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PHARMACOLOGY for NURSING CARE 7th ed. RICHARD A. LEHNE, PhD formerly, Lecturer, University of Arizona College of Nursing Lecturer, University of Virginia School of Nursing Research Assistant Professor, Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, Virginia IN CONSULTATION WITH Linda A. Moore, EdD, RN, APRN, BC (GNP/ANP), MSCN Associate Professor of Nursing, Adult Health Nursing, School of Nursing, University of North Carolina, at Charlotte Nurse Practitioner, Multiple Sclerosis Center, Carolinas HealthCare Systems, Charlotte, North Carolina Leanna J. Crosby, DNSc, G/ANP-C Nurse Practitioner in Primary Care, Southern Arizona Veterans Administration Healthcare System Adjunct Associate Professor, College of Nursing, University of Arizona, Tucson, Arizona Diane B. Hamilton, PhD, RN Professor Emerita, School of Nursing, Western Michigan University, Kalamazoo, Michigan 978-1-4160-6249-3 SAUNDERS ELSEVIER
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3251 Riverport Lane St. Louis, Missouri 63043 PHARMACOLOGY FOR NURSING CARE ISBN: 978-1-4160-6249-3
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Pharmacology for Nursing Care, 7th Edition ISBN: 978-1-4160-6249-3 Copyright © 2010, 2007, 2004, 2001, 1998, 1994, 1990 by Saunders, an imprint of Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Permissions may be sought directly from Elsevier's Rights Department: phone: (+1) 215 239 3804 (US) or (+44) 1865 843830 (UK); fax: (+44) 1865 853333; e-mail:
[email protected]. You may also complete your request on-line via the Elsevier website at http://www.elsevier.com/permissions. Notice Knowledge and best practice in this field are constantly changing. As new research and experience broaden our knowledge, changes in practice, treatment and drug therapy may become necessary or appropriate. Readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of the practitioner, relying on their own experience and knowledge of the patient, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the author assume any liability for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this book. The Publisher ISBN: 978-1-4160-6249-3 Library of Congress Cataloging-in-Publication Data Lehne, Richard A., 1943Pharmacology for nursing care / Richard A. Lehne; in consultation with Linda A. Moore, Leanna J. Crosby, Diane B. Hamilton. — 7th ed. p. ; cm. Includes index. ISBN 978-1-4160-6249-3 (pbk. : alk. paper)
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Pharmacology for Nursing Care, ISBN 978-1-4160-6249-3 (pbk. : alk. paper)7th Edition 1. Pharmacology. 2. Nursing. I. Title. [DNLM: 1. Pharmacology—Nurses' Instruction. 2. Drug Therapy—Nurses' Instruction. 3. Pharmaceutical Preparations—Nurses' Instruction. QV 4 L523p 2009] RM301.P457 2009 615′.1—dc22 2009025070 Acquisitions Editor: Kristin Geen Senior Developmental Editor: Lauren Lake Publishing Services Manager: Jeff Patterson Senior Project Manager: Anne Konopka Design Direction: Teresa McBryan Printed in Canada. Last digit is the print number: 9 8 7 6 5 4 3 2 1
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Pharmacology fornumber: Nursing Last digit is the print 9 8 7Care, 6 5 4 3 7th 2 1 Edition Front Matter I. INTRODUCTION 1
CHAPTER 1 Orientation to Pharmacology
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CHAPTER 2 Application of Pharmacology in Nursing Practice
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CHAPTER 3 Drug Regulation, Development, Names, and Information II. BASIC PRINCIPLES OF PHARMACOLOGY
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CHAPTER 4 Pharmacokinetics
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CHAPTER 5 Pharmacodynamics
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CHAPTER 6 Drug Interactions
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CHAPTER 7 Adverse Drug Reactions and Medication Errors
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CHAPTER 8 Individual Variation in Drug Responses III. DRUG THERAPY ACROSS THE LIFE SPAN
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CHAPTER 9 Drug Therapy During Pregnancy and Breast-Feeding
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CHAPTER 10 Drug Therapy in Pediatric Patients
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CHAPTER 11 Drug Therapy in Geriatric Patients IV. PERIPHERAL NERVOUS SYSTEM DRUGS Introduction
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CHAPTER 12 Basic Principles of Neuropharmacology
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CHAPTER 13 Physiology of the Peripheral Nervous System
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Introduction to Cholinergic Drugs Cholinergic Drugs
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Pharmacology Nursing Care, 7th Edition Cholinergicfor Drugs 15
CHAPTER 14 Muscarinic Agonists and Antagonists
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CHAPTER 15 Cholinesterase Inhibitors and Their Use in Myasthenia Gravis
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CHAPTER 16 Drugs That Block Nicotinic Cholinergic Transmission: Neuromuscular Blocking Agents and Ganglionic Blocking Agents Adrenergic Drugs
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CHAPTER 17 Adrenergic Agonists
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CHAPTER 18 Adrenergic Antagonists
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CHAPTER 19 Indirect-Acting Antiadrenergic Agents V. CENTRAL NERVOUS SYSTEM DRUGS Introduction
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CHAPTER 20 Introduction to Central Nervous System Pharmacology Drugs for Neurodegenerative Disorders
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CHAPTER 21 Drugs for Parkinson's Disease
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CHAPTER 22 Alzheimer's Disease
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CHAPTER 23 Drugs for Multiple Sclerosis Neurologic Drugs
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CHAPTER 24 Drugs for Epilepsy
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CHAPTER 25 Drugs for Muscle Spasm and Spasticity Drugs for Pain
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CHAPTER 26 Local Anesthetics
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Pharmacology Nursing Care, 7th Edition CHAPTER for 26 Local Anesthetics 28
CHAPTER 27 General Anesthetics
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CHAPTER 28 Opioid (Narcotic) Analgesics, Opioid Antagonists, and Nonopioid Centrally Acting Analgesics
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CHAPTER 29 Pain Management in Patients with Cancer
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CHAPTER 30 Drugs for Headache Psychotherapeutic Drugs
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CHAPTER 31 Antipsychotic Agents and Their Use in Schizophrenia
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CHAPTER 32 Antidepressants
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CHAPTER 33 Drugs for Bipolar Disorder
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CHAPTER 34 Sedative-Hypnotic Drugs
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CHAPTER 35 Management of Anxiety Disorders
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CHAPTER 36 Central Nervous System Stimulants and Attention-Deficit/ Hyperactivity Disorder Drug Abuse
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CHAPTER 37 Drug Abuse I: Basic Considerations
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CHAPTER 38 Drug Abuse II: Alcohol
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CHAPTER 39 Drug Abuse III: Major Drugs of Abuse (Other Than Alcohol) VI. DRUGS THAT AFFECT FLUID AND ELECTROLYTE BALANCE
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CHAPTER 40 Diuretics
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CHAPTER 41 Agents Affecting the Volume and Ion Content of Body Fluids VII. DRUGS THAT AFFECT THE HEART, BLOOD VESSELS, AND BLOOD
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CHAPTER 42 Review of Hemodynamics
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Pharmacology Nursing Care, 7th Edition CHAPTER 42forReview of Hemodynamics 44
CHAPTER 43 Drugs Acting on the Renin-Angiotensin-Aldosterone System
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CHAPTER 44 Calcium Channel Blockers
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CHAPTER 45 Vasodilators
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CHAPTER 46 Drugs for Hypertension*
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CHAPTER 47 Drugs for Heart Failure
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CHAPTER 48 Antidysrhythmic Drugs
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CHAPTER 49 Prophylaxis of Coronary Heart Disease: Drugs That Help Normalize Cholesterol and Triglyceride Levels
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CHAPTER 50 Drugs for Angina Pectoris
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CHAPTER 51 Anticoagulant, Antiplatelet, and Thrombolytic Drugs
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CHAPTER 52 Management of ST-Elevation Myocardial Infarction
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CHAPTER 53 Drugs for Hemophilia
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CHAPTER 54 Drugs for Deficiency Anemias
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CHAPTER 55 Hematopoietic Growth Factors VIII. DRUGS FOR ENDOCRINE DISORDERS
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CHAPTER 56 Drugs for Diabetes Mellitus
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CHAPTER 57 Drugs for Thyroid Disorders
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CHAPTER 58 Drugs Related to Hypothalamic and Pituitary Function
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CHAPTER 59 Drugs for Disorders of the Adrenal Cortex IX. WOMEN'S HEALTH
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CHAPTER 60 Estrogens and Progestins: Basic Pharmacology and Noncontraceptive Applications
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Pharmacology forNoncontraceptive Nursing Care, 7th Edition Applications 62
CHAPTER 61 Birth Control
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CHAPTER 62 Drug Therapy of Infertility
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CHAPTER 63 Drugs That Affect Uterine Function X. MEN'S HEALTH
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CHAPTER 64 Androgens
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CHAPTER 65 Drugs for Erectile Dysfunction and Benign Prostatic Hyperplasia XI. ANTI-INFLAMMATORY, ANTIALLERGIC, AND IMMUNOLOGIC DRUGS
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CHAPTER 66 Review of the Immune System
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CHAPTER 67 Childhood Immunization
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CHAPTER 68 Immunosuppressants
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CHAPTER 69 Antihistamines
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CHAPTER 70 Cyclooxygenase Inhibitors: Nonsteroidal Anti-inflammatory Drugs and Acetaminophen
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CHAPTER 71 Glucocorticoids in Nonendocrine Diseases XII. DRUGS FOR BONE AND JOINT DISORDERS
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CHAPTER 72 Drug Therapy of Rheumatoid Arthritis
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CHAPTER 73 Drug Therapy of Gout
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CHAPTER 74 Drugs Affecting Calcium Levels and Bone Mineralization XIII. RESPIRATORY TRACT DRUGS
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CHAPTER 75 Drugs for Asthma
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CHAPTER 76 Drugs for Allergic Rhinitis, Cough, and Colds
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Pharmacology Nursing Care, 7th Edition CHAPTER 76forDrugs for Allergic Rhinitis, Cough, and Colds XIV. GASTROINTESTINAL DRUGS 78
CHAPTER 77 Drugs for Peptic Ulcer Disease
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CHAPTER 78 Laxatives
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CHAPTER 79 Other Gastrointestinal Drugs XV. NUTRITION
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CHAPTER 80 Vitamins
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CHAPTER 81 Drugs for Obesity XVI. CHEMOTHERAPY OF INFECTIOUS DISEASES
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CHAPTER 82 Basic Principles of Antimicrobial Therapy
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CHAPTER 83 Drugs That Weaken the Bacterial Cell Wall I: Penicillins
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CHAPTER 84 Drugs That Weaken the Bacterial Cell Wall II: Cephalosporins, Carbapenems, Vancomycin, Aztreonam, Teicoplanin, and Fosfomycin
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CHAPTER 85 Bacteriostatic Inhibitors of Protein Synthesis: Tetracyclines, Macrolides, and Others
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CHAPTER 86 Aminoglycosides: Bactericidal Inhibitors of Protein Synthesis
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CHAPTER 87 Sulfonamides and Trimethoprim
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CHAPTER 88 Drug Therapy of Urinary Tract Infections
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CHAPTER 89 Antimycobacterial Agents: Drugs for Tuberculosis, Leprosy, and Mycobacterium avium Complex Infection
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CHAPTER 90 Miscellaneous Antibacterial Drugs Fluoroquinolones, Metronidazole, Daptomycin, Rifampin, Bacitracin, and Polymyxins
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Pharmacology forPolymyxins Nursing Care, 7th Edition 92
CHAPTER 91 Antifungal Agents
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CHAPTER 92 Antiviral Agents I: Drugs for Non-HIV Viral Infections
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CHAPTER 93 Antiviral Agents II: Drugs for HIV Infection and Related Opportunistic Infections
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CHAPTER 94 Drug Therapy of Sexually Transmitted Diseases
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CHAPTER 95 Antiseptics and Disinfectants XVII. CHEMOTHERAPY OF PARASITIC DISEASES
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CHAPTER 96 Anthelmintics
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CHAPTER 97 Antiprotozoal Drugs I: Antimalarial Agents
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CHAPTER 98 Antiprotozoal Drugs II: Miscellaneous Agents
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CHAPTER 99 Ectoparasiticides XVIII. CANCER CHEMOTHERAPY
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CHAPTER 100 Basic Principles of Cancer Chemotherapy
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CHAPTER 101 Anticancer Drugs I: Cytotoxic Agents
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CHAPTER 102 Anticancer Drugs II: Hormonal Agents, Biologic Response Modifiers, and Targeted Drugs XIX. ADDITIONAL IMPORTANT DRUGS
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CHAPTER 103 Drugs for the Eye
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CHAPTER 104 Drugs for the Skin
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CHAPTER 105 Drugs for the Ear
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CHAPTER 106 Miscellaneous Noteworthy Drugs XX. ALTERNATIVE THERAPY
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Pharmacology for Nursing Care, 7th Edition XX. ALTERNATIVE THERAPY 108
CHAPTER 107 Dietary Supplements XXI. TOXICOLOGY
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CHAPTER 108 Management of Poisoning
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CHAPTER 109 Potential Weapons of Biologic, Radiologic, and Chemical Terrorism Back Matter
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APPENDIX A Adult Immunization, United States, 2009
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APPENDIX B Guide to Gender-Related Drugs
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APPENDIX C Commonly Used Abbreviations
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APPENDIX D Canadian Drug Information
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APPENDIX E Major Drug Classes and Their Prototypes
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APPENDIX F Very New Drugs and Important New Formulations of Older Drugs
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Special Interest Topics
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Pharmacology for Nursing Care, 7th Edition iii
Front Matter
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Dedication for Bill and Jean My Good Friends
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About the Author Richard A. Lehne, PhD, earned his BA from Drew University and his PhD in pharmacology from George Washington University. His involvement in nursing education began 30 years ago at the University of Virginia School of Nursing, where he taught undergraduate and graduate pharmacology courses and was voted best teacher by his students. He has also taught at the University of Arizona in both the School of Nursing and School of Pharmacy. For the past 24 years, most of his time has been devoted to creating and revising this book. Dr. Lehne (rhymes with zany or rainy) lives in Charlottesville, VA, where he likes to bike and walk/jog (as age, weather, and editors permit), practice cooking (it's like being back in the lab, but more fun), and cheer on Nancy (his SO) in her equestrian activities.
