compared MR imaging to surgical findings in 17 patients with severe softtissue infection caused by either NF (11 cases) or cellulites (6 cases) (37). MR was able to identify all 11 cases of NF; however, one false-positive case of cellulites was over interpreted and was thought to be NF. The authors concluded that MR has high sensitivity in the diagnosis of NF, with its characteristic findings of thickening and fluid collections along deep fascial sheaths; but can be associated with false-positive results. Radiologic studies should not delay surgical evaluation if necrotizing soft tissue infection is highly suspected. Rather they should serve to expedite and direct surgical intervention.

Therapy The approach to management of necrotizing soft tissue infections requires expeditious evaluation, with prompt surgical intervention (1-5,38). Kaul and coworkers reported that the death rate of patients with NF approached 100% if appropriate surgical intervention was not done (27). McHenry and colleagues reported that survival of NF correlated with timing of surgery (39). Thus regardless of the antimicrobial cause, the primary therapy is urgent surgery and accompanied with antibiotics active against the most likely pathogens (these include Streptococci, Staphylococci, Clostridium species, and mixed aerobic and anaerobic flora).

Surgical Therapy In patients with signs of NF, expeditious and extensive surgical débridement has been the standard recommended therapeutic strategy. The goals of surgery are threefold: to remove all necrotic tissue by radical débridement, to preserve as much viable skin as possible, and to maintain hemostasis. Amputation can be necessary to remove all nonviable tissues (this is particularly important for myonecrosis). A second-look procedure can be and is often

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necessary within 12 to 24 hours to reculture and further remove all necrotic and infected materials that were missed. Multiple débridements are often necessary: McHenry and coworkers recorded a case series of 65 patients with NF, each of whom needed an average of three operative débridements and several of whom needed amputations to control the infection (40). The general principles in the care of NF that apply to many other necrotizing soft tissue infections as listed by Stevens include the following: (41) ●

●

●

●

●

Patients with NF or myonecrosis who do not undergo exploration and débridement will surely die. Devitalized tissue, including muscle, fascia, and skin must be removed. Appropriate surgical débridement in certain locations of the body (e.g., head, neck, thorax, abdomen) can be virtually impossible. Multiple débridements over the course of several weeks are usually necessary. Extensive reconstructive surgery is generally necessary.

Although early aggressive surgery has been the conventional approach, a recent report suggests that surgical débridement can be limited or delayed until the patient is stabilized by the use of high-dose intravenous immunoglobulin (IVIG). This can allow a more conservative approach. Muller described six patients with severe group A streptococcal diseases and soft tissue involvement who were managed conservatively with treatment of clindamycin, a beta-lactam, and high-dose IVIG (40). Only one patient had a limited exploratory surgery without débridement. All patients survived. Such an approach can present an effective alternative to aggressive surgery that in many cases is mutilating (42). However, more experience is needed before such an approach can be generally recommended.

Empiric Antimicrobial Therapy It is difficult to determine the antimicrobial cause on the basis of the clinical presentation; therefore, empiric antibiotic therapy should be started as soon as these serious infections are suspected (Table 35-2). Unless there is specific evidence of the pathogens, antimicrobial agents chosen should have activity against streptococci, staphylococci, clostridium, and mixed aerobic and anaerobic organisms particularly if polymicrobial flora is possible (1-5). If GAS is considered likely, the combination of a beta-lactam plus clindamycin is recommended. Although streptococcus remains very susceptible to the beta-lactam antibiotics, studies in experimental animals have shown that penicillin is not always effective in the presence of a large inoculum of bacteria because the growth of the streptococci is not in a rapidly growing phase (38). In a mouse model of GAS, Stevens and colleagues demonstrated a better outcome with clindamycin than with penicillin (43). The efficacy of clindamycin is not affected by inoculum size or stage of growth. In addition

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Table 35-2 Antimicrobial Treatment of Necrotizing Soft Tissue Infections First-Line Agent(s)

Adult Dosage

Alternative Therapy/Comment

Mixed Infection* Ampicillin-sulbactam† or Piperacillin-tazobactam or Clindamycin plus ciprofloxacin or levofloxacin or Imipenem/Cilastatin or Meropenem or Ertapenem* or Cefotaxime* plus metronidazole or clindamycin Streptococcal infection Penicillin plus clindamycin

1.5-3.0 g q6-8h

Clindamycin (600-900 mg q8h) or metronidazole (500 mg q6h) with an aminoglycoside (gentamicin or tobramycin 7 mg/kg QD, amikacin 20 mg/kg QD or fluoroquinolone (ciprofloxacin 400 mg q8-12h‡; levofloxacin 750 mg 2 24 h)

Staphylococcus aureus infection Nafcillin or Oxacillin or Cefazolin If MRSA, vancomycin If CA-MRSA consider clindamycin

3.375-4.5 g q6h 600-900 mg q8h 400 mg q12h‡ 750 mg q24h 0.5-1 g q6-8h 1 g q8h 1 g q24h 2 g q6h 500 mg q6h 600-900 mg q8h 2-4 MU q4-6h

1-2 g q4h 1-2 g q4h 1 g q8h

Cephalosporin (cefotaxime 2 g q6h; ceftriaxone 1-2 g q24h) plus clindamycin (600-900 mg q8h); vancomycin (30 mg/kg/d in two divided doses), linezolid (600 mg q12h), daptomycin (4 mg/kg q24h) Vancomycin (30 mg/kg/d in two divided doses), linezolid (600 mg q12h), daptomycin (4 mg/kg q24h)

30 mg/kg/d in Linezolid (600 mg q12h), two divided doses daptomycin (4 mg/kg q24h) 600-900 mg q8h Potential of cross-resistance and emergence of resistance in erythromycin-resistant strains; inducible resistance in MRSA

Modified with permission from Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis. 2005;41:1373-406. * For empirical therapy the addition of clindamycin to a beta-lactam agent is recommended—see text for explanation. † Does not cover Pseudomonas aeruginosa. ‡ The dose of ciprofloxacin should be q8h if P. aeruginosa is a concern. Abbreviations: CA-MRSA, community-acquired methicillin-resistant S. aureus; h, hour; MRSA, methicillinresistant S. aureus; q, every; QD, daily.

clindamycin suppresses bacterial toxin synthesis, facilitates the phagocytosis of S. pyogenes by inhibiting M-protein synthesis, has a longer postantibiotic effect than beta-lactams, and suppresses LPS-induced monocyte synthesis of TNF-alpha. Thus, the efficacy of clindamycin can be related to the combination of its antimicrobial effect and its capacity to modulate the immune response. In a recent retrospective analysis of streptococcal TSS cases,

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Zimbelman and coworkers found improved survival in patients who received clindamycin compared to those treated with beta-lactams (44). The combination of a broad spectrum beta-lactam (i.e., betalactam/beta-lactam inhibitor combination, a carbapenem, or extended cephalosporin) and clindamycin is an appropriate consideration for empirical therapy. For patients who cannot tolerate a beta-lactam, the combination of clindamycin and fluoroquinolone effective for Enterobacteriaceae and Pseudomonas species (or an aminoglycoside) is an appropriate alternative. Once the results of appropriate cultures are available, antimicrobial therapy should be specified for the pathogens isolated. The duration of therapy will vary based on the extent of infection, the course of the infection, and whether or not metastatic infection is present; however, a minimum of 2 weeks is usually required.

Other Therapies Hyperbaric oxygen is debated as a therapy for these diseases (1-5). It has long been recommended for the treatment of clostridial myonecrosis and more recently has been applied to other necrotizing infections. However, the role of hyperbaric oxygen is at best adjunctive. The benefits are far clearer in clostridial myonecrosis than in other necrotizing infections because hyperbaric oxygen is bacteriocidal for C. perfringens, and it can reduce generation of exotoxin in clostridial myonecrosis (but it will not neutralize toxin already present). Hyperbaric oxygen should be limited to specialized centers where complications can be kept to a minimum, and it should never take precedent over surgical debridement. IVIG has been shown to have some beneficial effect in TSS associated with GAS-NF (45-47). This effect can be caused by its ability to neutralize superantigen. Kaul and colleagues saw a beneficial effect of IVIG for patients with GAS TSS in 21 consecutive patients who were treated with IVIG (single dose of 2 gm/kg with a repeated dose at 48 hours if the patent remained unstable) (46). The proportion of cases with 30-day survival was higher in patients treated with IVIG compared to a control group (67% vs. 34%; p = .02). The findings of this study must be tempered on the basis that the control group was a historical one and that IVIG treated patients were more likely to have had surgery and were more likely to have received clindamycin. It is unlikely that a randomly assigned, controlled trial to test the use of this therapy can be done. At the present time it seems reasonable to consider IVIG for patients with severe GAS NF.

Prevention Because necrotizing soft tissue infections often occur as complications of less serious cutaneous infections (i.e., diabetic lower extremity ulcers),

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attention should be focused on preventing pressure ulcers and wounds in patients with identifiable risk factors. Patients with conditions such as diabetes need to be educated about their predisposition to infections and alerted to the early signs of infection. Hopefully early treatment of superficial infections in such patients can ward off the serious complication of necrotizing, deep infections. The occurrence of outbreaks of GAS necrotizing infections (especially clusters of TSS and NF) has raised the concern about the transmissibility of these invasive strains and the need for prophylaxis. Although this strategy is supported by some, it has not been verified by clinical data. Based on several observations of familial and health care provider transmission, some have recommended two possible strategies: to administer preventive treatment to those in contact with secretions, or to culture specimens from close contacts and treat those for whom cultures are positive (31). Chemoprophylaxis (i.e., a 10-day course by a beta-lactam) can be considered in contacts of invasive GAS (i.e., household contacts, or persons cases who have had direct mucous membrane contact with oral or nasal secretions of a case within 76 days before case patient illness) presenting with TSS, NF, or death within 7 days of diagnosis. There are no controlled studies to support such recommendations; but based on the present state of knowledge, this seems a reasonable approach.

Summary Necrotizing soft tissue infections are much less common than usual pyogenic soft tissue infections (i.e., cellulitis, carbunculosis, etc.). However, they are associated with a much greater illness and death rate. Early recognition and expeditious surgical therapy are required in most patients for optimal outcomes. Initial antimicrobial therapy often needs to be directed against various pathogens, which include Streptococcus and Staphylococcus species, gram-negative bacilli, and anaerobes. Recent advances in the care of patients with NF caused by GAS include the use of IVIG, which can neutralize some of the detrimental effects of superantigens.

REFERENCES 1. File TM. Necrotizing Soft Tissue Infections. Curr Infect Dis Rep. 2003;5:407-415. 2. Infectious Diseases Society of America. Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis. 2005;41:1373-406. 3. Gorbach SL. IDCP Guidelines: Necrotizing skin and soft tissue infections. Part I: Necrotizing fasciitis. Infect Dis Clin Pract. 1996;5:406-11. 4. Gorbach SL. IDCP Guidelines: Necrotizing skin and soft tissue infections. Part II: Myositis, Meleney’s gangrene, pyomyositis, necrotizing cellulitis, nonclostridial cellulitis, and Fournier’s gangrene. Infect Dis Clin Pract. 1996;5:463-72. 5. Majeski JA, John JF Jr. Necrotizing soft tissue infections: a guide to early diagnosis and initial therapy. South Med J. 2003;96:900-5.

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6. Dellinger EP. Severe necrotizing soft-tissue infections. Multiple disease entities requiring a common approach. JAMA. 1981;246:1717-21. 7. File TM Jr., Tan JS. The triple threat of gram-positive cocci, gram-negative bacilli, and anaerobes. In: Nord CE, ed. The Role of Piperacillin/Tazobactam in the Treatment of Skin and Soft Tissue Infections. Montreal: PharmaLibri; 1994. 8. Weinstein WM, Onderdonk AB, Bartlett JG, Gorbach SL. Experimental intra-abdominal abscesses in rats: development of an experimental model. Infect Immun. 1974;10: 1250-5. 9. Brook I. Synergistic aerobic and anaerobic infections. Clin Ther. 1987;20(suppl A):19-35. 10. Kelly MJ. The quantitative and histological demonstration of pathogenic synergy between Escherichia coli and Bacteroides fragilis in guinea pig wounds. J Med Microbiol. 1978;11:511-22. 11. Mackowiak PA. Microbial synergism in human infections (second of two parts). N Engl J Med. 1978;298:83-7. 12. Stevens DL. Invasive group A streptococcus infections. Clin Infect Dis. 1992;14:2-11. 13. File TM Jr.,Tan JS. Group A streptococcus necrotizing fasciitis. Compr Ther. 2000;26:73-81. 14. Stevens DL, Bryant AE, Hackett SP, Chang A, Peer G, Kosanke S, et al. Group A streptococcal bacteremia: the role of tumor necrosis factor in shock and organ failure. J Infect Dis. 1996;173:619-26. 15. Norrby-Teglund A,Thulin P, Gan BS, Kotb M, McGeer A, Andersson J, et al. Evidence for superantigen involvement in severe group A streptococcal tissue infections. J Infect Dis. 2001;184:853-60. 16. Trent JT, Kirsner RS. Necrotizing fasciitis. Wounds. 2002;14(8):284-92. 17. Chen JL, Fullerton KE, Flynn NM. Necrotizing fasciitis associated with injection drug use. Clin Infect Dis. 2001;33:6-15. 18. Jarrett P, Ha T, Oliver F. Necrotizing fasciitis complicating disseminated cutaneous herpes zoster. Clin Exp Dermatol. 1998;23:87-8. 19. Chan AT, Cleeve V, Daymond TJ. Necrotising fasciitis in a patient receiving infliximab for rheumatoid arthritis. Postgrad Med J. 2002;78:47-8. 20. Smith RJ, Berk SL. Necrotizing fasciitis and nonsteroidal anti-inflammatory drugs. South Med J. 1991;84:785-7. 21. Barnham M, Anderson AW. Non-steroidal anti-inflammatory drugs (NSAIDs). A predisposing factor for streptococcal bacteraemia? Adv Exp Med Biol. 1997;418:145-7. 22. Stevens DL. Could nonsteroidal antiinflammatory drugs (NSAIDs) enhance the progression of bacterial infections to toxic shock syndrome? Clin Infect Dis. 1995;21:977-80. 23. Guibal F, Muffat-Joly M, Terris B, Garry L, Morel P, Carbon C. Effects of diclofenac on experimental streptococcal necrotizing fasciitis (NF) in rabbit. Arch Dermatol Res. 1998;290:628-33. 24. Giuliano A, Lewis F Jr., Hadley K, Blaisdell FW. Bacteriology of necrotizing fasciitis. Am J Surg. 1977;134:52-7. 25. Childers BJ, Potyondy LD, Nachreiner R, Rogers FR, Childers ER, Oberg KC, et al. Necrotizing fasciitis: a fourteen-year retrospective study of 163 consecutive patients. Am Surg. 2002;68:109-16. 26. Kiliç A,Aksoy Y, Kiliç A. Fournier’s gangrene: Etiology, treatment, and complications. Ann Plast Surg 2001;47:523-527. 27. Kaul R, McGeer A, Low DE, Green K, Schwartz B. Population-based surveillance for group A streptococcal necrotizing fasciitis: Clinical features, prognostic indicators, and microbiologic analysis of seventy-seven cases. Ontario Group A Streptococcal Study. Am J Med. 1997;103:18-24. 28. Ontario Group A Streptococcal Study Group. Severe group A streptococcal soft-tissue infections in Ontario: 1992-1996. Clin Infect Dis. 2002;34:454-60. 29. Dahl PR, Perniciaro C, Holmkvist KA, O’Connor MI, Gibson LE. Fulminant group A streptococcal necrotizing fasciitis: clinical and pathologic findings in 7 patients. J Am Acad Dermatol. 2002;47:489-92. 30. DiPersio JR, File TM Jr., Stevens DL, Gardner WG, Petropoulos G, Dinsa K. Spread of serious disease-producing M3 clones of group A streptococcus among family members and health care workers. Clin Infect Dis. 1996;22:490-5. 31. Gamba MA, Martinelli M, Schaad HJ, Streuli RA, DiPersio J, Matter L, et al. Familial transmission of a serious disease—producing group A streptococcus clone: case reports and review. Clin Infect Dis. 1997;24:1118-21. 32. Miller LG, Perdreau-Reminington R, Rieg G, et al. Necrotizing fasciitis caused by communityassociated methicillin-resistant Staphylococcus aureus in Los Angeles. N Engl J Med. 2005;352-53.

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33. Hossain A, Reis ED, Soundararajan K, Kerstein MD, Hollier LH. Nontropical pyomyositis: analysis of eight patients in an urban center. Am Surg. 2000;66:1064-6. 34. Majeski J, Majeski E. Necrotizing fasciitis: improved survival with early recognition by tissue biopsy and aggressive surgical treatment. South Med J. 1997;90:1065-8. 35. Wall DB, de Virgilio C, Black S, Klein SR. Objective criteria may assist in distinguishing necrotizing fasciitis from nonnecrotizing soft tissue infection. Am J Surg. 2000;179:17-21. 36. Simonart T, Simonart JM, Derdelinckx I, et al. Value of standard laboratory tests for the early recognition of group A beta-hemolytic streptococcal necrotizing fasciitis. Clin Infect Dis. 2001;32(1):E9-12. 37. Schmid MR, Kossmann T, Duewell S. Differentiation of necrotizing fasciitis and cellulitis using MR imaging. AJR Am J Roentgenol. 1998;170:615-20. 38. Norrby-Teglund A, Norrby SR, Low DE. The Treatment of Severe Group A Streptococcal Infections. Curr Infect Dis Rep. 2003;5:28-37. 39. McHenry CR, Piotrowski JJ, Petrinic D, et al. Determinants of mortality for necrotizing soft tissue infections. Ann Surg. 1995;221:556-63. 40. Muller MP, McGeer A, Low DE, Ontario Group A Streptococcal Study Group. Successful outcomes in six patients treated conservatively for suspected necrotizing fasciitis (NF) due to group A streptococcus (GAS). Poster Presented 41st ICAAC Abstracts, Chicago, Illinois, September 22-25, 2001. 41. Stevens DL. Necrotizing fasciitis: Don’t wait to make a diagnosis. Infect Med. 1997; 14:684-88. 42. Low DE. New concepts in the therapy of severe streptococcal infections. Poster Presented 42nd ICAAC Abstracts, San Diego, California, September 27-30, 2002. 43. Stevens DL, Gibbons AE, Bergstrom R, Winn V. The Eagle effect revisited: efficacy of clindamycin, erythromycin, and penicillin in the treatment of streptococcal myositis. J Infect Dis. 1988;158:23-8. 44. Zimbelman J, Palmer A,Todd J. Improved outcome of clindamycin compared with beta-lactam antibiotic treatment for invasive Streptococcus pyogenes infection. Pediatr Infect Dis J. 1999;18:1096-100. 45. Norrby-Teglund A, Kaul R, Low DE, McGeer A, Newton DW, Andersson J, et al. Plasma from patients with severe invasive group A streptococcal infections treated with normal polyspecific IgG inhibits streptococcal superantigen-induced T cell proliferation and cytokine production. J Immunol. 1996;156:3057-64. 46. Kaul R, McGeer A, Norrby-Teglund A, Kotb M, Schwartz B, O’Rourke K, et al. Intravenous immunoglobulin therapy for streptococcal toxic shock syndrome—a comparative observational study. The Canadian Streptococcal Study Group. Clin Infect Dis. 1999;28:800-7. 47. Basma H, Norrby-Teglund A, Guedez Y, McGeer A, Low DE, El-Ahmedy O, et al. Risk factors in the pathogenesis of invasive group A streptococcal infections: role of protective humoral immunity. Infect Immun. 1999;67:1871-7.

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Chapter 36

Foot Infections in Patients with Diabetes Mellitus WARREN S. JOSEPH, DPM JAMES S. TAN, MD

Key Learning Points 1. For all but the most severe or chronic infection the majority of these infections are caused by aerobic gram positive cocci. Therefore, empiric therapy directed against those pathogens is frequently sufficient 2. Aggressive surgical intervention is often necessary to control diabetic foot infections 3. Superficial swab cultures of either infected or non-infected diabetic foot ulcerations is unnecessary and often leads to the isolation of non pathogenic organisms 4. Methicillin-resistant Staphylococcus aureus is becoming a more frequent isolate from these infections 5. Empiric antibiotic therapy for moderate to severe infections includes drugs such as ertapenem or pipercillin/tazobactam

F

oot infections in diabetic patients are responsible for 50% to 70% of all non–trauma-related amputations done in hospitals throughout the United States. The American Diabetes Association estimates that there are roughly 90,000 lower extremity amputations each year as a result of diabetic foot infections. Of limbs that are amputated, 85% had a diabetic foot ulceration as a predisposing factor. The 5-year survival rate of a unilateral diabetic amputee averages 50% (1). The average hospital stay for the diabetic patient with foot infection has been reported to range from 22 to 36 days, and in some areas more than 40% of patients remain hospitalized for 3 months (2,3). Considering that 6% to 12% of the population of the United States has diabetes (either diagnosed or undiagnosed) (4), it is easy to recognize that the 663

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New Developments in the Management of Foot Infections Associated with Diabetes Mellitus ●

●

●

●

Two organizations, including the International Working Group on the Diabetic Foot and the Infectious Diseases Society of America, have published evidence based treatment guidelines for diabetic foot infections. Methicillin-resistant Staphylococcus aureus (MRSA) has become a pathogen of concern. New antibiotics effective against severe MRSA skin and skin structure infections have been approved including linezolid, daptomycin, and tigecycline. More studies have been conducted on antibiotic therapy for diabetic foot infections leading to drugs with specific FDA approved package insert indications for their use against these infections. Specifically, both ertapenem and linezolid have been studied and received the indication.

incidence of diabetic foot infections reaches massive proportions. Therefore, the prevention and optimal management of this disease is of paramount importance in decreasing the illness, death, and financial burden it incurs.

Pathophysiology The diabetic patient’s susceptibility to foot infection is caused by 3 metabolic abnormalities associated with the disease: neuropathy, vasculopathy, and immunopathy. These abnormalities are highly prevalent in diabetic patients. Neuropathy is manifested by autonomic nerve dysfunction, peripheral mononeuropathy, and polyneuropathy, all of which affect the lower extremities to a greater extent than the upper extremities. Autonomic nerve dysfunction reduces sweating and impairs vasomotor responses, resulting in dryness, fissuring, and cracking of the skin and in the formation of calluses at points of increased stress on the skin. Insensitivity to pain may result in physical trauma, thermal or chemical injury, or ischemic damage from unperceived shoe tightness or chronic pressure. The patient may walk on parts of the foot that are injured or poorly adapted for weight bearing, leading to microfractures, ligament tears, and progressive articular damage (Charcot osteoarthropathy). Neuropathy also may result in uneven weakening of the extrinsic muscles of the foot, leading to toe deformity, prominent metatarsal heads on the plantar side, loss of the plantar arch, or foot drop. Vasculopathy may result in both macro- and microangiopathy. The vascular disease process, in conjunction with autonomic vasomotor impairment, may cause local hypoxia, atrophy, and necrosis. The combination of neuropathy and vasculopathy may accelerate the process of soft tissue breakdown. Deficient circulation may retard wound healing, and open wounds invite infection.

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Immunopathy manifests in several ways. Metabolic abnormalities have been implicated in defects in polymorphonuclear leukocyte function (adherence, chemotaxis, phagocytosis, and microbial killing) (5-7). Poor wound healing, defective granuloma formation, and prolonged persistence of abscesses have been described in animals rendered experimentally diabetic (8,9).

Clinical Manifestations and Classification Foot infections in diabetes can vary in both severity and clinical presentation (10). Most infections arise from some type of trauma, whether from improperly fitting footwear or from puncture or other mechanical injury of the foot. Infections of the diabetic foot can range in severity from the relatively mild (e.g., early infection of a ruptured blister, infected abrasion, corn, or callus; an early web-space infection; paronychia; infected superficial ulcer; mild cellulitis) to the more severe (e.g., crepitant anaerobic cellulitis, abscess of the plantar space, infected gangrene, osteomyelitis, necrotizing fasciitis, nonclostridial myonecrosis). Approximately 15% of all diabetic patients develop foot ulcers during the course of their illness (11). Spread of infection from the ulcer may result in deep-space infection and may be responsible for three fourths of all foot amputations among diabetic patients (12). Neuropathic ulcers are commonly found on the soles of the feet at the sites of bony prominences, such as metatarsal heads, and are often surrounded by a halo of hyperkeratinization but generally have a good blood supply (mal perforans). Ulcers that are caused by vascular insufficiency are usually seen at the tips of the toes or on the heel. Recently, 2 fairly similar evidence based systems classifying diabetic foot infections have been published. In 2003 The International Working Group on the Diabetic Foot published its International Consensus Guidelines on Diagnosing and Treating Diabetic Foot Infections (13). This system used a 4-grade classification and introduced the acronym PEDIS standing for perfusion, extent/size, depth/tissue loss, infection and sensation. Many members of that committee along with the authors of this chapter participated in a Diabetic Foot Guidelines Committee of the Infectious Diseases Society of America (IDSA). These guidelines, published in 2004, mirror the international system in many ways and are the focus of this discussion (14). The IDSA guidelines classify diabetic foot infections based on the clinical severity of the presentation. Wounds are looked at as being uninfected or presenting with a mild, moderate or severe infection (Table 36-1). An uninfected wound lacks purulence or any manifestations of inflammation. This is an important point, because it is clear that the diagnosis of infection in these ulcerations should be made on a clinical basis. Microbiological testing of such lesions will lead to a false-positive result

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Table 36-1 Clinical Classification of a Diabetic Foot Infection Clinical Manifestations of Infection

Wound lacking purulence or any manifestations of inflammation Presence of ≥2 manifestations of inflammation (purulence, or erythema, pain, tenderness, warmth, or induration), but any cellulitis/erythema extends ≤2 cm around the ulcer, and infection is limited to the skin or superficial subcutaneous tissues; no other local complications or systemic illness Infection (as previously mentioned) in a patient who is systemically well and metabolically stable but has ≥1 of the following characteristics: cellulitis extending >2 cm, lymphangitic streaking, spread beneath the superficial fascia, deep-tissue abscess, gangrene, and involvement of muscle, tendon, joint or bone Infection in a patient with systemic toxicity or metabolic instability (e.g., fever, chills, tachycardia, hypotension, confusion, vomiting, leukocytosis, acidosis, severe hyperglycemia, or azotemia)

Infection Severity

PEDIS Grade*

Uninfected

1

Mild

2

Moderate

3

Severe

4

* Printed with permission from: Lipsky BA, et al. International consensus on the diabetic foot. Clin Infect Dis. 2004;39:885-910. Note: Foot ischemia may increase the severity of any infection, and the presence of critical ischemia often makes the infection severe. Abbreviation: PEDIS = perfusion, extent/size, depth/tissue loss, infection and sensation.

because many colonizing bacteria will invariably grow from a swab culture. This may lead to the mistaken conclusion that these are infected lesions that need antibiotic treatment. Work by Chantelau demonstrated that using antibiotics in clinically uninfected wounds adds no benefit over standard therapy without antibiotics (15). Theoretically, in addition to other adverse drug effects, using inappropriate antibiotics in clinically uninfected wounds could lead to resistance. The first reported case in the United States of vancomycinresistant S. aureus occurred in such a case. Clinically uninfected wounds should be managed with local wound care including débridement, dressings, and off-loading (Fig. 36-1a). A wound with a mild infection presents with purulence or at least 2 manifestations of inflammation including erythema, pain, tenderness, warmth, or induration. The cellulitis must be localized, extending no more than 2 cm around the ulcer. These are superficial infections with no systemic complications. A moderate infection is one in which the patient is both systemically well and metabolically stable, but the patient has at least 1 of the following characteristics: cellulitis spreading beyond 2 cm around the ulcer, streaking, a deep tissue abscess, gangrene, or deep tissue spread. Finally, a severe infection presents with all the clinical findings in the moderate category but in a patient who is metabolically unstable, systemically unwell, or with significant peripheral arterial disease.

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Diabetic patient with a foot wound

Cleanse, debride, and probe wound Determine the depth and tissues involved Assess for neuropathy (protective sensation) and food deformity Assess for ischemia (pedal pulses)+ Assess for evidence of inflammation

Is the wound clinically infected?

No

Ensure appropriate wound care Off-load local foot pressure Ensure proper footwear Optimize glycemic control Consult (podiatrist, vascular surgeon, etc.) as needed No antimicrobial therapy

Yes

See Figure 36-1b

Is the wound healing?

Yes

Monitor until healed Reinforce preventive foot care

No Re-evaluate wound management Check patient's woundcare compliance Re-evaluate for infection Re-evaluate vascular status Consider foot radiographs

Figure 36-1a Algorithm for the assessment and management of a foot wound in patients with diabetes mellitus. (Republished with permission from Lipsky BA et al. International concensus on the diabetic foot. Clin Infect Dis. 2004;39:885-910.)

Microbiology Traditional thinking has diabetic foot infections being polymicrobial and caused by a vast array of organisms including gram-positives, gram-negatives, and anaerobes. One of the most salient points emphasized in both newer classification systems is the primary role of the aerobic gram-positive cocci, primarily S. aureus and group B Streptococcus, as the causative pathogen of most diabetic foot infections. This is particularly true of the mild and moderate classes of infection. Occasionally, gram-negative aerobic bacilli (e.g., Klebsiella, Proteus mirabilis, Pseudomonas aeruginosa) may be recovered

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from culture specimens; however, anaerobes are isolated infrequently from these types of lesions. Despite care in methodology to avoid isolating skincolonizing bacteria in cases of chronic, nonhealing ulcers (i.e., by débriding the base of the ulcer with a dermal curette or scalpel to avoid such contamination before specimen collection), it may be impossible to exclude completely such contamination in these types of lesions. However, it must be kept in mind that these organisms play little to no pathogenic role in the infection. Only in the more severe or longstanding infections are the other organisms thought to become more important. These more severe infections of the diabetic foot, especially when associated with necrotic tissue and/or gangrene, are generally polymicrobial (16-20). Sapico and coworkers (17) investigated quantitative deep tissue cultures of feet that were amputated from patients with moderately severe to severe diabetic foot infections, while meticulously avoiding potentially colonized open ulcers during the collection of specimens for culture. An average of 5 species per specimen were isolated, with anaerobes and aerobes almost equally represented. Of the 32 specimens studied, 25 yielded both aerobes and anaerobes, six yielded only aerobes, and one yielded only anaerobes. Anaerobes, when present, produced growth of a heavier density in culture than did aerobes. Table 36-2 shows the most common isolated representative species in the order of approximate frequency. Table 36-3 shows the pathogens associated with various clinical foot-infection syndromes. However, a special situation exists with osteomyelitis associated with puncture wounds, particularly when it occurs during the wearing of rubber sneakers. In these cases, P. aeruginosa has been isolated with remarkable frequency (20).

Table 36-2 Bacterial Species Isolated from Deep Tissue Cultures of Moderate to Severe Diabetic Foot Infections* Aerobes

Gram-negative bacilli ● Proteus mirabilis ● Escherichia coli ● Pseudomonas aeruginosa ● Enterobacter aerogenes ● Other organisms Gram-positive cocci Enterococcus species ● Staphylococcus aureus ● Streptococcus group B ● Other organisms ●

Anaerobes

Gram-negative bacilli Bacteroides fragilis ● Bacteroides ovatus ● Bacteroides ureolyticus ● Other Bacteroides species ●

Gram-positive cocci Peptostreptococcus magnus ● P. anaerobius ● Other Peptostreptococcus species ●

Gram positive bacilli Clostridium bifermentans ● Other Clostridium species ●

Republished with permission from: Sapico FL, Witte JL, Canawati HN, et al. The infected foot of the diabetic patient: Quantitative microbiology and analysis of clinical features. Rev Infect Dis. 1984;6(suppl 1): 171-6. * Listed in descending order of frequency.