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Pharmacology for Nursing Care, 7th Edition
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Consultants Linda A. Moore, EdD, RN, APRN, BC (GNP/ANP), MSCN, is an Associate Professor of Nursing at the University of North Carolina at Charlotte and a Nurse Practitioner in the Multiple Sclerosis Center of Carolinas HealthCare Systems. She received her BSN from Duke University and her MSN and EdD from the University of Virginia. Her teaching responsibilities encompass courses for undergraduate (RN to BSN) and graduate students. Her major clinical and research interests are multiple sclerosis, cardiovascular nursing, and gerontologic nursing. Dr. Moore is a member of the North Carolina Nurses' Association, Sigma Theta Tau, American Academy of Nurse Practitioners, and the International Organization of Multiple Sclerosis Nurses. Leanna J. Crosby, DNSc, G/ANP-C, received her diploma in nursing from St. Luke's Hospital School of Nursing, her baccalaureate and master's degrees from the University of Virginia, and her doctorate in nursing science from Catholic University of America. Also, she completed the adult nurse practitioner program at the University of Virginia and the gerontologic nurse practitioner program at the University of Arizona. Dr. Crosby has done extensive research in chronic rheumatoid disease, and has taught physiology and pathophysiology to a generation of appreciative graduate and undergraduate students. Currently, she is working as a nurse practitioner within the Department of Veteran Affairs, Southern Arizona Veterans Administration Healthcare System, and is an Adjunct Associate Professor at the University of Arizona College of Nursing. Dr. Crosby is a member of the American Nurses Association, Sigma Theta Tau, and the Arizona Nurses' Association, and serves on the Arizona State Board of Nursing Advanced Practice Committee. In addition, she serves as the VISN 18 (Arizona, Texas, and New Mexico) coordinator for the Advanced Practice Nursing Network. At the local level, she is Membership Chair for the Southern Arizona Nurse Practitioner Association, a member of the Professional Standards Board for Nursing at the Southern Arizona VA Medical Center, and Chair of the Tucson VA IACUC Animal Research Committee. Diane B. Hamilton, PhD, RN, received her BA from Northwestern University, her BSN from West Texas State University, her MA in Community Mental Health and Gerontologic Nursing from the University of Iowa, and her PhD in Psychosocial Nursing and Nursing History from the University of Virginia. She has extensive experience in psychiatric nursing, including serving as Attending Nurse at the Institute of Psychiatry of the Medical University of South Carolina. She has taught psychiatry and behavioral science to medical students, and gerontology, community health, psychiatric nursing, and nursing history to nursing students. She is a Professor Emerita from the School of Nursing at Western Michigan University, where she taught psychiatric nursing and nursing history and researched nursing history. Dr. Hamilton is a member of the American Nurses' Association, the American Association of the History of Nursing, the American Association for the History of Medicine, the American Association of University Women, and Sigma Theta Tau. In addition, Dr. Hamilton is a recipient of the Best of Image Award in nursing history, the Lavinia
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Pharmacology forthe Nursing 7th ofEdition History of Medicine, AmericanCare, Association University Women, and Sigma Theta Tau. In addition, Dr. Hamilton is a recipient of the Best of Image Award in nursing history, the Lavinia Dock Award for historical scholarship, the Best Investigator Award from the University of Rochester, the Golden Apple Teaching Award from the Medical University of South Carolina, and the Distinguished Scholar Award from Western Michigan University.
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Contributors Textbook Contributors Marilynn C. Frederiksen, MD Associate Professor of Clinical Obstetrics and Gynecology, Feinberg Medical School, Northwestern University, Chicago, Illinois Chapters 60, 61 Jack L. Le Frock, BA, MSC, PhD, MN, CPE Medical Director, 3 Dimensional Dosing, Sarasota, Florida Chapters 92, 93 Timothy McGuire, PharmD, BCOP, FCCP Associate Professor, Pharmacy Practice, University of Nebraska Medical Center, Omaha, Nebraska Chapters 100, 101, 102 Susan Paulsen, PharmD Assistant Dean, Student Affairs and Assessment Associate Professor, School of Pharmacy, Regis University, Denver, Colorado Chapter 107 John Rackham, PharmD Pharmacy Department, Deaconess Medical Center, Spokane, Washington Chapter 93
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Pharmacology Chapter 93for Nursing Care, 7th Edition Marshal Shlafer, PhD University of Michigan Medical School, Department of Pharmacology, Ann Arbor, Michigan Chapters 49, 56 Colleen Terriff, PharmD, BCPS (AQ-ID) Clinical Associate Professor, Washington State University College of Pharmacy, Deaconess Medical Center, Spokane, Washington Chapter 93 Trisha S.M. Tom, PharmD Pharmacy Department, Deaconess Medical Center, Spokane, Washington Chapter 93 Contributors to Teaching and Learning Resources Sylvia Baack, RN, MSN Geriatrics and Extended Care Nurse Educator, Central Texas Veterans Health Care System, Waco, Texas Test Bank Jean Blank, RN, MSN Associate Professor of Nursing, Gordon E. Inman College of Health Sciences and Nursing, Belmont University, Nashville, Tennessee NCLEX© Examination Review Questions Martha M. Buckner, PhD, RN Associate Professor of Nursing, Gordon E. Inman College of Health Sciences and Nursing, Belmont University, Nashville, Tennessee NCLEX © Examination Review Questions
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Pharmacology for Nursing Care, 7th Edition NCLEX © Examination Review Questions Stephanie C. Butkus, RN, MSN, CPNP, CLC Assistant Professor, Division of Nursing, Kettering College of Medical Arts, Kettering, Ohio Critical Thinking Case Studies in Instructor's Manual Jennifer Donwerth, RN, MSN, ANP-BC, GNP-BC Instructor, Department of Nursing, Tarleton State University, Stephenville, Texas Lecture Outlines in Instructor's Manual Sheila Grossman, PhD, FNP-BC Professor and FNP Specialty Track Coordinator, Fairfield University School of Nursing, Fairfield, Connecticut Test Bank Rhonda Lawes, RN, MS, CNE Interim Director of Nursing Education, College of Nursing, University of Oklahoma, Glendale, Oklahoma PowerPoint Slides Lois S. Marshall, PhD, RN Nurse Education Consultant, LSM Educational Consulting, Miami, Florida Test Bank Sherry Neely, MSN, RN, CRNP Associate Professor, Butler County Community College, Butler, Pennsylvania Study Guide Lynne D. Palma, DNP, FNP-BC, CDE
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Pharmacology for Nursing Care,CDE 7th Edition Lynne D. Palma, DNP, FNP-BC, Graduate Clinical Coordinator, Christine E. Lynn College of Nursing, Florida Atlantic University, Boca Raton, Florida Flashcards Donna Russo, RN, MSN, CCRN, CNE Instructor, School of Nursing, Frankford Hospital, Philadelphia, Pennsylvania Test Bank Sharon Souter, PhD, RN, CNE Dean and Associate Professor, College of Nursing, University of Mary Hardin-Baylor, Belton, Texas Quizzes in Instructor's Manual, Key Points, and Test Bank Jo A. Voss, PhD, RN, CNS Associate Professor, South Dakota State University, Rapid City, South Dakota Audience Response System Questions
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Reviewers Kenneth Bromberg, MD, FAAP, FIDSA Weill Medical College of Cornell University, New York, New York Christopher Case, MD Jefferson City Medical Group, Jefferson City, Missouri Dennis J. Cheek, RN, PhD, FAHA Harris College of Nursing and Health Sciences & School of Nurse Anesthesia, Texas Christian University, Fort Worth, Texas Wesley W. Emmons, III MD, FACP
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Pharmacology Nursing Care, 7th Edition Wesley W.for Emmons, III MD, FACP Thomas Jefferson University, Philadelphia, Pennsylvania Mary Kay Flynn, RN, PhD Grand Canyon University, Phoenix, Arizona Marilynn C. Frederiksen, MD Northwestern University Feinberg Medical School, Chicago, Illinois Steve Krau, PhD, RN, CT Vanderbilt University Medical Center, Nashville, Tennessee Jack L. Le Frock, BA, MSC, PhD, MN, CPE 3 Dimensional Dosing, Sarasota, Florida Leonard Lichtblau, PhD University of Minnesota School of Nursing, Minneapolis, Minnesota Lisa A. Michaels, MD University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey Jim Middleton, Pharmacist Miller College/Kellogg Community College, Battle Creek, Michigan Brenda Condusta Pavill, RN, PhD, FNP, IBCLC Misericordia University, Dallas, Pennsylvania Joshua J. Neumiller, PharmD, CDE, CGP, FASCP Assistant Professor of Pharmacotherapy, Washington State University, Spokane, Washington Mary Ann Picone, MD
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Pharmacology Nursing Care, 7th Edition Mary Annfor Picone, MD Multiple Sclerosis Center at Holy Name Hospital, Teaneck, New Jersey Joseph D. Schwartzman, MD Dartmouth Medical School, Dartmouth-Hitchcock Medical Center, Hanover, New Hampshire Stephen M. Setter, PharmD, DVM, CDE, CGP, FASCP Associate Professor of Pharmacotherapy, Washington State University, Spokane, Washington Sharon Souter, PhD, RN, CNE University of Mary Hardin-Baylor College of Nursing, Belton, Texas Dennis L. Stevens, MD, PhD Veterans Affairs Medical Center, Boise, Idaho Nehal P. Vadhan, PhD New York State Psychiatric Institute, Substance Use Research Center, New York, New York
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Welcome to Our Seventh Edition Welcome to the seventh edition of Pharmacology for Nursing Care, the pharmacology text that students like to read. Really! This edition, like the first six, was written to be a true textbook—that is, a book that focuses on essentials and plays down secondary details. To give the book focus, four primary techniques are employed: (1) teaching through prototypes, (2) using large print for essential information and small print for secondary information, (3) limiting discussion of adverse effects and drug interactions to information that matters most, and (4) using evidence-based clinical guidelines to determine what content to stress. To reinforce the relationship between pharmacologic knowledge and nursing practice, nursing implications are integrated into the body of each chapter. Also, to provide rapid access to nursing content, nursing implications are summarized at the end of most chapters, using a nursing process format. In addition, key points are summarized at the end of each chapter. As in prior editions, this edition emphasizes conceptual material, thereby reducing rote memorization, promoting comprehension, and increasing reader friendliness. For a description of the book's classic distinguishing features, please refer to the Preface, which follows on page xii.
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Pharmacology for Nursing Care, 7th book's classic distinguishing features, please referEdition to the Preface, which follows on page xii. WHAT'S NEW IN THE BOOK? Pharmacology for Nursing Care has been revised cover to cover. Topics with significantly expanded coverage include diabetes, drugs affecting the renin-angiotensin-aldosterone system, drug therapy of cancer, and dietary supplements. This edition introduces a host of new drugs and four new Special Interest Topics. In addition, new treatment guidelines have been added, and older guidelines have been updated.
New Drugs More than new 90 drugs have been added. Among these are • Varenicline [Chantix], the most effective pharmacologic aid to smoking cessation • HPV vaccine [Gardasil], the first vaccine to protect against cervical cancer (and genital warts too) • Sitagliptin [Januvia], the first representative of a new class of antidiabetic drugs, the gliptins • Ranolazine [Ranexa], the first new type of drug for angina in over 25 years • Febuxostat [Uloric], the first new drug for gout in over 40 years • Aliskiren [Tekturna], the first direct renin inhibitor • Two new types of drugs for HIV infection—maraviroc [Selzentry], the first CCR5 antagonist, and raltegravir [Isentress], the first integrase inhibitor • Sixteen anticancer drugs, including azacitidine [Vidaza], a hypomethylating agent; sorafenib [Nexavar], an oral tyrosine kinase inhibitor; and lapatinib [Tykerb], an oral HER2 inhibitor
Restructured Content One chapter from the prior edition—Drugs for Rheumatoid Arthritis and Gout—has been divided into two chapters: Drugs for Arthritis and Drugs for Gout. The title of another chapter— Herbal Supplements—has been changed to Dietary Supplements, to reflect inclusion of glucosamine and other nonherbal agents that are marketed as supplements. For several chapters, the internal structure has been modified. In most cases, these changes are minor. However, for two chapters—Anticoagulant, Antiplatelet, and Thrombolytic Drugs (Chapter 51) and Drugs for Asthma (Chapter 75)—restructuring is extensive. Three appendices—Weights and Measures, Normal Laboratory Values, and Techniques of Drug Administration—have been moved from
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Pharmacology for75)—restructuring Nursing Care,is extensive. 7th Edition Asthma (Chapter Three appendices—Weights and Measures, Normal Laboratory Values, and Techniques of Drug Administration—have been moved from the book to our web site—http://evolve.elsevier.com/Lehne. and one appendix—Poison Control Centers in the United States— has been dropped, because your local center can now be contacted through a nationwide hotline: 1-800-222-1222.
New Special Interest Topics This edition has 27 boxes on Special Interest Topics, which address issues that I find especially engaging and think you might too. Some boxes discuss cutting-edge therapies, some discuss ongoing controversies, some discuss topics of general interest, and some discuss issues featured in the popular press. Four boxes are new: • Did Kisses Kill Calvin? • Gastroesophageal Reflux Disease • Chronic Obstructive Pulmonary Disease • Methicillin-Resistant Staphylococcus aureus Two boxes have been substantially revised: • Inflammation, C-Reactive Protein, and Cardiovascular Risk • Emergency Contraception A complete list of Special Interest Topics appears on the inside back cover.
LEARNING SUPPLEMENTS FOR STUDENTS Evolve Student Resources To accompany this edition, we have seven online resources: Flashcards, an Audio Drug
Glossary, Key Points (Audio), NCLEX© Examination Review Questions, Clinical References (audio and printable), Study Guide Answer Key, and WebLinks. All of these resources are available at http://evolve.elsevier.com/Lehne. • Flashcards summarize the need-to-know information for more than 100 key drugs. These printable flashcards include the following for each drug: generic name, trade name, category, mechanism of action, uses, and adverse effects. • The Audio Drug Glossary contains sound files that pronounce the generic names of the 300 most commonly prescribed drugs. As discussed in Chapter 3, if drugs were assigned generic names whose pronunciation was obvious, a glossary such as this would be
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Pharmacology forcommonly Nursing Care, drugs. 7th Edition 300 most prescribed As discussed in Chapter 3, if drugs were assigned generic names whose pronunciation was obvious, a glossary such as this would be unnecessary. I look forward to the day when that's the case. • Key Points for each chapter, which can be downloaded to a CD or MP3 player to listen to and review at your leisure. You can also print the Key Points. • Approximately 700 NCLEX® Examination Review Questions help build confidence in test taking and help ensure comprehension in an engaging way. • Clinical References includes a concise overview of drug administration techniques, normal laboratory values, and much more. • The Study Guide Answer Key allows you to compare your answers to the answer guidelines from the Study Guide author. • The WebLinks represent a large and dynamic library of links to drug-related web sites, keyed to the table of contents of this edition.
Pharmacology Online Pharmacology Online for Pharmacology for Nursing Care, 7th edition (ISBN: 978-1-4160-6247-9), is a dynamic, online course resource that includes interactive self-study modules, a collection of interactive learning resources, and a media-rich library of supplemental resources: • Self-Study Modules cover the basic principles of pharmacology and key drug content, with animations and NCLEX examination-style questions to help you assess your understanding of pharmacology concepts. • Interactive Case Studies immerse you in true-to-life scenarios that require you to make important choices in patient care and patient teaching. • “Roadside Assistance” Video Clips use humor and analogy in a uniquely fun and engaging way to teach key concepts. • Also includes Interactive Learning Activities, Flashcards, Practice Quizzes for the NCLEX Examination, and much more!