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Table 36-3 Pathogens Associated with Various Clinical Foot-Infection Syndromes Foot-Infection Syndrome

Pathogens

Cellulitis without an open skin wound

Beta-hemolytic streptococcus* and Staphylococcus aureus S. aureus and beta-hemolytic streptococcus* S. aureus, beta-hemolytic streptococcus, and Enterobacteriaceae

Infected ulcer and antibiotic naive† Infected ulcer that is chronic or was previously treated with antibiotic therapy‡ Ulcer that is macerated because of soaking‡ Long duration nonhealing wounds with prolonged, broad-spectrum antibiotic therapy‡§

Fetid foot: extensive necrosis or gangrene, malodorous‡

Pseudomonas aeruginosa (often in combination with other organisms) Aerobic gram-positive cocci (S. aureus, coagulase-negative staphylococci, and enterococci), diphtheroids, Enterobacteriaceae, Pseudomonas species, nonfermentative gram-negative rods, and, possibly, fungi Mixed aerobic gram-positive cocci, including enterococci, Enterobacteriaceae, nonfermen-tative gram-negative rods, and obligate anaerobes

* Groups A, B, C, and G. † Often monomicrobial. ‡ Usually polymicrobial. § Antibiotic-resistant species (e.g., methicillin-resistant S. aureus, vancomycin-resistant enterococci, or extended-spectrum beta-lactamase producing gram-negative rods) are common.

When confronted with a diabetic foot infection of any severity grade, the role of MRSA must be considered. As in many types of infection both community associated MRSA (CA-MRSA) and hospital associated (HA-MRSA) strains have become much more prevalent in the past few years. A 1996 study by Goldstein showed that MRSA was isolated in 20% of his diabetic foot infection cases (21). This has increased to greater than 40%. In their paper “Methicillin Resistant Staphylococcus Aureus in the Diabetic Foot Clinic: A Worsening Problem” Dang and colleagues noted that the number of diabetic foot patients in which MRSA was isolated doubled between 1999 and 2003 (22). Fortunately, they also comment that in most cases the MRSA was eradicated with topical antibiotics, débridement, and isolation without the use of specific anti-MRSA therapy. Empiric therapy for CA-MRSA should be considered in cases where the patient is at an increased risk for presenting with an MRSA infection. This occurs in patients who have had a previous infection with MRSA, those exposed to many courses of antibiotics in the past year, and those with hospital or nursing home admissions in their recent past. Appropriate material must be submitted for culture if the results are to be accurate. In the case of infected ulcers, the necrotic tissue that overlies the base of the ulcer must be removed surgically, and culture specimens must be taken from the underlying tissue. Swab cultures are unreliable and lead to spuriously positive results. Specimens taken with a dermal curette or tissue removed with a scalpel are the preferred specimens. Abscesses need to be drained

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completely by incision and drainage or aspiration, and the pus must be sent for culture. Specimens for culture also may be obtained at the time of surgery, and anaerobic transport media must be used for the culture of anaerobes.

Diagnosis Diabetic patients with foot infections require a thorough examination that includes evaluation of the patient’s vascular and neurological status. The patient should be asked about foot symptoms (e.g., burning, tingling, numbness, pain, coldness), nocturnal pain (or pain while at rest, especially if relieved by dependency of the foot), and intermittent claudication. The evaluation for vascular compromise may be done initially by noninvasive means. Doppler ultrasonography with waveform analysis is a timehonored procedure that has shown good reliability in evaluating blood flow. However, always remember that noncompliant sclerotic arteries can produce ratios of lower- to upper-extremity flow that exceed 1.0, despite significant circulatory impairment in the legs and feet. Alternative studies include transcutaneous oximetry and magnetic resonance angiography. Contrast arteriograms are invasive and generally are reserved for patients who need vascular reconstruction. Computed tomography (CT) may be valuable in assessing the extent of soft tissue involvement in diabetic foot infections in which edema and gas accumulation may be seen along the fascial planes, such as in necrotizing fasciitis. However, early osteomyelitis may not be detected readily with CT. Triple-phase bone scans are very sensitive but lack specificity in the diagnosis of osteomyelitis. Gallium-67 (67Ga) scans and Indium-111–labeled leukocyte scans are sometimes insufficiently sensitive, especially when the bone infection is chronic. Sequential bone and 67Ga scans show better specificity than do bone scans alone, but the results do not seem to be as good as those with magnetic resonance imaging (MRI), which has a sensitivity of approximately 98% and a specificity of approximately 80% (23-25). Although false-positive MRI results may occur in cases of neuropathic osteoarthropathy, especially if it is of relatively acute onset, this may still be the best single technique available for the evaluation of osteomyelitis.

Treatment In managing infections in diabetic patients, the existing disordered metabolic state should be controlled promptly and aggressively. The effects of sepsis (e.g., hypotension) must be controlled with intravenous hydration and, if necessary, with vasopressor drugs (Figure 36-1b). The extent of tissue involvement, including the extent of cellulitis, tissue necrosis, and gangrene, must be assessed. The adequacy of the patient’s vascularity,

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Assess severity of infection: depth and tissue involved, evidence of systemic infection, presence of metabolic instability, and critical limb ischemia Plain radiographs of the foot Review patient's comorbid conditions Assess psychosocial status

Is hospitalization required?

No

671

Debride and probe the wound Obtain appropriate wound specimen(s) for culture Prescribe wound-care regimen Initiate an empirical (usually oral) antimicrobial regimen Re-evaluate in 3–5 days (or sooner if worsening) Set up any necessary consultations

Yes Medically stablize patient (fluid, electrolytes, insulin, etc ) Surgical (e.g., orthopedic, vascular, podiatric) consultation for wound debridement, revascularization. pr amputation Obtain appropriate specimens (wound and blood) for cultures Consider additional imaging (CT, MRI, and radionuclide scans) Intitiate empirical (usually parenteral) antimicrobial therapy Re-evaluate the patient at least daily

Infection improving?

Yes


No Yes

No

Figure 36-1c

Reassess antimicrobial regimen; consider narrower-spectrum, less-expensive, and more-convenient agent(s), if possible Review wound- care regimen Prepare patient for discharge (if hospitalized) Set up return appointments in 1–2 weeks

Figure 36-1b Approach to treating a diabetic patient with a foot infection. (Republished with permission from LIPSKY BA et al.)

severity of neuropathy, and presence and extent of underlying osteomyelitis must be measured (Figure 36-2). If the patient exhibits inadequate metabolic control of diabetes despite taking oral antidiabetic agents, the treatment should be replaced by insulin. Surgical intervention is often necessary to control diabetic foot infections. A decision may have to be made about the need for ablative surgery. Infected ulcers may have to be débrided thoroughly. Early incision and drainage decrease the inoculum size of infecting microorganisms and may accelerate local healing. Before definitive surgery, a trial of appropriate antimicrobial therapy may be indicated to maximize control of cellulitis and minimize the extent of infection at the intended surgical site. As much of

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Poor response to treatment

Was appropriate tissue specimen obtained for culture?

No

Obtain appropriate culture specimens by aspiration, curettage, or biopsy

No

Change regimen to cover all isolated organisms likely to be pathogens

No

Reconsult appropriate surgical specialist for further procedures

No

Correct any metabolic disorders Reassess wound-care regimen and offloading compliance Reduce any limb odoma Consider adjunctive treatments (e.g., hyperbaric oxygen and hematopoietic factors)

No

Reconsult vascular surgeon Consider further diagnostic evaluation (e.g., angiography and TcPO2 measurement) Consider lower extremity revascuarization

Yes Are all pathogens covered by current antibiotic regimen? Yes Was surgical debridement, drainage, or resection adequate? Yes Has metabolic status and wound care been obtimized? Yes

Is limb perfusion adequate?

Yes Continue antibiotic therapy Consider amputation at appropriate level

Figure 36-1c Approach to assessing a diabetic patient with a foot infection who is not responding well to treatment. (Republished with permission from LIPSKY et al.) Abbreviation: TCPO2, transcutaneous partial pressure of O2.

the limb as is necessary must be preserved for future rehabilitation and ambulation, but not so much that it compromises control of the infectious state. Localized osteomyelitis often requires limited surgical ablation, such as toe amputation, ray resection, transmetatarsal amputation, or throughthe-ankle (Syme) amputation. Removal of the infected bone decreases the duration of need for antimicrobial therapy, hastens recovery, and decreases the incidence of relapse. Recent studies have shown that early and limited surgical intervention with aggressive antimicrobial therapy may reduce the number of days of hospitalization, the incidence of relapse, and the need for above-ankle amputation in cases of diabetic foot infection (26,27).

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Initial empirical antimicrobial therapy for diabetic foot infections must be directed at the organisms most likely to be involved (Figure 36-3). Generally, severe infections call for broader-spectrum antimicrobial coverage. More severe infections are associated with extensive cellulitis, tissue necrosis, gas formation, gangrene, and/or bone involvement. Once a patient has begun antimicrobial therapy, it may be adjusted according to the results of culture and susceptibility testing. However, the clinician should be cautioned that isolation of anaerobic bacteria depends heavily on proper specimen collection, the use of anaerobic transport media, and the use of good anaerobic microbiology technique on the part of the clinical laboratory. If any criteria have not have been met and if the infectious

Longstanding or deep ulcer? Elevated levels of inflamatory markers? Yes No Is bone visible or palpable by probe?

No

Plain foot radiograph findings compatible with1 osteomyelitis?

No

Yes

Yes

Yes

No

High clinical suspicion of osteomyelitis?

Severe peripheral neuropathy?

Yes

Consider additional diagnostic imaging (e.g., MRI or radionuclide scan) No

Presumptive osteomylitis Consider bone biopsy for definitive diagnosis or susceptibility testing on causative organism

Scan suggestive of osteomyelitis?

Yes

No Biopsy2 shows osteomyelitis

Treat for soft-tissue infection Repeat plain radiography in 2 weeks

No

Yes Treat for osteomyelitis


No

Surgical resection (if not previously done), or Amputation

Yes Continue therapy as planned Monitor for at least 1 year

Figure 36-2 Algorithm for the management approach to the patient with diabetes mellitus with longstanding or deep ulcers of the feet. (Republished with permission from LIPSKY et al.)

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process is likely to involve anaerobes (e.g., there is an associated foul smell, necrotic tissue is present, gangrene is evident), coverage of anaerobes is strongly recommended despite the failure to isolate these organisms by culture (see Chapter 35, Necrotizing Soft Tissue Infections). Generally, mild-grade infections can be managed on an outpatient basis with antimicrobial therapy directed specifically at the aerobic grampositive cocci. For outpatient antimicrobial therapy, an oral agent (e.g., cephalexin, clindamycin, amoxicillin–clavulanate) may be used empirically. Subsequent culture and susceptibility-testing results may dictate changes in the treatment regimen, especially if there is no clinical response to the originally chosen drug. If hospitalization is required for other reasons (e.g., for control of the patient’s metabolic state), parenteral therapy may be given with a first- or second-generation cephalosporin (e.g., cefazolin, cefuroxime). Moderate to severe infections of the diabetic foot, may require coverage of a broader-spectrum of potential pathogens. Recently, emphasis has been given to the use of cost-effective, single-drug regimens that provide broad-spectrum coverage. Antimicrobial agents for these regimens include ertapenem, ampicillin-sulbactam, ticarcillin-clavulanate, and piperacillin-tazobactam (2830). Another possible option, especially in a beta-lactam–allergic patient is moxifloxacin, which has a very broad spectrum of antimicrobial coverage (including anaerobes) and can be given on an oral once-daily basis. Although no studies have specifically addressed the efficacy of moxifloxacin in the treatment of the infected diabetic foot, the drug is indicated for complicated skin and skin structure infections, and there are in vitro and clinical trials that suggest that it should be an effective antibiotic (31-32). All these drugs have a broad spectrum of activity that includes not only the aerobic gram-positive cocci but also many gram-negative rods and anaerobic pathogens. As of this writing, ertapenem and piperacillin-tazobactam are the only drugs to carry specific FDA indications for use in diabetic foot infections. Lipsky and colleagues (28) specifically studied ertapenem versus piperacillin-tazobactam in 445 infected diabetic feet. This was the largest study to date in moderate to severe diabetic foot infections and demonstrated that ertapenem doses of 1 g once daily is at least as effective as piperacillin-tazobactam 3.375 g every 6 hours for the first 5 days, after which patients were given oral amoxicillin/clavulanate 875/125 mg every 12 hours. Based on this study the FDA granted ertapenem a specific indication for diabetic foot infections without osteomyelitis. Linezolid, daptomycin, tigecycline or vancomycin may need to be added or begun empirically, especially in institutions where MRSA is a frequent clinical isolate, in patients with positive MRSA cultures, or in patients at high risk for MRSA infection including those with previous MRSA infection, those who have been hospitalized or living in nursing homes, or those who have received many courses of different antibiotics over the previous 24 months. For less severe infections caused by MRSA, oral antibiotics such as trimethoprim-sulfamethoxazole, doxycycline, or minocycline may be

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Table 36-4 Suggested Route, Setting, and Durations of Antibiotic Therapy, by Clinical Syndrome Site, by Severity or Extent, of Infection

Route of Administration

Setting for Therapy

Mild

Topical or oral

Outpatient

Moderate

Oral (or initial Outpatient/ parenteral) inpatient Initial parenteral, Inpatient, switch to oral then when possible outpatient

Duration of Therapy

Soft-Tissue Only

Severe

1-2 wk; may extend up to 4 wk if slow to resolve 2-4 wk 2-4 wk

Bone or Joint

No residual Parenteral or oral Inpatient, infected tissue then (e.g., postamputation) outpatient Residual infected soft Parenteral or oral Inpatient, tissue (but not bone) then outpatient Residual infected Initial parenteral, Inpatient, (but viable) bone then consider then oral switch outpatient No surgery, or Initial parenteral, Inpatient, residual dead bone then consider then postoperatively oral switch outpatient

2-5 d

2-4 wk

4-6 wk

>3 mo

Abbreviations: d = day; wk = week.

useful. Of these anti-MRSA antibiotics, only linezolid has been specifically studied in the diabetic foot infection and carries an FDA indication for diabetic foot (33). Milder soft tissue infections of the diabetic foot may require no more than 10 to 14 days of antimicrobial therapy (Table 36-4). More severe infections require longer therapy, especially if bone involvement is present. Limited ablative surgery to remove localized bone infection may decrease the duration of therapy and incidence of relapse. If bone infection is not ablated completely, prolonged therapy (involving a minimum of 4 weeks of intravenous or 10 weeks of combined intravenous and oral therapy) may be required (34,35). Management in the event of poor response to treatment is outlined in Figure 36-1c.

Prevention The prevention of infection is the cornerstone of diabetic foot care (33). The basic principles of such prevention include good control of the diabetic

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Foot infection established Appropriate specimen for culture collected Pathogens not known initially Initiate empirical antimicrobial therapy on the basis of available clinical and laboratory data Reassess after 24–72 hours Causative organisms isolated?

No


No

Reconsider need for surgical procedure Perform cultures again (with optimal specimen collection)

Continue empirical regimen Re-evaluate after 1–2 weeks

No

Broaden antimicrobial spectrum to include gram-negative rods and anaerobes Consider adding coverage for MRSA and resistant gram-negative rods

No

Yes Infection improving?

Yes

Yes Select the safest, narrowest-spectrum, most-convenient regimen.

Continued improvement?

Yes

Yes

No

Causative organism isolated?

Re-evaluate wound care Re-evaluate spectrum of antimicrobial coverage Re-evaluate need for surgery (revascularization, amputation, etc.)

No

Consider changing to safer, narrowerspectrum, cheaper, or more-convenient regimen, based on results of susceptibility testing, if available Complete course of therapy

improving?

Yes

Figure 36-3 Algorithm for the treatment of foot infections in patients with diabetes mellitus. (Republished with permission from LIPSKY et al.)

state, weight reduction, smoking avoidance, and a diet low in fat and cholesterol. Appropriate footwear is of paramount importance, and special shoes and/or orthotic devices may have to be made for diabetic patients, especially if they have foot deformities. Patients should take the primary responsibility for their own foot care, inspecting their feet at least once daily. Hand mirrors may be used for this, and the help of family members or friends should be solicited if the patient’s vision is too poor for adequate self-examination. The feet should be washed daily with nonmedicated soap and tepid water, temperature first tested with the fingers (but only if significant sensory neuropathy does not

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exist in the upper extremities as well). The feet, including the interdigital areas, should be dried thoroughly after washing, and then a light coat of lubricating lotion or talcum powder may be applied. Woolen socks should be used when the feet feel cold; hot water bottles or heating pads should never be used to warm the feet. To prevent ingrown toenails, the toenails should be cut straight across with nail clippers, without rounding at the corners. Ingrown toenails should be discussed with the patient’s primary care physician and/or podiatrist. Diabetic patients should avoid walking barefoot, indoors and outdoors. They also should refrain from removing corns or calluses without professional help and from using caustic chemicals on the feet. Open-toed footwear should be avoided. Primary care physicians should be familiar with their responsibilities to the diabetic patient. Physical examination for vascular and neurological status should be done at least twice yearly or more often if problems exist. Specialized examinations, such as Doppler studies, should be done when indicated. Studies of shoe fitting and foot-loading patterns may occur when necessary. Referral for a podiatric examination should be considered in all diabetic patients, especially those at higher risk for ulceration because of neuropathy, foot deformity or a history of previous ulceration.

Summary Total care of the diabetic patient requires the coordination of specialists in various fields of health care, including the primary care physician, podiatrist, orthopedist, shoe specialist, orthoses specialist, vascular surgeon, physical therapist, diabetologist and/or endocrinologist, dietician, neurologist, and infectious disease specialist. Despite the knowledge gained and progress made in diabetic foot care over the past several decades, considerable illness is still associated with diabetic foot infections. More effort should be given to preventing such infections, and education about the preventive aspects of diabetic foot care should be directed not only to the patient but also to the patient’s primary care physician. REFERENCES 1. American College of Foot and Ankle Surgeons. Diabetic foot disorders: a clinical practice guideline. American College of Foot and Ankle Surgeons. J Foot Ankle Surg. 2000;39:S1-60. 2. Lipsky BA, Pecoraro RE,Wheat L J. The diabetic foot. Soft tissue and bone infection. Infect Dis Clin North Am. 1990;4:409-32. 3. Bridges RM Jr., Deitch EA. Diabetic foot infections. Pathophysiology and treatment. Surg Clin North Am. 1994;74:537-55. 4. Minow M. The role of families in medical decisions. Utah Law Rev. 1991;1991:1-24. 5. Bagdade JD, Root RK, Bulger R J. Impaired leukocyte function in patients with poorly controlled diabetes. Diabetes. 1974;23:9-15. 6. Repine JE, Clawson CC, Goetz FC. Bactericidal function of neutrophils from patients with acute bacterial infections and from diabetics. J Infect Dis. 1980;142:869-75.

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7. Tan JS,Anderson JL,Watanakunakorn C, Phair JP. Neutrophil dysfunction in diabetes mellitus. J Lab Clin Med. 1975;85:26-33. 8. Bessman AN, Sapico FL,Tabatabai M, Montgomerie JZ. Persistence of polymicrobial abscesses in the poorly controlled diabetic host. Diabetes. 1986;35:448-53. 9. Mahmoud AA, Rodman HM, Mandel MA, Warren KS. Induced and spontaneous diabetes mellitus and suppression of cell-mediated immunologic responses. Granuloma formation, delayed dermal reactivity and allograft rejection. J Clin Invest. 1976;57:362-7. 10. Sapico FL, Bessman AN. Diabetic foot infections. In Frykberg RG, ed. The High Risk Foot in Diabetes Mellitus. New York, NY: Churchill Livingstone; 1991:197-211. 11. Todd WF,Armstrong DG, Liswood P J. Evaluation and treatment of the infected foot in a community teaching hospital. J Am Podiatr Med Assoc. 1996;86:421-6. 12. Edmonds ME, Blundell MP, Morris HE, et al. The diabetic foot: Impact of a foot clinic. Q J Med. 1986;232:763-71. 13. International Working Group on the Diabetic Foot. International consensus on the diabetic foot (CD-ROM). Brussels, Germany: International Diabetes Foundation, May 2003. 14. Infectious Diseases Society of America. Diagnosis and treatment of diabetic foot infections. Clin Infect Dis. 2004;39:885-910. 15. Chantelau E,Tanudjaja T, Altenhöfer F, Ersanli Z, Lacigova S, Metzger C. Antibiotic treatment for uncomplicated neuropathic forefoot ulcers in diabetes: a controlled trial. Diabet Med. 1996;13:156-9. 16. Louie T J, Bartlett JG,Tally FP, Gorbach SL. Aerobic and anaerobic bacteria in diabetic foot ulcers. Ann Intern Med. 1976;85:461-3. 17. Sapico FL, Witte JL, Canawati HN, et al. The infected foot of the diabetic patient: Quantitative microbiology and analysis of clinical features. Rev Infect Dis. 1984;6(suppl 1):171-6. 18. Scher KS, Steele F J. The septic foot in patients with diabetes. Surgery. 1988;104:661-6. 19. Hughes CE, Johnson CC, Bamberger DM, Reinhardt JF, Peterson LR, Mulligan ME, et al. Treatment and long-term follow-up of foot infections in patients with diabetes or ischemia: a randomized, prospective, double-blind comparison of cefoxitin and ceftizoxime. Clin Ther. 1987;10 Suppl A:36-49. 20. Glober GA,Wilkerson JA. Biliary cirrhosis following the administration of methyltestosterone. JAMA. 1968;204:170-3. 21. Goldstein E J, Citron DM, Nesbit CA. Diabetic foot infections. Bacteriology and activity of 10 oral antimicrobial agents against bacteria isolated from consecutive cases. Diabetes Care. 1996;19:638-41. 22. Dang CN, Prasad YD, Boulton A J, Jude EB. Methicillin-resistant Staphylococcus aureus in the diabetic foot clinic: a worsening problem. Diabet Med. 2003;20:159-61. 23. Wang A,Weinstein D, Greenfield L, Chiu L, Chambers R, Stewart C, et al. MRI and diabetic foot infections. Magn Reson Imaging. 1990;8:805-9. 24. Yul W, Carson J, Baraimewski H. Osteomyelitis of the foot in diabetic patients: Evaluation with plain film 99Te-MDP bone scintigraphy and MR imaging. Am J Roentgenol. 1989;152:795-800. 25. Beltran J, Campanini DS, Knight C, McCalla M. The diabetic foot: magnetic resonance imaging evaluation. Skeletal Radiol. 1990;19:37-41. 26. Tan JS, Friedman NM, Hazelton-Miller C, Flanagan JP,File TM Jr. Can aggressive treatment of diabetic foot infections reduce the need for above-ankle amputation? Clin Infect Dis. 1996;23:286-91. 27. Eckman MH, Greenfield S, Mackey WC,Wong JB, Kaplan S, Sullivan L, et al. Foot infections in diabetic patients. Decision and cost-effectiveness analyses. JAMA. 1995;273:712-20. 28. Lipsky BA, Armstrong DG, Citron DM, Tice AD, Morgenstern DE, Abramson MA. Ertapenem versus piperacillin/tazobactam for diabetic foot infections (SIDESTEP): prospective, randomised, controlled, double-blinded, multicentre trial. Lancet. 2005;366:1695-703. 29. Grayson ML, Gibbons GW, Habershaw GM, Freeman DV, Pomposelli FB, Rosenblum BI, et al. Use of ampicillin/sulbactam versus imipenem/cilastatin in the treatment of limb-threatening foot infections in diabetic patients. Clin Infect Dis. 1994;18:683-93. 30. Tan JS, Wishnow RM,Talan DA, Duncanson FP, Norden CW. Treatment of hospitalized patients with complicated skin and skin structure infections: double-blind, randomized, multicenter study of piperacillin-tazobactam versus ticarcillin-clavulanate. The Piperacillin/Tazobactam Skin and Skin Structure Study Group. Antimicrob Agents Chemother. 1993;37:1580-6. 31. Giordano P, Song J, Pertel P, Herrington J, Kowalsky S. Sequential intravenous/oral moxifloxacin versus intravenous piperacillin-tazobactam followed by oral amoxicillin-clavulanate for the treatment of complicated skin and skin structure infection. Int J Antimicrob Agents. 2005;26:357-65.

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32. Edmiston CE, Krepel C J, Seabrook GR, Somberg LR, Nakeeb A, Cambria RA, et al. In vitro activities of moxifloxacin against 900 aerobic and anaerobic surgical isolates from patients with intraabdominal and diabetic foot infections. Antimicrob Agents Chemother. 2004;48:1012-6. 33. Lipsky BA, Itani K, Norden C. Treating foot infections in diabetic patients: A randomized, multicenter, open-label trial of linezolid versus ampicillin-sulbactam/amoxicillin-clavulanate. Clinical Infect Dis. 2004;38:17-24. 34. Bamberger DM, Daus GP, Gerding DN. Osteomyelitis in the feet of diabetic patients. Long-term results, prognostic factors, and the role of antimicrobial and surgical therapy. Am J Med. 1987;83:653-60. 35. Sapico FL. Foot infections in patients with diabetes mellitus. J Am Podiatr Med Assoc. 1989;79:482-5.

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Chapter 37

Bite-Wound Infections JOSEPH P. MYERS, MD

Key Learning Points 1. Initial and appropriate wound irrigation and débridement are the most important initial steps in the treatment of bite wounds. The most common error made in the treatment of bite wounds is failure to adequately perform such irrigation and débridement. 2. Prophylactic antibiotic therapy is really presumptive treatment of microbially contaminated tissue. Such antibiotic therapy should be used in high-risk clinical circumstances such as in moderate to severe injury less than eight (8) hours old especially with crush injury, in clinical situations where there is high suspicion for bone or joint penetration/inoculation, in any hand bite wound, in any foot bite wound, in any bite wound in a compromised patient, in any bite wound adjacent to a prosthetic joint and in any bite wound to the genital area. Every patient should be assessed for risk of tetanus and for the possibility of rabies virus, human immunodeficiency virus, hepatitis B virus and hepatitis C virus exposure depending upon the clinical situations encountered during the patient evaluation.

A

nimal and human bite wounds are common injuries to adults and children and account for an estimated 1% of U.S. emergency room visits. It has been estimated that more than 1 million domestic animal bites are inflicted per year in the United States. The true estimate can be significantly higher given the nonreporting of many of the more trivial of these injuries (1-5). Many of these bites are innocuous, but some can be serious in nature. Ten to twenty fatal animal bites are reported per year in 680

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New Developments in the Management of Bite-Wound Infections ●

●

●

Some of the newer antimicrobial agents should allow cost effective and/or microbially effective treatment of patients with complicated bite-wound infections and coexistent antibiotic allergies. Agents in this category include daptomycin, ertapenem, tigecycline, and linezolid. Rabies immunization in wild animal populations can be induced by bait drops in which wild animals are immunized by exposure to oral rabies animal vaccine encased in bait packets dropped by air into high-risk areas for wild animal rabies transmission/spread. Ongoing education about the need for aggressive irrigation and débridement of bite wounds of all types is not truly new, but it is of the greatest necessity because the lack of this aggressive approach is the single most important reason for initial failure of treatment of bite-wound infections.

the United States (6). Significant bite-wound illness can result from direct traumatic injury or infectious complications such as osteomyelitis, septic arthritis, tenosynovitis, cellulitis, and septicemia (7). The true incidence of human-bite wounds is uncertain because many of these injuries, especially those of the clenched-fist variety, are concealed by the victim because of embarrassment or fear of legal ramifications (1,3,8). Wild-animal bites follow dog, cat, and human bites in frequency of occurrence and can have infectious and noninfectious complications (1). This chapter reviews the infectious complications of dog, cat, and human-bite wounds with occasional references to other types of bite wounds. Several excellent publications review the zoonotic diseases transmitted by domestic and wild animals. Please refer to these articles for detailed information (6,9-12).

Epidemiology Dog-Bite Wounds Although fatalities from dog bites are rare (4,5), dog-bite wounds are common (1,13,14) and account for up to 1% of all emergency room visits in the United States (1,4,13,14). Most dog-bite injuries are inflicted by family or neighborhood dogs and not by stray dogs (7,8). Dog-bite victims are commonly men with a 2:1 predominance and usually younger than 16 years of age (4,6,7). It has been estimated that up to 20% of all children in the United States will be bitten by a dog at some time in their lives (7). Children are more likely than adults to be bitten by dogs because children are less intimidating to animals, more likely to be engaged in inadvertently provocative behavior and less likely to recognize and thereby avoid threatening behavior in animals (7). It is estimated that dog-bite wounds account for 70% to

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93% of the mammalian bites seen in emergency rooms throughout the United States (4,11).

Cat-Bite Wounds Almost half a million people are bitten by a cat each year in the United States (1,6). Cat bites are twice as common in women as in men and occur primarily on the upper extremities (7). In one prospective study of cat bites presenting in the emergency room, 45% of all cat bites occurred to the hand; 22% were sustained on the arm above the hand; 13% occurred on the lower extremity; and the remainder of the bites (20%) occurred on the head, neck, or trunk (15). It has been estimated that cat bites account for 3% to 15% of all patients with bite wounds admitted to emergency rooms in the United States (4). The incidence of cat bites is highest in people aged 21 to 35 years, with women accounting for most of cat-bite victims (4). In the prospective study of cat bites previously referenced (15), the cat inflicting the bite wound was a pet or an acquaintance of the owner in 55% of the bite wounds and was a stray or wild cat in 42% of cases. Only 3% of cat-bite wounds were inflicted by cats of unknown origin (15).

Human-Bite Wounds Human-bite wounds generally are classified into three types: self-inflicted paronychia, occlusional bite wounds, and clenched-fist injuries. Self-inflicted paronychia can be the result of nail biting, thumb sucking, or similar activities. Occlusional bite wounds usually are intentionally inflicted injuries that occur during a physical confrontation. Clenched-fist injuries are unintentionally induced injuries occurring to the hand of an offensive-minded pugilist (1,3,8,16). Human-bite wounds are the third most common type of bite wound encountered in emergency rooms (1). Human-bite wounds also can be sustained during passionate sexual activity (3). Common locations for human-bite wounds in children are the scalp and face, whereas the distal portion of the index or middle finger is the most common site for occlusional bite wounds (1,3). The ear, nose, forearm, breast, penis, scrotum, and vulva can be affected in adult bite wounds resulting from passionate or pugilistic activity (3). The clenched-fist injury usually produces a wound over the third, fourth, or fifth metacarpal head of the dominant hand (1). Any injury at this site should be presumed to be caused by an inadvertent human-bite wound until proven otherwise (1,17). Patients with clenched-fist injuries often provide the physician with false information about the exact circumstances of the injury because of embarrassment or fear of legal ramifications (1,3). Approximately 60% to 70% of all human-bite wounds are sustained to the hand and upper extremities, 15% to 20% to the head or neck, 10% to 20% to the trunk, and 5% to the lower extremities, with other sites accounting for the remaining 5% to 10% of human-bite wounds (18).

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Pathophysiology Animal-bite wounds can cause severe tissue injury and severe infection. Large animal bites can generate up to 450 lb per square inch of pressure, more than sufficient force to perforate even light sheet metal. This pressure can produce a severe crush injury to human tissue (7,19). Edema and necrosis of crushed tissue in the area surrounding a bite wound predisposes the tissue to infection. Normal human cutaneous microflora and normal animal oral microflora can thrive in this necrotic, edematous tissue, causing further predisposition to infection (7).

Etiology and Microbiology In the evaluation and management of patients with mammalian bites, the species of the biting animal can help the physician assess the most likely type of injury and the potentially associated microbiologic pathogens (1,13,14,20). Cat-bite wounds are more likely than other bite wounds to become infected, which is probably related to the aforementioned puncture-type wounds normally inflicted by the sharp, piercing feline teeth. A significant percentage of human-bite wounds subsequently develop active infectious complications (3,7). Dog-bite wounds are the least likely to become infected because the usual avulsion-type injury produced in canine bites allows for open drainage at the wound site (7). Wound factors that predispose to infection include bite wounds older than 12 hours, bite wounds on the hand or foot, bite wounds caused by clenched-fist injury, and bite wounds that are pure puncture wounds (7). Victim factors that predispose to infection include a victim older than 50 years of age, chronic alcohol abuse, diabetes mellitus, malignancy, or other immunocompromised state caused by radiotherapy, chemotherapy, immunosuppressive medication, or asplenism (7). These factors should be explored carefully in the historic evaluation of patients with documented or potential bite-wound injuries. The presence of any of these factors suggests the need for initiation of prophylactic antimicrobial therapy in patients with bite-wound injuries evaluated within 8 hours of infliction and in which there is no definitive sign of clinical infection. Meticulous wound care is more effective than antimicrobial prophylaxis in preventing bite-wound infection (7). Débridement of devitalized tissue at the initial time of bite-wound management has been shown to reduce infection rates from 62% to 2% in one study (7). Other studies have shown a significant increase in the infection rate when débridement is omitted from the management regimen (21). Irrigation of the wound decreases the infection rate by 6 to 10 times (7). Puncture wounds are infection-prone, at least partially because they are extremely difficult to débride and irrigate (7).

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Most infections complicating mammalian and human-bite wounds are polymicrobial with mixed aerobic and anaerobic microflora usually isolated in culture (3,4). Sources of infecting organisms include the oral and gingival microflora of the biting animal species, the skin of the bitten person, and the environmental microflora (e.g., water, soil) pertinent to the clinical situation in which the bite wound occurred (13,14). Common aerobic isolates from bite-wound infections include alpha-hemolytic streptococci, Staphylococcus aureus, Streptococcus pyogenes, Staphylococcus intermedius, coagulase-negative staphylococci, Capnocytophaga canimorsus, Pasteurella multocida, Centers for Disease Control and Prevention (CDC) alphanumerically designated bacteria such as EF-4 and M-5, and many anaerobic microflora (1). A prospective study showed Pasteurella species, streptococci, staphylococci, Neisseria species, Corynebacterium species, and Moraxella species as the most common aerobic isolates from dog and cat-bite wounds (22).

Dog-Bite Wounds The oral microflora of dogs includes up to 64 species of bacteria that can be potential human pathogens. Staphylococci, streptococci, P. multocida, other Pasteurella species, Pseudomonas species, other gram-negative aerobes, and many anaerobic species are most commonly isolated from infected bite wounds (7,16,22). Staphylococcus intermedius is a coagulasepositive Staphylococcus species that is a normal component of the canine oral microflora. It can be mistaken for S. aureus and has been reported as a cause of dog-bite wound infection (16,23). S. intermedius displays sensitivity and resistance patterns similar to methicillin-sensitive S. aureus. Therefore, confusion in the identification of this organism should not affect therapy. Pasteurella multocida is isolated less frequently from infected dog bites than from infected cat-bite wounds (1,7,22). Capnocytophaga canimorsus, formerly CDC alphanumeric designation DF-2 can be a normal component of the canine oral microflora. It can cause a devastating infectious illness in patients who are immunocompromised and asplenic (4,13,14).

Cat-Bite Wounds Most cat-bite wound infections are caused by P. multocida, a facultative anaerobic gram-negative organism that is a normal component of the oral flora of most feline species (7,15). Polymicrobial infections are common; staphylococci, streptococci, and aerobic enteric gram-negative bacilli are isolated often from cat-bite wound infections (7,13,14). Bartonella henselae, the cat scratch bacillus, is an unusual cause for infection complicating cat bites or scratches but must be considered in certain clinical situations (1).

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Human-Bite Wounds Under healthy circumstances, the human mouth can harbor more than 40 species of bacteria. Almost 200 species of potentially pathogenic bacterial species have been described in the presence of gingivitis and periodontal disease (7). More than 50% of human-bite wound infections contain mixed gramnegative and gram-positive bacteria (7,13,14). Anaerobes are found in more than 60% of human-bite wounds, and it has been estimated that if sophisticated anaerobic culture techniques are used, up to 100% of human-bite wounds can include anaerobic species. The most common bacterial isolates from human-bite wounds are alpha-hemolytic streptococci (40% to 50%), staphylococci (25% to 50%), and Eikenella corrodens (10% to 35%) (7,9,16).

Wild-Animal Bite Wounds The medical literature is replete with isolated cases of bite-wound infections caused by exotic and/or wild animals. Infections caused by specific microorganisms have been associated with the bites of certain animals (4). Consult the appropriate reference resources for specific animal-microorganism associations (1,4,7,13,14,24).

Other Infections Risk factors for tetanus and the patient’s previous immunization status against Clostridium tetani must be evaluated in the treatment of every bitewound injury. Standard CDC guidelines and protocols should be used to evaluate the adequacy of previous tetanus immunization (Table 37-1) (25). All cat, dog, and wild-animal bite wounds should be evaluated for the potential transmission of rabies virus infection. The likelihood of the biting

Table 37-1 Tetanus Prophylaxis in Wound Management History of absorbed tetanus toxoid (doses)

Unknown or < three ≥ Three (§)

Clean, minor wounds 1

‡

2

All other wounds (*)

Td ( )

TIG

Td (‡)

TIG

Yes No (¶)

No No

Yes No (**)

Yes No

* Such as, but not limited to, wounds contaminated with dirt, feces, soil, and saliva; puncture wounds; avulsions; and wounds resulting from missiles, crushing, burns and frostbite. ‡ For children < 7 years old; DTP3 (DT4, if pertussis vaccine is contraindicated) is preferred to tetanus toxoid alone. For persons > 7 years of age, Td is preferred to tetanus toxoid alone. § If only three doses of fluid toxoid have been received, then a fourth dose of toxoid, preferably an absorbed toxoid, should be given. ¶ Yes, if > 10 years since last dose. ** Yes, if > 5 years since last dose. More frequent boosters are not needed and can accentuate side effects. 1 Td: Tetanus and Diptheria Toxoids Adsorbed for Adult use 2 TIG: Tetanus Immune Globulin 3 DTP: Diptheria and Tetanus Toxoids and Pertussis Vaccine Adsorbed for Pediatric use 4 DT: Diptheria and Tetanus Toxoids Adsorbed for Pediatric use

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animal carrying the rabies virus should be evaluated on an individual basis depending on the genus and species of the biting animal and on local epidemiologic information about the potential transmission of the rabies virus. Standard CDC guidelines and protocols should be consulted to evaluate the need for rabies immunization based on the type of animal exposure (26). Table 37-2 contains detailed information about the rabies virus postexposure prophylaxis protocol (26). Because monkeys are kept as pets, used in medical research, cared for in zoos, and encountered in the wild, their bites can be encountered more frequently in the medical care setting than would be anticipated. A review of simian-bite wound infection by Goldstein and colleagues (24) suggests a microbiologic picture similar to human-bite wound infection, and antimi-

Table 37-2 Rabies Postexposure Prophylaxis Schedule Vaccination Status

Treatment

Regimen*

Not previously vaccinated

Local wound cleansing

All postexposure treatment should begin with immediate cleansing of all wounds with soap and water. If available, a virucidal agent such as a povidone-iodine solution should be used to irrigate the wounds. 20 IU/kg body weight. If anatomically feasible, the full dose should be infiltrated around the wounds and any remaining volume should be administered IM at an anatomical site distant from vaccine administration. Also, RIG should not be administered in the same syringe as vaccine. Because RIG can partially suppress active production of antibody, no more than the recommended dose should be given. HDCV, RVA, or PCEC 1.0 mL, IM into deltoid area†, one each on days 0, 3, 7, 14, and 28. All postexposure treatment should begin with immediate thorough cleaning of all wounds with soap and water. If available, a virucidal agent such as a povidone-iodine solution should be used to irrigate the wounds. RIG should not be administered. HDCV, RVA, or PCEC 1.0 mL, IM into deltoid area†, one each on days 0 and 3.

RIG

Vaccine Previously vaccinated‡

Local wound cleansing

RIG Vaccine

* These regimens are applicable for all age groups, including children. † The deltoid area is the only acceptable site of vaccination for adults and older children. For younger children, the outer aspect of the thigh can be used. Vaccine should never be administered in the gluteal area ‡ Any person with a history of preexposure vaccination with HDCV, RVA, or PCEC; prior postexposure prophylaxis with HDCV, RVA, or PCEC; or previous vaccination with any other type of rabies vaccine and a documented history of a response to the prior vaccination. Abbreviations: HDCV, human diploid cell vaccine; IM, intramuscularly; PCEC, purified chick embryo cell vaccine; RVA, rabies vaccine adsorbed; RIG, rabies immune globulin.

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crobial therapy should include agents effective against Eikenella corrodens. This study documents that infection after a simian bite is common, and complications such as osteomyelitis and flexion contractures of the hand are frequent. Of added significance is the transmission of herpesvirus simiae (B-virus) by Old World (Macaca) monkeys. Therefore, information about the type of monkey implicated in a simian-bite wound is critical in evaluating the need for prophylactic acyclovir treatment of such bite wounds (27). Many other infectious diseases can be transmitted by animal bites. Brucellosis (Brucella species), blastomycosis (Blastomyces dermatitidis), tularemia (Francisella tularensis), cat scratch disease (Bartonella henselae), rat bite fever (Streptobacillus moniliformis and Spirillum minor), bubonic plague (Yersinia pestis), leptospirosis (Leptospira species), Erysipelothrix (Erysipelothrix rhusiopathiae), and seal finger (possible Mycoplasma species) are some of the other infections that can be transmitted by various domestic and wild animals (1,6-8,27,28). Human-bite wounds should be evaluated on an individual basis for the potential transmission of infectious agents other than the usual bacterial pathogens that cause bite-wound infection. Hepatitis B virus, hepatitis C virus, human immunodeficiency virus, Treponema pallidum, and Mycobacterium tuberculosis, can be transmitted by bite wounds (1,29-31). The treating physician should ask the patient about the health and disease status of the assailant biter if such information is available.

Classification Bite wounds are classified as tears (avulsions), punctures, or scratches (1,13,14,20). Tear wounds can have an associated component of crush injury (1). Tear injuries or avulsions are more commonly seen with dog-bite wounds (9). Puncture wounds most commonly occur when the bite wound is inflicted by a cat (9). Such puncture wounds are the result of the sharp, piercing feline teeth that usually puncture the skin and inoculate oral microflora into the subcutaneous tissue including tendons, joint spaces, and bones. Human-bite wounds are classified as self-inflicted, occlusional, or clenched-fist (1,3,8,16). Self-inflicted bites tend to be relatively superficial although complicated paronychial infections can occur. Violent, occlusional bite wounds frequently cause full-thickness injury resulting in deep soft tissue infection, osteomyelitis or even traumatic amputation of the digit (1). Clenched-fist injuries usually occur during pugilistic activity and can present a challenging diagnostic and therapeutic scenario to the physician. The true diagnosis is often obscured by a cover-up story, and the injury often causes serious infectious complications because of the retraction of polymicrobial mouth flora deep into the soft tissues of the hand with extension of the fingers after the clenched-fist injury (3,32).

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Clinical Manifestations Two distinct groups of patients eventually seek medical care for animal and human-bite wounds. Members of the first group are seen within 8 hours of the original injury. These patients usually seek immediate wound care and fear rabies or tetanus related to the bite wound. The second group of patients seeks treatment more than 8 hours after the injury (or often much later) and almost always after infection has been established. In this second group, a gray malodorous discharge can exude from the bite wound with concomitant localized pain, tenderness, and erythema. Patients from the first group can seek treatment without evidence of clinical infection and must be fully evaluated for risk factors for infection. Patients in the second group usually have active infection, and a treatment strategy must be established immediately (1,13,14,20).

Complications Infectious complications of bite wounds include cellulitis, wound infection, septic arthritis, osteomyelitis, tenosynovitis, lymphangitis, bacteremia, meningitis, brain abscess, sepsis, and disseminated intravascular coagulation (3,6,16). Noninfectious complications include: peripheral neuropathy, direct or indirect; osseous crush injury and skeletal fracture; soft tissue crush injury; and cosmetic damage to skin and soft tissue (3,8). Potential delayed infectious complications include tetanus, rabies virus infection, Herpes simiae (Bvirus) infection, HIV infection, hepatitis B virus infection, hepatitis C virus infection, cat scratch disease, and others (1,7,25-27,29-31).

Diagnosis History Detailed information about the biting animal or person should be obtained. Animal-related information should include the type of animal; the immunization status, health, and behavior of the animal; whether or not the bite was provoked; the situation and/or environment in which the bite occurred; the exact time of the biting incident; and whether the source animal was captured and isolated for rabies observation (1,4). If the injury is a human bite, the physician should determine who bit the patient, whether the biting human has hepatitis B, hepatitis C, syphilis, herpes simplex infection, or HIV infection and the date, time, and exact circumstances of the human-bite injury. Important patient-related information should include antibiotic allergies, current medications, especially immunosuppressive therapy, a history of previous splenectomy, mastectomy, or

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chronic liver disease, and any self-administered treatment that occurred before the patient sought medical care.

Physical Examination The number, type, anatomic site, and depth of all wounds should be recorded in exquisite detail. Detailed diagrams should be made part of the medical record, and photographic documentation should be procured, if available. Other factors that should be recorded include range of motion of joints adjacent to the injury, examination for the possibility of joint penetration, the presence of edema or crush injury, nerve and tendon function, clinical extent of infection (e.g., erythema), purulent drainage, and the presence of necrotic tissue. The odor of any exudate should be recorded. Pertinent findings during physical examination should be noted and recorded. These should include: number, depth, and type of wounds; tissue edema and erythema; purulent drainage; presence of crush injury; nerve damage; tendon damage; presence of necrotic tissue; malodorous exudates; range of motion of involved joints; an evaluation of joint penetration; detailed wound diagrams; and photographs or videotapes of the involved areas of injury (1,4,7,15,25).

Cultures If possible, aerobic and anaerobic cultures should be obtained from all bite wounds. Some deep puncture wounds do not have drainage that is accessible to culture. Viral, mycobacterial, and fungal cultures should be obtained when clinical, environmental, or epidemiologic data dictate.

Radiographs If fracture or bone or joint penetration is a consideration, radiographic examination of the involved area should be obtained. These radiographs can be compared to subsequent radiographic studies in the event that osteomyelitis of the affected area is eventually suspected. More detailed radiographic testing with computerized axial tomographic scanning or magnetic resonance imaging can be indicated in complicated infections (7,13,14).

Treatment Irrigation All bite wounds should be irrigated with copious amounts (≥ 200 mL) of normal saline. If possible, puncture wounds should be irrigated with a highpressure jet using a 20-mL syringe and an 18-gauge needle or catheter tip to

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access the wound. However, some puncture wounds are tiny and relatively inaccessible to irrigation (7,13,14). Appropriate wound irrigation can produce a 6- to 10-fold reduction in bite-wound infection rates compared to bite wounds not receiving irrigation (7).

Débridement The most common error made in the treatment of bite wounds is failure to adequately débride and irrigate the wounds (7). Devitalized or necrotic tissue should be cautiously débrided and foreign bodies and all other debris should be removed fastidiously from the wound. Appropriate and adequate anesthesia should be provided to make the procedure tolerable for the patient (1,4,7,13,14). Appropriate débridement decreased bite-wound infection rates from 62% to 2% in one study (33) and by 2.5 times in another study (21).

Wound Closure Primary wound closure can be indicated for some uninfected wounds, especially facial wounds. However, closure of other types of bite wounds is not usually indicated. Wound edges should be approximated with adhesive strips in certain cases, and healing by secondary intention or by delayed closure can be indicated when infectious complications have been addressed (13,14).

Antimicrobial Therapy If a bite wound shows signs of active infection such as cellulitis, purulent drainage, or evidence of deep tissue infection, appropriate antimicrobial therapy should be administered immediately. Antibiotics should be directed against the usual intra-oral pathogens of the biting animal, the usual human cutaneous pathogens of humans, and the pertinent environmental pathogens. Antibiotic therapy should be directed against S. aureus, S. pyogenes, and the mouth microflora of dogs, cats, or humans (including alphahemolytic streptococci and many anaerobic species). Ampicillin/sulbactam can be administered intravenously for patients who are hospitalized. Other beta-lactam/beta-lactamase inhibitor compounds such as ticarcillin/clavulanic acid and piperacillin/tazobactam, or carbapenems such as imipenem, meropenem, or ertapenem (34), provide excellent broad-spectrum antimicrobial coverage of the microorganisms commonly isolated from patients with severe bite-wound infections. Amoxicillin/clavulanic acid is an excellent selection for oral therapy (14,18,35). Patients who are allergic to penicillin or other beta-lactam antibiotics can be treated with a combination of clindamycin plus a fluoroquinolone such as ciprofloxacin or levofloxacin, or with clindamycin plus trimethoprim/sulfamethoxazole. Cefoxitin can be

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administered intravenously for the treatment of bite-wound infections in patients with non–life-threatening reactions to penicillin. Moxifloxacin (36) has excellent activity against most nonfusobacterial bite-wound pathogens and seems to be an excellent single-agent treatment of most bite-wound infections. When culture results are available, antimicrobial therapy should be tailored to the most cost-effective regimen for the isolated microorganisms. Table 37-3 contains detailed information about the antimicrobial susceptibility patterns of microorganisms commonly implicated as pathogens in patients with bite-wound infection (1,6,13,14,34,36-37). The duration of antibiotic therapy depends on the severity of the infectious process. Osteomyelitis and septic arthritis generally require longer courses of antibiotic therapy than cellulitis and soft tissue infection require and can require concomitant surgical intervention. A difficult decision for the treating physician is whether to use prophylactic antibiotics for a bite wound that is not yet clinically infected. Few prospective studies evaluate this issue. Prophylactic antibiotic therapy is presumptive treatment of microbially contaminated tissue at the site of the bite wound. Prophylactic antibiotic therapy should be administered when clinical circumstances predict a high likelihood of subsequent infection after bite-wound injury. These high-risk clinical circumstances include moderate to severe injury less than 8 hours old especially if edema or crush injury are present, documentation of or high suspicion for bone or joint penetration and inoculation, any hand bite wound, any foot bite wound, any bite wound in an immunocompromised patient, any bite wound adjacent to a prosthetic joint, and any bite wound to the genital area. Amoxicillin/clavulanic acid, clindamycin plus a fluoroquinolone, clindamycin plus a tetracycline, or clindamycin plus trimethoprim/sulfamethoxazole would be reasonable oral treatment regimens in the clinical setting of a presumptively infected bite wound (1,4,7,13,14). Table 37-3 contains detailed information about antimicrobial susceptibility patterns of pathogenic microorganisms commonly encountered in infected bite wounds (13,14,34,36-37). Table 37-4 contains specific antibiotic recommendations for prophylaxis within 12 hours of the bite injury or for presumptive treatment of clinically established infection.

Immunizations A thorough history of the bite victim’s immunization status should be obtained when the patient seeks treatment. Standard tetanus immunization guidelines should be followed in all circumstances and appropriate vaccine or tetanus immune globulin should be administered as required (25). Bite wounds from domestic animals, wild animals, and humans are at risk for the development of tetanus. If information about the bite victim’s primary tetanus immunization series is inadequate, the primary immunization series should be initiated immediately, and tetanus immune globulin (TIG) should be administered concomitantly. See Table 37-1 for more information (25).

+ ± + ± − + ± − − − + + + + +

+ + + ND ND + + + ND + + + + + ±

+

± + − − − ± + ± − ± + ± ± −

+

Eikenella corrodens

+

Capnocytophaga canimorsus

+

Anaerobes

+ ± + − + + − − − + + − − +

+

+

Haemophilus species

+ + + − + ± − − − + + + + +

+

+

Pasteurella multocida

Abbreviations: ND, no data available; +, good antimicrobial activity; ±, variable antimicrobial activity; −, poor antimicrobial activity. * Does not refer to methicillin-resistant S. aureus (MRSA); for MRSA, (See Chapter 34).

Amoxicillin/ Clavulanic acid Ampicillin/ Sulbactam Azithromycin Cefoxitin Cefuroxime Cephalexin Ciprofloxacin Clarithromycin Clindamycin Dicloxacillin Erythromycin Levofloxacin Moxifloxacin Penicillin Tetracycline Trimethoprim/ Sulfamethoxazole

Antimicrobial Agents

+ + + + + + + + + + + − + +

+

+

Staphylococcus aureus*

ND ND ND + + ND + + + + + ± ND ND

+

+

Staphylococcus intermedius

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Table 37-3 Antimicrobial Agent Activity Versus Selected Bite-Wound Pathogens

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Table 37-4 Antimicrobial Therapy of Infected Bite Wounds Type of Bite


Dog and Cat

Intravenous

Oral

Antibiotic Regimen

Ampicillin/Sulbactam 1. Cefoxitin 2. Ticarcillin/clavulanate 3. Piperacillin/tazobactam 4. Imipenem/cilastatin 5. Meropenem 6. Ertapenem 7. Clindamycin PLUS 8. Levofloxacin 9. Clindamycin PLUS 9. Ciprofloxacin 10. Clindamycin PLUS 10. Trimethoprim/ Sulfamethoxazole 11. Moxifloxacin 11. 1. Amoxicillin/ 1. Clavulanate 2. Clindamycin PLUS 2. Ciprofloxacin 3. Clindamycin PLUS Levofloxacin

Human

Intravenous

Oral

Dosages of Antibiotics

1. 2. 3. 4. 5. 6. 7. 8.

3.

4. Clindamycin PLUS 4. Trimethoprim/ Sulfamethoxazole 5. Clindamycin PLUS 5. Doxycycline 6. Cefuroxime axetil PLUS 6. Metronidazole 7. Moxifloxacin 7. 1. Ampicillin/Sulbactam 1. 2. Cefoxitin 2. 3. Ticarcillin/clavulanate 3. 4. Piperacillin/tazobactam 4. 5. Imipenem/cilastatin 5. 6. Meropenem 6. 7. Ertapenem 7. 8. Clindamycin PLUS 8. Ciprofloxacin 9. Clindamycin PLUS 9. Levofloxacin 10. Clindamycin PLUS 10. Trimethoprim/ Sulfamethoxazole 11. Moxifloxacin 11. 1. Amoxicillin/ 1. Clavulanate

1.5 - 3.0 g IV q6h 2.0 g IV q6h 3.1 g IV q6h 3.375 g IV q6h 500 mg IV q6h 1.0 g IV q8h 1.0 g IV q24h 600-900 mg IV q8h 500-750 mg IV q24h 600-900 mg IV q8h 400 mg IV q12h 600-900 mg IV q8h 160/800-320/1600 mg IV q8h 400 mg IV q24h 500/125 mg PO TID to 875/125 mg PO BID 300 mg PO TID or QID 500-750 mg PO BID 300 mg PO TID or QID 500-750 mg PO QD 300 mg PO TID or QID 160/800 mg PO BID or TID 300 mg PO TID or QID 100 mg PO BID 500 mg PO BID 500 mg PO TID 400 mg PO QD 1.5-3.0 g IV q6h 2.0 g IV q6h 3.1 g IV q6h 3.375 g IV q6h 500 mg IV q6h 1.0 g IV q8h 1.0 g IV q24h 600-900 mg IV q8h 400 mg IV q12h 600-900 mg IV q8h 500-750 mg IV q24h 600-900 mg IV q8h 160/800 mg IV BID or TID 400 mg IV QD 500/125 mg PO TID to 875/125 mg PO BID Continued

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Table 37-4 Continued Type of Bite


Antibiotic Regimen

2. Clindamycin PLUS Ciprofloxacin 3. Clindamycin PLUS Levofloxacin 4. Clindamycin PLUS Trimethoprim/ Sulfamethoxazole 5. Moxifloxacin

Dosages of Antibiotics

2. 300 mg PO TID or QID 500-750 mg PO BID 3. 300 mg PO TID or QID 500-750 mg PO QD 4. 300 mg PO TID or QID 160/800 mg PO BID or TID 5. 400 mg PO QD

Abbreviations: BID, twice daily; h, hour; IV, intravenously; PO, orally; q, every; QD, daily; QID, 4 times daily; TID, 3 times daily.

Domestic and wild-animal bites should be investigated for the risk of rabies virus infection (25). Standard protocols and local knowledge about the presence of the rabies virus in the animal population, domestic and wild, should be used to evaluate the risk factors for rabies virus infection (25). Patients at significant risk for rabies virus exposure through the bite wound should receive human diploid cell rabies vaccine and rabies immune globulin per standard protocol (26). The recommendations of the Advisory Committee on Immunization Practices (26) and Table 37-2 contain detailed information about prevention of rabies virus infection.

Hospitalization Patients with bite wounds should be hospitalized if any of the following criteria are present: fever greater than 38.1ºC (100.5ºF); evidence of clinical sepsis; progressive cellulitis; septic arthritis; osteomyelitis; failure of previous outpatient management; immunocompromised status of the patient; infection that has spread across a joint; hand or foot infection; severe crush injury; tendon or nerve injury; tenosynovitis; and patient noncompliance with therapy (1,7,13,14).

Consultation Appropriate consultation to general surgery, orthopedic surgery, hand surgery, plastic surgery, infectious disease medicine, rehabilitative medicine, and other appropriate services in the care of patients with bite wounds should be initiated as dictated by the severity and nature of the bite-wound injuries (7,20).

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Elevation and Immobilization Elevation of the involved extremity alleviates edema and prevents the spread of infection in the immediate proximity to the bite-wound site (13,14,20). Failure of the patient to appropriately elevate the involved extremity is a common cause of treatment failure in patients with bite wounds. Bite wounds to the hand should be immobilized with a splint that allows the patient’s hand to remain in the functional position (13,14,17).

Reporting Local government regulations can require reporting bite wounds to the health department. In the absence of local reporting requirements, appropriate consultation with the local health department can be necessary to ascertain the likelihood of rabies virus transmission by domestic and wild animal species in the area (7,13,14).

Follow-Up The appropriate management of bite wounds on an outpatient basis requires follow-up 24 and possibly 48 hours after initial evaluation. During the follow-up visit, the patient should be fully evaluated for infectious and noninfectious complications of the original injury and for side effects of antibiotics or other medications prescribed during the initial visit (3,16).

Surgical Management Surgical intervention often is required during the management of patients with bite-wound infection. Irrigation and débridement of the bite wound should be part of the standard management protocol when the patient initially seeks medical care. Further surgical treatment can be required for therapeutic evacuation of purulent drainage, for therapeutic relief of tissue tension, for decompression to abort peripheral nerve injury and neuropathy, and for the diagnostic recovery of microorganisms from the site of a closed-space infection such as septic arthritis, osteomyelitis, or tenosynovitis. Other indications for surgery include repair of vascular, muscular, or neurologic tissue and cosmetic repair of disfiguring skin and soft tissue injuries (4,13,14,19).

Common Perils and Pitfalls of Bite-Wound Management The most common error in the management of bite wounds is the failure to adequately irrigate and débride the wound. Other common mistakes include failure to dress the wound with bulky dressings, failure to elevate the extremity for 24 to 48 hours, failure to recognize a clenched-fist injury as a human-bite wound, failure to recognize wounds to the genitalia as

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human-bite wounds, failure to obtain appropriate cultures during the initial evaluation of the patient, and failure to recognize wounds that are unresponsive to oral antimicrobial therapy (7). Other causes of therapeutic failure in the treatment of animal and human-bite wounds include incorrect selection of antimicrobial agents, insufficient duration of antimicrobial therapy, inappropriately low antimicrobial dosage, antibiotic-resistant microbial isolates, and failure to recognize the presence of abscess, osteomyelitis or pyarthrosis (13,14,20).

Medical-Legal Considerations Many states require that animal bites be reported to public health authorities (13,14). Because animal bites often result in civil litigation against the owner of the biting animal, it is prudent to thoroughly document all injuries and all diagnostic and therapeutic regimens. Although detailed diagrams and drawings are certainly appropriate, photographs or videotapes are extremely useful adjuncts to the initial evaluation of and follow-up documentation of bite-wound injuries (2-4,7,13,14,20). Photographs and videotapes provide graphic documentation of the exact nature of the injuries and can help clarify issues about the extent and severity of injury should litigation eventually ensue. The medical-legal ramifications of disease transmission by a human bite are extremely complex and only sparsely addressed in the legal literature (7).

Summary Bite-wound injuries and infections are common. Dog, cat, and human bites are the bite wounds most frequently encountered in clinical practice. Bitewound injuries are underreported and some, especially human bites (7), are actively concealed. The cornerstones of bite-wound management include scrupulous irrigation and débridement with surgical care appropriate to the individual case. Antimicrobial therapy should be administered in cases of active infection. In cases in which there is no evidence of clinical infection, broad-spectrum empiric antimicrobial therapy is frequently appropriate as prophylactic treatment when the likelihood of infection is high. Immunization for tetanus and rabies virus should be provided as required by standard CDC protocols (25,26). Special circumstances, such as monkey bites, and human bites from individuals known to be infected with HIV, can dictate the initiation of specialized evaluation and treatment protocols (27,38). There must be a detailed assessment of bite-wound complications in all patients who have sustained a bite injury. Judicious and expedient follow-up is essential for optimal clinical outcome after bite injury.

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REFERENCES 1. Goldstein E J,Talan DA. Bite wounds. In: Hoeprich PD, Jordan MC, eds. Infectious Diseases, A Treatise of Infectious Processes. Philadelphia: JB Lippincott; 1994; 1420-3. 2. McDonough J J, Stern P J,Alexander J W. Management of animal and human bites and resulting human infections. Curr Clin Top Infect Dis. 1987;8:11-36. 3. Wahl RP, Eggleston J, Edlich R. Puncture wounds and animal bites. 4th ed. In: Tintinalli JE, Krome RL, eds. Emergency Medicine. A Comprehensive Study Guide. New York: McGraw-Hill; 1996:317-22. 4. Weber D J, Hansen AR. Infections resulting from animal bites. Infect Dis Clin North Am. 1991;5:663-80. 5. Weiss HB, Friedman DI, Coben JH. Incidence of dog bite injuries treated in emergency departments. JAMA. 1998;279:51-3. 6. Bowman M JA. Animal bites in infants and children: An approach to diagnosis and treatment. Pediatr Emerg Med Rep. 1999;4:53-62. 7. Newton E. Mammalian bites. In: Schwartz GR, Roth PB, Cohen JS, eds. Principles and Practice of Emergency Medicine. Philadelphia: Lea & Febiger; 1992:2750-61. 8. Goldstein EJ, Richwald GA. Human and animal bite wounds. Am Fam Physician. 1987;36:101-9. 9. Chretien JH, Garagusi VF. Infections associated with pets. Am Fam Physician. 1990;41:831-45. 10. Plaut M, Zimmerman EM, Goldstein RA. Health hazards to humans associated with domestic pets. Ann Rev Public Health. 1996;17:221-45. 11. Tan JS. Human zoonotic infections transmitted by dogs and cats. Arch Intern Med. 1997;157:1933-43. 12. Weber DJ, Weinberg AN. Animal-associated human infections. Infect Dis Clin North Am. 1991;5:1-181. 13. Goldstein E J. Bites. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas and Bennett’s Principles and Practice of Infectious Diseases. New York: Churchill Livingstone; 1995:2765-9. 14. Goldstein E J, Bites. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas and Bennett’s Principles and Practice of Infectious Diseases. Philadelphia: Churchill Livingstone; 2000:3202-6. 15. Dire DJ. Cat bite wounds: Risk factors for infection. Ann Emerg Med. 1991;20:973-9. 16. Moran G J,Talan DA. Hand infections. Emerg Med Clin Norh Am. 1993;11:601-19. 17. McGrath MH. Infections of the hand. In: May MJG, Littler JW, eds. Plastic Surgery. Philadelphia: WB Saunders: 1990;5529-56. 18. Brook I. Human and animal bite infections. J Fam Pract. 1989;28:713-8. 19. Chambers GH, Payne JF. Treatment of dog bite wounds. Minn Med. 1969;52:427-30. 20. Goldstein E J. Human and animal bites. In: Schlossberg D, ed. Current Therapy of Infectious Disease. St. Louis: Mosby; 1996:66-8. 21. Callaham ML. Treatment of common dog bites: Infection risk factors. JACEP. 1978;7:83-7. 22. Talan DA, et al. Bacteriologic analysis of infected dog and cat bites. N Engl Med J. 1999;340(2):85-92. 23. Talan DA. Staphylococcus intermedius: Clinical presentation of a new human dog bite pathogen. Ann Emerg Med. 1989;18:427-30. 24. Goldstein E J. Simian bites and bacterial infection. Clin Infect Dis. 1995;20:1551-2. 25. Immunization Practices Advisory Committee (ACIP). Diphtheria, tetanus, and pertussis: Recommendations for vaccine use and other preventive measures: Recommendations of the Immunization Practices Advisory Committee. MMWR Recomm Rep. 1991;40(RR-10):1-28. 26. Immunization Practices Advisory Committee (ACIP). Human rabies prevention—United States 1999. MMWR Recomm Rep. 1999;48(RR-1):1-21. 27. Holmes GP, Chapman LE, Stewart JA. Guidelines for prevention and treatment of B-virus infections in exposed persons. Clin Infect Dis. 1995;20:421-39. 28. Baker AS, Ruoff KL, Madoff S. Isolation of Mycoplasma species from a patient with seal finger. Clin Infect Dis. 1998;27:1168-70. 29. HIV transmission by a human bite. Infect Control Hosp Epidemiol. 1996;17:707. 30. Andreo SM, Barra LA, Costa L J, Sucupira MC, Souza IE, Diaz RS. HIV type 1 transmission by human bite. AIDS Res Hum Retroviruses. 2004;20:349-50. 31. Vidmar L, Poljak M,Tomazic J, Seme K, Klavs I. Transmission of HIV-1 by human bite [Letter]. Lancet. 1996;347:1762. 32. Edlich RF, Spengler MD, Rodeheaver GT. Mammalian bites. Compr Ther. 1983;9:41-7. 33. Callaham M. Prophylactic antibiotics in common dog bite wounds: a controlled study. Ann Emerg Med. 1980;9:410-4.