Study Guide The Study Guide (ISBN: 978-1-4160-6248-6), which is keyed to the book, includes multiplechoice questions, critical thinking questions, and case studies. Answers are provided on the Evolve web site. This edition features an increased emphasis on prioritization of nursing care to
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Pharmacology for critical Nursing Care, 7th Edition choice questions, thinking questions, and case studies. Answers are provided on the Evolve web site. This edition features an increased emphasis on prioritization of nursing care to enhance preparation for the NCLEX exam.
TEACHING SUPPLEMENTS FOR INSTRUCTORS Evolve Instructor Resources The Instructor Resources for the seventh edition are available online. There are five components: an Instructor's Manual, a Test Bank, PowerPoint Slides, Audience Response System Questions, and an Image Collection. • The Instructor's Manual, which has been thoroughly revised, emphasizes creative learning strategies to help students apply knowledge of pharmacology to nursing practice. Included for each chapter are learning objectives, key terms, chapter focus, chapter outline, classroom strategies, collaborative/active learning activities, clinical laboratory strategies, web-related activities, quizzes, and critical thinking case studies. Answers for the quizzes and case studies are also provided. • The Test Bank has 1200 NCLEX examination-style questions presented in versatile ExamView software, which allows faculty to customize paper-based and/or online exams through an easy-to-use, intuitive interface. For each question, we indicate the correct answer, rationale, text page reference, cognitive level, nursing process step, and NCLEX ® Client Need category. • The PowerPoint Slides have been updated, with images from the book inserted where applicable. The 700 or so slides may be used as-is, or adapted for classroom or online presentation. • The Audience Response System Questions contain approximately 225 questions appropriate for use with clickers/audience response systems. • The Image Collection contains nearly every illustration from the book—about 170 all told, most in full color. The images are presented in electronic format to facilitate classroom projection or online teaching.
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Pharmacology for Nursing Care, 7th Edition Make the most of your time with Evolve eBooks. With easy access from your computer or any Internet browser, you and your students can: • Search across an entire library of Elsevier e-textbooks simultaneously • Create focused, customized study documents • Make and share notes, highlights, and more Evolve eBooks revolutionizes the way your students study and learn. To obtain these resources, contact your Elsevier Educational Sales Representative. If you don't know who your rep is, you can find out by checking the Sales Representative Locator at http:// us.elsevierhealth.com/replocator.jsp or by calling Elsevier Faculty Support at 1-800-222-9570.
PLEASE WRITE I'd like to hear from you. All feedback is welcome. Suggestions for improving the book are especially helpful, as are reports of mistakes you may spot. Of course, I also like to hear from
readers who simply have something nice to say. You can reach me by e-mail at
[email protected], or by U.S. Mail at 1619 Willow Dale Lane, Charlottesville, VA, 22911. Or feel free to leave a note on my Facebook page. Richard A. Lehne 1
This e-mail address—
[email protected]—is permanent, unlike the address I gave in the sixth edition, which died when my internet service provider was absorbed by a stronger company. I apologize to those of you who tried to contact me and were informed that the email address was no longer valid.
xi xii
Preface Pharmacology pervades all phases of nursing practice and relates directly to patient care and patient education. Yet, despite its importance, many students—and even some teachers—are often uncomfortable with the subject. Why? Because, traditional texts have stressed memorizing details rather than understanding. In this text, the guiding principle is to establish a basic understanding of drugs, after which secondary details can be learned as needed. Judging from the acceptance of this book, my departure from tradition has been welcome. I wrote this text with two major objectives: To help you, the nursing student, establish a knowledge base in the basic science of drugs, and to show you how that knowledge can be applied in clinical practice. To achieve these goals, I have used several innovative techniques, which are described
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Pharmacology for Nursing Care, 7thyou Edition base in the basic science of drugs, and to show how that knowledge can be applied in clinical practice. To achieve these goals, I have used several innovative techniques, which are described below.
Laying Foundations in Basic Principles In order to understand drugs, you need a solid foundation in basic pharmacologic principles. To establish this foundation, I have dedicated major chapters to the following topics: basic principles that apply to all drugs (Chapter 4 through 8), basic principles of drug therapy across the life span (Chapters 9 through 11), basic principles of neuropharmacology (Chapter 12), basic principles of antimicrobial therapy (Chapter 82), and basic principles of cancer chemotherapy (Chapter 100).
Reviewing Physiology and Pathophysiology To understand the actions of a drug, you must first understand the biologic systems that the drug influences. Accordingly, for all major drug families, relevant physiology and pathophysiology are reviewed. In almost all cases, these reviews are presented at the beginning of each chapter, rather than in a systems review at the beginning of a unit. This juxtaposition of pharmacology, physiology, and pathophysiology is designed to help you understand how these topics interrelate.
Teaching Through Prototypes Within each drug family, we can usually identify a prototype: a representative agent that characterizes all members of the group. Because other family members are very similar to the prototype, to know the prototype is to know the basic properties of all family members. The benefits of teaching through prototypes can be appreciated with an example. Let's consider the nonsteroidal anti-inflammatory drugs (NSAIDs), a family that includes aspirin, ibuprofen [Motrin, others], naproxen [Aleve, others], celecoxib [Celebrex], and more than 20 other drugs. Traditionally, information on these drugs is presented in a series of paragraphs describing each drug in turn. When attempting to study from such a list, students are likely to learn many drug names and little else; the important concept of similarity among family members is easily lost. In this text, the family prototype—aspirin—is discussed first and in depth. After this, instruction is completed by pointing out the relatively minor ways in which individual NSAIDs differ from aspirin. Not only is this approach more efficient than the traditional approach, it is also more effective, in that similarities among family members are emphasized.
Large Print and Small Print: A Way to Focus on Essentials Pharmacology is exceptionally rich in detail. There are many drug families, each with multiple members and each member with its own catalogue of indications, contraindications, adverse effects, and drug interactions. This abundance of detail confronts teachers with the difficult
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Pharmacology for Nursing Care, 7th Edition members and each member with its own catalogue of indications, contraindications, adverse effects, and drug interactions. This abundance of detail confronts teachers with the difficult question of what to teach, and confronts students with the equally difficult question of what to study. Attempting to answer these questions can frustrate teachers and students alike. Even worse, in the presence of myriad details, basic concepts can be obscured. To help you focus on essentials, I use two sizes of type. Large type is intended to say, “On your first exposure to this topic, this is the core of information you should learn.” Small type is intended to say, “Here is additional information that you may want to learn after mastering the material in large type.” As a rule, I reserve large print for prototypes, basic principles of pharmacology, and reviews of physiology and pathophysiology. Small print is used for secondary information about the prototypes and for discussion of drugs that are not prototypes. This technique allows the book to contain a large body of detail without having that detail cloud the big picture. Furthermore, because the technique highlights essentials, it minimizes questions about what to teach and what to study. The use of large and small print is especially valuable for discussing adverse effects and drug interactions. Most drugs are associated with many adverse effects and interactions. As a rule, however, only a few of these are noteworthy. In traditional texts, practically all adverse effects and interactions are presented, creating long and tedious lists. In this text, I use large print to highlight the few adverse effects and interactions that are especially characteristic; the rest are noted briefly in small print. The result? Rather than overwhelming you with long and forbidding lists, this text delineates a moderate body of information that's truly important, and thereby facilitates comprehension.
Using Clinical Reality to Prioritize Content This book contains two broad categories of information: pharmacology (ie, basic science about drugs) and therapeutics (ie, clinical use of drugs). To ensure that content is clinically relevant, I use evidence-based treatment guidelines as a basis for deciding what to stress and what to play down. Unfortunately, clinical practice is a moving target: When effective new drugs are introduced, and when clinical trials reveal new benefits or new risks of older drugs, the guidelines change—and hence large sections of this book must be rewritten. Consider the following examples:
xii xiii
• When the first edition of this book published, heart failure was considered an absolute contraindication to the use of beta blockers. After all, in patients with heart failure, cardiac contractility is greatly reduced, and beta blockade can reduce contractility even further. Nonetheless, we now know that, when dosed properly, beta blockers can be of great benefit in heart failure, and hence these drugs are now considered first-line therapy—rather than
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Pharmacology for we Nursing 7thdosed Edition Nonetheless, now knowCare, that, when properly, beta blockers can be of great benefit in heart failure, and hence these drugs are now considered first-line therapy—rather than drugs to be avoided. • When the third edition of this book published, experts recommended that all postmenopausal women consider using estrogen replacement therapy long term to prevent osteoporosis and heart disease; adverse effects were considered trivial. Today, we know that the benefits of postmenopausal estrogen therapy are much smaller than previously believed, and the risks are greater. As a result, guidelines now recommend that estrogen therapy be used only to relieve severe menopausal symptoms, and that women use the lowest dosage possible for the shortest time necessary. These examples illustrate two problems. First, because clinical practice is subject to change, I have to work hard to keep this book current. Second, despite my best efforts, the book and clinical reality may not agree: Some treatments discussed here will be considered inappropriate before the eighth edition comes out. Furthermore, in areas where there is controversy, the treatments discussed here may be considered inappropriate by some clinicians right now.
Nursing Implications: Demonstrating the Application of Pharmacology in Nursing Practice The principal reason for asking you to learn pharmacology is to enhance your ability to provide patient care and education. To show you how pharmacologic knowledge can be applied to nursing practice, nursing implications are integrated into the body of each chapter. That is, as specific drugs and drug families are discussed, the nursing implications inherent in the pharmacologic information are discussed side-by-side with the basic science. To facilitate access to nursing content, nursing implications are also summarized at the end of most chapters. These summaries serve to reinforce the information presented in the chapter body. In chapters that are especially brief or that address drugs that are infrequently used, summaries of nursing implications have been omitted. However, even in these chapters, nursing implications are incorporated into the chapter body.
About Dosage Calculations Unlike many nursing pharmacology texts, this one has no section on dosage calculation. Why? First, adequate discussion of this important subject simply isn't feasible in a text dedicated to the basic science of drugs; the amount of space that can be allotted is too small. Second, thanks to the availability of excellent publications on the subject (eg, Calculate with Confidence, 4th edition, by Deborah Gray Morris), there is no need to include this content in a pharmacology text.
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Pharmacology for Nursing Care, Edition Deborah Gray Morris), there is no need to7th include this content in a pharmacology text. Ways to Use This Textbook Thanks to its focus on essentials, this text is especially well suited to serve as the primary text for a course dedicated specifically to pharmacology. In addition, the book's focused approach makes it a valuable resource for pharmacologic instruction within an integrated curriculum and for selfdirected learning by students, teachers, and practitioners. Richard A. Lehne
xiii xiv
Acknowledgments I want to begin by thanking all involved members of my extended publishing family at Elsevier Health Sciences. For 24 years, these good people have provided support, encouragement, and guidance, along with the latitude to write the book I had hoped to create. Of equal importance, they committed the human and monetary resources required to make a high quality product—a concept that seems almost quaint in today's grab-all-the-bucks-you-can world. Of course, to make a good product, you need a good team. For this edition, the Dream Team, who gave you the sixth edition, returned en masse. Who are these winners? Well, playing senior editor, we have Kristin—The Longsuffering—Geen; in the senior developmental editor slot, there's Lauren —The Comforting—Lake; as senior project manager, there's Anne—Mistress of Detail—Konopka; our proofreader is Judi—The Awe-inspiring—May; playing copyeditor, for her fifth season, is Megan—The Incomparable—Westerfeld; and in the role of publishing services manager, we have Jeff—Keeper of Rules—Patterson. Our executive publisher is Loren Wilson, and our designer, once again, is Teresa McBryan, senior book designer. My appreciation and respect for the Dream Team is hard to describe. By the time they begin work on this project, I've already devoted nearly a year of full-time work to revising the manuscript, which means I'm on the verge of exhaustion—with very little energy left for production. Happily, because of the Dream Team, I don't need much. These guys are so good at their jobs, that I feel 100% comfortable turning my baby over to their capable hands. The result, which you hold in your hands, is, I believe, the best that any publishing team could produce. If you agree, you too can thank the Dream Team—for their dedication, proficiency, and commitment to quality. For this edition, it's been my pleasure to work with five contributors: Marshal Shlafer, PhD (Chapters 49 and 56, Marilynn Frederiksen, MD (Chapters 60 and 61, Jack Le Frock, BA, MSC, PhD, MN, CPE (Chapters 92 and 93, Tim McGuire, PharmD, BCOP, FCCP (Chapters 100, 101, and 102), and Susan Paulsen, PharmD (Chapter 107), Four of these people—Drs Frederiksen, Le Frock, McGuire, and Paulsen—are experts in the areas they wrote about. The fifth contributor—Marshal Shlafer—although not an expert in the areas he wrote about (diabetes and hyperlipidemias), is
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Pharmacology for Nursing 7th they Edition McGuire, and Paulsen—are expertsCare, in the areas wrote about. The fifth contributor—Marshal Shlafer—although not an expert in the areas he wrote about (diabetes and hyperlipidemias), is someone even more valuable: a beloved and respected teacher, and an accomplished author in his own right (the first edition of his pharmacology text published a few months before the first edition of this text). The input of all five contributors has greatly improved the chapters they revised. In addition to the Dream Team and the contributors, I want to recognize the following people for their contributions: • I profoundly thank Stephen Setter, PharmD, DVM, CDE, CGP, FASCP, and his colleague, Joshua Neumiller, PharmD, CDE, CGP, FASCP, for reviewing every chapter to ensure that information on drug formulations, dosages, and usage is accurate, current, and complete. Their Herculean efforts have contributed hugely to the quality of this book. • I thank Sherry Neely, MSN, RN, CRNP, who wrote the Study Guide for this edition (as well as the prior edition), and I thank all of the other people, whose names are presented on pages viiviii, who wrote other ancillary materials that accompany this edition. • I thank Alfred J. Rémillard, PhD, who wrote the appendix on Canadian drug information for the first edition of this book, and has revised that appendix for each edition since. • I am grateful for the suggestions offered by a small army of reviewers, whose names are listed on page ix. All of these experts are practicing clinicians. As a result, their input has helped keep the book in tune with current clinical reality. • I thank Alan Agins, PhD, my friend and colleague, for the use of his drug animations. Alan created these clips to illustrate his lectures on pharmacology, which he delivers to nursing audiences around the country. So, if you need a great speaker, look him up. • And I thank all members of the Elsevier educational sales force, whose professionalism and determination have contributed immeasurably to the book's continued success. Finally, I thank you, Nancy, for your support, patience, and love—all of which were mightily tested over the course of this revision.