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34. Goldstein E J, Citron DM, Merriam CV, Warren YA,Tyrrell K, Fernandez H. Comparative in vitro activity of ertapenem and 11 other antimicrobial agents against aerobic and anaerobic pathogens isolated from skin and soft tissue animal and human bite wound infections. J Antimicrob Chemother. 2001;48:641-51. 35. Goldstein E J, Reinhardt JR, Murray PM. Animal and human bite wounds, a comparative study: Augmentin vs. a penicillin + dicloxacillin. Postgrad Med J. 1984;60(suppl):105-10. 36. Goldstein E J, Citron DM, Hudspeth M, Hunt Gerardo S, Merriam CV. In vitro activity of Bay 128039, a new 8-methoxyquinolone, compared to the activities of 11 other oral antimicrobial agents against 390 aerobic and anaerobic bacteria isolated from human and animal bite wound skin and soft tissue infections in humans. Antimicrob Agents Chemother. 1997;41:1552-7. 37. Goldstein E J. Animal bite infections. In: Stevens DL, ed. Skin, Soft Tissue, Bone, Joint Infections. Philadelphia: Churchill Livingstone; 1995:4.1-16. 38. Centers for Disease Control and Prevention. Antiretroviral postexposure prophylaxis after sexual, injection-drug use, or other nonoccupational exposure to HIV in the United States: Recommendations from the US Department of Health and Human Services. MMWR Recomm Rep. 2005;54(RR-2):1-20.

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Chapter 38

Viral Exanthems BLAISE L. CONGENI, MD

Key Learning Points 1. The diagnosis of a specific viral exanthem can usually be made by carefully considering the epidemiology as well as the characteristics of the rash. 2. Establishing the diagnosis may be crucial in order that complications might be recognized and appropriately treated as in the case of rubeola, mononucleosis or varicella. 3. Certain of these exanthems can be prevented following exposure with appropriate use of active or passive immunization as in the case of rubeola, varicella and possibly rubella. 4. Infection with these viruses may be particularly hazardous for the pregnant woman, as in the case of rubella, erythema infectiousum, varicella or enterovirus.

A

combination vaccine has recently been released that combines the antigens of measles-mumps-rubella (MMR) with Varivax, the antigen of varicella zoster virus (VZV). This vaccine enables the physician to immunize for these 4 diseases with a single injection. Coverage rates for MMR has consistently been greater than 90% in the United States. All states in the United States currently have a school-entry requirement for measles immunization. It is hoped that the new combination vaccine will improve coverage for the varicella component. High coverage rates for immunization against measles, mumps, and rubella have been achieved in the United States. This has led to complete eradication of both rubella and congenital rubella syndrome in the United States. Health officials can now turn their efforts to achieving eradication on a 699

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New Developments in the Management of Viral Exanthems ●

●

●

●

●

●

●

A combination vaccine has recently been released which combines the antigens of MMR-V, measles, mumps and rubella, with Varivax, the antigen of varicella zoster virus. This vaccine will enable the physician to immunize for these four diseases with a single injection. Coverage rates for MMR has consistently been greater than 90% in the U.S. All states in the U.S. currently have a school-entry requirement for measles immunization. It is hoped that the new combination vaccine will improve coverage for the varicella component. High coverage rates for immunization against measles, mumps and rubella have been achieved in the U.S. This has led to complete eradication of both rubella and congenital rubella syndrome in the U.S. Health officials can now turn their efforts to achieving eradication on a global basis. Immunization of children from households with pregnant women does not pose a risk. Rubella vaccine or MMR should not be administered to women who are pregnant or become pregnant within 28 days. Arthralgia and transient arthritis are more common in post-pubertal susceptible recipients of the vaccine than pre-pubertal recipients. It is important to note that joint manifestations are more common following natural disease than active immunization. Pregnancy is also a contraindication for active immunization with the varicella vaccine or the combination ProQuad vaccine, MMR-V. While most primary infections with HHV-7 are mild or asymptomatic, some may present as roseola. This then could result in a second or recurrent case of roseola. Increasingly, outbreaks of varicella have been reported. Some of the patients reported in these outbreaks are vaccinated children. Breakthrough disease also occurs as a significant proportion of all cases currently seen in the U.S. given the sharp decline in wild type disease. Breakthrough disease is generally milder, shorter in duration, with 2-5 days of fever, and these children have fewer lesions, less than 50, which are more often described as papular. Administration of a second dose of Varivax is apparently more efficacious in preventing disease and providing durable immunity. A recommendation for universal use of a second dose of varicella vaccine has recently been made by the Advisory Committee on Immunization Practice of the CDC. This second dose is to be administered at age 4-6 years. Zoster (shingles) remains a common and debilitating problem especially seen in the elderly. The varicella vaccine has been reformulated into a zoster vaccine, Zostavax®. This vaccine containes substantially more plaque-forming units of virus than the vaccine used to immunize. VZIG will no longer be produced. For patients needing passive protection following exposure to varicella, Immune Serum Globulin (ISG) is now recommended.

global basis. Immunization of children from households with pregnant women does not pose a risk. Neither rubella vaccine nor MMR should be administered to women who are pregnant or may become pregnant within 28 days. Arthralgia and transient arthritis are more common in postpubertal susceptible recipients of the vaccine than prepubertal recipients. It is important to note that joint manifestations are more common after natural disease than active immunization. Pregnancy is also a contraindication for active immunization with the varicella vaccine or the combination ProQuad vaccine, MMR-V.

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Although most primary infections with HHV-7 are mild or asymptomatic, some may present as roseola. This then could result in a second or recurrent case of roseola. Increasing numbers of varicella outbreaks have been reported. Some patients reported in these outbreaks are vaccinated children. Breakthrough disease also occurs as a significant proportion of all cases currently seen in the United States given the sharp decline in wild type disease. Breakthrough disease is generally milder, shorter in duration, and with 2 to 5 days of fever; these children have fewer lesions, less than 50, which are more often described as papular. Administration of a second dose of Varivax is apparently more efficacious in preventing disease and providing durable immunity. A recommendation for universal use of a second dose of varicella vaccine has recently been made by the Advisory Committee on Immunization Practice of the Centers for Disease Control and Prevention. This second dose is to be administered at age 4 to 6 years. Zoster (shingles) remains a common and debilitating problem especially seen in the elderly. The varicella vaccine has been reformulated into a zoster vaccine, Zostavax. This vaccine contains substantially more plaque-forming units of virus than the vaccine used to immunize. Varicella-zoster immune globulin (VZIG) will no longer be produced. For patients needing passive protection after exposure to varicella, Immune Serum Globulin (ISG) is now recommended. Because the skin is the largest of the body’s organs, it is not surprising that skin involvement is seen in the course of various infectious diseases. This is especially the case for viral infections. An exanthem, eruption, or rash may be the only manifestation of an infection and the only reason that a patient may seek medical care. Furthermore, frequently the physician is able to arrive at a diagnosis from the dermatologic manifestation of an infection purely on clinical grounds. By paying careful attention to the characteristics of the exanthem, the physician can at least develop a differential diagnosis (before laboratory results are available). Common viral exanthems are listed in Table 38-1.

Table 38-1 Viral Exanthems Disease

Common Name

Etiologic Agent

Rubeola Rubella Mononucleosis Exanthem subitum Erythema infectiosum Varicella Boston exanthem

Measles German measles Mononucleosis Roseola Fifth disease Chicken pox Roseola Petechiae

Morbillivirus Rubella virus EBV, CMV HHV-6, HHV-7 Parvovirus B-19 Varicella–zoster virus Echovirus 16, 25 Coxsackie; A49; B2-4; echovirus 4,7,9 Coxsackie, echovirus, enterovirus

Hand–foot–mouth disease

CMV = cytomegalovirus; EBV = Epstein–Barr virus; HHV = human herpesvirus.

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Measles (Rubeola) Measles was one of the earliest viral exanthems to be recognized. An accurate diagnosis of this disease can be made on the basis of the rash and associated symptomatology alone. Traditionally, measles has been distinguished from another childhood disease called rubella, or German measles. Both derive their name from the Latin ruber, meaning red or reddish. Generally, immunization for both diseases is given simultaneously; however, the significance of both infections is quite different. Measles causes significant illness and even occasional death through its complications; in the prevaccine era, measles killed more people than did polio. In the prevaccine era, virtually all children became infected with the measles virus. After widespread immunization became available in 1963, the incidence of measles steadily declined until 1983 (1). The number of reported cases then steadily increased, and many outbreaks occurred in school children and college students (2). Approximately one half of these cases occurred in unvaccinated preschool children and the other half in previously vaccinated students between the ages of 5 and 24 years (3). For this reason, a two-dose vaccination strategy was adopted in the early 1990s, and subsequently the incidence of measles has been very low (4).

Etiology Measles virus (Morbillivirus) is a member of the Paramyxovirus family. Other members of this family include respiratory syncytial virus, parainfluenza virus, influenza virus, and mumps virus. The measles virus contains a single-stranded ribonucleic acid (RNA) genome with a lipid envelope. The hemagglutinin of the virus is a surface protein that facilitates its attachment to cells. In contrast with the influenza virus, the measles virion lacks a neuraminidase. Only one antigenic type of the virus exists, and, because humans are the only hosts, measles seems to be an excellent candidate for worldwide eradication after universal immunization.

Clinical Manifestations Measles is a highly contagious infection, with approximately 90% of susceptible exposed individuals becoming infected. In contrast to most viral infections, subclinical disease seems to occur infrequently in measles virus infection. After an incubation period of 8 to 12 days, the individual exposed to the measles virus develops symptoms of a common cold. This prodrome lasts 2 to 4 days, with fever, cough, conjunctivitis, photophobia, and coryza being prominent. A faint scarlatinal rash that quickly fades may then be seen. Then Koplik spots, which are pathognomonic for measles and look like small grains of sand on an erythematous base, appear on the buccal

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mucosa. The Koplik spots disappear within 12 to 18 hours, and the characteristic exanthem of measles appears within 1 to 2 days thereafter. This rash is first noted on the face, neck, and behind the ears, later spreading down the body. It may start as a macular rash, becoming maculopapular and then finally coalescing, especially on the trunk. Within 2 to 3 days the rash begins to fade and takes on a darker color, which is when desquamation may occur. Additionally, the rash can have a hemorrhagic appearance. Complications of measles (e.g., otitis media, pneumonia) are primarily secondary to bacterial infection. However, pneumonia may be caused by the measles virus itself. Encephalitis is the most feared complication of measles, occurring in 1 to 2 cases per 1000, with a death rate as high as 10% and a substantial number of survivors suffering sequelae.

Atypical Measles Children who received the killed measles vaccine between 1963 and 1968 and who later either received live vaccine or were exposed naturally to measles virus frequently developed atypical measles (5). The clinical disease seen in these children was more severe than what is usually seen, and approximately three fourths of them required hospitalization. Koplik spots were notably absent, and the rash developed after a fever of abrupt onset. Prodromal symptoms were less conspicuous than the typical manifestation. The exanthem was noted to include papules and vesicles and was seen to start distally, in contrast with typical measles. Additionally, peripheral edema, cough, and pulmonary complications were noted more commonly.

Diagnosis The diagnosis of measles is usually made on clinical grounds alone. A history of exposure, presence of prodromal symptoms (e.g., cough, conjunctivitis, coryza, Koplik spots), and typical rash are sufficient to make the diagnosis. Symptoms in previously vaccinated patients may be mild. Cultivating the measles virus from nasopharyngeal secretions, conjunctiva, blood, or urine is seldom done. Serology is used more often to confirm the diagnosis in suspected cases. The presence of immunoglobulin M (IgM) antibody or a 4-fold increase in acute and convalescent antibody titers also confirms the diagnosis. The serologic tests generally used for measles are complement fixation, hemagglutination inhibition, or enzyme immunoassay. Neutralization assays are less likely to be available and are more difficult to do.

Treatment The treatment of measles is primarily supportive. Appropriate antibiotic therapy is indicated for any of the bacterial complications that may occur,

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such as otitis media or pneumonia. Low serum concentrations of vitamin A have been associated with severe measles. Consequently, vitamin A therapy should be considered for children diagnosed as having measles under the following circumstances: ● ● ●

Children from countries associated with vitamin A deficiency Children 6 to 12 months of age hospitalized with measles Children older than 12 months of age with the risk factors of immunodeficiency, ophthalmologic evidence of vitamin A deficiency, incomplete intestinal absorption of vitamin A, moderate to severe malnutrition, or recent immigration from countries known to have high measles-related death rates

Measles is susceptible to ribavirin in vitro. Controlled studies that have documented a clinical benefit of ribavirin in immunosuppressed or other patients are unavailable.

Prevention Since the mid-1960s, the prevention of measles has been accomplished with a live measles virus vaccine. Several significant changes have occurred since 1963 about the recommendations for the initiation of measles immunization. Currently, it is recommended that all children receive measles vaccine after their first birthday unless there are contraindications. Usually, the first dose is given as a part of the standard MMR at the age of 12 to 15 months (6). A second dose of measles vaccine is given on entry into school at an age of 4 to 6 years, but this dose can be given as early as 1 month after the initial dose. All children should have their immunization records reviewed at 11 to 12 years of age.

Rubella The rash and clinical features of rubella were initially described early in the 19th century. The importance of diagnosing rubella was thought to derive primarily from the ability to distinguish it from rubeola (measles) and scarlet fever, 2 illnesses known to be associated with significant illness. The notion that rubella was a trivial disease continued until 1941, when Australian ophthalmologist Norman Gregg noticed congenital cataracts in 58 infants in association with maternal rubella early in pregnancy (7). Congenital heart disease and failure to thrive also were seen in many of these infants. Within a few years, it became apparent that microcephaly, deafness, and mental retardation were a part of the congenital rubella syndrome as well. Throughout the first half of the 20th century, rubella was noted to occur in epidemics in 7- to 10-year cycles. The last major epidemic in the United

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States occurred in 1964 and resulted in 20,000 infants born with congenital defects and perhaps as many fetal deaths (8,9). The first of many live vaccines for rubella was introduced in 1969, and its widespread use was achieved within a year (10). Since then, the number of cases of congenital rubella syndrome has declined steadily.

Etiology The rubella virus is a member of the togavirus family and is the only member of the Rubivirus genus. It is an enveloped, spherical virion that measures 60 nm in diameter and has a single-stranded RNA genome. There is only one serotype. Humans are usually the only natural hosts of the virus, but other species have been infected, including monkeys and ferrets.

Clinical Manifestations In most patients with rubella, clinical disease is mild or unapparent. Patients with clinically recognizable disease are noted to have a mild prodrome of malaise and low-grade fever after an incubation period of 14 to 21 days. Swelling of lymph nodes in the suboccipital and postauricular region is then noted, which may be followed by mild, transient conjunctivitis. The lymph nodes remain swollen. Within a few days, a rash—most often described as a fine, discrete, maculopapular eruption starting on the face and trunk—is noted. By the second day, the rash spreads to involve the arms and trunk and then may become confluent. In another day, the rash begins to fade. Within 3 to 4 days of its onset, the rash is gone. As in children, adults with rubella often have clinically unapparent disease. At times, however, the disease in adults may be more severe and prolonged, especially in women in whom rubella may be associated with polyarthralgia or even arthritis. Complications are rare but include encephalitis or thrombocytopenia.

Diagnosis As with measles, the diagnosis of rubella is almost always based on clinical grounds alone. Although rubella virus can be cultured from the throat, blood, urine, cerebrospinal fluid, and cataracts, most clinicians rely on serology to confirm the diagnosis when confirmation is necessary (11). Growing the virus in tissue cultures is time consuming and not done routinely, but it is generally available by special request. Rubella virus grows well in various primary and continuous cell lines, including monkey kidney cells. This has no cytopathic effect, but after several days the culture is challenged with a picornavirus and inhibition of growth is seen.

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Traditionally, the hemagglutination inhibition antibody test has been used for serologic testing for rubella; however, more recently, various other assays have replaced this test in most clinical laboratories. These newer tests include passive hemagglutination, latex agglutination, fluorescent immunoassay, and enzyme immunoassay. A 4-fold increase in titer or a positive rubella-specific IgM-antibody test is needed to confirm the diagnosis.

Treatment and Prevention Treatment of rubella is supportive, and specific antiviral chemotherapy is unavailable. Rubella immunization is now accomplished with a live vaccine in a 2 dose regimen. The vaccine is given as a part of the standard measles, mumps, and rubella vaccine. Generally, the first dose is administered at 12 to 15 months of age and the second dose at 4 to 6 years of age. Primary vaccine failures have not been a significant problem with the rubella vaccine, but the addition of a second dose has added a measure of safety. Because the primary target population for immunization against rubella consists of women of childbearing age, the immunization of susceptible postpubertal individuals (e.g., college students, military recruits, health care workers) remains a priority. Contraindications to immunization with the live rubella virus vaccine include pregnancy, immunodeficiency, and having received intravenous gammaglobulin or blood products within the previous 3 to 4 months, depending on the dose of gammaglobulin. The care of an individual with rubella, especially a pregnant woman, primarily involves confirming the diagnosis. If serologic testing indicates that the exposed individual is susceptible to rubella, a second serum specimen should be examined in 3 to 4 weeks to check for seroconversion. Vaccination after exposure to rubella has not clearly been demonstrated to prevent infection, and the administration of immune serum globulin after exposure generally is not recommended. However, administration of vaccine within 3 days of exposure could theoretically prevent infection and therefore immunization of nonpregnant susceptible individuals should be considered. Studies have suggested that immune serum globulin may modify or attenuate the course of disease but that it does not necessarily prevent viremia or fetal infection.

Infectious Mononucleosis Infectious mononucleosis (IM) is an illness characterized by fever, pharyngitis, and adenopathy. The 20th century saw the gradual emergence of the association of IM with atypical lymphocytes, heterophilic antibodies, and the Epstein-Barr virus (EBV).

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Infections with EBV occur commonly during childhood; however, primary infection in children is usually either mild or asymptomatic (12,13). Consequently, 50% of college freshmen in the United States already have antibodies to EBV. Approximately 10% to 20% of the susceptible population are expected to seroconvert every year during college. Most of these infections, however, tend to be asymptomatic (14).

Etiology Epstein-Barr virus is the responsible agent in approximately 90% of patients who present with typical IM. Cytomegalovirus (CMV) infection is responsible for most of the remaining patients. Both closely related viruses are members of the herpes family. The virion of EBV is 110 nm in diameter and has a genome of double-stranded deoxyribonucleic acid (DNA). EBV infects cells of the lymphoreticular system exclusively.

Clinical Manifestations The onset of IM is often heralded by constitutional reports, including headache, chills, myalgia, and cough, followed within a week by sore throat and dysphagia. Sweats associated with fever are common. These symptoms frequently last 7 to 10 days and are followed by malaise, fatigue, and anorexia that persist from several days to weeks (Table 38-2). Between 83% and 100% of IM patients have abnormal liver function studies, but the serum bilirubin level is invariably below 5 mg/dL. Thirty percent of these patients have an associated positive throat culture for group A streptococci. Skin manifestations occur in approximately 3% to 10% of IM cases (15,16). In most patients a macular or maculopapular or morbilliform rash is seen, which generally involves the trunk but also may involve the extremities and palms and soles. Occasionally, this rash has been described as petechial, erythema multiforme, or even papulovesicular or urticarial (17,18).

Table 38-2 Clinical Features of Infectious Mononucleosis Symptoms

Frequency

Adenopathy Malaise and fatigue Sweats Anorexia Nausea Chills Fever Pharyngitis Splenomegaly

100% 90%–100% 80%–95% 50%–80% 50%–70% 40%–60% 80%–95% 65%–85% 50%–60%

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Because IM patients often have a sore throat and a positive throat culture for group A streptococci, antibiotics are commonly prescribed. Patients who are treated with antibiotics are much more likely to develop a rash, and 69% to 100% of patients who receive ampicillin and 14% of those treated with either penicillin or tetracycline have been noted to develop a rash (15). One fourth of patients also have an enanthem, which is most often described as palatal petechiae. Various complications can be seen with IM (Table 38-3); other clinical manifestations of IM may not be obvious, and patients may lack heterophilic antibodies (19). Generally, patients with IM caused by CMV who are negative for heterophilic antibodies are slightly older than those with IM caused by EBV. Additionally, pharyngitis and adenopathy are often not as striking, and a rash also may be a part of this syndrome. Often, primary infection with perinatally acquired CMV also is associated with an erythematous and maculopapular rash. However, the rash of congenital CMV acquired in utero is most often petechial and a consequence of thrombocytopenia.

Diagnosis Physicians frequently arrive at a tentative diagnosis of IM on the basis of fever, marked adenopathy, pharyngitis, and splenomegaly. Confirming a diagnosis of IM rests primarily on serologic methods. EBV culture is technically difficult and not generally available. The presence of atypical lymphocytosis often can be helpful, especially in children younger than 5 years of age, who often lack heterophilic antibodies (18). The presence of heterophilic antibodies is documented with the Paul-Bunnell test or the slide agglutination (monospot) test. Although these tests are not very sensitive in children younger than 5 years of age, their sensitivity approaches 90% in older children and adults (20). Various specific serologic tests are available to document EBV infection. Tests for both IgG and IgM antibody to the viral capsid antigen are readily available. The presence of IgM antibody suggests an acute, recent infection. Antibody to early antigen also suggests an acute or recent infection and

Table 38-3 Complications of Infectious Mononucleosis Neurological Guillain–Barré seizures Meningoencephalitis Peripheral neuritis Bell’s palsy Hematologic Hemolytic anemia Thrombocytopenia Aplastic anemia

Liver Necrosis Cirrhosis Cardiac Myocarditis Pericarditis Spleen Splenic rupture

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may be helpful in the diagnosis. Occasionally, antibody to EBV nuclear antigen can be identified in a patient whose other antibody test results are confusing relative to the time of infection occurrence. Because antibody to EBV nuclear antigen develops at a late stage and is not present during an acute infection, its absence is consistent with other serologic findings that indicate acute infection. This specific EBV test should be done only when the monospot test is negative. Patients who present with IM in the absence of serologic evidence for EBV infection may be infected with CMV. CMV can be cultured readily from the throat and from urine. Serologic methods are used less often to confirm infection with CMV than they are with EBV.

Treatment and Prevention The treatment of IM is primarily supportive. Antiviral chemotherapy for EBV is ineffective. Steroids are probably used more often than indicated. In severe IM caused by EBV, the use of steroids shortens the duration of fever (21). Additional indications for steroid use include impending airway obstruction, hemolytic anemia, and thrombocytopenia. Possible indications for steroids include neurological complications of IM, pericarditis, and myocarditis. Neither active nor passive immunization is currently available to prevent EBV-associated IM.

Roseola (Exanthem Subitum) Roseola is a common pediatric exanthematous illness that occurs in children between the ages of 3 months and 3 years. It has often been overdiagnosed by physicians who care for children, many of whom typically assign this diagnosis to any child with an acute febrile illness who develops a rash after defervescence. Subsequent to the identification of the causative agent-human herpesvirus 6 (HHV-6), a better understanding of the clinical disease has emerged (22). Primary infection has been reported occasionally in adults who presented either with hepatitis or mononucleosis syndrome. Infection also has been reported in immunocompromised patients (e.g., transplant recipients, HIV-infected individuals, patients with malignancy). The role of HHV-6 in the manifestations of the diseases seen in these patients is often unclear. Few children escape infection with HHV-6 during the first 2 years of life (23,24). Acquisition of antibody to the virus occurs at an age earlier than with either CMV or EBV. Within the first 6 months of life, the titer of maternal antibody to HHV-6 decreases, and the illness caused by the virus becomes common. By the age of 2 years, few children have had recognizable disease, yet virtually all of them have acquired antibody to HHV-6.

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Etiology As with other members of the herpesvirus family, HHV-6 is enveloped, has a double-stranded DNA genome, and demonstrates tropism to T lymphocytes, especially activated CD4 cells. Two serogroups of the virus (A and B) have been identified.

Clinical Manifestations Primary infection with HHV-6 is a major cause of undifferentiated febrile illness in children younger than 2 years of age. In a recent study, 14% of acutely ill febrile children younger than 2 years of age who presented to an emergency room had documented HHV-6 infection (23). Although a wide variety of clinical manifestations were seen, rash was present in only 18% of the patients. Fever in excess of 40ºC, malaise, irritability, inflamed tympanic membranes, and nasal congestion were seen in most patients. However, febrile seizures occurred in only 1 of 34 (3%) patients. The average leukocyte count was lower in HHV-6-infected patients than in control individuals. An exanthem was noted in only 18% of the patients in the study described previously; it most often involved the face and trunk and was defined as macular or maculopapular (23). In slightly more than half of patients with the rash it was noted to have appeared after fever had abated. Therefore, it seems that the characteristic rash of roseola occurs infrequently in HHV-6–infected patients and even less often after the fever has disappeared. Infection with HHV-7, a closely related virus, is also universal but generally occurs slightly later than does infection with HHV-6. Primary infection with HHV-7 is believed to result in an acute, undifferentiated, febrile illness that occasionally is accompanied by a rash similar to that seen with HHV-6.

Diagnosis Confirmation of roseola is not readily available. A reduction in the total leucocyte count, especially the presence of lymphocytosis in a child who presents with a typical clinical picture, is helpful in suggesting the diagnosis. Growth in tissue culture of HHV-6 remains investigational. Various serologic assays are available for identifying HHV-6 infection, including an indirect immunofluorescent antibody assay and enzyme immunoassay. The presence of maternal antibody, viral reactivation, and cross-reacting antibody occasionally may make serologic results difficult to interpret.

Treatment and Prevention Treatment of roseola remains supportive, and neither passive nor active immunization is available.

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Erythema Infectiosum (Fifth Disease) For more than 100 years, physicians have recognized a distinct syndrome named erythema infectiosum (EI) and have endeavored to distinguish it from rubella. At around the turn of the 20th century, 6 common childhood exanthems were described in detail and numbered. EI was the fifth such disease described and thus received its common name, Fifth disease. In 1975, investigators identified a virus designated parvovirus (B19), which in 1983 was identified as the cause of EI (25,26).

Etiology Parvovirus B19, a member of the Parvoviridae family, is a small (20-25 nm in diameter) enveloped virus. A recent study has demonstrated 5 separate genotypes of B19, but no clinical significance has been attached to this finding.

Clinical Manifestations Erythema infectiosum is seen most commonly in children aged 5 to 15 years. Ten percent of cases occur in children younger than 5 years of age, and 20% occur in adults (26a). Because approximately half of all adults have antibody to parvovirus B19 and because few recall having had characteristic disease, it can be assumed that a substantial proportion of primary cases of EI are asymptomatic (26a). Two studies of EI found that 17% to 25% of infections were asymptomatic (25,26b). The incubation period of EI is 4 to 14 days. Approximately half of patients with the disease experience mild prodromal symptoms including malaise, sore throat, coryza, and low-grade fever. A characteristic rash then appears on the cheeks. The cheeks seem erythematous and warm, with an associated circumoral pallor. In the second phase of the illness, the rash spreads to the extremities and is usually morbilliform, annular with central clearing, or reticular. The rash is less likely to involve the trunk, palms, or soles. In this phase of the illness, the rash occasionally is described as petechial or purpuric. In the final phase of the illness, which may last for several weeks, the rash remits and recurs with stress, exercise, or bathing. Associated symptoms in patients with EI vary, but most children feel well. Various other symptoms have been described and include coryza, vomiting, diarrhea, adenopathy, conjunctivitis, and arthritis. Arthralgia, arthritis, and myalgia are seen occasionally in children with EI, but these symptoms occur in half of all infected adults. The role of parvovirus B19 in causing disease in other hosts is summarized in Table 38-4.

Diagnosis The demonstration of parvovirus B19 by culture or polymerase chain reaction remains investigational. Confirmation of infection or documentation of

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Table 38-4 Associated Clinical Syndromes in Parvovirus Infection Host

Syndrome

Chronic hemolytic anemia Pregnancy Immunodeficiency Adults Children

Transient aplastic anemia Spontaneous abortion Chronic anemia Arthritis Encephalitis, Henoch–Schönlein purpura, pneumonitis

immunity rests on serologic methods. Assays for serum IgG and IgM antibodies to the virus are available.

Treatment and Prevention No specific antiviral chemotherapy or vaccine is currently available for EI. Exposure of women of childbearing age to EI is a problem that is encountered not infrequently in clinical practice. Approximately half of all adults are already immune, and immune status can be evaluated in the exposed individual. From 30% to 50% of susceptible exposed individuals become infected, and the risk of fetal death in a pregnant woman (even with primary infection) is approximately 10%. On the basis of these figures, an exposed, susceptible pregnant woman can anticipate an upper-limit risk of fetal death of 1.5% to 2.5% (27). On the basis of currently available information and of the difficulty in obtaining serologic data for EI, it does not seem reasonable to recommend the screening of all pregnant women for susceptibility to the disease. Certain teachers and day care personnel have an increased risk of acquiring EI (28), and physicians must deal with issues of occupational exposure on an individual basis (29).

Varicella and Zoster (Chicken Pox and Shingles) Chicken pox (varicella) is a vesicular exanthematous illness that few children escape unless they are vaccinated against it. Asymptomatic disease occurs rarely, if ever (30), and repeated infection is documented rarely in a normal host. Ninety-five percent of adults are immune to varicella even if they have a negative history for the disease. Varicella is extremely contagious, with 90% of susceptible household contacts developing the disease. Infectivity rates are lower with lessintense exposure, such as in the school setting. Interestingly, cases caused by household exposure are more severe. Adults, neonates born to nonimmune mothers, and immunocompromised patients also have more severe disease.

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After the resolution of clinical disease, the VZV remains latent in cells of the dorsal root ganglia. Reactivation may occur later in life, and shingles (zoster) represents a secondary infection with VZV.

Etiology The VZV that causes both chicken pox and shingles is a member of the herpes virus family, is closely related to herpes simplex virus, and has a double-stranded DNA genome. (CMV and EBV are also members of the herpes virus family.)

Clinical Manifestations After an incubation period of 10 to 21 days, patients with varicella develop mild prodromal symptoms of a low-grade fever, headache, and malaise. The characteristic skin lesions are noted within 24 to 48 hours, usually on the trunk, face, or scalp. The lesions start as papules but rapidly become vesicular, with clear, fluid-filled lesions noted on an erythematous base—the so-called tear drop on a rose petal. These lesions progress to the pustular and then crusted stages. New crops of lesions occur with a centrifugal spread. As new crops of lesions become apparent, papules, vesicles, and pustules all may be present at the same time. Involvement by lesions of mucous membranes, including those of the mouth and eyes, is frequent. The lesions in these sites are intensely pruritic and may become secondarily infected, with a resultant increase in surrounding erythema. The patient may continue to have new lesions for up to 7 days. Besides the pruritus of varicella, patients with the disease are likely to have fever (occasionally as high as 41ºC [106ºF]), malaise, and anorexia that are most pronounced during the first few days of illness. As with varicella, the characteristic skin lesions of shingles (zoster) are also vesicular and occur in a dermatomal distribution, involving 1 or more adjacent dermatomes. New lesions appear for up to 7 days. Zoster in children is milder than that which is seen in adults and is accompanied less often by neuritis or postherpetic neuralgia. The most common complications are related to bacterial coinfection. Severe cellulitis, fasciitis, and toxic shock syndrome caused by Streptococcus pyogenes, when seen in children, frequently follow infection with VZV (31). Other complications of infections with VZV include various hematologic or neurological manifestations, especially ataxia and, rarely, Reye syndrome.