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Pharmacology over the course offor this Nursing revision. Care, 7th Edition Weights and Measures VOLUME EQUIVALENTS 1 milliliter
1 liter
fluid ounce
= 0.271
fluid dram
= 16.2
minims
= 1000
milliliters
= 33.8
fluid ounces
= 2.11
pints
= 1.06
quarts
= 0.26
gallon
1 cubic centimeter = 1
milliliter
1 minim
= 0.062
milliliter
1 fluid dram
= 3.70
milliliters
= 60
minims
= 29.6
milliliters
=2
tablespoons
=8
fluid drams
1 teaspoon
=5
milliliters
1 tablespoon
= 15
milliliters
=3
teaspoons
= 237
milliliters
=8
fluid ounces
= 16
tablespoons
= 473
milliliters
= 16
fluid ounces
=2
cups
= 946
milliliters
= 32
fluid ounces
=2
pints
= 3785
milliliters
= 128
fluid ounces
=4
quarts
1 fluid ounce
1 cup
1 pint
1 quart
1 gallon
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= 0.034
Page 19 of 38
Pharmacology for Nursing Care, 7th Edition MASS EQUIVALENTS 1 milligram
= 0.0154
grain (apothecaries')
= 1000
micrograms
= 15.4
grains (apothecaries')
= 0.0322
ounce (apothecaries')
= 0.0353
ounce (avoirdupois)
= 0.257
dram (apothecaries')
= 64.8
milligrams
= 0.0021
ounce (apothecaries')
= 0.0023
ounce (avoirdupois)
= 0.0167
dram (apothecaries')
= 3.89
grams
1 ounce (apothecaries') = 31.1
grams
1 ounce (avoirdupois)
= 28.4
grams
1 pound (avoirdupois)
= 454
grams
= 0.454
kilogram
= 16
ounces (avoirdupois)
= 2.20
pounds (avoirdupois)
1 gram
1 grain (apothecaries')
1 dram (apothecaries')
1 kilogram
TEMPERATURE CONVERSION (Celsius degrees × 9/5) + 32
= Fahrenheit degrees
(Fahrenheit degrees −32) = 5/9 = Celsius degrees
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Page 20 of 38
Pharmacology for Nursing Care, 7th Edition
xiv f1
Normal Laboratory Values PART I. HEMATOLOGY Conventional Units
SI Units*
Acid hemolysis test (Ham)
No hemolysis
No hemolysis
Alkaline phosphatase, leukocyte
Total score 14–100
Total score 14–100
Males
4.6–6.2 million/mm3
4.6–6.2 × 1012/L
Females
4.2–5.4 million/mm3
4.2–5.4 × 1012/L
Children (varies with age)
4.5–5.1 million/mm3
4.5–5.1 × 1012/L
4500–11,000 mm3
4.5–11 × 109/L
Cell counts Erythrocytes
Leukocytes Total Differential
Percentage Absolute
Absolute
Myelocytes
0
0/mm3
0/L
Band neutrophils
3–5
150–400/mm3
150–400 × 106/L
Segmented neutrophils
54–62
3000–5800/mm3
3000–5800 × 106/L
Lymphocytes
25–33
1500–3000/mm3
1500–3000 × 106/L
Monocytes
3–7
300–500/mm3
300–500 × 106/L
Eosinophils
1–3
50–250/mm3
50–250 × 106/L
Basophils
0–1
15–50/mm3
15–50 × 106/L
Platelets
150,000–400,000/mm3
150–400 × 109/L
Reticulocytes
25,000–75,000/mm3 (0.5– 25–75 × 109/L 1.5% of erythrocytes)
Coagulation tests Bleeding time (template)
2.75–8 min
2.75–8 min
Coagulation time (glass tubes)
5–15 min
5–15 min
D-Dimer
2 days/week, but not daily
Daily
Throughout the day
Nighttime awakenings
≤2 times/month
3–4 times/month
>Once a week, but not nightly
Often 7 times/week
SABA used to control symptoms (but not to prevent EIB)
≤2 days/week
>2 days/week, but not daily, and not more than once on any day
Daily
Several times a day
Impact on normal activity
None
Minor limitation
Some limitation
Severe limitation
Lung function tests
• Normal FEV1 between exacerbations
• FEV1 >80% of predicted
• FEV1 >80% of predicted
• FEV1/FVC normal*
• FEV1 >60% but • FEV1 70 yr
900
90
15*
15
120*
1.2
1.3
16
1.7
400
2.4i
5*
30*
9–13 yr
600
45
5*
11
60*
0.9
0.9
12
1
300
1.8
4*
20*
14–18 yr
700
65
5*
15
75*
1
1
14
1.2
400h
2.4
5*
25*
19–30 yr
700
75
5*
15
90*
1.1
1.1
14
1.3
400h
2.4
5*
30*
31–50 yr
700
75
5*
15
90*
1.1
1.1
14
1.3
400h
2.4
5*
30*
51–70 yr
700
75
10*
15
90*
1.1
1.1
14
1.5
400
2.4j
5*
30*
>70 yr
700
75
15*
15
90*
1.1
1.1
14
1.5
400
2.4j
5*
30*
≤18 yr
750
80
5*
15
75*
1.4
1.4
18
1.9
600i
2.6
6*
30*
19–30 yr
770
85
5*
15
90*
1.4
1.4
18
1.9
600i
2.6
6*
30*
31–50 yr
770
85
5*
15
90*
1.4
1.4
18
1.9
600i
2.6
6*
30*
≤18 yr
1200
115
5*
19
75*
1.4
1.6
17
2
500
2.8
7*
35*
19–30 yr
1300
120
5*
19
90*
1.4
1.6
17
2
500
2.8
7*
35*
31–50 yr
1300
120
5*
19
90*
1.4
1.6
17
2
500
2.8
7*
35*
Children
Males
Females
Pregnancy
Lactation
Data from a summary table in Food and Nutrition Board, Institute of Medicine: Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC: National Academy Press, 2002:770– 771. However, except for the information on vitamins A and K, all of the information in this table was first released in the earlier publications listed in Table 80-1. NOTE: This table presents recommended dietary allowances (RDAs) in bold type and Adequate Intakes (AIs) in ordinary type followed by an asterisk (*). RDAs and AIs may both be used as goals for individual intake. RDAs are set to meet the needs of almost all (97% to 98%) individuals in a group. For healthy breast-fed infants, the AI is the mean intake. The AI for other life-stage and gender groups is believed to cover needs of all individuals in the group, but lack of data or uncertainty in the data prevent being able to specify with confidence the percentage of individuals covered by this intake.
CHAPTER 80 Vitamins
Page 9 of 26
Pharmacology for Nursing Care, 7th Edition a
As retinol activity equivalents (RAEs): 1 RAE = 1 mcg retinol, 12 mcg beta-carotene, 24 mcg alpha-carotene, or 24 mcg beta-cryptoxanthin. To calculate RAEs from retinol equivalents (REs) of provitamin A carotenoids in foods, divide the REs by 2. For preformed vitamin A in foods or supplements and for provitamin A carotenoids in supplements, 1 RE = 1 RAE.
b
As cholecalciferol: 1 mcg cholecalciferol = 40 IU vitamin D.
c
In the absence of adequate exposure to sunlight.
d
As alpha-tocopherol. Alpha-tocopherol includes RRR-alpha-tocopherol, the only form of alpha-tocopherol that occurs naturally in foods, and the 2R-stereoisomeric forms of alpha-tocopherol (RRR-, RSR-, RRS-, and RSS-alpha-tocopherol) that occur in fortified foods and supplements. It does not include the 2S-stereoisomeric forms of alphatocopherol (SRR-, SSR-, SRS-, and SSS-alpha-tocopherol), also found in fortified foods and supplements.
e
As niacin equivalents (NE): 1 mg of niacin = 60 mg of tryptophan; 0–6 months = preformed niacin (not NE).
f
As dietary folate equivalents (DFEs): 1 DFE = 1 mcg food folate = 0.6 mcg of folic acid from fortified food or as a supplement consumed with food = 0.5 mcg of a supplement taken on an empty stomach.
g
In 2008, the American Academy of Pediatrics recommended that all children—from infancy through adolescence—take in 10 mcg cholecalciferol (400 IU of vitamin D) each day.
h
In view of evidence linking folate deficiency with neural tube defects in the fetus, it is recommended that all women capable of becoming pregnant consume 400 mcg from supplements or forti-fied foods in addition to intake of food folate from a varied diet.
i
It is assumed that women will continue consuming 400 mcg from supplements or fortified food until their pregnancy is confirmed and they enter prenatal care, which ordinarily occurs after the end of the periconceptional period—the critical time for formation of the neural tube.
j
Because 10% to 30% of older people may absorb food-bound B12 poorly, it is advisable for those older than 50 years to meet their RDA mainly by consuming foods fortified with B12 or by consuming a supplement containing B12.
CHAPTER 80 Vitamins
Page 10 of 26
Pharmacology for Nursing Care, 7th Edition 81.2.4.3.1 81.2.4.3.1.1
BOX 80-1 Special Interest Topic LOSING HOPE FOR ANTIOXIDANTS On April 10, 2000, the National Academy of Sciences issued a report stating there is no conclusive evidence that megadoses of dietary antioxidants can protect against cancer, heart disease, Alzheimer's disease, or any other chronic disorder. Furthermore, they noted that excessive doses can cause harm. Accordingly, they recommended limiting intake of antioxidants to amounts that will prevent nutritional deficiency, and recommended avoiding doses that are potentially harmful. The report, titled Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids, is available from the National Academy Press. On February 28, 2007, the conclusions of this report were strongly reinforced by a study published in JAMA that found that antioxidants do not help users live longer, and may actually increase the risk mortality. Dietary antioxidants are defined as substances present in food that can significantly decrease cellular and tissue injury caused by highly reactive forms of oxygen and nitrogen, known as “free radicals.” These free radicals, which are normal by-products of metabolism, readily react with other molecules. The result is tissue injury known as “oxidative stress.” Antioxidants help reduce oxidative stress by neutralizing free radicals before they can cause harm. There is no question that dietary antioxidants can decrease injury. However, the available data are insufficient to prove that taking large doses can reduce the risk of chronic disease. Which dietary constituents function as antioxidants? There is good evidence that three compounds—selenium, vitamin C, and vitamin E—exert significant antioxidant actions. Data for beta-carotene (a precursor of vitamin A) are less clear: Although beta-carotene has antioxidant activity in vitro, convincing evidence of in vivo antioxidant activity is lacking. How might antioxidants protect against chronic disease? By reducing oxidative damage to DNA, they could reduce the risk of cancer. By reducing oxidation of LDL cholesterol, a critical step in the formation of atherosclerotic plaque, they could protect against heart disease. Reducing oxidation of other biologic molecules could explain protection against other diseases. Researchers have been studying the clinical effects of antioxidants for more than a decade. Unfortunately, although initial findings were encouraging, more recent studies indicate that benefits are generally lacking.
CHAPTER 80 Vitamins
Page 11 of 26
Pharmacology Nursing Care, 7th Edition indicatefor that benefits are generally lacking. When evaluating antioxidants for clinical effects, scientists have conducted two kinds of studies: observational studies and randomized controlled trials (RCTs). Observational studies are based on patient histories: for example, what did patients eat, and what was their medical status? In contrast, RCTs are rigorous, prospective studies in which patients are randomly assigned to either an experimental group or a placebo group; conclusions are based on differences between the two. The results of RCTs are much more reliable than the results of observational studies. Nearly all of the early studies on antioxidants were observational. These studies indicated that daily consumption of vegetables rich in antioxidants is associated with a reduced risk of heart disease and several types of cancer. The problem is, these results have more than one interpretation. Yes, they may mean that antioxidant vitamins protected against heart disease and cancer. However, they may also mean that protection was conferred by some other component of the diet (eg, high fiber content and/or low content of cholesterol and saturated fat). Or, perhaps diet had nothing to with it: Maybe protection resulted from a generally healthy lifestyle, and not from a healthy diet. Hence, although observational studies suggest that antioxidants may protect against heart disease and cancer, they certainly don't prove it. To establish definitive proof of cardiovascular benefits, scientists conducted large RCTs. The outcomes were both unexpected and discouraging. Two studies on vitamin E are especially noteworthy: (1) the Heart Outcomes Prevention Evaluation (HOPE) Study and (2) the GISSI-Prevenzione trial. Results of HOPE, the most definitive RCT on antioxidants to date, were reported in the January 20, 2000, issue of the New England Journal of Medicine. The HOPE trial enrolled 9541 patients ages 55 and older, of whom 80% had cardiovascular disease and 40% had diabetes. Half the patients were given 400 IU of vitamin E daily, and half received a placebo. In addition, the patients were randomly assigned to receive either ramipril (an angiotensinconverting enzyme inhibitor) or a second placebo. After 4.5 years, the results were conclusive: Ramipril provided clear protection against cardiovascular events, whereas vitamin E provided none. A 2.5-year extension of the HOPE trial, known as HOPE-TOO (for HOPE–The Ongoing Outcomes) reinforced the original data: Over a median interval of 7 years, vitamin E was no better than placebo at preventing cancer, cancer deaths, or the combined endpoint of stroke, myocardial infarction (MI), or cardiovascular death. In August 1999, an Italian group reported similar results in the British journal Lancet. Their study, the GISSI-Prevenzione trial, involved 11,000 patients who had suffered an MI. Half were randomly assigned treatment with vitamin E (300 IU daily) and half were given placebo. After 3.5 years, the incidence of nonfatal MI and death from coronary heart disease was the same for both groups, indicating no protection from vitamin E. Results of other RCTs support the results
CHAPTER 80 Vitamins
Page 12 of 26
Pharmacology for Nursing incidence of nonfatal MI Care, and death7th fromEdition coronary heart disease was the same for both groups, indicating no protection from vitamin E. Results of other RCTs support the results of these two. Not only has vitamin E failed to protect against cardiovascular disease in RCTs, there are data suggesting it may actually cause harm. In the HOPE trial, vitamin E was associated with an increased risk of heart failure. Furthermore, a recent meta-analysis of 19 clinical trials involving 135,967 subjects indicated that high-dose vitamin E (400 IU a day or more) increased the risk of all-cause mortality. Do the HOPE trial and other RCTs tell us that antioxidants confer virtually no protection against cardiovascular disease? With each new study, the possibility of protective effects seems less and less likely. However, before we give up on antioxidants entirely, we need to investigate the following: • Prolonged treatment—RCTs to date were conducted for a relatively short time (3.5 to 7 years). Perhaps giving vitamin E for a longer time would reveal benefits. However, the Physician's Health Study argues against this: 12 years of treatment with beta-carotene (a suspected antioxidant) offered no benefit. • Effect in healthy subjects—RCTs to date have been conducted on people with preexisting heart disease. Perhaps antioxidants can prevent heart disease in healthy subjects, even if they can't reverse it in sick ones. • Combination vitamin therapy—Most RCTs to date evaluated monotherapy with vitamin E. Perhaps benefits would be revealed if vitamin E were combined with other antioxidants, as occurs when we eat vitamin-containing foods. Even if vitamin E and other antioxidants prove devoid of cardiovascular benefits, the story doesn't end there. These agents may still offer protection against other disorders. For example, recent data indicate that vitamin E may delay the progression of age-related macular degeneration. Other target disorders under investigation include cataracts, Alzheimer's disease, the common cold, and advanced renal failure. Results of ongoing RCTs should provide further insight. 81.2.4.4
Pharmacokinetics. Intestinal absorption of the natural forms of vitamin K (phytonadione and vitamin K2) is adequate only in the presence of bile salts. Menadione and menadiol do not require bile salts for absorption. Following absorption, vitamin K is concentrated in the liver. Metabolism and secretion occur rapidly. Very little is stored.
CHAPTER 80 Vitamins
Page 13 of 26
Pharmacology for Nursing Care, 7th Edition secretion occur rapidly. Very little is stored. 81.2.4.5
Deficiency. Vitamin K deficiency produces bleeding tendencies. If the deficiency is severe, spontaneous hemorrhage may occur. In newborns, intracranial hemorrhage is of particular concern. An important cause of deficiency is reduced absorption. Since the natural forms of vitamin K require bile salts for their uptake, any condition that decreases availability of these salts (eg, obstructive jaundice) can lead to deficiency. Malabsorption syndromes (sprue, celiac disease, cystic fibrosis of the pancreas) can also decrease vitamin K uptake. Other potential causes of impaired absorption are ulcerative colitis, regional enteritis, and surgical resection of the intestine. Disruption of intestinal flora may result in deficiency by eliminating vitamin K–synthesizing bacteria. Hence, deficiency may occur secondary to use of antibiotics. In infants, diarrhea may cause bacterial losses sufficient to result in deficiency. The normal infant is born vitamin K deficient. Consequently, in order to rapidly elevate prothrombin levels, and thereby reduce the risk of neonatal hemorrhage, it is recommended that all infants receive a single injection of phytonadione (vitamin K1) immediately after delivery. As discussed in Chapter 51, the anticoagulant warfarin acts as an antagonist of vitamin K, and thereby decreases synthesis of vitamin K–dependent clotting factors. As a result, warfarin produces a state that is functionally equivalent to vitamin K deficiency. If the dosage of warfarin is excessive, hemorrhage can occur secondary to lack of prothrombin.
81.2.4.6
Adverse Effects. Severe Hypersensitivity Reactions. Intravenous phytonadione can cause serious reactions (shock, respiratory arrest, cardiac arrest) that resemble anaphylaxis or hypersensitivity reactions. Death has occurred. Consequently, phytonadione should not be administered IV unless other routes are not feasible, and then only if the potential benefits clearly outweigh the risks.
81.2.4.6.1
Hyperbilirubinemia. When administered parenterally to newborns, vitamin K derivatives can elevate plasma levels of bilirubin, thereby posing a risk of kernicterus. The incidence of hyperbilirubinemia is greater in premature infants than in full-term infants. Although all forms of vitamin K can elevate bilirubin levels, the risk is higher with menadione and menadiol than with phytonadione.
CHAPTER 80 Vitamins
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Pharmacology for Nursing Care, 7th Edition phytonadione. 81.2.4.7
Therapeutic Uses and Dosage. Vitamin K has two major applications: (1) correction or prevention of hypoprothrombinemia and bleeding caused by vitamin K deficiency, and (2) control of hemorrhage caused by overdose with warfarin.
81.2.4.7.1
Vitamin K Deficiency. As discussed, vitamin K deficiency can result from impaired absorption and from insufficient synthesis of vitamin K by intestinal flora. Rarely, deficiency results from inadequate diet. For children and adults, the usual dosage for correction of vitamin K deficiency ranges between 5 and 15 mg/day. As noted above, infants are born vitamin K deficient. To prevent hemorrhagic disease in neonates, it is recommended that all newborns be given an injection of phytonadione (0.5 to 1 mg) immediately after delivery.
81.2.4.7.2
Warfarin Overdose. Vitamin K reverses hypoprothrombinemia and bleeding caused by excessive dosing with warfarin, an oral anticoagulant. Bleeding is controlled within hours of vitamin K administration (see Chapter 51 for dosage).
81.2.4.8
Preparations and Routes of Administration. Phytonadione (vitamin K1) is available in 5-mg tablets, marketed as Mephyton, and in parenteral formulations (2 and 10 mg/mL) sold generically. Parenteral phytonadione may be administered IM, subQ, and IV. However, since IV administration is dangerous, this route should be used only when other routes are not feasible, and only if the perceived benefits outweigh the substantial risks.
81.3
WATER-SOLUBLE VITAMINS The group of water-soluble vitamins consists of vitamin C and members of the vitamin B complex (thiamin, riboflavin, niacin, pyridoxine, pantothenic acid, biotin, folic acid, and cyanocobalamin). The B vitamins differ widely from one another in structure and function. They are grouped together because they were first isolated from the same sources (yeast and liver). Vitamin C is not found in the same foods as the B vitamins, and hence is classified by itself. DRIs for the B vitamins were revised in 1998. DRIs for vitamin C were revised in 2000.
CHAPTER 80 Vitamins
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Pharmacology for Nursing Care, 7th Edition revised in 1998. DRIs for vitamin C were revised in 2000. Two compounds—pangamic acid and laetrile—have been falsely promoted as B vitamins. Pangamic acid has been marketed as “vitamin B15” and laetrile as “vitamin B17.” There is no proof these compounds act as vitamins or have any other role in human nutrition. 81.3.1
Vitamin C (Ascorbic Acid)
81.3.1.1
Actions. Vitamin C participates in multiple biochemical reactions. Among these are synthesis of adrenal steroids, conversion of folic acid to folinic acid, and regulation of the res-piratory cycle in mitochondria. At the tissue level, vitamin C is required for production of collagen and other compounds that comprise the intercellular matrix that binds cells together. In addition, vitamin C has antioxidant activity (see Box 80-1) and facilitates absorption of dietary iron.
81.3.1.2
957 958
Sources. The main dietary sources of ascorbic acid are citrus fruits and juices, tomatoes, potatoes, strawberries, melons, spinach, and broccoli. Orange juice and lemon juice are especially rich sources.
81.3.1.3
Requirements. The RDAs for vitamin C were revised in 2000. The new RDAs (see Table 80-2) are higher than those set in 1989. As in the past, RDAs increase for women who are pregnant or breast-feeding. For smokers, the RDA is increased by 35 mg/day.
81.3.1.4
Deficiency. Deficiency of vitamin C can lead to scurvy, a disease that is rare in the United States. Symptoms include faulty bone and tooth development, loosening of the teeth, gingivitis, bleeding gums, poor wound healing, hemorrhage into muscles and joints, and ecchymoses (skin discoloration caused by leakage of blood into subcutaneous tissues). Many of these symptoms result from disruption of the intercellular matrix of capillaries and other tissues.
81.3.1.5
Adverse Effects. Excessive doses can cause nausea, abdominal cramps, and diarrhea. The mechanism is direct irritation of the intestinal mucosa. To protect against GI disturbances, the Food and Nutrition Board has set 2 gm/day as the adult UL for vitamin C.
CHAPTER 80 Vitamins
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Pharmacology Nursing Care, Edition Board has setfor 2 gm/day as the adult UL7th for vitamin C. 81.3.1.6
Therapeutic Use. The only established indication for vitamin C is prevention and treatment of scurvy. For severe, acute deficiency, parenteral administration is recommended. The usual adult dosage is 0.3 to 1 gm/day. Vitamin C has been advocated for therapy of many conditions unrelated to deficiency, including cancers, asthma, osteoporosis, and the common cold. Claims of efficacy for several of these conditions have been definitively disproved. Other claims remain unproved. Studies have shown that large doses do not reduce the incidence of colds, although the intensity or duration of illness may be reduced slightly. Research has failed to show any benefit of vitamin C therapy for patients with advanced cancer, atherosclerosis, or schizophrenia. Vitamin C does not promote healing of wounds.
81.3.1.7
Preparations and Routes of Administration. Vitamin C is available in formulations for oral and parenteral administration. Oral products include tablets (ranging from 25 to 1500 mg), timed-release capsules (500 mg), and syrups (20 and 100 mg/mL). For parenteral use, vitamin C is available as ascorbic acid, sodium ascorbate, and calcium ascorbate. Administration may be subQ, IM, or IV.
81.3.2
Niacin (Nicotinic Acid) Niacin has a role as both a vitamin and a medicine. In its medicinal role, niacin is used to reduce cholesterol levels; the doses required are much higher than those used to correct or prevent nutritional deficiency. Discussion in this chapter focuses on niacin as a vitamin. Use of nicotinic acid to reduce cholesterol levels is discussed in Chapter 49.
81.3.2.1
Physiologic Actions. Before it can exert physiologic effects, niacin must first be converted into nicotinamide adenine dinucleotide (NAD) or nicotinamide adenine dinucleotide phosphate (NADP). NAD and NADP then act as coenzymes in oxidation-reduction reactions essential for cellular respiration.
81.3.2.2
Sources. Nicotinic acid (or its nutritional equivalent, nicotinamide) is present in many foods of plant and animal origin. Particularly rich sources are liver, poultry, fish, potatoes, peanuts, cereal bran, and cereal germ.
CHAPTER 80 Vitamins
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Pharmacology for Nursing Care, 7th Edition and cereal germ. In humans, the amino acid tryptophan can be converted to nicotinic acid. Hence, proteins can be a source of the vitamin. About 60 mg of dietary tryptophan is required to produce 1 mg of nicotinic acid. 81.3.2.3
Requirements. RDAs for nicotinic acid are stated as niacin equivalents (NEs). By definition, 1 NE is equal to 1 mg of niacin (nicotinic acid) or 60 mg of tryptophan. Revised RDAs for niacin (see Table 80-2) were established in 1998.
81.3.2.4
Deficiency. The syndrome caused by niacin deficiency is called pellagra, a term that is a condensation of the Italian words pelle agra, meaning “rough skin.” As suggested by this name, a prominent symptom of pellagra is dermatitis, characterized by scaling and cracking of the skin in areas exposed to the sun. Other symptoms involve the GI tract (abdominal pain, diarrhea, soreness of the tongue and mouth) and central nervous system (irritability, insomnia, memory loss, anxiety, dementia). All symptoms are readily reversed with niacin replacement therapy.
81.3.2.5
Adverse Effects. Nicotinic acid has very low toxicity. Small doses are completely devoid of adverse effects. When taken in large doses, nicotinic acid can cause vasodilation with resultant flushing, dizziness, and nausea. Using flushing as an index of excess niacin consumption, the Food and Nutrition Board has set 50 mg as the adult UL for the vitamin. Toxicity associated with highdose therapy is discussed in Chapter 49. Nicotinamide, a compound that can substitute for nicotinic acid in the treatment of pellagra, is not a vasodilator, and hence does not produce the adverse effects associated with large doses of nicotinic acid. Accordingly, nicotinamide is often preferred to nicotinic acid for treating pellagra, which requires high doses.
81.3.2.6
Therapeutic Uses. In its capacity as a vitamin, nicotinic acid is indicated only for the prevention or treatment of niacin deficiency. As noted, if given in large doses, nicotinic acid may also be used to lower cholesterol levels (see Chapter 49).
CHAPTER 80 Vitamins
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Pharmacology for (see Nursing 7th Edition cholesterol levels ChapterCare, 49). 81.3.2.7
Preparations, Dosage, and Administration. Nicotinic acid (niacin) is available in standard tablets (50 to 500 mg), controlled-release tablets (250 to 1000 mg), and extended-release capsules (125 to 500 mg). Dosages for mild deficiency range from 10 to 20 mg/day. For treatment of pellagra, daily doses may be as high as 500 mg. Dosages for hyperlipidemia are given in Chapter 49. Nicotinamide (niacinamide) is available in 100- and 500-mg tablets. For treatment or prevention of pellagra, dosages range from 150 to 500 mg/day. Unlike nicotinic acid, nicotinamide has no effect on plasma lipoproteins, and hence is not used to treat hyperlipidemias.
81.3.3
Riboflavin (Vitamin B2)
81.3.3.1
Actions. Riboflavin participates in numerous enzymatic reactions. However, in order to exert physiologic effects, the vitamin must first be converted into one of two active forms: flavin adenine dinucleotide (FAD) or flavin mononucleotide (FMN). In the form of FAD or FMN, riboflavin acts as a coenzyme for multiple oxidative reactions.
81.3.3.2
Sources and Requirements. In the United States, most dietary riboflavin comes from milk, yogurt, cheese, bread products, and fortified cereals. Organ meats are also rich sources. Revised RDAs for riboflavin (see Table 80-2) were established in 1998.
81.3.3.3
Toxicity. Riboflavin appears devoid of toxicity to humans. When large doses are administered, the excess is rapidly excreted in the urine. Because large doses are harmless, no UL has been set.
81.3.3.4
Use in Riboflavin Deficiency. Riboflavin is indicated only for prevention and correction of riboflavin deficiency, which usually occurs in conjunction with deficiency of other B vitamins. In its early state, riboflavin deficiency manifests as sore throat and angular stomatitis (cracks in the skin at the corners of the mouth). Symptoms that may appear later include cheilosis (painful cracks in the lips), glossitis (inflammation of the tongue), vascularization of the cornea, and itchy dermatitis of the scrotum or vulva. Oral riboflavin is used for treatment. The dosage is 10 to 15 mg/day.
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Page 19 of 26
Pharmacology Nursing Care, 7th Edition or vulva. Oralfor riboflavin is used for treatment. The dosage is 10 to 15 mg/day. 81.3.3.5
Use in Migraine Headache. As discussed in Chapter 30, riboflavin can help prevent migraine headaches. The daily dosage is 400 mg—much higher than the dosage for riboflavin deficiency.
81.3.4
Thiamin (Vitamin B1)
81.3.4.1
Actions and Requirements. The active form of thiamin (thiamin pyrophosphate) is an essential coenzyme for carbohydrate metabolism. Thiamin requirements are related to caloric intake, and are greatest when carbohydrates are the primary source of calories. For maintenance of good health, thiamin consumption should be at least 0.3 mg/1000 kcal in the diet. The 1998 revised RDAs for thiamin appear in Table 80-2. As indicated, thiamin requirements increase significantly during pregnancy and lactation.
81.3.4.2
Sources. In the United States, the principal dietary sources of thiamin are enriched, fortified, or wholegrain products, especially breads and ready-to-eat cereals. The richest source of the natural vitamin is pork.