Diagnosis Usually, the diagnosis of VZV is made on clinical grounds alone. The appearance of the typical exanthem in a susceptible host occurring after exposure and an appropriate incubation period usually suggests the

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diagnosis. Identification of the virus in tissue culture with specimens of vesicular fluid can be used to confirm the diagnosis. More rapid confirmation is possible by scraping material from the base of a vesicle and looking for multinucleated giant cells or by the direct immunofluorescence using a monoclonal antibody to VZV. Cytologic methods lack sufficient sensitivity and fail to distinguish VZV from herpes simplex virus infections. Serology with enzyme immunoassay methods is used primarily to assess susceptibility to varicella in adults. These results can help the physician make decisions about active versus passive immunization after exposure to VZV (30). IgM-antibody techniques are generally not useful outside the research setting.

Treatment In certain clinical situations, VZV infections are treated with acyclovir. Generally, VZV infections in immunocompromised hosts require intravenous therapy (32). In all patients, it is imperative to initiate treatment as early as possible. Recommendations for treating VZV infection are listed in Table 38-5 (33).

Prevention A cell-free, attenuated, live-virus vaccine for varicella has been available in the United States for 6 years. This vaccine is highly effective in preventing serious disease but has been underused in the United States (34). Compliance with the recommendation for universal varicella immunization is now approaching 90%. Occasionally, recipients develop a rash, and in rare cases there is transmission of the vaccine strain of the virus to susceptible individuals. The duration of immunity conferred by vaccination seems to be excellent, and the subsequent development of shingles actually occurs less frequently than in individuals otherwise infected with virus. Contraindications for this vaccine are similar to those seen with other live vaccines and include moderate to severe febrile illness, immunocompromise, current steroid therapy in children, pregnancy, recent treatment with immunoglobulin, use of salicylates, or allergy to vaccine components. Passive protection against varicella is possible after exposure to VZV through the use of immune serum globulin, intravenous gammaglobulin, or VZIG (35). VZIG is preferred and indicated for susceptible individuals after a significant exposure. Individuals for whom VZIG should be considered include immunocompromised patients, newborn infants whose mothers had chicken pox between 5 days before to 2 days after delivery, premature infants of more than 28-weeks’ gestation and whose mothers have no history of chicken pox, and premature infants of less than 28-weeks’ gestation regardless of the maternal history. For additional details, consult the Report of the Committee on Infectious Diseases, 24th edition (35a).

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Table 38-5 Therapy for Varicella and Zoster Infections Patient Group Varicella Immunocompetent persons Neonates Children d4T > ZDV surgery for facial lipoatrophy IDV > other PIs, not ATV; More common in women, d4T > ZDV > ddI control weight, switch drug, metformin, growth hormone or testosterone, liposuction IDV, r-LPV > f-APV > Familial history, obesity, SQV; worse with d4T/ddI dietary control, conventional management, switch drug NVP (E), ATV (E→L) Chronic viral hepatitis, select appropriate CD4 number for NVP according to gender, switch drug ATV > IDV Pharmacogenetic predisposition, switch drug r-IDV > r-LPV > r-APV > Familial history, dietary r-SQV > NLV; EFV > NVP; control, switch drug, d4T/ddI > ZDV/3TC > conventional TDF/FTC management d4T/ddI > d4T > ddI > More common in women, ZDV > ddC > 3TC or FTC possible racial > ABC > TDF difference, switch drug r-LPV > r-IDV > r-APV > More common in women, r-SQV > NLV switch drug, conventional management IDV > TDF IDV from nephrolithiasis, fluid intake ddI/TDF > ddI No alcohol, reduce triglycerides ddC/d4T > ddC > d4T/ddI Avoid other neuropathic > d4T > ddI hydroxyurea drugs, switch drug, antidepressant, analgesic, massage, acupuncture? NVP, ABC > EFV NVP rash usually accompanied by hepatitis, switch drug, never attempt rechallenge, worse with Continued

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Table 39-5 Continued Ranking of Risk for Adverse Event

Adverse Event

Thrombocytopenia (L)

ZDV, hydroxyurea

Comment/Management

steroid. EFV rash may be transient Search for ITP or TTP, switch drug

* Adverse events of antiretroviral agents are commonly divided into early or late. The relative risk is ranked according to descending order of severity or likelihood. Some common combinations are also listed in the ranking. E1 = early or less than 3 months; L2 = late or 3 months or more; d4T/ddI = combination. Abbreviations: 3TC, lamivudine; ABC, abacavir; ATV, atazantavir; d4T, didehydrodideoxythymidine; ddI, dideoxyinosine; ddI3; EFV, efavirenz; f-APV, amprenavir; FTC, emtrictabine; IDV, indinavir; ITP, immune thrombocytopenia; NLV; NVP, nevirapine; PI, protease inhibitor; r-APV; r-IDV; r-LPV; r-SQV; SQV, saquinavir; TDF, tenofovir disoproxil fumarate; TTP, thrombotic thrombocytopenic purpura; ZDV, zidovudine.

Table 39-6 Commercially Available Nucleoside or Nucleotide Reverse Transcriptase Inhibitors* Agent (abbreviation)

Abacavir (ABC)

Trade Name

Elimination

Adult Dose

Available Formulation

Ziagen GlaxoSmith-Kline (GSK)

Hepatic 300 mg PO 300-mg glucuronidation q12h or 600 tablet, 20and carboxymg daily (QD) mg/mL lation solution Didanosine Videx™ and Cellular 400 mg PO QD buffered (ddI) Videx EC metabolism for ≥60 kg or chewable Bristol-Myers250 mg PO tablet and Squibb QD for entericcoat 350/mL. Abbreviations: h, hour; NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, nonnucleoside reverse transcriptase inhibitor; PO, orally; q, every; QD, daily; QHS, at bedtime.

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Table 39-8 Inhibitors of the HIV Protease Enzyme* Agent (abbreviation) Trade Name

Elimination

Adult Dose

Formulation

Atazanavir (ATV)

Reyataz Bristol- hepatic P-450 400 mg PO QD 100, 150, 200Myers-Squibb or 300 mg mg capsule with 100 mg ritonavir PO QD Darunavir (DNV) Prezista hepatic P-450 600 mg with 300-mg tablet Tibotec 100 mg ritonavir PO q12h Fosamprenavir Lexiva Glaxo- hepatic P-450 1400 mg PO 700-mg tablet (f-APV) Smith-Kline q12h or 700 mg with 100 mg ritonavir PO q12h Indinavir (IDV) Crixivan Merck hepatic P-450 800 mg PO 100, 200, 333, renal q8h or 800 mg 400-mg with 100 mg capsule ritonavir PO q12h Lopinavir + ritonavir Kaletra Abbott hepatic P-450 Two tablets PO 200-mg coformulation q12h, or 5 mL lopinavir (r-LPV) solution PO 50-mg q12h ritonavir fixed dose tablet, 80mg lopinavir 20-mg ritonavir per mL solution Nelfinavir (NFV) Viracept hepatic P-450 1250 mg PO 250, 625-mg Agouron q12h tablet Ritonavir (RTV) Norvir Abbott hepatic P-450 600 mg PO 100-mg q12h capsule 80mg/mL solution Saquinavir (SQV) Invirase hepatic P-450 1000 mg with 500-mg tablet Hoffman100 mg LaRoche ritonavir PO q12h Tipranavir (TPV) Aptivus hepatic P-450 500 mg with 250-mg Boehringer200 mg capsule Ingelheim ritonavir PO q12h * There are nine commercially available protease inhibitors. Ritonavir is almost never used alone because of its high rate of intolerance at therapeutic dose. It is used mainly to enhance the levels of other protease inhibitors except nelfinavir. Only products that are presently marketed in the United States are shown in the table. Abbreviations: h, hour; PO, orally; q, every; QD, daily.

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(Invirase and Fortovase by Hoffman-LaRoche) and the ritonavir (Norvir by Abbott) liquid were replaced by better products. The gel-cap coformulation of lopinavir/ritonavir (Kaletra by Abbott) was recently replaced by a new tablet.

HIV Targets for Antiretroviral Agents The reverse transcriptase (RT), the protease, and the envelope protein GP120 have been successfully targeted for drug development during the last 20 years. Two classes of drugs have been developed to block the function of RT: nucleoside or nucleotide (nucleoside monophosphate) analog RT inhibitors (NRTIs), which act to short-circuit DNA chain elongation and act as competitive inhibitors of RT; and nonnucleoside RT inhibitors (NNRTIs), which bind to the catalytic site of RT and act as noncompetitive antagonists of enzyme activity. All four normal nucleoside substrates (adenosine, cytosine, thymidine, and guanidine) are being targeted by inhibitory analogues (Table 39-9). NRTIs that compete with the same nucleoside substrate should not be administered together because the combinations tend to be antagonistic (AZT and didehydrodideoxythymidine [d4T]), mutually exclusive (lamivudine [3TC] and emtricitabine [FTC]), or potentially toxic (tenofovir disoproxil fumarate [TDF] and dideoxyinosine [ddI]). In general, combining two analogues targeting different nucleoside substrates reduces viral production more effectively than any one alone. Nonnucleoside reverse transcriptase inhibitors (NNRTIs) include compounds with widely divergent chemical structures (see Table 39-7). They do not require phosphorylation or intracellular processing. They inhibit RT function by binding at sites distinct from the NRTIs. These drugs do not have activity against HIV-2. Combining drugs of this class (two NNRTIs simultaneously) does not result in more effective antiviral activity (10). The HIV protease is a 99-amino acid aspartyl proteolytic enzyme that exists as a homodimer to give a symmetrical structure. Most of the approved protease inhibitors (PIs) (see Table 39-8) are synthetic peptide mimetics containing the phenylalanine-proline sequence designed to com-

Table 39-9 Nucleoside or Nucleotide Analogue that Inhibits the HIV-1 Reverse Transcriptase Enzyme* Adenosine Didanosine (ddI) Tenofovir2 (TDF)

Cytosine Zalcitabine (ddC) Lamivudine (3TC) Emtricitabine (FTC)

Thymidine Zidovudine (ZDV1) Stavudine (d4T)

Guanosine Abacavir (ABC)

* These drugs compete with the normal nucleoside substrates for the reverse transcriptase during viral DNA synthesis. Combining analogues that target different substrates provides synergistic activity, but combining analogues that target the same substrate can be detrimental. 1 ZDV is often used interchangeably with AZT. 2 Tenofovir is a nucleotide or a nucleoside monophosphate.

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pete with one of the eight cleavage sites within the gag-pol polyprotein precursor (11). These drugs do not require any additional processing in the body, and the serum trough level must exceed the level necessary to inhibit at least 50% of the virus by in-vitro assays. This inhibitory concentration (IC50) measurement is quite similar to the concept of minimum inhibitory concentration (MIC50) in bacteriology. It has been established by clinical trials that the higher the inhibitory quotient, defined as the ratio of the trough level of a PI over the IC50 of a viral isolate, the more effective is the drug against that particular virus. Among resistant HIV isolates, the IC50 can be many folds higher than that of a wild type virus. The process of HIV-1 entry into host cells is complex and consists of several distinct steps, each of which forms a separate target for inhibition. Enfuvirtide (T-20 or Fuseon by Hoffman-LaRoche) is a 36-amino-acid synthetic peptide that acts as a competitive decoy that disrupts the formation of a six-helix configuration by the exposed transmembrane gp41 protein, a process that is essential for the fusion of the viral envelope and the host cell membrane (12). It has similar activity against HIV-1 strains that use different coreceptors (chemokine receptor 5 [CCR5] or chemokine-related receptor [CXCR4]), but it has no activity against HIV-2. With subcutaneous injections at a dose of 90 mg (1 mL) for an adult, the half-life of the drug is 3.8 hours, necessitating two administrations daily. Enfuvirtide is available as a powder in single-use vials and must be reconstituted with sterile water immediately before each administration. Resistance to the drug is correlated with mutations of the HR1 coding region of the gp41 protein.

Principles of Optimal Highly Active Antiretroviral Therapy (HAART) Some principles on the selection and application of HAART have emerged since 1996 through many clinical trials and expert consensus (9). They can be summarized as follows: ●

●

At least three fully effective antiretroviral drugs should be administered together for a drug-naïve patient as the first regimen. They should be selected from two different classes of agents. Classsparing strategy with triple NRTIs has been shown to be less reliable. A four-drug combination initially has not been shown to be more effective in achieving undetectable viral load or CD4+ recovery. It is not necessary to combine three classes of drugs in the first triple HAART regimen regardless of the plasma level of HIV-RNA. Exposing a patient to three classes of drugs early in the treatment time course can restrict subsequent choices because drug resistance usually crosses over to other drugs within the same class.

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●

●

●

●

When a patient develops virologic failure while on his or her first regimen (usually defined as greater than 1000 copies of HIV-RNA despite 12 weeks of HAART or reemergence after being undetectable previously), the virus can remain fully susceptible if the patient took less than 50% of the prescribed doses. It is advisable to modify the HAART regimen according to in-vitro resistance tests (see Drug Resistance). Simple addition of a new drug to a failing regimen will often be inadequate to suppress the viral load to undetectable level and will likely lead to more resistance. However, most early failure is the result of viral resistance against only one or two drug components of the triple regimen. Therefore, some drugs can still be included or reusable in the next regimen. A second HAART regimen is more likely to be successful if it consists of at least one new drug from a different class; such as a PI if the first regimen had two NRTIs plus one NNRTI, or an NNRTI if the first regimen had two NRTIs plus a PI. There are only four classes of antiretroviral agents available at present; therefore, the patient can use up all the class options after the third regimen. If a patient develops intolerable adverse events while remaining fully suppressed, it is acceptable to change only the offending drug without interrupting the treatment. Treatment interruption must take into account the different drug half-lives to avoid exposing the virus to a single drug with low genetic barrier to resistance development. This is often the case with two NRTIs and efavirenz (very long half-life). Most experts recommend substituting efavirenz with a PI for 5 to 7 days before the final discontinuation. The trough level of any PI correlates well with viral suppression; therefore, enhancing the trough level of a PI by inhibiting its hepatic metabolism has been shown to be a successful strategy. This is often accomplished by administering a PI with ritonavir, a powerful inhibitor of hepatic cytochrome P-450 enzymes. The only exception is nelfinavir because of its unique pathway of metabolism.

Drug Resistance Development of Drug Resistance HIV has a very high propensity to generate genetic variants because of the enormous number of virions turning over daily in a single patient and the notoriously error-prone RT transcribing viral RNA into DNA. On the average, a mistake is likely to be introduced after each genome transcribed. Most errors are base substitutions but deletion, insertion, duplication, and combinations

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of these processes have been demonstrated. Even in a treatment-naïve patient, the likelihood of a tiny population of viruses that have already mutated to be a single drug-resistant genotype at random is high. Drug resistance actually develops quite readily in situations where the drug combination was insufficient to reduce viral replication to an undetectable level but sufficient enough to apply selective pressure on the still replicating viruses (13). Contrary to common misconception, drug resistance is the consequence of treatment failure and not the cause. Treatment failure was the norm before the HAART era. At present, virologic failure occurs when a patient is nonadherent to the dosing protocol, or drug interactions that can reduce therapeutic drug levels were not suspected by the prescribing clinician. Inadequate HAART regimens should be rare if the clinician follows the recommended treatment guidelines (9,14). Signature or key mutations for most drugs have been described, and they can be detected easily by appropriate commercially available resistant genotype tests. Because the transmission of resistant HIV has been increasing in urban areas with large infected-patient populations, it is advisable to request a resistant genotype assay before initiating the first regimen. Clinical failure is far more costly than any resistance assay.

Commercial Resistance Assays Drug resistance generally increases with the accumulation of mutational changes within the various drug targets so it develops gradually over a range of drug concentrations and over time. When a patient develops virologic failure because of a few mutations in the RT or the protease gene, resistance has not reached maximal levels. Additional mutations associated with further increase in resistance can occur without any change of the treatment regimen. Therefore, it is recommended to change the failing regimen early to avoid more cross-resistance to develop within the same class of drugs. Because cross-resistance is common, selection of a new regimen cannot be made on the simple assumption that other drugs of the same class as the failing regimen remain effective. In an effort to facilitate the selection of an efficacious alternative regimen, tests have been developed to determine the susceptibility of HIV to each individual drug. Two types of assays are currently available: genotypic assays, which detect the presence of resistance mutations; and phenotypic assays (Phenosense by Mongram, South San Francisco, CA), which measure the susceptibility of the virus to various drugs in tissue-culture systems. VirtualPhenotype (by Virco, Mechelen, Belgium) is a commercially available interpretation tool based on computer matching of the patient’s genotype with a large database of genotype-phenotype pairs. Clinical correlations have shown that these tests are more reliable in predicting treatment failure than treatment success (13).

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When to Initiate Antiretroviral Therapy in HIV-1–Infected Adults One of the most controversial topics in the medical management of HIV disease is the optimal time to initiate HAART in HIV-1–infected adults. This controversy applies not only to an individual but also to a society. Premature treatment can lead to more resistant viruses and more unwanted toxicities whereas delayed treatment can lead to reduced therapeutic benefit and wider spread of the epidemic (15). Almost everyone agrees that HAART should not be given for an asymptomatic patient with 350 CD4+ cells or more (the early group) (Figure 39-2). Most also agree that HAART should be given for any symptomatic patients, for any patient with less than 200 CD4+ cells (the late group), and for a woman who is pregnant. Two key areas of uncertainty involve asymptomatic patients with HIV-RNA greater than 100,000 copies/mL

HIV-infected adult

CD4 & HIV RNA

Symptomatic

Asymptomatic

CD4 350

Monitor every 3 months except with other risks

CD4 105, age >50, rapid rate of CD4 decline (>15/m), no pre-existing resistance, low CV and metabolic risk, readiness, psychosocial stability, coinfection with hepatitis C, no alcohol, no drug

Initiate HAART

Figure 39-2 The decision to initiate highly active antiretroviral therapy is often difficult and should be made individually rather than strictly adhering to published guidelines.

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and those patients with CD4+ cells between 200 and 350 (the intermediate group). More recent clinical trials with more potent HAART regimens did not find any difference in the proportion of patients achieving undetectable level even if the baseline HIV-RNA was greater than 100,000 copies (16). The difference of disease progression between the early group and the intermediate group was significant from observational cohorts on no therapy. However, the relative risks for disease progression for both groups after HAART were so low that observational studies could not determine the optimal timing of initiation. The lack of a randomly assigned clinical trial to address this issue directly has resulted in the substantial variability among international consensus guidelines about the optimal timing of HAART initiation (9,15). There are other risk factors besides the absolute CD4+ cell count that can influence the decision on the timing of initiation. A flow chart is presented to assist clinicians to individualize their decision (Figure 39-3). Those patients

Candidate for HAART

CD4 8 years old 75-100 mg/kg/day, maximum dose 2 grams/day. Cefotaxime. Adults 2 grams Q8 hours. Children 150 mg/kg/day, maximum 6 grams/day. Penicillin G. Adults 5 million units Q6 hours. Children > 1 month old 250,000 units/kg/day, maximum 18 million units/day. Data from Steere AC. Borrelia burgdorferi (Lyme disease, Lyme borreliosis. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases, 6th ed. Philadelphia: Elsevier Chruchill Livingstone; 2005:2798-809; Steere AC. Lyme disease N Engl J Med. 2001;345:115-25;Wormser GP, Nadelman RB, Dattwyler RJ, et al. Practice guidelines for the treatment of Lyme disease. The Infectious Diseases Society of America. Clin Infect Dis. 2000;31(Suppl 1):1-14.

PO or IV route

IV route

Meningitis Carditis

Arthritis Acrodermatitis

Oral or IV route

Arthritis Facial nerve palsy

Late disease

Oral route

Skin

Early disseminated disease

Oral route

Antibiotic administration

Skin

Disease manifestation(s)

Early localized Disease

Clinical Stage

Table 43-3 Recommended adult and pediatric antibiotic treatment of early and late stage Lyme borreliosis (Lyme disease)*.The oral and IV drugs are listed in order of preference. Appropriate drug doses are indicated in the footnote.

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Intravenous therapy with ceftriaxone for 14 to 28 days is recommended for treatment of patients older than age 8 years who have early disseminated Lyme borreliosis complicated by meningitis or third-degree heart block (3,10). Children younger than age 8 years old should be treated with cefotaxime rather than ceftriaxone because ceftriaxone therapy in young children has been associated with biliary sludge formation and acute cholecystitis. Thirddegree heart block usually responds quickly to parenteral therapy, but insertion of a temporary pacemaker may be necessary in some circumstances. Patients who have persistent objective arthritis with recurrent joint swelling after a recommended course of oral antibiotic therapy may benefit from treatment with another 4-week course of oral antibiotic or a 2- to 4-week course of intravenous ceftriaxone (3,10). There is no published scientific support for therapy for Lyme borreliosis extending beyond 6 to 8 weeks (10,13). Symptoms of Lyme borreliosis may persist beyond the period of antibiotic therapy. This is especially common when treatment is instituted later in the course of clinical disease; and persistence of symptoms should be managed with adjunctive medications, which may include nonsteroidal anti-inflammatory agents and antidepressants, rather than prolonged antibiotic therapy. There is currently insufficient data to recommend routine use of singledose antimicrobial prophylaxis after a tick bite (10,15). Consider a prophylactic single dose of doxycycline hyclate (200 mg adults; 4 mg children) when tick identified as Ixodes and is attached ≥36 hrs; prophylaxis started ≤72 hrs of tick removal; local rate of B. burgdorferi-infected ticks >20% and doxycycline not contraindicated (10). Persons who remove attached ticks from their skin should be monitored closely for the next 30 days for the development of EM rash at the site of the tick bite, or fever with rigors which may suggest HGA or babesiosis (another Ixodes species tick-transmitted infection caused by Babesia microti) (10).

Human Monocytotropic Ehrlichiosis Etiology Ehrlichia chaffeensis is an obligate intracellular bacterium of the order Rickettsiales, family Anaplasmataceae. This bacterium may be transmitted to humans by tick bites and can cause infections in animals and humans (16). Ehrlichia species are small (0.2-1.0 µm), obligate, intracellular gram-negative organisms (17). They infect predominantly bone marrow–derived cells in mammalian hosts, mostly mononuclear leukocytes and macrophages, where they form intracytoplasmic microcolonies named morulae from the Latin word for mulberry (Table 43-4). Ehrlichia species are easily seen in the peripheral blood smear when Wright or Giemsa stains are used and vary in appearance from highly basophilic loose or condensed aggregates to individual bacterial cells visualized within vacuoles now proven to be early endosomes.

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Table 43-4 Epidemiologic and demographic characteristics associated with Lyme disease*, human monocytotropic ehrlichiosis (HME) †, human granulocytotropic anaplasmosis (HGA)‡, and human granulocytotropic ewingii ehrlichiosis (HGEE)§. Clinical illness

Lyme borreliosis

HME

HGA

HGEE

Year first reported Tick vector americanum

1976

1987

1994

1999

I. scapularis

A. americanum I. scapularis

I. pacificus B. burgdorferi

E. chaffeensis

Causative agent Tissue Target

Skin Joints Monocyte Nerve tissue Macrophage Reported cases* > 150,000 >1,924 Endemic range North East Upper South Central (in United Midwest South East States) Pacific coast Mid-Atlantic

I. pacificus A. phagocytophilum Granulocyte

A.

E. ewingii Granulocyte

>2,497 29 North East South Central Upper Midwest Pacific coast

* Data from references 3 and 10. † Data from references 19, 20, and 45. ‡ Data from references 27, 30, 33, and 35. § Data from references 36 and 45. ¶ Personal communication A. Chapman, Centers for Disease Control and Prevention, July 13th, 2005

Epidemiology E. chaffeensis cycles in nature within Amblyomma americanum, the Lone Star tick and mammalian reservoir hosts. This tick species is found widely in the south central and south eastern United States across the region stretching from southern New York to Texas. All 3 tick stages (larva, nymph, and adult) feed on small rodents, such as the white-footed mouse (Peromyscus leucopus), and large ungulates, especially the white-tailed deer (Odocoileus virginianus) (18). Lone Star ticks are aggressive and feed willingly on humans; the endemic areas where E. chaffeensis infections occur closely overlap the endemic areas for the tick vector. The human illness that is associated with E. chaffeensis infection is called human monocytotropic ehrlichiosis or HME. The first case of HME was described in a man from Detroit, Michigan, in 1986, a few weeks after he had acquired tick bites in Arkansas (17). Since the discovery, the CDC has identified at least 3,190 cases of HME as of the end of 2006 (1,19,28). Although only infrequently diagnosed, active surveillance for cases identified has estimated incidence rates to be as high as 138 cases/100,000 population in some areas of southeastern Missouri.

Clinical Manifestations Most patients contract HME between May and August, and as many as 75% of clinically symptomatic patients may need to be admitted to a hospital for

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the initial part of their care (19,20). The median patient age is 44 years, and men become infected 3 to 4 times more frequently than women. However, elderly individuals and patients who are immunocompromised from HIV infection, organ transplantation, cancer or corticosteroid therapy are more prone to develop a serious illness or even death (20,21). The reported case fatality rate ranges between 1% to 3% (19). HME can have a wide range of clinical presentations, and the clinical illness varies from asymptomatic or clinically mild infection to severe or fatal disease (21,22). Symptoms typically develop abruptly 1 to 2 weeks after tick exposure or a documented tick bite. HME presents most frequently as undifferentiated, nonspecific fever accompanied by anorexia, headache, myalgias, and malaise (Table 43-2). Approximately one third of infected patients, especially children, have reported a nonspecific rash, ranging from erythematous maculopapules to petechiae (19,21). Significant complications of HME include a toxic or septic shock-like syndrome, respiratory distress that requires mechanical respiration, meningoencephalitis, hemorrhage, renal failure, cardiac failure, and opportunistic infections. Although these bacteria live in the blood and an incubation period of 1 week or more is typical before clinical manifestations appear, no cases of transfusion-related HME have been documented (23). Severe illness or death has been associated with delayed diagnosis or institution of antimicrobial therapy, which does not include a tetracycline drug (19). Laboratory test abnormalities are nonspecific and include various permutations of leukopenia, thrombocytopenia, or both as well as mild to significant increases in serum hepatic aminotransferase concentrations (19-21). Mild to profound thrombocytopenia occurs in approximately 50% of patients. The differential leukocyte count often reveals a marked left shift with increased proportions of neutrophil and band leukocytes owing to relative and absolute lymphopenia during the initial phase of illness. An absolute neutropenia can also be detected in some patients. Pancytopenia occurs despite bone marrow examinations that have showed normocellular or hypercellular marrow architecture. The changes in blood counts and serum aminotransferases are transient, and abnormal variables often revert back to the normal range with prolonged (untreated) illness (19). Treatment with doxycycline usually induces a rapid normalization of blood counts. A minority of infected patients will develop reactive lymphocytosis, including atypical lymphocytes, that becomes apparent during the second or third week of illness or after completion of antibiotic therapy.

Diagnosis Examination of the peripheral blood smear may demonstrate typical morulae in the cytoplasm of monocytes in between 1% and 20% of patients during the early phase of infection (19-21). However, blood smear microscopy is very insensitive, nonspecific, and rarely reveals the diagnosis even when

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Table 43-5 Case definitions and laboratory criteria for probable and confirmed cases of HME and HGA*. Case definition

Laboratory test result for HME

Laboratory test result for HGA

Probable infection

Morulae in peripheral blood Morulae in peripheral blood smear neutrophilsa smear mononuclear cella or Single titer E. chaffeensis serum or Single titer A. phagocytophilum serum IFAc ≥ IFAb ≥ 64 or Positive 64 or Positive A. phagocyE. chaffeensis PCRd of blood tophilum PCRe of blood Confirmed infection IFA seroconversion or serorever- IFA seroconversion or seroreversionf or Isolation sionf or Isolation of of A. phagocytophilum E. chaffeensis from bloodg or Single E. chaffeensis serum from bloodh or Single A. phagocytophilum serum IFAb ≥ 256 and a clinically compatible illness, or Single IFAc ≥ 64 and Morulae in peripheral blood smear E. chaffeensis serum IFAb ≥ 64 and Morulae in peripheral neutrophilsa or Positive A. phagocytophilum PCRe blood smear mononuclear cella or Positive E. chaffeensis PCRd of blood of blood

* Data from Bakken JS, Jumler JS. Ehrlichiosis and anaplasmosis. Infect Med. 2004;21:433-51; Walker DH, Bakken JS, Brouqui P, et al. Diagnosing human ehrlichioses: current status and recommendations. Am Society Micorbiol News. 2000;5:287-93. a Light microscopy of Wright stained peripheral acute phase blood; Indirect immunofluorescent antibody test with E. chaffeensis b or A. phagocytophilum c antigen; Polymerase chain reaction with specific E. chaffeensis d or A. phagocytophilum e primers; Fourfold or greater change in serum antibody titer f; Isolation of E. chaffeensis g or A. phagocytophilum h in tissue culture inoculated with acute phase blood.

done by experienced microscopists. Amplification of E. chaffeensis–specific DNA by polymerase chain reaction (PCR) done on acute phase blood is a rapid and specific diagnostic method that may permit early diagnosis in between 60% and 85% of infections (24). However, only a small number of clinical and hospital laboratories offer PCR on a routine basis. Thus, the diagnosis of HME is most often made retrospectively based on demonstration of a serologic response to E. chaffeensis (Table 43-5). Most patients have increased IgM and IgG antibodies in serum (polyclonal immunofluorescent antibody [IFA] titer ≥ 64) or seroconvert 14 to 21 days after the onset of illness (19,21,22). Current data suggest that IgM serology provides no additional benefit in the diagnosis of HME. (For information on therapy, please see the section “Treatment of Human Ehrlichiosis, and Human Anaplasmosis,” later in this chapter.)

Human Granulocytotropic Anaplasmosis Etiology A. phagocytophilum are obligate intracellular bacteria that are members of the order Rickettsiales, family Anaplasmataceae. These bacteria share simi-

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lar morphologic characteristics with E. chaffeensis, may be transmitted to humans by tick bites, and can cause infections in animals and humans (16). Anaplasma species are small (0.2-1.0 µm), obligate, intracellular gramnegative organisms (25); and they infect predominantly bone marrow– derived cells in mammalian hosts, mostly polymorphonuclear (neutrophil) leukocytes, where they grow to form characteristic intracytoplasmic microcolonies (morulae) (Table 43-4).

Epidemiology Human granulocytotropic ehrlichiosis (HGE) was described in 1990 as a nonspecific febrile illness that occurred among a group of older men who were bitten by ticks in the upper Midwest (25). The cause of HGE was initially attributed to Ehrlichia phagocytophila (also known as the HGE agent); but recent revisions in the taxonomy and nomenclature of the family Anaplasmataceae have reclassified the human granulocytic ehrlichiosis agent as A. phagocytophilum, mandating a change in the disease name to human granulocytic anaplasmosis, or HGA (26). Ixodes species ticks are the established vectors for Anaplasma phagocytophilum (18,27). The infectious cycles of A. phagocytophilum as well as B. burgdorferi are maintained in nature when Ixodes ticks feed on transiently or persistently infected animal reservoir hosts that potentially include small rodents such as Peromyscus leucopus, the white-footed mouse, and large ungulates like Odocoileus virginianus, the white-tailed deer. All 3 developmental tick stages (larva, nymph, and adult) feed willingly on humans, but only the nymphal and adult stages are infectious because there is no established transovarial passage of bacteria from the adult female to eggs. The CDC recorded more than 4276 cases of HGA in the United States between 1994 and the end of 2006, and 790 cases were reported in 2006 alone, the last year for complete data (28). Seroepidemiologic investigations have suggested that HGA is generally a mild infection; and case reports have shown that most patients recover uneventfully after 1 to 2 weeks, even in the absence of specific antibiotic therapy (29). The estimated HGA case fatality rate is low (0.5% to 1%). However, it may be difficult to prospectively identify patients likely to develop serious or fatal disease (27,30), and prompt institution of active antibiotic therapy is therefore advocated for all symptomatic patients who have been diagnosed with HGA (14). Epidemiologic studies have also provided evidence of high-risk regions and populations. Seroprevalence rates as high as 14.9% were recently reported in Wisconsin (31), and studies of at-risk B. burgdorferi–seropositive populations in New York State showed that as many as 35.6% also had antibodies to A. phagocytophilum (32). Passive surveillance studies of some highly endemic regions of Connecticut (1) and Wisconsin (30) have demon-

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strated incidence rates as high as 52 to 58 cases in 100,000 of the population. Despite high seroprevalence rates in endemic regions, only a single case of transfusion-related HGA has been documented, underscoring the rarity of this event.

Clinical Manifestations HGA is a clinical syndrome most commonly manifested by nonspecific fever, chills, headache, and myalgias (Table 43-2) (25,27,30,33). The symptoms and signs range from asymptomatic infection to fatal disease and the clinical severity of HGA varies directly with increasing patient age and/or comorbid illnesses. Most symptomatic patients have reported tick exposure or a tick bite 1 to 2 weeks before the onset of symptoms, and most symptomatic infections are acquired between May and August (16,30). The median patient age is 69 years, and men become infected 3 to 4 times more frequently than women (30). HGA can be severe with nearly half of patients requiring hospitalization and up to 17% requiring admission to an intensive care unit (30). Although the case fatality rate is low, complications can occur and include a septic or toxic shock–like syndrome, respiratory insufficiency, invasive opportunistic infections with both viral and fungal agents, rhabdomyolysis, pancarditis, acute renal failure, hemorrhage, and neurological diseases such as brachial plexopathy and demyelinating polyneuropathy. Various permutations of leukopenia, a left shift (often higher than 25% band neutrophils), thrombocytopenia, and hepatic aminotransferase elevations are present in most patients and provide suggestive clues to the diagnosis (33-35). Although both leukopenia and thrombocytopenia are present in many patients at presentation, these abnormalities are transient and usually normalize by the end of the second week. At least 20% and up to 80% of patients present with morulae in peripheral blood neutrophils that confirm the diagnosis (33,34).

Diagnosis The diagnosis can be confirmed by blood smear examination and PCR analysis during the early phase of infection, and by serologic testing (IFA) in late infection or convalescence (Table 43-5). PCR amplification of A. phagocytophilum DNA from acute phase blood (30,33) or isolation of A. phagocytophilum in HL-60 promyelocytic leukemia cell cultures inoculated with acute phase blood (30,33) can confirm the diagnosis, but these test modalities are available in only a limited number of laboratories. Patients who have a clinical illness compatible with HGA should be considered for specific antibiotic treatment (14,16,27). Blood samples should be secured before the patient begins antibiotic treatment because therapy will rapidly reduce the detectable quantities of infected cells or bacterial DNA.

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Serologic testing using a polyvalent IFA method with demonstration of 4fold antibody titer change or seroconversion has been used most commonly to confirm HGA (29). IgM tests are only reactive during the first 45 to 50 days after infection, and these tests are not more sensitive than those that detect IgG antibodies. (For information on therapy, please see the section “Treatment of Human Ehrlichiosis, and Human Anaplasmosis,” later in this chapter.)

Human Granulocytotropic Ewingii Ehrlichiosis Etiology and Epidemiology In 1999 Ehrlichia ewingii was identified in blood by PCR conducted on samples collected from several old and immunocompromised patients from Missouri and Oklahoma (36). Buller demonstrated that approximately 1% of patients believed to be infected with E. chaffeensis actually were infected with E. ewingii (36). E. ewingii was previously known only as a pathogen of dogs. Just like E. chaffeensis these organisms cycle within Amblyomma americanum ticks for part of their life cycle. The associated infectious syndrome is called human granulocytotropic ewingii ehrlichiosis (HGEE). HGEE has so far only been reported in patients living in Missouri, Oklahoma, and Arkansas. In contrast to E. chaffeensis, which infects monocytes and macrophages, E. ewingii lives predominantly in peripheral blood neutrophils. To date, less than 30 patients have been reported to the CDC, and many of the patients have had concurrent HIV infection or have received organ transplants.

Clinical Manifestations and Diagnosis Infected patients have reported a nonspecific febrile illness after tick exposure or a tick bite, but overall the severity of HGEE seems lower than for either HME or HGA, and no fatalities have been reported. The usual presentation is a mild summertime febrile illness that occurs after tick exposure. Reported symptoms include fever, myalgias, and malaise; and many patients presented with leukopenia, thrombocytopenia, and increased serum alanine aminotransferase or aspartate aminotransferase concentrations. PCR can be attempted for diagnosis early in illness, but few laboratories offer the specific assay required. E. ewingii has not been cultivated in vitro, and reliable rapid diagnostic tests do not currently exist. However, E. ewingii is closely related to E. chaffeensis, which results in serologic crossreactivity in IFA assays. It is therefore likely that some patients who are serodiagnosed with HME may actually be infected by E. ewingii (21,36).

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Treatment of Human Ehrlichiosis and Human Anaplasmosis Ehrlichia and Anaplasma species are uniformly susceptible to tetracycline antibiotics in vitro (37,38). Doxycycline hyclate has traditionally been the agent of choice because of favorable pharmacokinetic properties compared with other tetracycline derivatives. Because of the potential for serious or even fatal HME and HGA infection, all patients with suspected or documented HME or HGA should be treated with oral or intravenous doxycycline hyclate in the absence of specific contraindications to tetracycline drugs (Table 43-6) (16,1921,27). Doxycycline is also the drug of choice for children who are seriously ill regardless of age (39). Doxycycline therapy characteristically leads to clinical improvement in 24 to 48 hours (10,14,16,19-21,27). Thus, patients who fail to respond to treatment within this time frame should be reevaluated for an alternative diagnosis and treatment. The optimal duration of doxycycline therapy has not been established. Patients who have been treated for 7 to 10 days have resolved their infections completely, and relapse or chronic infection has never been reported, even for patients who were never treated with an active antibiotic. However, adult patients who are considered at risk for coinfection with B. burgdorferi should continue doxycycline therapy for a full 14 days. A shorter course of doxycycline (5-7 days) has been advocated for pediatric patients because of the potential risk for adverse effects (dental staining) seen occasionally in young children. Rifamycins have demonstrated excellent in vitro activity against Ehrlichia and Anaplasma species (37,38). A small number of pediatric patients and pregnant women with HGA have been treated successfully

Table 43-6 Recommended adult and pediatric antibiotic treatment of human monocytotropic ehrlichiosis*, human granulocytotropic anaplasmosis†, and human granulocytotropic ewingii ehrlichiosis‡. Antibiotic

Dose (adults)

Dose (children)

Doxycycline hyclate Tetracycline hydrochloride Rifampine,f

100 mg IVa or POb Q 12 hours 500 mg PO Q 6 hours 300 mg PO Q 12 hours

2.2 mg/kg IV or PO Q 12 hoursc 25-50 mg/kg/day PO in 4 divided dosesc 10 mg/kg PO Q 12 hours

a

Duration (days)

5-14d 5-14d 7

Intravenous administration Oral administration Until fever has resolved and for three additional days d 14 days recommended when co-incubating B. burgdorferi infection is suspected e Active against E. chaffeensis in-vitro. No clinical experience reported for treatment of HME f In-vitro activity against E. ewingii is unknown. No clinical experience reported for treatment of HGEE * Data from references 14, 19, 20, and 38. † Data from references 14, 27, 33, and 39. ‡ Data from references 30 and 45. b c

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with rifampin (40-42). Thus, patients who are deemed unsuited for tetracycline treatment because of a history of drug allergy or pregnancy, and children younger than 8 years of age who are not seriously ill should be considered for rifampin therapy. There are no published reports about the clinical efficacy of rifampin for the treatment of HME or HGEE. Studies with levofloxacin and trovafloxacin (no longer a registered medication) demonstrated some activity against A. phagocytophilum in vitro (37). However, there is no published information available about the usefulness of these antibiotic drugs or other fluoroquinolones as clinical agents in vivo.

Acute and Long-Term Prognosis of Lyme Borreliosis, Ehrlichiosis, and Anaplasmosis Lyme disease responds well to treatment, but the responses are best when treatment is instituted early in the clinical infection. A small percentage of appropriately treated patients continues to have lingering subjective symptoms called post-Lyme disease syndrome similar to chronic fatigue syndrome or fibromyalgia (10,43). However, most patients recover eventually over a period of months with minimal or no residual deficits (7,10). Epidemiologic studies and case report series indicate that HGA often is a mild, self-limited illness that resolves even without antibiotic treatment; and the long-term prognosis is favorable (31,35,44). HME may be a moderately severe infection evidenced by a death rate of approximately 3%, which is higher than for HGA (60

Medium Low

Medium Low

High Low Low

Serologic test (IFA)

Low Medium High High High

Republished with permission from Dumler JS, Walker DH. Tick-borne ehrlichioses. Lancet Infect Dis. 2001:1:21-28. Note:* Wright or Giemsa stained peripheral blood smear examination. †DH82 cells for Ehrlichia chaffeensis, HL-60 cells for Anaplasma phagocytophilum. §Different specific primers required for Ehrlichia chaffeensis and Anaplasma phagocytophilum

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Acknowledgements This work was supported in part by grant R01 AI44102 from the National Institutes of Allergy and Infectious Diseases. REFERENCES 1. McQuiston JH, Paddock CD, Holman RC, Childs JE. The human ehrlichioses in the United States. Emerg Infect Dis. 1999;5:635-42. 2. Bakken JS, Dumler JS. Ehrlichiosis and anaplasmosis. Infections in Medicine. 2004;21:433-51. 3. Steere AC. Borrelia burgdorferi (Lyme disease, Lyme borreliosis). In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 6th ed. Philadelphia, Pa: Elsevier Churchill-Livingstone; 2005:2798-809. 4. Steere AC, Malawista SE, Snydman DR, Shope RE,Andiman WA, Ross MR, et al. Lyme arthritis: an epidemic of oligoarticular arthritis in children and adults in three Connecticut communities. Arthritis Rheum. 1977;20:7-17. 5. Spielman A, Hodgson JC. The natural history of ticks: A human health perspective. In: Cunha BA, ed. Tickborne Infectious Diseases: Diagnosis and Management. New York, NY: Marcel Decker; 2000:1-14. 6. Steere AC. Lyme disease. N Engl J Med. 2001;345:115-25. 7. Shadick NA, Lew RA, Liang MH. Outcomes of Lyme Disease. Ann Intern Med. 2000;133:746-747. 8. Anonymous. Recommendations for test performance and interpretation from the Second National Conference on Serologic Diagnosis of Lyme Disease. MMWR Morb Mortal Wkly Rep. 1995;44:590-1. 9. Bakken LL, Case KL, Callister SM, Bourdeau NJ, Schell RF. Performance of 45 laboratories participating in a proficiency testing program for Lyme disease serology. JAMA. 1992;268:891-5. 10. Wormser GP, Dattwyler RJ, Shapiro ED, Halperin JJ, Steere AC, Klempner MS, et al. The clinical assessment, treatment and prevention of Lyme disease, human granulocytic anaplasmosis and babesiosis: Clinical practice guidelines by the Infectious Disease Society of America. Clin Infect Dis 2006;43:1089–1134. 11. Johnson BJ, Robbins KE, Bailey RE, Cao BL, Sviat SL, Craven RB, et al. Serodiagnosis of Lyme disease: accuracy of a two-step approach using a flagella-based ELISA and immunoblotting. J Infect Dis. 1996;174:346-53. 12. Wormser GP, Nowakowski J, Nadelman RB. Duration of treatment for Lyme borreliosis: time for a critical reappraisal. Wien Klin Wochenschr. 2002;114:613-5. 13. Wormser GP, Ramanathan R, Nowakowski J, McKenna D, Holmgren D, Visintainer P, et al. Duration of antibiotic therapy for early Lyme disease. A randomized, double-blind, placebocontrolled trial. Ann Intern Med. 2003;138:697-704. 14. Bakken JS, Dumler JS. Ehrlichia and anaplasma species. In: Yu V, Weber R, Raoult D, eds. Antimicrobial Therapy and Vaccine. 2nd ed. New York, NY: Apple Trees Productions; 2002:875-82. 15. Tick Bite Study Group. Prophylaxis with single-dose doxycycline for the prevention of Lyme disease after an Ixodes scapularis tick bite. N Engl J Med. 2001;345:79-84. 16. Dumler JS,Walker DH. Tick-borne ehrlichioses. Lancet Infect Dis. 2001;1:21-8. 17. Maeda K, Markowitz N, Hawley RC, Ristic M, Cox D, McDade JE. Human infection with Ehrlichia canis, a leukocytic rickettsia. N Engl J Med. 1987;316:853-6. 18. Anderson JF. The natural history of ticks. Med Clin North Am. 2002;86:205-18. 19. Fishbein DB, Dawson JE, Robinson LE. Human ehrlichiosis in the United States, 1985 to 1990. Ann Intern Med. 1994;120:736-43. 20. Olano JP,Walker DH. Human ehrlichioses. Med Clin North Am. 2002;86:375-92. 21. Paddock CD, Childs JE. Ehrlichia chaffeensis: a prototypical emerging pathogen. Clin Microbiol Rev. 2003;16:37-64. 22. Standaert SM, Dawson JE, Schaffner W, Childs JE, Biggie KL, Singleton J Jr., et al. Ehrlichiosis in a golf-oriented retirement community. N Engl J Med. 1995;333:420-5. 23. McQuiston JH, Childs JE, Chamberland ME,Tabor E. Transmission of tick-borne agents of disease by blood transfusion: a review of known and potential risks in the United States. Transfusion. 2000;40:274-84. 24. Standaert SM, Yu T, Scott MA, Childs JE, Paddock CD, Nicholson WL, et al. Primary isolation of Ehrlichia chaffeensis from patients with febrile illnesses: clinical and molecular characteristics. J Infect Dis. 2000;181:1082-8. 25. Bakken JS, Dumler JS, Chen SM, Eckman MR,Van Etta LL,Walker DH. Human granulocytic ehrlichiosis in the upper Midwest United States. A new species emerging? JAMA. 1994;272:212-8.

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26. Dumler JS, Barbet AF, Bekker CP, Dasch GA, Palmer GH, Ray SC, et al. Reorganization of genera in the families Rickettsiaceae and Anaplasmataceae in the order Rickettsiales: unification of some species of Ehrlichia with Anaplasma, Cowdria with Ehrlichia and Ehrlichia with Neorickettsia, descriptions of six new species combinations and designation of Ehrlichia equi and ‘HGE agent’ as subjective synonyms of Ehrlichia phagocytophila. Int J Syst Evol Microbiol. 2001;51:2145-65. 27. Bakken JS, Dumler JS. Human granulocytic ehrlichiosis. Clin Infect Dis. 2000;31:554-60. 28. Anonymous. Summary of provisional cases of selected notifiable diseases, United States, cumulative week ending Dec. 30, 2006. 29. Bakken JS, Haller I, Riddell D,Walls JJ, Dumler JS. The serological response of patients infected with the agent of human granulocytic ehrlichiosis. Clin Infect Dis. 2002;34: 22-7. 30. Bakken JS, Krueth J,Wilson-Nordskog C,Tilden RL,Asanovich K, Dumler JS. Clinical and laboratory characteristics of human granulocytic ehrlichiosis. JAMA. 1996;275:199-205. 31. Bakken JS, Goellner P, Van Etten M, Boyle DZ, Swonger OL, Mattson S, et al. Seroprevalence of human granulocytic ehrlichiosis among permanent residents of northwestern Wisconsin. Clin Infect Dis. 1998;27:1491-6. 32. Aguero-Rosenfeld ME, Donnarumma L, Zentmaier L, Jacob J, Frey M, Noto R, et al. Seroprevalence of antibodies that react with Anaplasma phagocytophila, the agent of human granulocytic ehrlichiosis, in different populations in Westchester County, New York. J Clin Microbiol. 2002;40:2612-5. 33. Aguero-Rosenfeld ME, Horowitz HW, Wormser GP, McKenna DF, Nowakowski J, Muñoz J, et al. Human granulocytic ehrlichiosis: a case series from a medical center in New York State. Ann Intern Med. 1996;125:904-8. 34. Bakken JS, Aguero-Rosenfeld ME, Tilden RL, Wormser GP, Horowitz HW, Raffalli JT, et al. Serial measurements of hematologic counts during the active phase of human granulocytic ehrlichiosis. Clin Infect Dis. 2001;32:862-70. 35. Wallace BJ, Brady G,Ackman DM,Wong SJ, Jacquette G, Lloyd EE, et al. Human granulocytic ehrlichiosis in New York. Arch Intern Med. 1998;158:769-73. 36. Buller RS,Arens M, Hmiel SP, Paddock CD, Sumner JW, Rikhisa Y, et al. Ehrlichia ewingii, a newly recognized agent of human ehrlichiosis. N Engl J Med. 1999;341:148-55. 37. Maurin M, Bakken JS, Dumler JS. Antibiotic susceptibilities of Anaplasma (Ehrlichia) phagocytophilum strains from various geographic areas in the United States. Antimicrob Agents Chemother. 2003;47:413-5. 38. Brouqui P, Raoult D. In vitro antibiotic susceptibility of the newly recognized agent of ehrlichiosis in humans, Ehrlichia chaffeensis. Antimicrob Agents Chemother. 1992;36:2799-803. 39. Anonymous. Ehrlichia infections (human ehrlichioses). In: Pickering LK, ed. Red Book: 2003, Report of the Committee of Infectious Diseases. 26th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2003:266-9. 40. Buitrago MI, Ijdo JW, Rinaudo P, Simon H, Copel J, Gadbaw J, et al. Human granulocytic ehrlichiosis during pregnancy treated successfully with rifampin. Clin Infect Dis. 1998;27:213-5. 41. Elston DM. Perinatal transmission of human granulocytic ehrlichiosis [Letter]. N Engl J Med. 1998;339:1941-2; author reply 1942-3. 42. Krause PJ, Corrow CL, Bakken JS. Successful treatment of human granulocytic ehrlichiosis in children using rifampin. Pediatrics. 2003;112:e252-3. 43. Shadick NA, Phillips CB, Sangha O, Logigian EL, Kaplan RF,Wright EA, et al. Musculoskeletal and neurologic outcomes in patients with previously treated Lyme disease. Ann Intern Med. 1999;131:919-26. 44. Belongia EA, Reed KD, Mitchell PD, Mueller-Rizner N,Vandermause M, Finkel MF, et al. Tickborne infections as a cause of nonspecific febrile illness in Wisconsin. Clin Infect Dis. 2001;32:1434-9. 45. Paddock CD, Folk SM, Shore GM, Machado LJ, Huycke MM, Slater LN, et al. Infections with Ehrlichia chaffeensis and Ehrlichia ewingii in persons coinfected with human immunodeficiency virus. Clin Infect Dis. 2001;33:1586-94. 46. Walker DH, Bakken JS, Brouqui P, et al. Diagnosing human ehrlichioses: Current status and recommendations. Am Society Microbiol News. 2000;5:287-93. 47. Bakken JS, Dumler JS. Ehrlichiosis In: Cunha BA, ed. Tickborne Infectious Diseases. Diagnosis and Management. New York, NY: Marcel Decker; 2000:139-68. 48. Bacon RM, Mead PS, Kool JL, Postema AS, Staples JE. Lyme disease: United States 2001-2002. MMWR Morb Mortal Wkly Rep. 2004;53:365-9.

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Chapter 44

Malaria KEITH B. ARMITAGE, MD CHARLES H. KING, MD

Key Learning Points 1. Malaria continues to be major cause of morbidity and mortality in many parts of the developing world. 2. With Plasmodium infection, travelers from developed contries are highly likely to develop clinically severe malaria because they lack any prior immunity. 3. Optimal strategies for prevention and treatment of malaria continue to evolve rapidly due to the emergence of resistant organisms and the consequent introduction of many classes of anti-malarial drugs. 4. The clinical presentation of malaria is heterogeneous, with fever being the only sign or symptom that is reliably present. 5. Malaria should always be suspected and tested for in any traveler who presents with fever after returning from malarial areas.

A

mong parasitic infections, malaria is the leading cause of death worldwide. An estimated 500 million cases occur in the world per year, with one to two million deaths (1,2). Among immigrants and travelers returning from malarious areas, malaria should be considered as a possible diagnosis in any individual with fever, and diagnostic steps should be promptly undertaken to exclude infection with the Plasmodium parasites that cause malaria (3). The four species of Plasmodium that cause malaria (i.e., P. falciparum, P. vivax, P. ovale, and P. malariae) are widely distributed throughout the world in tropical and subtropical areas where the insect vector of malaria, the anopheline mosquito, thrives (Table 44-1). Malaria is common in Africa, India, Pakistan, Southeast Asia, Papua New Guinea, the southwestern Pacific 853

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New Developments in the Management of Malaria ●

●

●

Changing patterns of drug resistance make it essential to review the latest prescribing information when giving drugs for treatment or prevention of malaria. The CDC web site is reliable and up-to-date. Malarone (atovaquone/proguanil) is a useful alternative to mefloquine for prevention of chloroquine-resistant P. falciparum malaria, and can be used in patients who have experienced neuropsychiatric side effects from mefloquine. Artemesinin compounds, traditionally used to treat fever in China, have strong antimalarial activity, and produce rapid clinical improvement in infected patients. However, when used alone, they are associated with a high risk for relapse, and they should always be used in combination with other anti-malarial drugs. Artemesinins are currently not available in the United States.

States, Haiti, and parts of South America. In the United States, it is often the primary care provider who plays a crucial role in recognizing risk for malaria among immigrants and travelers, and in implementing a diagnostic evaluation to rule out malaria at the earliest signs of possible symptomatic infection. The post-World War II optimism about eliminating malaria by controlling its mosquito vectors or through mass treatment of human cases has given way to the reality of a world in which Plasmodium species are re-expanding their territory and are now multiply drug-resistant (1,4). Today, there is an increasing resurgence of malaria in many parts of the world (2,5). Nonetheless, except for rare instances of secondary transmission of the disease from imported cases, malaria transmission has been eliminated from the United States, Puerto Rico, Jamaica, Chile, Israel, Lebanon, North Korea, and Europe. However, malaria is still found in varying degrees in all other areas of the world in which the climate is tropical or subtropical. In some parts of the world, notably sub-Saharan Africa, transmission occurs in both urban and rural settings. In most of Central and South America, malaria is found primarily in rural areas.

Etiology Malaria is transmitted by the bite of the female anopheline mosquito during the taking of a blood meal. The infectious sporozoite form of the Plasmodium parasite leaves the salivary glands of the mosquito and enters the host’s skin. Sporozoites quickly enter the circulation to reach the liver. There, they invade hepatocytes and reproduce asexually for 10 to 14 days. After this asymptomatic incubation phase, Plasmodium merozoites emerge from the liver to infect host erythrocytes within the circulation. From this point forward, growth and reproduction of malaria parasites take place within the erythrocyte. Two to three days after an erythrocyte is infected,

No 8–25 days (average 12 days) Multiple infected RBCs, predominate rings, double nuclei, banana-shaped gametocytes

Central and South America, Haiti, Dominican Republic, SubSaharan Africa, India Pakistan, Southeast Asia High parasitemia, severe anemia, (often) daily spiking fevers, cerebral malaria, renal failure, , jaundice pulmonary edema, death Yes

P. vivax

Yes, in Southeast Asia Yes 8–27 days (average 14 days) Enlarged RBCs with Schuffner’s dots; trophozoite cytoplasm may be ameboid

Anemia, splenic rupture

Sub-Saharan Africa, Central and South America Asia

P. ovale

Yes 8–17 days (average 15 days Oval RBCs with fringed edges, compact cytoplasm

No

Anemia, splenic rupture

Sub-Saharan Africa, Southeast Asia, New Guinea

P. malaria

No 15–30 days (average 15 days) RBCs unchanged

No

Persistent infection nephritis

Sub-Saharan Africa,

Malaria

RBC = red blood cells.

Appearance on thin film

Chloroquine resistance Relapse Incubation period

Clinical features

Geographic distribution

Plasmodium falciparum

Table 44- 1 Summary of Plasmodium Species

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the parasite completes its growth and asexual division. A new generation of merozoites then matures and emerges into the plasma by rupturing the erythrocyte wall. Each merozoite is then capable of infecting a new erythrocyte. In this cyclic manner, the level of infected erythrocytes increases in geometric fashion. The process of parasite development within the erythrocyte cytoplasm takes 48 hours in the case of P. falciparum, P. vivax, and P. ovale, and 72 hours in the case of P. malariae. Typically, cyclic systemic inflammation occurs in conjunction with the synchronous rupture of several infected erythrocytes, accounting for the periodicity of fever in malaria (6). In the case of P. falciparum, the merozoite is capable of infecting erythrocytes of all ages and stages of development, with the potential for massive hemolysis, severe anemia, and renal failure (7). Other Plasmodium species are not capable of infecting erythrocytes in all stages of development, and so, generally do not cause such severe complications. Malaria caused by P. vivax and P. ovale is, therefore, not so potentially lethal as malaria caused by P. falciparum. The life cycle of malaria parasites is completed when a subpopulation of merozoites develops into male and female gametocytes. When these are taken in a blood meal by a female anopheline mosquito, they mate (in sexual reproduction) within the insect abdomen and ultimately produce new sporozoites. These sporozoites migrate to the mosquito’s salivary glands to initiate infection of a new host during the next blood meal (1). Without the continued presence of mosquitoes of the right vector species, endemic transmission of malaria cannot occur. In temperate areas such as the United States, brief epidemics can occur rarely in the summer months if anopheline mosquitoes flourish in a region where chronically infected humans are harboring asymptomatic malaria (8). This is extremely uncommon, and the great majority of malaria in the United States is seen in immigrants from or travelers to endemic areas (9). Other North American cases have been caused by blood-borne transmission of malaria parasites (i.e., by transfusion or by needle sharing among injection-drug abusers). This is because merozoites in donor erythrocytes can directly infect new erythrocytes in the recipient’s circulation. In transfusion-transmitted malaria, there is no initial liver stage of infection. Because of this, late recrudescence of malaria from dormant liver hypnozoites will not occur with transfusion-associated malaria, although this often happens after initial treatment of mosquitotransmitted P. vivax and P. ovale malaria.

Clinical Manifestations Infection with malaria parasites leads to hemolysis, anemia, tissue hypoxia, and secondary immunopathologic processes caused by the release of inflammatory cytokines (6). Together, these processes account for the clinical signs and symptoms of malaria, which in the case of P. falciparum malaria can be

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severe or fatal. The symptoms of acute malaria can be variable, depending on both parasite and host factors. High fevers and rigors are the hallmark of acute malaria, and malaria should be considered in any individual with an exposure history and any type of fever (3). In addition, malaise, headaches (often severe), myalgias, and fatigue frequently occur. Other symptoms, such as nausea, diarrhea, and cough can mimic abdominal disease or pneumonia. Patients may not have a synchronous infection, and the classic periodicity of fever (quartan or tertian fever) does not have to be present. In particular, patients with P. falciparum infection often present with daily spiking fevers. Patients can also have double infection with two or more species of malaria parasite (10). This frequently results in an inconstant pattern of fever spikes. Hepatosplenomegaly, pallor, and mild jaundice are common clinical signs in patients with acute malaria. Highly immune adults from endemic areas can be infected but minimally symptomatic or asymptomatic. Such infection is often documented among recent immigrants and refugees. In this setting, if anopheline mosquitoes are also locally present, then there is the potential for personto-person transmission of malaria in the immediate neighborhood, even within nontropical climates (8). Cerebral malaria is the most severe form of malaria, causing more than 80% of fatalities from malaria (11,12). It is caused only by P. falciparum infection and occurs in 0.5% to 1% of cases, with a death rate of approximately 50%. Patients with cerebral malaria often present with seizures, stupor, and focal neurological symptoms (1). The other severe complications of falciparum malaria include acute renal failure, pulmonary edema, hypoglycemia, and shock. Partly-treated patients, or those with partial immunity, can have continued subclinical P. falciparum infection, and symptomatic relapse with falciparum malaria can occur for up to 1 year. Late relapses caused by a latent phase of infection in the liver are seen in P. vivax and P. ovale infection, but unlike P. vivax and P. ovale, P. falciparum does not have a latent liver phase, and will be eradicated if the erythrocyte stage of disease is eliminated (4).

Diagnosis The clinical gold-standard diagnosis of malaria rests on microscopy, with the demonstration of the parasites on Giemsa-stained blood smears. Thick blood smears are used as a sensitive screening test, whereas thin blood smears are necessary for species identification and estimation of the percentage of erythrocytes infected (3). This latter number gauges the severity of infection. The presence of the parasites in the blood can fluctuate, and many smears (separated by approximately 12 hours) should be done during the 24 to 48 hour fever cycle—many negative smears are required before the diagnosis of malaria can be ruled out. Even if blood smears are

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initially negative, treatment should not be delayed if the clinical suspicion of severe malaria is high (3). Detection of circulating antigen is an alternative approach to diagnosis of falciparum malaria. Sensitivity and specificity are good, but does not exceed the performance characteristics of expert microscopy. Polymerase chain reaction (PCR)-based diagnosis is an emerging tool for diagnosis in research settings, with a much greater sensitivity for mixed Plasmodium species infections than with microscopy (10,13).

Treatment Antimalarial drugs are used for both the prophylaxis and treatment of infection caused by Plasmodium species. Decisions on the choice of therapy are based on: (a) the clinical suspicion of P. falciparum as the causative organism, (b) the severity of the infection, and (c) the known drug-resistance patterns for the areas in which the patient has traveled. Given the complexity of treatment regimens, consultation with an infectious disease specialist or other highly experienced clinician is appropriate when contemplating treatment of possible cases of symptomatic malaria. The selection of a specific drug or drug combination depends on the malaria species involved, local drug availability, and whether the patient is treated as an inpatient or outpatient. Resistance patterns of malaria parasites continue to evolve, and new therapeutic agents, such as the artemether compounds, are becoming more generally available. It is imperative to have up-to-date information when treating malaria. The Centers for Disease Control and Prevention (CDC) Malaria Hotline (770-488-7788, M-F 8 a.m.-4:30 p.m.; 770-488-7100 other times) and the CDC Internet site (www.cdc.gov) are good sources for up-to-date information.

Chloroquine Phosphate Chloroquine phosphate is a 4-aminoquinoline used primarily for the treatment and prevention of infection by P. vivax, P. malariae, P. ovale, and sensitive strains of P. falciparum. Chloroquine-sensitive strains of P. falciparum are now rare, and are found in only a few geographic areas. Chloroquine can be given orally with food or injected parenterally. Parenteral dosing can be associated with respiratory depression, hypotension, cardiac arrest, and seizures, particularly after rapid administration of chloroquine. Parenteral therapy should be used only for patients unable to take oral medicine, and patients should be switched to the oral route as soon as possible. Oral doses of chloroquine are absorbed to an extent exceeding 90%, and intramuscular and subcutaneous doses are also rapidly absorbed. Because of the large volume of distribution of chloroquine, a loading dose is required. The drug undergoes extensive metabolism, and the kidney

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excretes approximately 50%. Renal failure does not change the therapeutic dose of chloroquine, but prophylactic doses should be reduced. The precise mechanism of action of chloroquine is unknown; it is known that chloroquine raises the pH of lysosomal vesicles of Plasmodium, and inhibits the proteolysis of hemoglobin. In treating malaria, chloroquine is active against the asexual erythrocytic stages of sensitive strains of the causative parasites, and its administration leads to rapid clinical improvement. Chloroquine is therefore indicated for the erythrocytic stage of development of sensitive strains of Plasmodium species. Unfortunately, in most areas of the world P. falciparum is chloroquine-resistant, and can be resistant to second-line drugs as well (4); in addition, there have been reports of P. vivax chloroquine resistance in Papua New Guinea and Indonesia (3). Chloroquine has no exoerythrocytic activity and therefore is of no use against tissue stages of the life cycle of malarial parasites. When used to treat the erythrocytic stages of P. vivax and P. ovale, it must be followed with an agent such as primaquine that is active against the tissue hepatic phase, to completely eradicate infection (i.e., effect a radical cure). Chloroquine phosphate (Aralen) is supplied as 250- and 500-mg tablets (containing 150- and 300-mg base). Hydroxychloroquine sulfate (Plaquenil) is supplied in 200-mg tablets, and for dosing purposes, 400 mg of hydroxychloroquine sulfate is equal to 500 mg of chloroquine phosphate. Chloroquine hydrochloride for injection is supplied at a concentration of 50 mg/mL. For malaria prophylaxis against sensitive strains, 500 mg of chloroquine is given once a week. Prophylactic dosing is started 1 to 2 weeks before exposure and is continued for 4 weeks after exposure (Table 44-2). The dose of chloroquine for treatment of acute infection is 1 g, followed by 500 mg 6 to 8 hours later, with subsequent dosing at 500 mg/day for 2 days, for a total dose of 2.5 g. Parenteral dosing schedules are not as well established, but chloroquine can be given in a dose of 3.5 mg/kg every 6 hours to a total dose of 2.5 g. Children should not be given more than 10 mg/kg of chloroquine base per day regardless of the route of administration (Table 44-3), and their usual prophylactic dosage of chloroquine base is 5 mg/kg/wk (see Table 44-2). Common side effects of the treatment dose of chloroquine (used in acute malaria attacks) include gastrointestinal upset, pruritus, headache, and visual disturbance. As noted earlier, intravenous preparations are available, but should be used cautiously, because rapid infusion of chloroquine can lead to cardiovascular collapse. The prophylactic dose is usually well tolerated, although prolonged use can lead to skin eruptions and changes in the fingernails. Prolonged use of chloroquine in high daily doses has been associated with more serious side effects such as myopathy and neuropathy. Chloroquine is contraindicated in severe hepatic disease, psoriasis, and porphyria.