81.3.4.3
Deficiency. Severe thiamin deficiency produces beriberi, a disorder having two distinct forms: wet beriberi and dry beriberi. Wet beriberi is so named because its primary symptom is fluid accumulation in the legs. Cardiovascular complications (palpitations, electrocardiogram abnormalities, highoutput heart failure) are common and may progress rapidly to circulatory collapse and death. Dry beriberi is characterized by neurologic and motor deficits (eg, anesthesia of the feet, ataxic gait, footdrop, wristdrop); edema and cardiovascular symptoms are absent. Wet beriberi responds rapidly and dramatically to replacement therapy. In contrast, recovery from dry beriberi can be very slow. In the United States, thiamin deficiency occurs most commonly among alcoholics. In this population, deficiency manifests as Wernicke-Korsakoff syndrome rather than frank beriberi. This syndrome is a serious disorder of the central nervous system, having neurologic and psychologic manifestations. Symptoms include nystagmus, diplopia, ataxia, and an inability to remember the recent past. Failure to correct the deficit may result in irreversible damage to the brain. Accordingly, if Wernicke-Korsakoff syndrome is suspected, parenteral thiamin should be administered immediately.
CHAPTER 80 Vitamins
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Pharmacology Nursing Care, 7th Edition administered for immediately. 81.3.4.4
Adverse Effects. When taken orally, thiamin is devoid of adverse effects. Accordingly, no UL for the vitamin has been established.
81.3.4.5
Therapeutic Use. The only indication for thiamin is treatment and prevention of thiamin deficiency.
81.3.4.6
Preparations, Dosage, and Administration. Thiamin is available in standard tablets (50, 100, and 250 mg) and enteric-coated tablets (20 mg) for oral use, and in solution (100 mg/mL) for IM or IV administration. For mild deficiency, oral thiamin is preferred. Parenteral administration is reserved for severe deficiency states (wet or dry beriberi, Wernicke-Korsakoff syndrome). The dosage for beriberi is 50 to 100 mg IM daily for 1 to 2 weeks, followed by 2.5 to 10 mg PO daily until recovery is complete.
81.3.5
Pyridoxine (Vitamin B6)
81.3.5.1
Actions. Pyridoxine functions as a coenzyme in the metabolism of amino acids and proteins. However, before it can influence biologic processes, pyridoxine must first be converted to its active form: pyridoxal phosphate.
81.3.5.2
Requirements. RDAs for pyridoxine were revised in 1998. For most people, and especially young people, the new RDAs (see Table 80-2) are considerably lower than the RDAs set in 1989. As in the past, RDAs increase significantly for women who are pregnant or breast-feeding.
81.3.5.3
Sources. In the United States, the principal dietary sources of pyridoxine are fortified, ready-to-eat cereals; meat, fish, and poultry; white potatoes and other starchy vegetables; and noncitrus fruits. Especially rich sources are organ meats (eg, beef liver) and cereals or soy-based products that have been highly fortified.
CHAPTER 80 Vitamins
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Pharmacology for Nursing that have been highly fortified.Care, 7th Edition 81.3.5.4
Deficiency. Pyridoxine deficiency may result from poor diet, use of isoniazid, and inborn errors of metabolism. Symptoms include seborrheic dermatitis, microcytic anemia, peripheral neuritis, convulsions, depression, and confusion. In the United States, dietary deficiency of vitamin B6 is rare, except among alcoholics. Within the alcoholic population, vitamin B6 deficiency has an incidence of about 20% to 30%, and occurs in combination with deficiency of other B vitamins. Isoniazid (a drug for tuberculosis) prevents conversion of vitamin B6 to its active form, and may thereby induce symptoms of deficiency (peripheral neuritis). Patients who are predisposed to this neuropathy (eg, alcoholics, diabetics) should receive daily pyridoxine supplements. Inborn errors of metabolism can prevent efficient utilization of vitamin B6, resulting in greatly increased pyridoxine requirements. Among infants, symptoms include irritability, convulsions, and anemia. Unless treatment with vitamin B6 is initiated early, permanent retardation may result.
81.3.5.5
Adverse Effects. At low doses, pyridoxine is devoid of adverse effects. However, if extremely large doses are taken, neurologic injury may result. Symptoms include ataxia and numbness of the feet and hands. To minimize risk, adults should not consume more than 100 mg/day, the UL for this vitamin.
81.3.5.6
Drug Interactions. Vitamin B6 interferes with the utilization of levodopa, a drug for Parkinson's disease. Accordingly, patients receiving levodopa should be advised against taking the vitamin.
81.3.5.7
Therapeutic Uses. Pyridoxine is indicated for prevention and treatment of all vitamin B6 deficiency states (dietary deficiency, isoniazid-induced deficiency, pyridoxine dependency syndrome).
81.3.5.8
Preparations, Dosage, and Administration. Pyridoxine is available in standard tablets (25 to 500 mg) and enteric-coated tablets (25 mg) for oral use, and in solution (100 mg/mL) for IM or IV administration. To correct dietary deficiency, the dosage is 10 to 20 mg/day for 3 weeks followed by 1.5 to 2.5 mg/day thereafter
CHAPTER 80 Vitamins
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Pharmacology Nursing Care, for 7th oral use, and for in solution (100 mg/mL) IMEdition or IV administration. To correct dietary deficiency, the dosage is 10 to 20 mg/day for 3 weeks followed by 1.5 to 2.5 mg/day thereafter for maintenance. To treat deficiency induced by isoniazid, the dosage is 50 to 200 mg/day. To protect against isoniazid-induced deficiency, the dosage is 25 to 50 mg/day. Pyridoxine dependency syndrome may require initial doses up to 600 mg/day followed by 25 to 50 mg/day for life. 81.3.6
Cyanocobalamin (Vitamin B12) and Folic Acid Cyanocobalamin (vitamin B12) and folic acid (folacin) are essential factors in the synthesis of DNA. Deficiency of either vitamin manifests as megaloblastic anemia. Cyanocobalamin deficiency produces neurologic damage as well. Because deficiency presents as anemia, folic acid and cyanocobalamin are discussed at length in Chapter 54 (Drugs for Deficiency Anemias).
81.3.6.1
RDAs and ULs. Revised RDAs for vitamin B12 and folate (see Table 80-2) were published in 1998. The new adult RDA for B12 (2.4 mcg) is about 20% higher than the RDA established in 1989, and the new adult RDA for folic acid (400 mcg) is 100% higher than the old one. Because adults over age 50 often have difficulty absorbing dietary vitamin B12, they should ingest at least 2.4 mcg/
959 960
day in the form of a supplement. A UL of 1000 mcg/day has been set for folic acid. Because of insufficient data, no UL has been set for B12. 81.3.6.2
Food Folate Versus Synthetic Folate. The form of folate that occurs naturally (food folate) has a different chemical structure than synthetic folate (pteroylglutamic acid). Synthetic folate is more stable than food folate, and has greater bioavailability. In the presence of food, the bioavailability of synthetic folate is at least 85%. In contrast, bioavailability of food folate is less than 50%. To increase folate in the American diet, the Food and Drug Administration issued the following order: Beginning January 1, 1998, all enriched grain products (eg, enriched bread, pasta, flour, breakfast cereal, grits, rice) must be fortified with synthetic folate—specifically, 140 mcg/100 gm of grain. As a result of grain fortification, the incidence of folic acid deficiency in the United States has declined dramatically. Unfortunately, the incidence of birth defects from folate deficiency (see below) has only dropped by 32%.
81.3.6.3
Folic Acid Deficiency and Fetal Development. Deficiency of folic acid during pregnancy can impair development of the central nervous system, resulting in neural tube defects (NTDs): anencephaly and spina bifida. Anencephaly (failure of the brain to develop) is uniformly fatal. Spina bifida, a condition characterized by
CHAPTER 80 Vitamins
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Pharmacology for inNursing Edition system, resulting neural tubeCare, defects7th (NTDs): anencephaly and spina bifida. Anencephaly (failure of the brain to develop) is uniformly fatal. Spina bifida, a condition characterized by defective development of the bony encasement of the spinal cord, can result in nerve damage, paralysis, and other complications. The time of vulnerability for NTDs is days 21 through 28 after conception. Hence, the damage can occur before a woman recognizes her pregnancy by missing a period. Because NTDs occur very early in pregnancy, it is essential that adequate levels of folic acid be present when pregnancy begins; women cannot wait until pregnancy is confirmed before establishing adequate intake. To ensure sufficient folate at the onset of pregnancy, the U.S. Public Health Service recommends that all women who may become pregnant consume 400 mcg of supplemental folic acid each day—in addition to the folate they get from food. Since pregnancy can occur despite birth control measures, this recommendation applies even to women who don't intend to become pregnant. 81.3.6.4
Folic Acid and Colorectal Cancer. Data from the Nurses' Health Study suggest that folate protects against colorectal cancer, the third most common cancer in the United States. In this study, women who took a vitamin supplement containing 400 mcg of folate every day for 15 or more years reduced their risk of colon cancer by 75%. Although the mechanism of protection is unknown, it may relate to the role of folate in DNA synthesis and repair: Researchers speculate that insufficient folate may predispose to cancer-causing genetic changes, whereas maintaining adequate folate may help protect against these changes.
81.3.7
Pantothenic Acid Pantothenic acid is an essential component of two biologically important molecules: coenzyme A and acyl carrier protein. Coenzyme A is an essential factor in multiple biochemical processes, including gluconeogenesis, intermediary metabolism of carbohydrates, and biosynthesis of steroid hormones, porphyrins, and acetylcholine. Acyl carrier protein is required for synthesis of fatty acids. Pantothenic acid is present in virtually all foods. As a result, spontaneous deficiency has not been reported. There are insufficient data to establish RDAs for pantothenic acid. However, the Food and Nutrition Board has assigned AIs (see Table 80-2). There are no reports of toxicity from pantothenic acid. Accordingly, no UL has been set. Pantothenic acid is available in singleingredient tablets and in multivitamin preparations. However, because deficiency does not occur, there is no reason to take supplements.
81.3.8
Biotin Biotin is an essential cofactor for several reactions involved in the metabolism of carbohydrates and fats. The vitamin is found in a wide variety of foods, although the exact amount in most foods has not been determined. In addition to being available in foods, biotin is synthesized by intestinal
CHAPTER 80 Vitamins
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Pharmacology for Nursing 7th Edition and fats. The vitamin is found in Care, a wide variety of foods, although the exact amount in most foods has not been determined. In addition to being available in foods, biotin is synthesized by intestinal bacteria. Biotin deficiency is extremely rare. In fact, in order to determine the effects of deficiency, scientists had to induce it experimentally. When this was done, subjects experienced dermatitis, conjunctivitis, hair loss, muscle pain, peripheral paresthesias, and psychologic effects (lethargy, hallucinations, depression). At this time, the data are insufficient to establish RDAs for biotin. However, as with pantothenic acid, the Food and Nutrition Board has assigned AIs (see Table 80-2). Biotin appears devoid of toxicity: Subjects given large doses experienced no adverse effects. Accordingly, no UL has been set. 81.3.8.1
KEY POINTS ▪ Vitamins can be defined as organic compounds, required in minute amounts, that promote growth and health maintenance by participating in energy transformation and regulation of metabolic processes. ▪ Recommended dietary allowances (RDAs) for vitamins, which are set by the Food and Nutrition Board of the National Academy of Sciences, represent the average daily dietary intake sufficient to meet the nutrient requirements of nearly all (97% to 98%) healthy individuals in a particular life-stage or gender group. ▪ The Tolerable Upper Intake Limit (UL) for a vitamin is the highest average daily intake that can be consumed by nearly everyone without a significant risk of adverse effects. The UL is simply an index of safety—not a recommendation to exceed the RDA. ▪ There is no evidence that taking daily multi vitamin supplements can decrease the risk of chronic disease. However, there is evidence that taking supplements of vitamin B12, folic acid, and vitamin D (plus calcium) can benefit certain individuals. ▪ Vitamins are divided into two major groups: fat-soluble vitamins (A, D, E, and K) and water-soluble vitamins (vitamin C and members of the vitamin B complex). ▪ Vitamin A deficiency can cause night blindness, xerophthalmia (a dry, thickened condition of the conjunctiva), and keratomalacia (degeneration of the cornea with keratinization of the corneal epithelium). ▪ Too much vitamin A can cause birth defects, liver injury, and bone abnormalities. Accordingly, vitamin A intake should not exceed the UL, set at 3000 mcg/day. ▪ Vitamin D plays a critical role in the regulation of calcium and phosphorus metabolism, and may help protect against breast cancer, colorectal cancer, type 1 diabetes, and overall mortality.
CHAPTER 80 Vitamins
960 961
Page 25 of 26
Pharmacology Nursing Care, 7th Edition overallfor mortality. ▪ In children, vitamin D deficiency causes rickets. In adults, deficiency causes osteomalacia. ▪ Vitamin K is required for synthesis of prothrombin and other clotting factors. ▪ Vitamin K deficiency causes bleeding tendencies. Severe deficiency can cause spontaneous hemorrhage. ▪ Vitamin K is used to treat vitamin K deficiency (including neonatal deficiency) and overdose with warfarin (an anticoagulant). ▪ Vitamin C deficiency can cause scurvy. ▪ Niacin (nicotinic acid) is both a vitamin and a drug. ▪ When niacin is used as a drug (to reduce cholesterol levels), doses are much higher than when niacin is used to prevent or correct deficiency. ▪ Niacin deficiency results in pellagra. ▪ Severe thiamin deficiency produces beriberi. ▪ In the United States, thiamin deficiency occurs most commonly among alcoholics. In this population, deficiency manifests as Wernicke-Korsakoff syndrome rather than beriberi. ▪ Pyridoxine (vitamin B6) deficiency can cause peripheral neuritis and other symptoms. ▪ Isoniazid, a drug for tuberculosis, prevents conversion of pyridoxine to its active form, and can thereby induce deficiency. ▪ Folic acid deficiency during early pregnancy can cause neural tube defects (anencephaly and spina bifida). To ensure folic acid sufficiency at the start of pregnancy, all women with the potential for becoming pregnant should consume 400 mcg of supplemental folic acid every day (in addition to food folate). ▪ At this time, there are no convincing data that large doses of antioxidants (eg, vitamin E, vitamin C) reduce the risk of cancer, heart disease, or any other chronic disorder.