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Table 44-2 Prophylaxis of Malaria Organism

Drug

Adult Dosage

Pediatric Dosage

Chloroquineresistant Plasmodium falciparum*

Mefloquine (Lariam)

250 mg/wk PO Begin 1 week before exposure Continue 4 weeks after exposure 100 mg/d PO Begin 2 days before exposure Continue 28 days after exposure Proguanil 200 mg/d PO plus chloroquine as below

5–9 kg: 1/8 tablet 10–19 kg: 1/4 tablet 20–30 kg: 1/2 tablet 31–45 kg: 3/4 tablet >45 kg: adult dosage Contraindicated in children 40 kg: adult dosage 8.3 mg/kg/wk (5-mg base)

PO = orally. * Chloroquine-resistant Plasmodium falciparum prophylaxis is also effective for Chloroquine-sensitive P. falciparum.

Mefloquine Mefloquine is a quinoline-carbinolamine compound active against chloroquine-resistant P. falciparum in most parts of the world, and is used for the prophylaxis and treatment of malaria where chloroquine resistance is likely. It is available only in oral form. Mefloquine has a long half-life, with an elimination time of 2 to 3 weeks. It is excreted in the feces, and dose adjustments do not need to be made in renal failure. The mechanism of action of mefloquine is unknown, but is probably similar to that of chloroquine. Like chloroquine, mefloquine is active only against the erythrocytic forms of P. falciparum. In the United States, mefloquine is sold under the trade name Lariam and is supplied as 250-mg tablets.

Quinine dihydrochloride++

10 mg/kg loading dose (maximum 600 mg) infused in NS over 1-2 hours, then 0.02 mg/kg/min for 72 hours+ 20 mg salt/kg loading dose in D5W over 4 hours, then 10 mg salt/kg over 2-4 hours every 8 hours (maximum

900 mg tid for 7 days 750 mg PO initial dose followed by 500 mg PO 6-12 h later 4 mg/kg/d PO for 3 days 750 mg PO initial dose followed by 500 mg PO 6-12 h later

250 mg qid for 7 days

Same as adult dosage


Continued

650 mg PO tid for 3-7 days 100 mg bid for 7 days

a

Quinine sulfate plus one of the following: Doxycycline OR Tetracycline OR Clindamycin Mefloquine (Lariam) also effective for chloroquineresistant P.vivax Artesunate++ plus Mefloquine Parenteral Therapy Quinidine gluconate

5 - 8 kg: 0.5 adult tablet per day 11-20 kg: 1 adult tablet per day 21-30 kg: 2 adult tablets per day 31-40 kg: 3 adult tablets per day 25 mg/kg/d divided in three doses for 3-7 days 4 mg/kg/d divided in 2 doses for 7 days* 25 mg/kg/d divided in 4 doses* for 7 days 20-40 mg/kg/d divided in 3 doses for 7 days 15 mg/kg PO as initial dose, followed by 10 mg/kg PO 6-12 h later 4 mg/kg/d PO for 3 days 15 mg/kg PO as initial dose, followed by 10 mg/kg PO 6-12 h later

4 tablets PO per day for 3 days

Atovaquone/ proguanil (Malarone)

Chloroquineresistant Plasmodium falciparum

Pediatric Dosage

Adult Dosage

Drug Options

Organism

Table 44-3 Treatment of Malaria

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Atovaquone/ proguanil (Malarone)

and (as needed) Primaquine phosphate# 30 mg/d base PO (52 mg phosphate salt) for 14 days, or 45 mg/week base PO for 8 weeks for more resistant strains 4 tablets PO per day for 3 days

.

5-8 kg: 0.5 adult tablet per day 11-20 kg: 1 adult tablet per day 21-30 kg: 2 adult tablets per day 31-40 kg: 3 adult tablets per day for 3 days

0.6 mg/kg/d base (1 mg/kg salt) for 14 days

15 mg/kg PO, followed by 7.5 mg/kg six hours later, then 7.5 mg/kg on days 2 and 3

Artemether++

Chloroquine phosphate (Aralen)


1800 mg/d) for 72 hours+ or until patient is able to take oral medication 3.2 mg/kg IM, then 1.6 mg/kg daily for 5-7 days 1000 mg PO, then 500 mg six hours later, then 500 mg on days 2 and 3

Footnotes: Abbreviations– PO = orally, NS = normal saline, D5W = 5% dextrose in water * not recommended for children less than 8 years old + cardiac, blood pressure, and glucose monitoring is required. Loading dose should be decreased in those who have previously received quinine or mefloquine. Switch to oral therapy when patient is stable. If prolonged parenteral therapy beyond 72h is required, quinine or quinidine dose should be reduced 30-50% after this initial period. ++ not available in the United States # for the prevention of relapse due to P. vivax and P. ovale

Alternative:

Chloroquinesensitive P. falciparum and P. vivax, P. ovale, and P. malariae

Pediatric Dosage

Adult Dosage

Drug Options

862

Organism

Table 44-3 Continued

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The most common prophylactic dosing schedule with mefloquine is 250 mg/week, beginning 1 week before travel. The drug should be continued for 4 weeks after the last exposure (see Table 44-2). A single dose of 1000 to 1500 mg of mefloquine is used for treating chloroquine-resistant falciparum malaria. Side effects are uncommon at doses of less than 1000 mg; nausea, vomiting, abdominal pain, and dizziness have been reported. Serious side effects of the central nervous system, such as seizures, hallucinations, psychosis, and depression, occur rarely at prophylactic doses (5% to 10%) or massive hemolysis should be treated with exchange transfusion in combination with drug therapy (3). Parenteral quinine is not available in the United States. Quinidine, a stereoisomer of quinine, can be used in its place for patients who need parenteral therapy for malaria. Quinidine is given by continuous intravenous infusion. The most commonly used dosing schedule is 10 mg/kg in

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a loading dose over 1 to 2 hours, followed by continuous infusion of 0.02 mg/kg/min until oral quinine therapy can be safely substituted (see Table 44-3). Quinidine undergoes hepatic metabolism and is excreted in the urine. Blood levels of this drug should be followed closely in patients with hepatic or renal failure. Because it has been for the most part supplanted as an anti-arrhythmic by newer drugs, parenteral quinidine gluconate can be difficult to obtain. If local hospital pharmacies or distributors do not have it in stock, the manufacturer, Eli Lilly Co, can be contacted directly (800-821-0538) to expedite shipment (3). Pending the availability intravenous therapy for severe malaria, intrarectal or intramuscular quinine therapy is an effective alternative (16). As for oral therapy, parenteral quinine or quinidine therapy should be combined with a second antimalarial, such as doxycycline (100 mg every 12 h) or clindamycin (5 mg base/kg every 8 hours), both of which can be given by infusion. Intravenous quinine and quinidine can cause hypotension and serious cardiac arrhythmias, particularly when given in bolus doses, and cardiac monitoring should be used during the entire period of their administration. The fatal oral dose of quinine for adults is 2 to 8 g, and care should be taken to keep this drug safe from children, who might accidentally overdose. Oral quinine is associated with various side effects including nausea, vomiting, diarrhea, and hypoglycemia, and can prove ineffective in pediatric cases because of patient refusal (17). Dosing with meals decreases gastrointestinal side effects. Dose-related side effects include tinnitus, headache, changes in vision, and vertigo. Tinnitus, optic neuritis, and hypersensitivity reactions are contraindications to the use of quinine.

Pyrimethamine Pyrimethamine is a dihydrofolate-reductase inhibitor that is highly active against this enzyme in malaria parasites. It is used in the prophylaxis and treatment of resistant falciparum malaria. Pyrimethamine is well absorbed orally and has an extremely long tissue half-life (80-95 hours). It is particularly effective when used in combination with other folic acid antagonists, and such combination therapy delays the emergence of resistance. A common pyrimethamine/sulfa drug combination used for malaria is Fansidar, which consists of pyrimethamine 25 mg and sulfadoxine 500 mg. In other countries, pyrimethamine in a dose of 12.5 mg is also available in combination with dapsone in a dose of 100 mg as Maloprim, but this formulation is not available in the United States. Pyrimethamine in a single dose of 75 mg in combination with a sulfa drug is used for treating acute attacks of falciparum malaria. However, increasing resistance of P. falciparum to the pyrimethamine/sulfa combination has been encountered in Asia and East Africa, and in these areas, antifolate drug therapy is no longer recommended as first-line treatment (4). In treating acute malaria, quinine is frequently used in combination with pyrimethamine,

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because pyrimethamine acts slowly in clearing parasitemia (see Table 44-3). The pediatric therapeutic dose of pyrimethamine is one fourth of a 25-mg tablet for children 2 to 11 months of age, one half of a tablet for children 1 to 3 years of age, one tablet for children 4 to 8 years of age, and two tablets for children 9 to 14 years of age. Children older than 14 years of age take the adult dose (three tablets). Long-term prophylactic use of pyrimethamine/sulfa combinations (Fansidar) has been associated with severe cutaneous skin reactions, and is no longer recommended. Mefloquine, atovaquone/proguanil, and doxycycline have largely supplanted the use of pyrimethamine/sulfa combinations (4,18). There have been no reports of fatal cutaneous reactions to Fansidar when the drug is used only for acute febrile episodes of malaria. High doses of pyrimethamine lead to megaloblastic anemia, which can be prevented with concurrent use of folinic acid (leucovorin).

Proguanil (Chloroguanide) Like pyrimethamine, proguanil (chloroguanide) is an inhibitor of protozoan dihydrofolate reductase. The drug is well absorbed orally, is readily excreted, and does not accumulate in the body. To be effective for prophylaxis of malaria it must be taken daily. Proguanil is used in the prophylaxis of resistant falciparum malaria (see Table 44-2), particularly as an alternative to pyrimethamine/sulfa in East Africa. For reasons that are not clear, proguanil is less effective in West Africa. The prophylactic dosage is 200 mg/day, and is associated with few side effects (occasional mouth ulcers, nausea, and diarrhea). In areas where P. falciparum is resistant to chloroquine, the combination of daily proguanil and weekly chloroquine is only approximately 75% effective in preventing falciparum malaria, as opposed to an efficacy of more than 95% for mefloquine. In addition, the need for a daily dose of proguanil (vs. weekly dosing with mefloquine) can lead to diminished compliance with its use. The more effective combination of proguanil/ atovaquone is described next.

Proguanil/Atovaquone (Malarone) In April 2000, the combination of proguanil and the hydroxynaphthoquinone antimalarial agent, atovaquone, was approved by the FDA for prophylaxis and therapy for malaria, including strains of P. falciparum that are resistant to chloroquine. The trade name for this combination of atovaquone 250 mg and proguanil 100 mg is Malarone. The pediatric-strength tablet contains 62.5 mg of atovaquone and 25 mg of proguanil. Malarone is generally well tolerated and should be taken with food. For prophylaxis, Malarone is given once daily, beginning 2 days before exposure and continuing for 7 days after exposure. Malarone prophylaxis is often used as an alternative

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to mefloquine if there are concerns about neuropsychiatric side effects. Malarone also can be used in the therapy for uncomplicated chloroquineresistant P. falciparum (and other strains of malaria) at a dosage of four pills per day for 3 consecutive days.

Primaquine Primaquine, an 8-aminoquinoline, is the prototype antimalarial drug for tissue stages of malarial infection. The drug is well absorbed orally and is extensively metabolized. Primaquine interferes with the mitochondrial function of Plasmodium species. It is primarily used to treat the liver phase of malaria caused by P. vivax and P. ovale. Patients treated for the blood phase of P. vivax or P. ovale malaria must receive treatment of the tissue phase to prevent relapse of their infection. By contrast, infection with P. falciparum does not have a long-term hepatic stage, and primaquine is not needed when the erythrocytic phase of falciparum malaria is successfully treated. However, patients who acquire P. falciparum malaria, and who are not taking chloroquine or other prophylaxis, should be treated with primaquine, because coinfection with another species of malarial parasite is quite common (10), and relapses of this latter P. vivax or P. ovale infection can occur if no treatment is given for the hepatic stage of those diseases. The dose of primaquine is expressed in terms of its base compound. Primaquine is supplied in tablets containing 26.3 mg of the salt, which is equal to 15 mg of free primaquine base. Primaquine at 30 mg/day in combination with chloroquine cures malaria caused by sensitive strains of P. vivax. For more resistant strains, 45 mg of primaquine is given with chloroquine weekly for 8 weeks (see Table 44-3). Primaquine should always be given with a schizonticidal agent (preferably chloroquine) in acute vivax or ovale malaria to prevent the development of resistance. At higher doses, primaquine can cause gastrointestinal distress; however, the major toxicity is related to the drug’s redox potential. In high doses primaquine can cause methemoglobinemia. In glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals, primaquine at its usual doses provokes hemolysis, and patients should be screened for G6PD deficiency before any primaquine prophylaxis or treatment. With higher doses of primaquine or in susceptible patients, the erythrocyte count should be followed. Primaquine can rarely cause central nervous system toxicity. Agranulocytosis has also been reported, and primaquine is contraindicated in patients with neutropenia. Primaquine should also not be used during pregnancy (3).

Artemisinin (Qinghaosu) The artemisinins (qinghaosu) are members of a group of related compounds, traditionally used to treat fever in China, that have recently been demonstrated to have strong antimalarial activity (19). Artemether and artesunate

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compounds are emerging as an alternative therapy for resistant falciparum malaria, and have been used extensively in Southeast Asia. These compounds (see next paragraph) are among the most rapidly schizonticidal drugs available. The mechanism of their action is not well understood, but is thought to be mediated by free radical damage to parasite membranes. Artesunate is commonly given orally or as a suppository for nonsevere malaria. The oral dose is 4 mg/kg/day given over a period of 3 days. Intramuscular administration of artemether is used in cases of severe malaria where other parenteral therapy is not available. For this route of administration, 3.2 mg/kg is given intramuscularly (IM) as a loading dose, followed by 1.6 mg/kg daily for 5 to 7 days. Recently, experts have suggested the use of combination therapy, that is, artemisinin (short-acting) along with a longacting agent such as mefloquine or lumefantrine, for optimal treatment of P. falciparum malaria, to effect rapid clearance and limit the risk of rebound recrudescence of infection (1,4). Severe toxicities with artemisinin and its related compounds are rare. Transient first-degree heart block, abdominal pain, diarrhea, fever, and cytopenias have been reported, but are uncommon, and artemisinin compounds described here are generally well tolerated. Although, their safety in pregnancy has not been formally established, risk-benefit evaluation in individual cases can favor their use in high-risk pregnant patients (15).

Halofantrine Halofantrine is a 9-phenathrenemethanol effective against chloroquinesensitive and chloroquine-resistant falciparum malaria. The drug is available only in oral form; it is best absorbed when taken with a fatty meal. Halofantrine is excreted in the feces. The mechanism of action of this drug is not known. Like chloroquine and mefloquine, it is active only against the intraerythrocytic stages of Plasmodium species. Halofantrine is used in areas where there is resistance to chloroquine and mefloquine. There is some evidence of cross-resistance with mefloquine, which can limit the future usefulness of halofantrine. Administration consists of three 500-mg doses given at 6-hour intervals for adults and children weighing more than 40 kg, and 8 mg/kg given at the same 6-hour intervals for children weighing less than 40 kg. A second course of treatment after 7 days is recommended for nonimmune patients who were not previously exposed to malaria. The most common side effects of halofantrine are headache, nausea, abdominal pain, diarrhea, and rash. The use of halofantrine is contraindicated in pregnancy and for lactating women.

Tetracycline Members of the tetracycline family can be used to treat multiply-drug–resistant falciparum malaria. They are slow to act and should be used with quinine. Tetracycline is given orally at a dosage of 250 mg four times daily. The

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equivalent dosage of doxycycline is 100 mg twice daily (see Table 44-3). Doxycycline can also be used for short-term prophylaxis of malaria at a dosage of 100 mg/day (see Table 44-2). Tetracyclines are associated with sun sensitization, and should not be used in children younger than 8 years of age, or during pregnancy (3,4,15).

Choice of Therapy In mild cases of malaria, oral quinine or proguanil/atovaquone should be used for treatment if falciparum malaria is suspected and is likely to be chloroquineresistant. Severe infections, especially those marked by infection of more than 5% of erythrocytes, as measured on a thin blood smear, require parenteral treatment with quinidine or quinine (if available) and close monitoring (3). Chloroquine-sensitive falciparum malaria and malaria caused by other Plasmodium species can be treated with oral or parenteral chloroquine, bearing in mind that rare chloroquine-resistant P. vivax have been reported in Papua New Guinea, Indonesia, and Oceania. Patients with P. vivax and P. ovale should also be treated with primaquine for the latent liver phase of disease and to prevent relapse (see Table 44-3).

Prevention Prevention of malaria is based on reducing mosquito exposure in endemic areas, and on the use of low-dose antimalarial therapy to inhibit the progression of early, subclinical infection. Among people residing in endemic areas, research data indicate that reduction in the overall number of mosquito bites per annum will significantly alter the risk of death from malaria. The same is true for reducing the exposure of travelers in malaria-endemic zones. Mosquito control can be achieved through the widespread or focused use of insecticides, by screening, and by the use of insect repellents. In the 1950s, many nations were able to significantly reduce their malaria prevalence through peridomestic spraying with dichlorodiphenyltrichloroethane (DDT). This approach proved to be environmentally toxic, however, and spraying programs have been significantly curtailed (1). In recent years, focused use of permethrin insecticide-impregnated bed nets has proven effective in reducing transmission of malaria in endemic populations. Personal use of insect repellent has also been shown to reduce the risk of infection in travelers (20). In addition to vector avoidance, drug prophylaxis with chloroquine, mefloquine, or proguanil/atovaquone, as described earlier in the section on treatment of malaria, further reduces the risk of acquiring symptomatic malaria (21). Antimalaria vaccines are under development, but are strictly investigational, and their usefulness is not yet proven.

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Summary In the first decade of the new millennia, malaria remains a threat to residents and visitors in most tropical and subtropical areas of the world. Changing epidemiology, evolving drug resistance, and the development of new drugs will continue to challenge internists and other providers in managing patients with malaria and advising appropriate prophylaxis. Providers should continue to seek the latest information when presented with these challenges. But despite these changes, the key management principle for physicians remains—malaria should always be suspected and looked for in travelers returning from malaria areas who present with fever.

REFERENCES 1. Greenwood BM, Bojang K,Whitty CJ,Targett GA. Malaria. Lancet. 2005;365:1487-98. 2. Krogstad DJ. Malaria as a reemerging disease. Epidemiol Rev. 1996;18:77-89. 3. Center for Disease Control and Prevention. Treatment of malaria (guidelines for clinicians). Available at: http://www.cdc.gov/malaria/pdf/clinicalguidance.pdf. 4. Baird JK. Effectiveness of antimalarial drugs. N Engl J Med. 2005;352:1565-77. 5. Olliaro P, Cattani J,Wirth D. Malaria, the submerged disease. JAMA. 1996;275:230-3. 6. Schofield L, Grau GE. Immunological processes in malaria pathogenesis. Nat Rev Immunol. 2005;5:722-35. 7. Chotivanich K, Udomsangpetch R, Simpson JA, Newton P, Pukrittayakamee S, Looareesuwan S, et al. Parasite multiplication potential and the severity of Falciparum malaria. J Infect Dis. 2000;181:1206-9. 8. Zucker JR. Changing patterns of autochthonous malaria transmission in the United States: a review of recent outbreaks. Emerg Infect Dis. 1996;2:37-43. 9. Angell SY, Cetron MS. Health disparities among travelers visiting friends and relatives abroad. Ann Intern Med. 2005;142:67-72. 10. Mehlotra RK, Lorry K, Kastens W, Miller SM,Alpers MP, Bockarie M, et al. Random distribution of mixed species malaria infections in Papua New Guinea. Am J Trop Med Hyg. 2000;62:225-31. 11. Engwerda CR, Good MF. Interactions between malaria parasites and the host immune system. Curr Opin Immunol. 2005;17:381-7. 12. Severe and complicated malaria. World Health Organization, Division of Control of Tropical Diseases. Trans R Soc Trop Med Hyg. 1990;84 Suppl 2:1-65. 13. Blossom DB, King CH, Armitage KB. Occult Plasmodium vivax infection diagnosed by a polymerase chain reaction-based detection system: a case report. Am J Trop Med Hyg. 2005;73:188-90. 14. Croft AMJ, Garner P. Mefloquine for preventing malaria in non-immune adult travelers. Cochrane Database Syst Rev. 2005;CD:000138. 15. Whitty CJ, Edmonds S, Mutabingwa TK. Malaria in pregnancy. BJOG. 2005;112:1189-95. 16. Eisenhut M, Omari A, MacLehose HG. Intrarectal quinine for treating Plasmodium falciparum malaria: a systematic review. Malar J. 2005;4:24. 17. Maitland K, Nadel S, Pollard AJ,Williams TN, Newton CR, Levin M. Management of severe malaria in children: proposed guidelines for the United Kingdom. BMJ. 2005;331: 337-43. 18. White NJ. The treatment of malaria. N Engl J Med. 1996;335:800-6. 19. Woodrow CJ, Haynes RK, Krishna S. Artemisinins. Postgrad Med J. 2005;81:71-8. 20. Fradin MS. Mosquitoes and mosquito repellents: a clinician’s guide. Ann Intern Med. 1998;128:931-40. 21. Chen LH, Keystone JS. New strategies for the prevention of malaria in travelers. Infect Dis Clin North Am. 2005;19:185-210.

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Appendix

Recommended Antimicrobial Regimens in Adults for Specific Infections JAMES S. TAN, MD TIMOTHY R. PASQUALE, PHARMD

Disease

BONE INFECTIONS Joint Infections Septic arthritis

Recommended Antimicrobial Therapy*†

Etiology

Staphylococcus aureus (methicillin sensitive)

S. aureus (methicillinresistant)

Staphylococcus epidermidis

Group A, B, C, G streptococci

Enterococcus faecalis

Nafcillin 2 g IV q4-6h for 2 wk Alternatives: Cefazolin 2 g IV q8h or clindamycin 900 mg IV q8h or vancomycin 15 mg/kg IV q12h for 2 wk Vancomycin 15 mg/kg IV q12h for 2 wk Alternatives: SXT ‡ 15-20 mg/kg/d IV divided q6-8h or doxycycline 100 mg IV q12h or linezolid 600 mg IV/PO q12h for 2 wk Vancomycin 15 mg/kg IV q12h for 2 wk Alternatives: SXT ‡ 15-20 mg/kg/d IV divided q6-8h or linezolid 600 mg IV/PO q12h for 2 wk Penicillin G 2 MU IV q4h for 2 wk Alternatives: Vancomycin 15 mg/kg IV q12h or cefazolin 2 g IV q8h for 2 wk Penicillin G 2 MU IV q4h or ampicillin 2 g IV q6h for 2 wk plus gentamicin 1 mg/kg IM/IV q8h for 2 wk Continued

871


872

Appendix

Appendix Continued Disease

Etiology


Neisseria meningitidis

Haemophilus influenzae (betalactamase negative)

H. influenzae (betalactamase positive)

Pseudomonas aeruginosa

Osteomyelitis

S. aureus (methicillin sensitive)

S. Aureus (methicillin resistant) and S. epidermidis (methicillin resistant)

Streptococcus pyogenes, Streptococcus agalactiae, and other penicillin sensitive streptococci


Alternatives: Vancomycin 15 mg/kg IV q12h for 2 wk plus gentamicin 1 mg/kg IM/IV q8h for 2 wk or linezolid 600 mg IV/PO q12h monotherapy for 2 wk Ceftriaxone 2 g IV q24h for 2 wk Alternatives: Ciprofloxacin 400 mg IV q12h or 500 mg PO bid or other fluoroquinolone for 2 wk|| Penicillin G 2 MU IV q4h for 2 wk Alternatives: Ceftriaxone 2 g IV q24h for 2 wk Ampicillin 2 g IV q6h for 2 wk Alternatives: Cefuroxime 1.5 g IV q6-8h or SXT ‡ 15-20 mg/kg/d IV divided q6-8h for 2 wk Ceftriaxone 2 g IV q24h for 2 wk Alternatives: SXT ‡ 15-20 mg/kg/d IV divided q 6 to 8 h for 2 wk Piperacillin 4 g IV q6h for 2 wk +/− tobramycin 5-7 mg/kg IV daily for 2 wk Alternatives: Cefepime 2 g IV q12h or ceftazidime 1-2 g IV q8h for 2 wk plus aminoglycoside or ciprofloxacin 400 mg IV q8h or 750 mg PO bid for 2 wk Nafcillin 2 g IV q4-6h for 4-6 wk Alternatives: Cefazolin 2 g IV q8h or clindamycin 900 mg IV q8h or vancomycin 15 mg/kg IV q12h for 4-6 wk Vancomycin 15 mg/kg IV q12h for 4-6 wk Alternatives: SXT ‡ 15-20 mg/kg/d IV divided q6-8h plus rifampin 300 mg IV/PO q12h for 4-6 wk or linezolid 600 mg IV/PO q12h monotherapy for 6 wk Penicillin G 2 MU IV q4h or ampicillin 2 g IV q4h for 4-6 wk Alternatives: Cefazolin 2 g IV q8h or ceftriaxone 2 g IV q24h for 4-6 wk


Appendix

873

Penicillin allergy: Vancomycin 15 mg/kg IV q12h or clindamycin 900 mg IV q8h for 4-6 wk Enterococcus species Ampicillin 2 g IV q4h for 4-6 wk and Streptococcus plus gentamicin 1 mg/kg IV/IM species with MIC q8h for 1-2 wk > 0.5 mcg/mL Alternatives: Vancomycin 15 mg/kg IV q12h for 4-6 wk plus (optional) gentamicin 1 mg/kg IV/IM q8h for 1-2 wk Escherichia coli, Proteus Ceftriaxone 2 g IV q24h for 4-6 wk mirabilis, Klebsiella Alternatives: species Ciprofloxacin 750 mg PO q12h or levofloxacin 750 mg PO q24h for 4-6 wk E. coli and Klebsiella Imipenem/cilastatin 500 mg IV q6h species (ESBLor meropenem 1 g IV q8h for producing bacteria) 4-6 wk or ertapenem 1 g IV q24h Alternatives: Based on susceptibility results Serratia marcescens Cefotaxime 2 g IV q6h +/− gentamicin 5 mg/kg/d divided up q8h or levofloxacin 500 mg IV/PO daily Alternatives: Ciprofloxacin 400 mg IV q12h or 500 mg PO q12h Pseudomonas Cefepime 2 g IV q12h for 4-6 wk aeruginosa Alternatives: Piperacillin 4 g IV q6h or imipenem/cilastatin 500 mg IV q6h or meropenem 1 g IV q8h or ciprofloxacin 400 mg IV q8h or 750 mg PO q12h for 4-6 wk Bacteroides fragilis Metronidazole 500 mg IV q6h for 4-6 wk Alternatives: Clindamycin 900 mg IV q8h for 4-6 wk; if a mixed infection, beta-lactam/beta-lactamase inhibitor§ combination or imipenem/cilastatin 500 mg IV q6h or meropenem 1 g IV q8h or ertapenem 1 g IV q24h (no Pseudomonas coverage) Peptostreptococcus Clindamycin 900 mg IV q8h species Alternatives: Penicillin G 2 MU IV q4h or metronidazole 500 mg IV q6h or beta-lactam/beta-lactamase inhibitors combination§ Continued


874

Appendix


Etiology

CENTRAL NERVOUS SYSTEM Brain Abscess Paranasal sinuses (frontal lobe)

Streptococci species, Haemophilus species, anaerobes (Bacteroides species, Fusobacterium, anaerobic streptococci) Inner ear (otitis Streptococci species, media) and mastoid Haemophilus species, sinus Enterobacteriaceae, Bacteroides species, anaerobic streptococci Metastatic from a Staphylococci species, distant focus Streptococcus species, (endocarditis, enteric gram-negative urinary tract bacilli, P. aeruginosa, infection, intraanaerobes abdominal infection, lung infection)

Post-traumatic/postoperative

Staphylococci species, Streptococci species, enteric gram-negative bacilli, P. aeruginosa, Clostridium species

Acute Viral Encephalitis Common viral Arboviruses, causes enteroviruses, HSV-1, mumps

Less common and rare viral causes


Metronidazole 500 mg IV q6h plus cefotaxime 1-2 g IV q4-8h or ceftriaxone 2 g IV q12h; 6-8 wk of parenteral antibiotic therapy has traditionally been recommended Metronidazole 500 mg IV q6h plus cefotaxime 1-2 g IV q4-8h or ceftriaxone 2 g IV q12h

If source is: Endocarditis: Nafcillin 2 g IV q4h or vancomycin (15 mg/kg) q12h plus gentamicin 3-5 mg/kg IV q8-12h Pulmonary lesion: Metronidazole 500 mg IV q6h plus cefotaxime 1-2 g IV q4-8h or ceftriaxone 2 g IV q12h. For Actinomycetes, add penicillin G 2-4 MU IV q4h. For Nocardia, add SXT ‡ 2-5 mg/kg PO q6h. Intra-abdominal infection: Metronidazole 500 mg IV q6h plus cefotaxime 1-2 g IV q4-8h or ceftriaxone 2 g IV q12h. For Enterococci species, add ampicillin 2 g IV q4h or vancomycin 15 mg/kg IV q12 h. Post-traumatic: Nafcillin 2 g IV q4h plus ceftriaxone 2 g IV q24h. For anaerobes, add metronidazole 500 mg IV q6h. Post-operative: Vancomycin 15 mg/kg IV q12h plus ceftazidime 1-2 g IV q8h.