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Pharmacology for Nursing Care, 7th Edition 962
82
CHAPTER 81 Drugs for Obesity Obesity is a public health epidemic. In the United States, nearly two-thirds of adults are overweight or obese. Excessive body fat increases the risk of morbidity from hypertension, coronary heart disease, stroke, type 2 diabetes, gallbladder disease, kidney stones, osteoarthritis, sleep apnea, dementia, and certain cancers. Among women, obesity also increases the risk of menstrual irregularities, amenorrhea, and polycystic ovary syndrome; during pregnancy, obesity increases the risk of morbidity and mortality for both the mother and child. Estimates of how many Americans die from obesity-related illnesses vary widely—from 120,000 a year to over 300,000. Regardless of which estimate is more accurate, obesity is still second only to smoking as the leading preventable cause of death. Pediatric obesity is a special concern. One-third of American children and adolescents are overweight or obese. Since 1963, the average weight of 10-year-old children has increased by 11 pounds. Among children ages 6 to 11, the prevalence of obesity has tripled since 1980. This extra weight is exacting a profound toll on health—increasing the risk of hypertension, heart disease, and asthma. In addition, type 2 diabetes, formerly seen almost exclusively in adults, has increased 10-fold among children and teens, and gallbladder disease has tripled. Because of obesity, and for the first time in history, American children could have a shorter life span than their parents. Obesity is now viewed as a chronic disease, much like hypertension and diabetes. Despite intensive research, the underlying cause remains incompletely understood. Contributing factors include genetics, metabolism, and appetite regulation, along with environmental, psychosocial, and cultural factors. Although obese people can lose weight, the tendency to regain weight cannot be eliminated. Put another way, obes-ity cannot yet be cured. Accordingly, for most patients, lifelong management is indicated. Several important guidelines on obesity management have been published. In 1998, the National Heart, Lung, and Blood Institute (NHLBI), in cooperation with the National Institute of Diabetes and Digestive and Kidney Diseases, released the first federal clinical guidelines on obesity, titled Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults: Evidence Report. Two years later, the NHLBI, in cooperation with the North American Association for the Study of Obesity, released a companion document—The Practical Guide: Identification, Evaluation, and Treatment of Overweight and Obesity in Adults—to give clinicians specific tools to help their patients lose weight and keep it off. In 2005, the American College of Physicians (ACP) released a new guideline—Pharmacologic and Surgical Management of Obes-ity in Primary Care— which addresses evidence-based treatments for obesity. Pediatric obesity is addressed in several guidelines, including Expert Committee Recommendations Regarding the Prevention, Assessment, and Treatment of Child and Adolescent Overweight and Obesity, released in 2007, and Prevention and Treatment of Pediatric Obesity: An Endocrine Society Clinical Practice Guideline Based on Expert
CHAPTER 81 Drugs for Obesity
Page 1 of 20
Pharmacology NursingOverweight Care, 7th Treatment of Child for and Adolescent andEdition Obesity, released in 2007, and Prevention and Treatment of Pediatric Obesity: An Endocrine Society Clinical Practice Guideline Based on Expert Opinion, released in 2008. 82.1
ASSESSMENT OF OBESITY-RELATED HEALTH RISK Health risk is determined by (1) the degree of obesity (as reflected in the body mass index), (2) the pattern of fat distribution (as reflected in the waist circumference measurement), and (3) the presence of obesity-related diseases and/or cardiovascular risk factors. Accordingly, all three factors must be assessed when establishing a treatment plan.
82.1.1
Body Mass Index. The body mass index (BMI), which is derived from the patient's weight and height, is a simple way to estimate body fat content. Studies indicate a close correlation between BMI and total body fat. The BMI is calculated by dividing a patient's weight (in kilograms) by the square of the patient's height (in meters). Hence, BMI is expressed in units of kg/m2. BMI can also be calculated using the patient's weight in pounds and height in inches (Fig. 81-1). According to the federal guidelines, a BMI of 30 or higher indicates obesity. Individuals with a BMI of 25 to 29.9 are considered overweight, but not obese. There is good evidence that the risk of cardiovascular disease and other disorders rises significantly when the BMI exceeds 25. When the BMI exceeds 30, there is an increased risk of death. These specific associations
Figure 81-1 Adult weight classification based on body mass index (BMI).
962 963
Adapted from National Heart, Lung, and Blood Institute: Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults: Evidence Report. Bethesda, MD: National Institutes of Health, 1998. between BMI and health risk do not apply to growing children or women who are pregnant or CHAPTER 81 Drugs for Obesity Page 2 of 20
Pharmacology for Nursing Care, 7th Edition between BMI and health risk do not apply to growing children or women who are pregnant or lactating. Nor do they apply to competitive athletes or bodybuilders, who are heavy because of muscle mass rather than excess fat. Table 81-1 summarizes weight classifications based on BMI.
TABLE 81-1 Disease Risk Based on BMI and WC Disease Risk*
BMI (kg/m2)
Weight Class
Obesity Class
Nonexcessive WC†
Excessive WC‡
Below 18.5
Underweight
—
—
—
18.5–24.9
Normal
—
—
—
25–29.9
Overweight
—
Increased
High
30–34.9
Obesity
I
High
Very high
35–39.9
Obesity
II
Very high
Very high
40 or more
Extreme obesity
III
Extremely high
Extremely high
Adapted from National Heart, Lung, and Blood Institute: Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults: Evidence Report. Bethesda, MD: National Institutes of Health, 1998.
82.1.2
*
Risk for hypertension, cardiovascular disease, and type 2 diabetes, relative to individuals of normal weight.
†
Nonexcessive WC = waist circumference of 40 inches or less for men, and 35 inches or less for women.
‡
Excessive WC = waist circumference above 40 inches for men, and above 35 inches for women.
Waist Circumference. Waist circumference (WC) is an indicator of abdominal fat content, an independent risk factor for obesity-related diseases. Accumulation of fat in the upper body, and especially within the abdominal cavity, poses a greater risk to health than does accumulation of fat in the lower body (hips and thighs). People with too much abdominal fat are at increased risk of insulin resistance, diabetes, hypertension, coronary atherosclerosis, ischemic stroke, and dementia. Fat distribution can be estimated simply by looking in the mirror: an apple shape indicates too much abdominal fat, whereas a pear shape indicates fat on the hips and thighs. Measurement of WC provides a quantitative estimate of abdominal fat. A WC exceeding 40 inches (102 cm) in men or 35 inches (88 cm) in women signifies an increased health risk—but only for people with a BMI between 25 and 34.9 (see Table 81-1).
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Pharmacology for 81-1). Nursing Care, 7th Edition and 34.9 (see Table 82.1.3
Risk Status.
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Overall obesity-related health risk is determined by BMI, WC, and the presence of obesity-related dis-eases and cardiovascular risk factors. Certain obesity-related diseases—established coronary heart disease, other atherosclerotic diseases, type 2 diabetes, and sleep apnea—confer a very high risk for complications and mortality. Other obesity-related diseases—gynecologic abnormalities, osteoarthritis, gallstones, and stress incontinence—confer less risk. Cardiovascular risk factors— smoking, hypertension, high levels of low-density lipoprotein (LDL) cholesterol, low levels of high-density lipoprotein (HDL) cholesterol, high fasting glucose, family history of premature coronary heart disease, physical inactivity, and advancing age—confer a high risk when three or more of these factors are present.
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Not surprisingly, health risk rises as BMI gets larger (see Table 81-1). In addition, the risk is increased by the presence of an excessive WC. The risk is further increased by obesity-related diseases and cardiovascular risk factors. In the absence of an excessive WC and other risk factors, health risk is minimal with a BMI below 25, and relatively low with a BMI below 30. Conversely, a BMI of 30 or more indicates significant risk. In the presence of an excessive WC, health risk is high for all individuals with a BMI above 25. 82.2
OVERVIEW OF OBESITY TREATMENT The strategy for losing weight is simple: take in fewer calories per day than are burned. Of course, implementation is tough. The key components of a weight-loss program are diet and exercise. Drugs and other measures are employed only as adjuncts.
82.2.1
Who Should Be Treated? According to the federal guidelines, weight-loss therapy is indicated for people with • A BMI of 30 or more • A BMI of 25 to 29.9 plus two risk factors • A WC greater than 40 inches (in men) or greater than 35 inches (in women) plus two risk factors
82.2.2
Benefits of Treatment It is well established that obesity increases morbidity and mortality. It is also well established that weight reduction reduces morbidity, and probably mortality. In overweight and obese people, weight reduction confers these proven benefits:
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Pharmacology for Nursing Care,benefits: 7th Edition weight reduction confers these proven • Reduction of high blood pressure in patients with hypertension • Improvement of blood lipid status (elevation of HDL cholesterol and reduction of LDL cholesterol, total cholesterol, and triglycerides) • Reduction of elevated blood glucose in patients with type 2 diabetes • Reduced mortality 82.2.3
Treatment Goal The goal of treatment is to promote and maintain weight loss. The initial objective is to reduce weight by 10% over 6 months. For patients with a BMI of 27 to 35, this can usually be achieved by reducing energy intake by 300 to 500 kcal/day, which should allow a loss of 0.5 to 1 pound a week—or 13 to 26 pounds in 6 months. More severely obese people (BMI above 35) require greater caloric restriction (500 to 1000 kcal/day) to lose 10% of their weight in 6 months. After 6 months, the goal for all patients is to prevent lost weight from returning. This can be accomplished by a combination of diet, physical activity, and behavioral therapy. If appropriate, additional weight reduction can be attempted.
82.2.4
Treatment Modalities Weight loss can be accomplished with five treatment modalities: diet therapy, physical activity, behavior therapy, drug therapy, and surgery. For any individual, the treatment mode is determined by the degree of obesity and personal preference.
82.2.4.1
Diet Therapy. A reduced-calorie diet is central to any weight-loss program. As noted, the only way to lose weight is to take in fewer calories than we burn. Depending on the individual, the caloric deficit should range from 300 to 1000 kcal/day. Because fats contain more calories than either carbohydrates or proteins (on an ounce-for-ounce basis), reducing dietary fat is the easiest way to reduce calorie intake. What's the best diet for losing weight? Answer: The one that you actually stick to. In one study, 160 overweight subjects were randomized to follow one of four popular diet plans: Atkins (lowcarbohydrate), Ornish (fat-restricted), Weight Watchers (portion- and calorie-restricted), and Zone (low-glycemic-index). Mean weight loss after 1 year was modest—ranging from 4.6 to 7.3 pounds—and did not differ significantly between the plans. However, what did matter was adherence: There was a direct correlation between weight lost and adherence to the plan, regardless of which plan was followed.
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Pharmacology Care, 7th Edition regardless of for whichNursing plan was followed. To succeed at losing weight, it helps to know just how many calories you take in each day and how many you burn. The following web sites, which are free, have databases on foods and physical activities, along with tools to calculate and log calories taken in and calories burned: • MyPyramid—www.mypyramidtracker.gov • Fitday—www.fitday.com • Sparkpeople—www.sparkpeople.com • NutritionData—www.nutritiondata.com 82.2.4.2
Exercise. Physical activity should be a component of all weight-loss and weight-maintenance programs. Exercise makes a modest contribution to weight loss by increasing energy expenditure. In addition, exercise can help reduce abdominal fat, increase cardiorespiratory fitness, and maintain weight once loss has occurred. According to federal guidelines, people trying to lose weight should exercise 60 minutes a day, and those trying to maintain weight loss should exercise 90 minutes a day.
82.2.4.3
Behavior Modification. Behavior therapy is directed at modifying eating and exercise habits. As such, behavior therapy can strengthen a program of diet and exercise. In the absence of continuing behavior therapy, most patients regain lost weight when treatment stops. Techniques of behavior therapy include self-monitoring of eating and exercise habits, stress management (because stress can trigger eating), and stimulus control (limiting exposure to stimuli that promote eating). There is no evidence that any one of these techniques is superior to others.
82.2.4.4
Drug Therapy. Drugs can be used as an adjunct to diet and exercise—but only for people at increased health risk, and only after a 6-month program of diet and exercise has failed. Drugs should never be used alone. Rather, they should be part of a comprehensive weight-reduction program—one that includes exercise, behavior modification, and a reduced-calorie diet.
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Pharmacology for Nursing Care, 7th includes exercise, behavior modification, andEdition a reduced-calorie diet. TABLE 81-2 Some Drugs for Weight Loss Weight Loss Beyond That with Placebo Adverse Effects
Schedule IV Controlled Substance
Drug
FDA-Approved Indications Mechanism
Sibutramine [Meridia]
Weight loss: long term
Appetite suppression: inhibits NE and 5HT reuptake
5%
Increased heart rate and blood pressure, insomnia, nervousness, headache
Yes
Orlistat [Alli, Xenical]
Weight loss: long term
Reduced fat absorption: inhibits lipase
3%
Oily spotting, flatulence, diarrhea, fecal urgency
No
Phentermine [Adipex-P, Ionamin]
Weight loss: short term
Appetite suppression: sympathomimetic amine
4%
Nervousness, insomnia, palpitations, tachycardia, mild increase in blood pressure
Yes
Diethylpropion Weight loss: (generic only) short term
Appetite suppression: sympathomimetic amine
3%
Same as phentermine
Yes
Rimonabant [Acomplia]
Appetite suppression: blocks cannabinoid receptors
5%
Nausea, diarrhea, anxiety, depression
—
Investigational drug in the U.S.
5-HT = serotonin, NE = norepinephrine.
Candidates for drug therapy should be at increased health risk owing to excessive body fat. Specifically, drugs should be reserved for patients whose BMI is 30 or greater (in the absence of additional risk factors), or 27 or greater (in the presence of additional risk factors). Drugs are not appropriate for patients whose BMI is relatively low. Benefits of drugs are usually modest. Weight loss attributable to drugs generally ranges between 4.4 and 22 pounds, although some people lose significantly more. As a rule, the majority of weight loss occurs during the first 6 months of treatment. Expert opinion regarding duration of therapy has changed. In the past, drug therapy was limited to a few months. Today, long-term treatment is recommended. Why? Because we now know that, when drugs are discontinued, most patients regain lost weight. This is similar to the return
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Pharmacology forToday, Nursing Care, 7th Edition to a few months. long-term treatment is recommended. Why? Because we now know that, when drugs are discontinued, most patients regain lost weight. This is similar to the return of high blood pressure when antihypertensive drugs are withdrawn. Accordingly, when treatment has been effective and well tolerated, it should continue indefinitely. At this time, only two drugs—sibutramine and orlistat—are approved for long-term use, and hence are preferred to other agents. Not everyone responds to drugs, and hence regular assessment is required. Patients should lose at least 4 pounds during the first 4 weeks of drug treatment. If this initial response is absent, further drug use should be questioned. For patients who do respond, ongoing assessment must show that (1) the drug is effective at maintaining weight loss, and that (2) serious adverse effects are absent. Otherwise, drug therapy should cease. In theory, drugs can promote weight loss in three ways: They can suppress appetite, reduce absorption of nutrients, or increase metabolic rate. With one exception—orlistat—all of the drugs used for obesity work by suppressing appetite. Orlistat works by reducing absorption of fat. None of the available drugs increases metabolic rate. Table 81-2 lists the major drugs for obesity, and summarizes approved indications, mechanism of action, major side effects, and status under the Controlled Substances Act (CSA). 82.2.4.5
Bariatric Surgery. Surgical procedures can produce significant weight loss. However, they are indicated only for severely obese patients—that is, people with a BMI of 40 or more (in the absence of comorbidity) or 35 or more (in the presence of comorbidity). Furthermore, surgery should be reserved for patients who have failed to respond to less invasive therapies and who are at high risk for obesity-related morbidity or mortality. The two most widely used procedures are gastric resection (vertical banded gastroplasty) and gastric bypass (Roux-en-Y procedure). Unlike surgeries used in the past, which were designed to reduce nutrient absorption, these procedures are designed to reduce food consumption. Surgery is highly effective: In 6 months to a year, patients can lose between 110 and 220 pounds. Furthermore, benefits are sustained. Unfortunately, although surgery is very effective, it can carry significant risk: In one study, mortality rates at 30 days, 90 days, and 1 year after gastric surgery were 2%, 2.8%, and 4.6%, respectively.