For HSV encephalitis, start acyclovir 10 mg/kg IV q8h. For other causes of viral encephalitis, treatment is usually supportive care. CMV, EBV, HIV, measles, Treatment is usually supportive VZV, adenovirus, care. Colorado tick fever


Appendix

875

virus, influenza A, parainfluenza, LCMV, rabies, rubella Acute Bacterial Meningitis Age 7-50 years

Cefotaxime 75 mg/kg IV q4-8h (not to exceed 2 g q4-6h) or ceftriaxone 100 mg/kg IV q1224h (not to exceed 2 g q12h) plus vancomycin 15 mg/kg IV q6-12h plus dexamethasone 0.15 mg/kg IV q6h to be given 10-20 min before antibiotics. Age >50 years S. pneumoniae, Listeria Vancomycin 15 mg/kg IV q8-12h monocytogenes, gramplus ampicillin 2 g IV q4h plus negative rods (rare) cefotaxime 2 g IV q4-6h or ceftriaxone 2 g IV q12h Impaired cellular L. monocytogenes, gram- Ampicillin 2 g IV q4h plus immunity suspected negative rods ceftazidime 2 g IV q8h or (e.g., alcoholics, including cefepime 2 g IV q8h high-dose P. aeruginosa corticosteroid treatment) Head trauma, postS. Aureus, coagulaseVancomycin 15 mg/kg IV q6-12h neurosurgery, or negative staphylococci, (depending on the renal function; cerebrospinal fluid gram-negative bacilli children and young adults require shunt including more frequent dosing) plus P. aeruginosa, ceftazidime 2 g IV q8h S. pneumoniae Recurrent episodes S. pneumoniae (most Cefotaxime 75 mg/kg IV q4-8h (not common) to exceed 2 g q4-6h) or ceftriaxone 100 mg/kg IV q12-24h (not to exceed 2 g q12h) plus vancomycin 15 mg/kg IV q6-12h Acute Viral Meningitis Common viral causes Enteroviruses, Supportive care arboviruses, HIV, (Acyclovir for HSV-2) HSV-2 Less common and HSV-1, HSV-6, LCMV, Supportive care rare viral causes mumps, adenoviruses, (Acyclovir for HSV) CMV, EBV, influenza virus, parainfluenza type 3, measles, rubella, VZV Chronic Meningitis Tuberculous Mycobacterium See Chapter 25 for treatment tuberculosis recommendations. Fungal Cryptococcus Treatment depends on etiology; no neoformans, urgent need for empiric treatment Coccidioides immitis, (see Chapters 28 and 40). Histoplasma capsulatum S. pneumoniae, N. meningitidis

Continued


876

Appendix


Etiology

GASTROINTESTINAL SYSTEM Infectious Diarrhea and Gastroenteritis Shigellosis

Shigella species

Salmonellosis

Salmonella enteritidis

Campylobacteriosis

Campylobacter jejuni

E. coli: enterotoxigenic (ETEC), enteropathogenic (EPEC), enteroinvasive (EIEC)

E. coli

E. coli: enterohemorrhagic (EHEC)

E. coli O157:H7, other enteric bacteria that produce Shiga-like toxin

Aeromonas/ Plesiomonas diarrhea

Aeromonas, Plesiomonas shigelloides

Antibiotic-associated diarrhea

Clostridium difficile


SXT ‡ 160/800 mg PO q12h for 3 d or a fluoroquinolone: ofloxacin 300 mg PO q12h for 3 d, norfloxacin 400 mg PO q12h for 3 d, or ciprofloxacin 500 mg PO q12h × 3 d Treatment is recommended for severe cases, for patients 50 years of age, and for patient with prosthesis, valvular heart disease, severe atherosclerosis, malignancy, or uremia. Adults: SXT ‡ 160/800 mg PO q12h for 3 d (if susceptible) or a fluoroquinolone: norfloxacin 400 mg PO q12h for 5-7 d, ciprofloxacin 500 mg PO q12h for 5-7 d, or ofloxacin 200 mg PO q12h for 5-7 d Azithromycin 500 mg PO daily for 5 d or erythromycin stearate 500 mg PO qid for 5 d or a fluoroquinolone as above. SXT ‡ 160/800 mg PO q12h for 3 d or a fluoroquinolone: ciprofloxacin 500 mg PO q12h × 3 d, ofloxacin 300 mg PO q12h × 3 d, or norfloxacin 400 mg PO q12h × 3 d Antibiotic therapy has no established effect on duration of acute diarrhea, and certain antibiotics can increase the release of toxin. SXT‡ 160/800 mg PO q12h for 3 d or a fluoroquinolone: ciprofloxacin 500 mg PO q12h × 3 d, ofloxacin 300 mg PO q12h × 3 d, or norfloxacin 400 mg PO q12h × 3 d. Discontinue the offending agent. Metronidazole 500 mg/PO 98º; 500 mg IV q 6º for 10-14 d or vancomycin 125 mg PO qid for 10-14 d. Bacitracin has also been used.


Appendix

Yersiniosis

Cholera

Giardiasis

Amebiasis

Cryptosporidiosis

Isosporiasis

Microsporidiosis Cyclosporiasis

877

Antimicrobial therapy is not usually required except for severe infections or associated bacteremia. For severe cases, use combination of doxycycline, aminoglycoside, SXT ‡, or fluoroquinolone. Vibrio cholerae Doxycycline 300 mg PO as a single dose or tetracycline 500 mg PO qid for 3 d or SXT ‡ 160/800 PO bid for 3 d or fluoroquinolone PO as a single dose Giardia lamblia Metronidazole 250-750 mg PO q8h for 7-10 d or tinidazole 2 g PO as a single dose or nitazoxanide 500 mg PO q12h for 3 d Entamoeba histolytica • Metronidazole 750 mg PO q8h for 5-10 d plus diiodohydroxyquin 650 mg q8h for 20 d. • Paromomycin 500 mg PO tid for 10 d or tinidazole 2 g PO daily for 3 d Cryptosporidium species None in most cases. Consider paromomycin 500 mg PO q8h for 7 d for severe cases; in patients with AIDS give 14-28 d, then q12h indefinitely or nitazoxanide 500 mg PO q12h for 3 d. Isospora species SXT ‡ 160-800 mg PO q12h for 7-10 d; in patients with AIDS give 320-1600 mg PO q12h for 2-4 wk, then 160-800 mg PO once daily indefinitely. Microsporidium species Albendazole 400 mg PO q12h for 3 wk Cyclospora species SXT ‡ 160-800 mg PO q6h for 10 d; in patients with AIDS give 3201600 mg PO q12h for 2-4 wk, then 160-800 mg PO once daily indefinitely. Yersinia enterocolitica

Biliary Tract Infections Cholecystitis, cholangitis

Enterobacteriaceae, Enterococcus species, anaerobes (Bacteroides, Clostridium)

Single agents: Ampicillin/sulbactam 3 g IV q6h or piperacillin/ tazobactam 3.375 g IV q6h or cefoxitin 2 g IV q 6-8 h. Combination therapy: (1) Ciprofloxacin 400 mg IV q12h or cefotaxime 1-2 g IV q8h plus metronidazole 500 mg IV q8h (2) Aztreonam 2 g IV q8h plus clindamycin 900 mg IV q8h Continued


878

Appendix


Etiology


If severe or life-threatening: Imipenem/cilastatin 500 mg IV q6h or piperacillin/tazobactam 3.375 g IV q6h

Viral Hepatitis Hepatitis A

No specific therapy has been shown to be of benefit. If within 2 wk of exposure, gamma-globulin 0.02 mL/kg IM one time is protective. Entecavir 0.5-1.0 mg PO daily, lamivudine 100 mg PO daily, adefovir 10 mg PO daily, or pegylated interferon alpha-2a (Pegasys) 180 mcg SQ q wk or interferon alpha-2b (Peg-Intron) 1.5 mcg/kg SQ q wk for 1 year. If genotype 1: Ribavirin (if 75 kg: 600 mg PO bid) plus pegylated interferon alpha-2a (Pegasys) 180 mcg SQ q wk or pegylated interferon alpha2b (PEG-Intron) 1.5 mcg/kg SQ q wk for 48 wk If genotype 2 or 3: Ribavirin 400 mg PO bid for 24 wk plus pegylated interferon alpha2a (Pegasys) 180 mcg SQ q wk or pegylated interferon alpha-2b (PEG-Intron) 1.5 mcg/kg SQ q wk for 24 wk. or ribavirin (if 75 kg: 600 mg PO bid) plus standard interferon alpha-3 MU SQ three times a wk for 24 wk. No specific therapy has been shown to be of benefit. No specific therapy has been shown to be of benefit.

Hepatitis B

Hepatitis C

Hepatitis D Hepatitis E

Peritonitis Primary peritonitis

Secondary peritonitis

Enterobacteriaceae, S. pneumoniae, Enterococcus species, anaerobes Enterobacteriaceae, Bacteroides species,

Cefotaxime 2 g IV q8h or piperacillin-tazobactam 3.375 g IV q6h (if Enterococcus and/or anaerobes are suspected). Single agents: Ampicillin-sulbactam 3 g IV q6h (no


Appendix

P. aeruginosa, Enterococcus species

Tertiary peritonitis

S. epidermidis, P. aeruginosa, Stenotrophomonas maltophilia, Candida species

879

Pseudomonas coverage) or piperacillin-tazobactam 3.375 g IV q6h IV Combination therapy: (1) Ertapenem 1 g q24h IV ± gentamicin 1.7 mg/kg IV q8h IV (2) Ciprofloxacin 400 mg IV q12h plus metronidazole 500 mg IV q8h Single agents: Imipenem-cilastatin 500 mg IV q6h or meropenem 1 g IV q8h (carbapenems have no activity against Stenotrophomonas maltophilia) Combination therapy: Cefepime 2 g IV q12h or ciprofloxacin 400 mg q12h IV plus vancomycin 15 mg/kg IV q12h

Intra-abdominal Abscess Liver abscess (pyogenic)

Anaerobes, Enterococcus Single agents: species, E. coli, Imipenem-cilastatin 500 mg IV q6h Klebsiella or meropenem 1 g IV q8h or pneumoniae, ertapenem 1 g IV d q24h (no Pseudomonas species, Pseudomonas coverage) or S. aureus, piperacillin-tazobactam 3.375 g IV Streptococcus viridans q6h or tigecycline 100 mg IV then 50 mg IV q12h (no Pseudomonas coverage) Combination therapy: (1) Ampicillin 1-2 g IV q6h plus gentamicin 1.5 mg/kg IV q8h plus metronidazole 500 mg IV q6h (2) Ceftazidime 2 g IV q8h or cefepime 2 g IV q12h plus metronidazole 500 mg IV q6h Penicillin allergy: Metronidazole 500 mg IV q6h plus ciprofloxacin 400 mg IV q12h (this combination lacks Streptococcus and Enterococcus coverage). Liver abscess (amebic) Entamoeba histolytica Metronidazole 750 mg PO tid for 7-14 d Splenic abscess E. coli, Salmonella Single agents: species, Ceftriaxone 2 g IV q24h or Staphylococcus levofloxacin 500 mg IV q24h species, Streptococcus Penicillin allergy: species Vancomycin 1 g IV q12h plus gentamicin 1.5 mg/kg IV q8h or Continued


880

Appendix


Pancreatic abscess

Appendiceal abscess

Diverticular abscess

Etiology


aztreonam 2 g IV q8h plus clindamycin 600-900 mg IV q8h Same as pyogenic liver abscess.

Bacteroides fragilis, Enterobacteriaceae, Enterococcus species, E. coli, K pneumoniae, P aeruginosa, S. aureus Bacteroides fragilis, Same as pyogenic liver E. coli, Peptostreptococcus species, P. aeruginosa Bacteroides fragilis, Single agents: E. coli Same as pyogenic liver cefoxitin 2 g IV q6h. Combination therapy: Same as pyogenic liver Penicillin-allergy: Same as pyogenic liver

abscess.

abscess or

abscess. abscess.

GENITOURINARY SYSTEM Common Sexually Transmitted Diseases Genital ulcers Chancroid

Haemophilus ducreyi

Herpes genitalis

Herpes simplex

Episodic recurrent herpes

Suppressive treatment

Granuloma inguinale (donovanosis)

Lymphogranuloma venereum

Chlamydia trachomatis

Azithromycin 1 g PO single dose or ceftriaxone 250 mg IM single dose or ciprofloxacin 500 mg PO bid for 3 d or erythromycin base 500 mg PO qid for 7 d Acyclovir 400 mg PO tid for 7-10 d or acyclovir 200 mg PO 5× daily for 7-10 d or famciclovir 250 mg PO tid for 7-10 d or valacyclovir 1 g PO bid for 7-10 d Acyclovir 400 mg PO bid for 5d or famciclovir 125 mg PO bid for 5d or valacyclovir 500 mg PO daily for 3d Acyclovir 400 mg PO bid or famciclovir 250 mg PO bid or valacyclovir 500 mg PO daily or 1000 mg PO daily (if > 9 recurrences/year) SXT ‡ 160/800 mg PO bid for a minimum of 3 wk or doxycycline 100 mg PO bid for a minimum of 3 wk Doxycycline 100 mg PO bid for 21 d


Appendix

Syphilis Primary/secondary

881

Treponema pallidum Penicillin G benzathine 2.4 MU IM single dose Alternative treatment: Doxycycline 100 mg PO bid for 2 wk or tetracycline 500 mg PO qid for 2 wk Penicillin G benzathine 2.4 MU IM single dose; consider giving another dose after 1 wk If patient is penicillin-allergic, treat with penicillin after desensitization. Do not give tetracyclines in pregnant patients. Same as primary syphilis. Penicillin G benzathine 2.4 MU IM weekly × 3 doses Alternative treatment: Doxycycline 100 mg PO bid for 4 wk or tetracycline 500 mg PO qid for 4 wk Penicillin G 18-24 MU IV (in 4-6 divided doses) daily for 10-14 d monotherapy or penicillin G procaine 2.4 MU IM daily plus probenecid 500 mg PO qid for 10-14 d. Penicillin G 100,000-150,000 U/kg/d (two divided doses for the first 7 d, three divided doses thereafter) for 10-14 d or penicillin G procaine 50,000 U/kg/d IM daily for 10-14 d If patient is penicillin allergic, treat with penicillin after desensitization.

Primary/secondary syphilis in pregnancy

Early latent Late latent, or latent of unknown duration, and late syphilis

Neurosyphilis

Congenital syphilis

Syphilis in HIV Primary, secondary, and latent

Penicillin G benzathine 2.4 MU IM weekly times three doses If patient is penicillin allergic, treat with penicillin after desensitization.

Urethritis and cervicitis Nongonococcal Chlamydia, ureaplasma urethritis Chlamydia

Chlamydia trachomatis

Chlamydia in pregnancy

C. trachomatis

Recurrent and persistent urethritis

Trichomonas, ureaplasma

Azithromycin 1 g PO as a single dose or doxycycline 100 mg PO bid for 7 d Azithromycin 1 g PO as a single dose or doxycycline 100 mg PO bid for 7 d Erythromycin base 500 mg PO qid for 7 d or azithromycin 1 g PO as a single dose Metronidazole 2 g PO in a single dose plus erythromycin base Continued


882

Appendix


Etiology

Gonococcal infections Neisseria gonorrhoeae (uncomplicated; when urethritis is present, it is reasonable to presume that the patient is infected with both gonococcal and nongonococcal agents) GC conjunctivitis Disseminated GC

GC meningitis or endocarditis Pelvic inflammatory disease


500 mg PO qid for 7 d or erythromycin ethylsuccinate 800 mg PO qid for 7 d (Single dose preferred) Cefixime 400 mg PO single dose or ceftriaxone 125 mg IM single dose If Chlamydia infection is not ruled out, add azithromycin 1 g PO single dose or doxycycline 100 mg PO bid for 7 d.

Ceftriaxone 1 g IM single dose Intravenous regimen: Ceftriaxone 1 g IM/IV q24h or cefotaxime 1 g IV q8h Penicillin-allergic patients: Ciprofloxacin 400 mg IV q12h⎢⎢ or ofloxacin 400 mg IV q12h⎢⎢ or levofloxacin 250 mg IV daily or Then complete at least 7 d of therapy with cefixime 400 mg PO bid or ciprofloxacin 500 mg PO bid⎢⎢ or ofloxacin 400 mg PO bid⎢⎢ or levofloxacin 500 mg PO daily ⎢⎢. Ceftriaxone 1-2 g IV q12h ● Meningitis: 10-14 d ● Endocarditis at least 4 wk Inpatient regimen A: Cefoxitin 2 g IV q6h plus doxycycline 100 mg IV or PO q12h Inpatient regimen B: Clindamycin 900 mg IV q8h plus gentamicin 1.5 mg/kg IV/IM q8h plus doxycycline Alternative regimen: Ofloxacin 400 mg IV q12h or levofloxacin 500 mg IV daily plus metronidazole 500 mg IV q8h or ampicillin/sulbactam 3 g IV q6h plus doxycycline 100 mg IV or PO q12h. Outpatient regimen A: Metronidazole 500 mg PO bid for 14 d plus ofloxacin 400 mg PO


Appendix

883

bid for 14 d or levofloxacin 500 mg PO daily for 14 d Outpatient regimen B: Cefoxitin 2 g IM single dose plus probenecid 1 g PO single dose or Ceftriaxone 250 mg IM in a single dose or other third-generation cephalosporin plus doxycycline 100 mg PO bid for 14 d with or without metronidazole 500 mg PO bid for 14 d Urinary Tract Infection Acute bacterial cystitis E. coli, (consider local resistance to SXT or fluoroquinolones) other gram-negative enteric bacteria, Staphylococcus saprophyticus

Acute pyelonephritis

Prostatitis Acute bacterial prostatitis

Chronic bacterial prostatitis

E. coli, (consider local resistance to SXT or fluoroquinolones) other gram-negative enteric bacteria

SXT ‡ 160/800 mg PO bid for 3 d (use with caution in pregnancy) or ciprofloxacin 500 mg PO q12h for 3 d (not recommended in pregnancy) or levofloxacin 250 mg PO q24h for 3 d (not recommended in pregnancy) or nitrofurantoin 100 mg PO qid for 7 d or cephalexin 500 mg PO qid for 7 d (ineffective for enterococci) SXT ‡ DS 160/800 mg PO q12h for 14 d or ciprofloxacin 500 mg PO q12h for 7 d or levofloxacin 500 mg PO q24h for 7 d or cephalexin 500 mg PO qid for 14 d Hospitalized patients (empiric therapy): Ampicillin 2 g IV q6h plus gentamicin 5 mg/kg IV q24h or ceftriaxone 1 g IV q24h or imipenem/cilastatin 500 mg IV q6h or piperacillin/ tazobactam 3.375 g IV q6h Each of the above regimens is given for 2-4 days; switch to oral therapy when susceptibility results are available.

Enterobacteriaceae Parenteral antibiotic: Ciprofloxacin (E. coli most common) or levofloxacin or SXT ‡ or doxycycline or penicillin plus aminoglycoside followed by oral antimicrobial for a total of 3-6 wk Enterobacteriaceae Ciprofloxacin 500 mg PO bid or (including Klebsiella, levofloxacin 500 mg PO q24h for Serratia, 4-6 wk or SXT ‡ 160/800 mg PO Pseudomonas, and bid for 1-3 months Proteus species), Enterococcus species Continued


884

Appendix


Etiology

Chronic abacterial prostatitis

Unknown; Chlamydia and ureaplasma are possible

Epididymitis Epididymo-orchitis Gonococci, Chlamydia (sexually transmit(heterosexual) ted, age 35 years) Vaginitis and Vaginosis Bacterial vaginosis

Trichomononiasis

Moniliasis


Doxycycline 100 mg PO bid for 2 wk or erythromycin for 2 wk

Ceftriaxone 250 mg IM in a single dose plus doxycycline 100 mg PO bid for 10 d Ofloxacin 300 mg PO bid for 10-14 d or ciprofloxacin 500 mg PO bid for 10-14 d

Metronidazole 800 to 1200 mg/d PO for 1 wk or metronidazole 2 g PO single dose Topical therapy: Metronidazole gel 0.75% for 5 d or clindamycin 2% once daily for 7 d Trichomonas vaginalis Metronidazole 500 mg PO bid for 7 d or metronidazole 2 g PO single dose Candida albicans, Fluconazole 150 mg PO single dose non-albicans Candida or ketoconazole 400 mg PO bid for 5 d or itraconazole 200 mg PO daily for 3 d (or bid for 1 d) Topical therapy: See Chapter 17.

HEART AND VASCULAR INFECTIONS Endocarditis Streptococcus viridans Streptococcus viridans, and Streptococcus Streptococcus bovis bovis with MIC ≤ 0.12 µg/mL

Native valve: Preferred: Penicillin G 12-18 MU IV/24 h either continuously or in 4-6 equally divided doses for 4 wk or ceftriaxone 2 g IV/IM q24h for 4 wk Alternative: Penicillin G 12-18 MU/24 h either continuously or in 6 equally divided doses for 2 wk plus gentamicin 3 mg/kg IV/IM q24h for 2 wk or ceftriaxone 2 g IV/IM q24h for 2 wk plus gentamicin 3 mg/kg IV/IM q24h for 2 wk For patients intolerant of penicillins and cephalosporins: Vancomycin 15 mg/kg IV q12h for 4 wk


Appendix

885

Prosthetic valve: Preferred: Penicillin G 24 MU/24 h IV either continuously or in 4-6 equally divided doses for 6 wk with or without gentamicin 3 mg/kg IV/IM q24h for 2 wk or ceftriaxone 2 g IV/IM q24h for 6 wk with or without gentamicin 3 mg/kg IV/IM q24h for 2 wk For patients intolerant of penicillins and cephalosporins: Vancomycin 15 mg/kg IV q12h for 6 wk Streptococcus viridans Streptococcus viridans, Native valve: and Streptococcus Streptococcus bovis Preferred: bovis with MIC Penicillin G 24 MU/24 h IV either continuously or in 4-6 equally ≥ 0.12 µg/mL to divided doses for 4 wk plus < 0.5 µg/mL gentamicin 3 mg/kg IV/IM q24h for 2 wk Or ceftriaxone 2 g IV/IM q24h for 4 wk plus gentamicin 3 mg/kg IV/IM q24h for 2 wk. For patients intolerant of penicillins and cephalosporins: Vancomycin 15 mg/kg IV q12h for 4 wk Prosthetic valve: Preferred: Penicillin G 24 MU/24 h IV either continuously or in 4-6 equally divided doses for 6 wk plus gentamicin 3 mg/kg IV/IM q24h for 6 wk Or ceftriaxone 2 g IV/IM q24h for 6 wk plus gentamicin 3 mg/kg IV/IM q24h for 6 wk. For patients intolerant of penicillins and cephalosporins: Vancomycin 15 mg/kg IV q12h for 6 wk Enterococci, E. faecalis, Enterococcus Native valve: streptococci with faecium Ampicillin 2 g IV q4h for 4-6 wk MIC > 0.5 µg/mL or penicillin G 24 MU/24 h IV continuously or in 6 equally divided doses plus gentamicin 1 mg/kg IV q8h or streptomycin 7.5 mg/kg (not to exceed 500 mg) q12h for 4-6 wk Penicillin-resistant organism, or penicillin allergy: Vancomycin 15 mg/kg IV q12h plus gentamicin 1 mg/kg IV q8h or streptomycin 7.5 mg/kg (not to exceed 500 mg) q12h for 6 wk. Continued


886

Appendix


Etiology

Other streptococci

Group A, B, C, G streptococci or S. pneumoniae

Staphylococci

S. aureus, coagulasenegative Staphylococcus


Prosthetic valve: Ampicillin 2 g IV q4h for 6 wk or penicillin G 24 MU/24 h IV continuously or in 6 equally divided doses plus gentamicin 1 mg/kg IV q8h or streptomycin 7.5 mg/kg (not to exceed 500 mg) q12h for 6 wk Penicillin-resistant organism, or penicillin allergy: Vancomycin 15 mg/kg IV q12h plus gentamicin 1 mg/kg IV q8h or streptomycin 7.5 mg/kg (not to exceed 500 mg) q12h for 6 wk Preferred: Penicillin G 2-3 MU IV q4h for 4 wk or ceftriaxone 2 g IV q24h for 4 wk Penicillin allergy: Vancomycin 15 mg/kg IV q12h for 4 wk (adjust dose in renal dysfunction) Staphylococcal (methicillinsensitive) native valve endocarditis: Preferred: Nafcillin or oxacillin 2 g IV q4h for 6 wk (optional, add gentamicin 1 mg/kg IV q8h for 3-5 d in seriously ill patients) For non-IgE mediated penicillin allergic patients: Cefazolin 2 g IV q8h for 6 wk For IV drug users with uncomplicated righ-sided endocarditis: Nafcillin or oxacillin 2 g IV q4h plus gentamicin 1 mg/kg IV q8h for 2 wk Staphylococcal (methicillin-resistant) native valve endocarditis or penicillin allergy: Vancomycin 15 mg/kg IV q12h for 6 wk Staphylococcal (methicillinsensitive) prosthetic valve endocarditis: Nafcillin or oxacillin 2 g IV q4h for ≥ 6 wk plus rifampin 900 mg/ 24 h in 3 divided doses for ≥6 wk


Appendix

HACEK microorganisms

Culture-negative endocarditis

Vascular Infections Mycotic aneurysm (infective endocarditis associated aneurysm)

Mycotic aneurysm (atherosclerotic vessel associated aneurysm and trauma-related false aneurysm) Vascular graft infection

Intravenous-line infection

887

plus gentamicin 1 mg/kg IV/IM q8h for 2 wk Staphylococcal (methicillin-resistant) prosthetic valve endocarditis or penicillin allergy: Vancomycin 15 mg/kg IV q12h for ≥6 wk plus rifampin 900 mg/24 h in 3 divided doses for ≥6 wk plus gentamicin 1 mg/kg IV/IM q8h for 2 wk. Haemophilus Native valve: aphrophilus/ Ceftriaxone 2 g IV/IM q24h for paraphrophilus, 4 wk or ampicillin/sulbactam 3 g Actinobacillus IV q6h for 4 wk or ciprofloxacin actinomycetemcomi400 mg IV q12h or 500 mg PO tans, Cardiobacterium q12h for 4 wk hominis, Eikenella Prosthetic valve: corrodens, Kingella Ceftriaxone 2 g IV/IM q24h for kingii 6 wk or ampicillin/sulbactam 3 g IV q6h for 6 wk or ciprofloxacin 400 mg IV q12h or 500 mg PO q12h for 6 wk Rule out other agents Treatment recommendation same as by culture or serology enterococcal endocarditis. for fungi, Chlamydia, Bartonella, Brucella, Coxiella Usually Staphylococcus species or Streptococcus species

Salmonella, Staphylococcus species, others

Staphylococcus species

Staphylococcus species

Based on culture and susceptibility testing, antimicrobial therapy for at least 4-6 wk. Surgical excision with extensive local debridement. Duration of antimicrobial therapy is similar to infective endocarditis. Based on culture and susceptibility testing, antimicrobial therapy for at least 4-6 wk. Surgical excision with extensive local debridement.

Based on culture and susceptibility testing, antimicrobial therapy for at least 4-6 wk. Surgical excision with extensive local debridement when abscess and necrotic areas are found. Based on culture and susceptibility testing, antimicrobial therapy for at least 2-6 wk. Remove catheter if due to S. aureus. Start vancomycin 15 mg/kg IV q12h before susceptibility results are available. Continued


888

Appendix


Septic Phlebitis Cavernous sinus

Lateral sinus

Sagittal sinus Cortical

Internal jugular vein

Great vein Pelvic veins, pylephlebitis

Peripheral

Etiology

S. aureus (70%), group A streptococci, Streptococcus pneumoniae, gramnegative bacilli, anaerobes Group A streptococci, S. aureus, Bacteroides, Proteus mirabilis, E. coli S. aureus, group A streptococci S. pneumoniae, Haemophilus influenzae, Neisseria meningitis S. aureus, gram-negative bacilli, Candida species


Vancomycin 15 mg/kg IV q12h plus ceftriaxone 2 g IV q12h (or cefotaxime 2 g IV q4-6h) plus metronidazole 500 mg IV q6h.

Vancomycin 15 mg/kg IV q12h plus ceftriaxone 2 g IV q12h (or cefotaxime 2 g IV q4-6h) plus metronidazole 500 mg IV q6h. Vancomycin 15 mg/kg IV q12h.

Vancomycin 15 mg/kg IV q12h plus ceftriaxone 2 g IV q12h. If brain abscess or sinus source, add metronidazole 500 mg IV q6h. Vancomycin 15 mg/kg IV q12h plus ceftriaxone 2 g IV q12h. If Candida suspected, add amphotericin B 0.6-1.0 mg IV q24h. S. aureus, gram-negative Vancomycin 15 mg/kg IV q12h plus bacilli ceftriaxone 2 g IV q12h. S. aureus, gram-negative • Ampicillin/sulbactam 3 g IV q6h aerobic rods, or ticarcillin/clavulanate 3.1 g IV anaerobes q6h or (Bacteroides fragilis), • Piperacillin/tazobactam 3.375 g microaerophilic IV q6h or imipenem/cilastatin streptococci 500 mg IV q6h or meropenem 1 g IV q8h plus an optional aminoglycoside (gentamicin or tobramycin 3-5 mg/kg IV in single or divided doses) or • Metronidazole 500 mg IV q6h plus gentamicin or tobramycin 1.5 mg/kg IV q8h S. aureus, group A Vancomycin 15 mg/kg IV q12h. Add streptococci an aminoglycoside if patient had prolonged hospitalization or prior antimicrobial agents.

IMMUNOCOMPROMISERELATED INFECTIONS HIV Infection

Preferred regimens (as recommended by Department of Health and Human Services guidelines, 4 May 2006): • Efavirenz 600 mg PO q h plus lamivudine 150 mg PO bid or


Appendix

889

emtricitabine 200 mg PO daily plus zidovudine 300 mg PO bid or tenofovir 300 mg PO daily or • Lopinavir/ritonavir 400/100 mg PO bid plus lamivudine 150 mg PO bid or emtricitabine 200 mg PO daily plus zidovudine 300 mg PO bid AIDS and Opportunistic Infections Pneumocystis jiroveci pneumonia (PCP) Acute therapy

Chronic maintenance

Preferred: SXT ‡ 15-20 mg/kg/d IV or PO q6-8h for 21 d. Alternative therapy for mild-tomoderate PCP: Dapsone 100 mg PO daily and TMP 15-20 mg/kg/d in 3 divided doses for 21 d or primaquine 15-30 mg (base) PO daily and clindamycin 300-450 mg orally q6-8h for 21 d or atovaquone 750 mg PO bid with food for 21 d Alternative therapy for severe PCP: Pentamidine 4 mg/kg IV daily infused over at least 60 min for 21 d or clindamycin 600-900 mg IV q8h and primaquine base 1530 mg/d orally for 21 d or trimetrexate 45 mg/m2 or 1.2 mg/kg IV daily with leucovorin 20 mg/m2 or 0.5 mg/kg IV or PO q6h (leucovorin must be administered for 3 d after the last dose of trimetrexate) for 21 d Preferred: SXT ‡ 160/800 mg PO daily or 80/400 mg PO daily Alternatives: SXT ‡ 160/800 mg PO three times a wk or dapsone 50 mg PO bid or 100 mg PO daily or dapsone 50 mg PO daily plus pyrimethamine 50 mg PO weekly plus leucovorin 25 mg PO weekly or dapsone 200 mg PO weekly plus pyrimethamine 75 mg PO weekly plus leucovorin 25 mg PO weekly or aerosolized pentamidine 300 mg nebulized monthly or atovaquone 1500 mg PO daily Continued


890

Appendix


Cerebral toxoplasmosis Acute therapy

Chronic maintenance

Cryptococcal meningitis

Etiology


First-line therapy: Pyrimethamine 200 mg PO × 1 dose, then 50-100 mg PO daily and sulfadiazine 1-2 g PO q6h plus leucovorin 10 mg PO daily for at least 6 wk Alternative therapy: Pyrimethamine 200 mg PO × 1 dose, then 50-100 mg PO daily plus leucovorin 10 mg PO daily plus one of the following: clindamycin 600 mg IV q6h or 300-450 mg PO q6h or azithromycin 1200-1500 mg/d PO or clarithromycin 1 g PO bid or atovaquone 750 mg q 6 h. First-line therapy: Pyrimethamine 25-75 mg/d PO plus leucovorin 10-25 mg/d PO plus sulfadiazine 500-1000 mg PO qid Alternative therapy: Pyrimethamine 25-75 mg/d PO plus leucovorin 10-25 mg/d PO plus clindamycin 300-450 mg PO q6-8h Induction and consolidation: • Amphotericin B 0.7-1.0 mg/kg/d IV plus flucytosine 100 mg/kg/d for 2 wk, then fluconazole 400 mg/d for a minimum of 8 wk or • Amphotericin B 0.7-1.0 mg/kg/d IV plus flucytosine 100 mg/kg/d for 6-10 wk or • Amphotericin B 0.7-1.0 mg/kg/d for 14 d, then fluconazole 400 mg/d for 8-10 wk or • Amphotericin 0.7-1.0 mg/kg/d IV for 6-10 wk or If CSF cryptococcal antigen

Infectious Diseases, Second Edition (EXPERT GUIDE SERIES- AMERICAN COLLEGE OF PHYSICIANS)

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Blueprints Series: Pediatric Infectious Diseases

Lippincott's Guide to Infectious Diseases

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Cytopathology of Infectious Diseases

Encyclopedia of Infectious Diseases

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Krugman's Infectious Diseases of Children (Infectious Diseases of Children ( Krugman's))

Emerging Infectious Diseases: Trends and Issues, Second Edition

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Molecular Diagnosis of Infectious Diseases

Krugman's Infectious Diseases of Children

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