82.3
WEIGHT-LOSS DRUGS APPROVED FOR LONG-TERM USE Sibutramine and orlistat are the only antiobesity drugs currently approved for long-term use. Sibutramine promotes weight loss by suppressing appetite; orlistat decreases absorption of fats. Because management of obesity requires prolonged treatment, these two drugs are preferred to all
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Pharmacology for Nursing Care, 7th Edition Sibutramine promotes weight loss by suppressing appetite; orlistat decreases absorption of fats. Because management of obesity requires prolonged treatment, these two drugs are preferred to all others. Both drugs are approved for use in adults and children. 82.3.1
Sibutramine, an Appetite Suppressant
82.3.1.1
Actions and Use Sibutramine [Meridia], in combination with a reduced-calorie diet, is indicated for promoting and maintaining weight loss in obese patients ages 16 and older. Candidates should have a BMI of 30 or greater (in the absence of other risk factors), or 27 or greater (in the presence of other risk factors, such as hypertension, diabetes, or hyperlipidemia). Sibutramine promotes weight loss by suppressing appetite, and possibly by increasing metabolic rate. The underlying mechanism is blockade of serotonin (5-hydroxytryptamine [5-HT]) and norepinephrine (NE) reuptake, which increases availability of these transmitters at synapses in the brain. Like other drugs that increase concentrations of 5-HT and/or NE, sibutramine has antidepressant actions.
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In clinical trials, sibutramine was moderately effective. In one 6-month trial, subjects taking sibutramine (5, 10, 15, or 20 mg/day) lost 6.8, 9.7, 11.7, and 12.8 pounds, respectively, compared with 2 pounds for those taking placebo. In a 12-month trial, subjects taking sibutramine (10 or 15 mg/day) lost 10 pounds and 14 pounds, respectively, compared with 3.5 pounds for those taking placebo. As a rule, early responders to sibutramine—that is, those who lose at least 4 pounds during the first 4 weeks of treatment—do better than late responders. The safety and efficacy of sibutramine beyond 1 year of use have not been studied. 82.3.1.2
Pharmacokinetics Sibutramine is well absorbed following oral administration. On its first pass through the liver, the drug is rapidly converted into two active metabolites by the 3A4 isozyme of cytochrome P450 (CYP3A4). Concentrations of the metabolites peak in 3 to 4 hours, and decline with halflives of 14 to 16 hours. The metabolites undergo enzymatic inactivation followed by excretion in the urine.
82.3.1.3
Adverse Effects The most common adverse effects are headache (30%), dry mouth (17%), constipation (11.5%), and central nervous system (CNS) stimulation, manifested as insomnia (10.7%), nervousness (5.2%), and anxiety (4.5%). Unlike two other serotonergic drugs—fenfluramine and dexfenfluramine (see below)—sibutramine has not been associated with valvular heart disease or primary pulmonary hypertension. Sibutramine has a low potential for abuse, and hence is classified under Schedule IV of the CSA.
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Pharmacology forSchedule Nursing 7th Edition classified under IV ofCare, the CSA. Sibutramine can elevate blood pressure. For most patients, the increase is small, only 1 to 3 mm Hg. However, in a few patients, a substantial increase has occurred. Accordingly, blood pressure should be measured before treatment and periodically thereafter. Sibutramine should be avoided in patients with uncontrolled hypertension or with a history of coronary artery disease, heart failure, dysrhythmias, or stroke. Sibutramine can increase heart rate. For most patients, the increase is small, only 4 to 5 beats/ min. Rarely, patients develop tachycardia (heart rate above 100 beats/min). 82.3.1.4 82.3.1.4.1
Drug Interactions Serotonergic Agents. Combining sibutramine with another serotonergic drug may cause serotonin syndrome, a potentially fatal reaction characterized by incoordination, myoclonus, hyperreflexia, tremor, fever, sweating, and mental changes (eg, agitation, anxiety, hallucinations). Accordingly, sibutramine should not be used with other drugs that enhance seroton-ergic transmission. Among these are selective serotonin reuptake inhibitors (eg, fluoxetine [Prozac]), serotonin agonists taken for migraine (eg, sumatriptan [Imitrex]), and lithium. Certain opioids— including meperidine [Demerol], fentanyl [Sublimaze], and pentazocine [Talwin]—also increase the risk of serotonin syndrome, and should be avoided.
82.3.1.4.2
Monoamine Oxidase Inhibitors. By blocking reuptake of NE, sibutramine can increase the risk of hypertensive crisis in patients taking monoamine oxidase inhibitors (MAOIs). Accordingly, MAOIs should be withdrawn at least 2 weeks before starting sibutramine, and sibutramine should be discontinued at least 2 weeks before starting an MAOI.
82.3.1.4.3
Sympathomimetics. Because sibutramine can elevate blood pressure, it should be used cautiously with other drugs that raise blood pressure. Among these are ephedrine and pseudoephedrine—drugs that are commonly found in over-the-counter (OTC) remedies for colds, allergies, and nasal congestion. Amphetamines should also be avoided.
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Pharmacology Nursing should Care,also 7th congestion.for Amphetamines be Edition avoided. 82.3.1.4.4
Cytochrome P450 3A4 Inhibitors. In theory, drugs such as ketoco-nazole and erythromycin, which inhibit CYP3A4, could slow the metabolism of sibutramine, and thereby alter its effects. However, in actual practice this interaction appears insignificant.
82.3.1.5
Preparations, Dosage, and Administration Sibutramine [Meridia] is available in 5-, 10-, and 15-mg capsules for oral dosing. The recommended initial dosage is 10 mg once a day, administered in the morning to minimize insomnia. For patients who fail to lose at least 4 pounds in the first 4 weeks, the prescriber should consider either increasing the dosage to 15 mg daily or discontinuing treatment. Dosages above 15 mg/day should be avoided. Although sibutramine is usually taken continuously, intermittent dosing may be just as effective. In one study, patients lost weight while taking sibutramine on a repeating cycle consisting of once-daily dosing for 12 weeks followed by 6 weeks off.
82.3.2
Orlistat, a Lipase Inhibitor
82.3.2.1
Actions and Use. Orlistat [Xenical, Alli] is a novel drug approved for promoting and maintaining weight loss in obese patients age 12 and older. Unlike most other weight-loss drugs, which act in the brain to curb appetite, orlistat acts in the GI tract to reduce absorption of fat. Specifically, the drug acts in the stomach and small intestine to inhibit gastric and pancreatic lipases, enzymes that break down triglycerides into monoglycerides and free fatty acids. If triglycerides are not broken down, they can't be absorbed. In patients taking orlistat, absorption of dietary fat is reduced about 30%. Like sibutramine, orlistat should be reserved for patients with a BMI of at least 30— or 27 in the presence of other risk factors (eg, diabetes, hypertension, hyperlipidemia). Patients must adopt a reduced-calorie diet in which 30% of calories come from fat. In clinical trials, orlistat produced modest but sustained benefits. When taken for 2 years, the drug enhanced weight loss, reduced regain of lost weight, and improved some obesity-related risk factors. Patients treated for 2 years lost an average of 19 pounds, compared with 12 pounds for those taking placebo. In addition, treatment reduced total and LDL cholesterol, raised HDL cholesterol, reduced fasting blood glucose, and lowered systolic and diastolic blood pressure. Safety and efficacy beyond 2 years of treatment have not been evaluated.
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Pharmacology for Nursing Care, 7th Edition Safety and efficacy beyond 2 years of treatment have not been evaluated. 82.3.2.2
Adverse Effects and Interactions. Orlistat undergoes less than 1% absorption, and hence systemic effects are absent. In contrast, GI effects are common. Patients frequently experience oily spotting (27%), flatulence with discharge (24%), fecal urgency (22%), fatty or oily stools (20%), oily evacuation (12%), increased defecation (11%), and fecal incontinence (8%). All of these are the direct result of reduced fat absorption, and all can be minimized by reducing fat intake. For many patients, these unpleasant effects provide strong motivation for adhering to a low-fat diet, and hence may be viewed as beneficial as well as adverse. Dosing with psyllium [Metamucil, others], a bulkforming laxative, can greatly reduce GI effects. The underlying mechanism is adsorption of dietary fat.
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By reducing fat absorption, orlistat can reduce absorption of fat-soluble vitamins (vitamins A, D, E, and K). To avoid deficiency, patients should take a daily multivitamin supplement. Administration should be done 2 hours before or 2 hours after taking orlistat. Vitamin K deficiency can intensify the effects of warfarin, an anticoagulant. In patients taking warfarin, anticoagulant effects should be monitored closely. Orlistat is contraindicated for patients with malabsorption syndrome or cholestasis. 82.3.2.3
Preparations, Dosage, and Administration. Orlistat is available in two strengths: 60-mg capsules sold as Alli, and 120-mg capsules sold as Xenical. Xenical requires a prescription; Alli does not. Of note, the efficacy and side effects of both products are nearly identical, even though one is twice the strength of the other. With either product, patients should take 1 capsule 3 times a day. Each dose should be administered during a major meal or up to 1 hour after. There is no benefit to exceeding three daily doses. Orlistat dosing can be omitted if a meal is missed, or if a meal has little or no fat.
82.4
MISCELLANEOUS APPETITE SUPPRESSANTS In this section, we consider a group of drugs that can suppress appetite. Unlike sibutramine and orlistat, none of these drugs is approved for long-term therapy of obesity. In fact, most are not approved for obesity at all.
82.4.1
Sympathomimetic Amines The sympathomimetic amines suppress appetite by increasing availability of NE at receptors in the brain. These drugs are approved for short-term use only (3 months or less). The sympathomimetics fall into two groups: amphetamines and nonamphetamines. The amphetamines
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Pharmacology Nursing Care, 7th Edition the brain. Thesefor drugs are approved for short-term use only (3 months or less). The sympathomimetics fall into two groups: amphetamines and nonamphetamines. The amphetamines have a much higher abuse potential than the nonamphetamines, and hence should be avoided. 82.4.1.1
Nonamphetamines: Diethylpropion and Phentermine. Of the four nonamphetamines approved for weight loss, two—diethylpropion (formerly available as Tenuate) and phentermine [Adipex-P, Ionamin]—are preferred. As with other drugs for obesity, drug-induced weight loss is modest: about 8 pounds with phentermine and 6.6 pounds with diethylpropion. Diethylpropion and phentermine are CNS stimulants. Consequently, like the amphetamines, they can increase alertness, decrease fatigue, and induce nervousness and insomnia. Because they can interfere with sleep, these drugs should be administered no later than 4:00 PM. Upon discontinuation of treatment, fatigue and depression may replace CNS stimulation. Like the amphetamines, the nonamphetamines have effects in the periphery as well as the CNS. Peripheral effects of greatest concern are tachycardia, anginal pain, and hypertension. Accordingly, these drugs should be used with caution in patients with cardiovascular disease. Although the risk of abuse with the nonamphetamine anorexiants is lower than with the amphetamines, abuse can nonetheless occur. Both diethylpropion and phentermine are regulated under Schedule IV of the CSA. To reduce the risk of abuse, try to identify abuse-prone patients prior to treatment. Tolerance is common and may be seen in 6 to 12 weeks. If tolerance develops, the appropriate response is to discontinue the drug rather than increase the dosage. For two reasons, these drugs are not recommended during pregnancy. First, they are not very effective during pregnancy, and hence there is little point in taking them. Second, in utero exposure to these agents poses an increased risk of cleft palate and congenital heart defects. Both diethylpropion and phentermine require a prescription. For diethylpropion, the recommended dosage is 25 mg 3 times a day taken 1 hour before meals (using immediaterelease tablets) or 75 mg once a day in midmorning (using sustained-release tablets). For phentermine, dosing options include 8 mg 3 times a day before meals or 15 to 37.5 mg once daily before breakfast.
82.4.1.2
Nonamphetamines: Phenylpropanolamine. Phenylpropanolamine (PPA) is a nonamphetamine sympathomimetic agent that had been widely available in over-the-counter (OTC) cold remedies and weight-loss products. The drug is effective for both applications, and had once been considered safe. However, a study released
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Pharmacology for Nursing(OTC) Care,cold 7th Edition available in over-the-counter remedies and weight-loss products. The drug is effective for both applications, and had once been considered safe. However, a study released on May 10, 2000—Phenylpropanolamine and Risk of Hemorrhagic Stroke: Final Report of the Hemorrhagic Stroke Project—showed that PPA increases the risk of hemorrhagic stroke in women, but not in men. This information led the Food and Drug Administration (FDA) to conclude that the benefits from using PPA for nasal decongestion or weight loss do not justify exposing users to the risk of stroke—even though that risk is very small. Accordingly, on November 6, 2000, the FDA requested, but did not demand, that PPA be removed from all OTC cold remedies and weight-loss products. As a result, OTC products containing PPA are no longer available. For people with colds, there are many OTC alternatives to PPA. In contrast, for people trying to lose weight, there is no OTC alternative to PPA: All other weight-loss drugs require a prescription. 82.4.1.3
Amphetamines. Because of their ability to suppress appetite, the amphetamines have been employed as adjunctive aids in programs for weight loss. However, because of their high abuse potential, and because they offer no advantages over less dangerous sympathomimetics, amphetamines are not recommended—nor are they approved by the FDA for either short-term or long-term therapy of obesity.
82.4.2
Bupropion Bupropion [Wellbutrin, Zyban], a drug indicated for depression (see Chapter 32) and smoking cessation (see Chapter 39), can also suppress appetite although it is not approved for this use. Benefits are thought to result from blocking reuptake of dopamine and NE. In three clinical trials, the average weight loss was modest—about 6 pounds after 6 to 12 months. Dosage for weight loss is 300 to 400 mg/day, using a sustained-release formulation. The basic pharmacology of bupropion is discussed in Chapter 32.
82.4.3
Fluoxetine Fluoxetine [Prozac, Sarafem], our most widely used antidepressant, causes weight loss with initial use, but weight gain later on. Like sibutramine, fluoxetine increases serotonin availability at synapses in the brain. Presumably, the increase in serotonin depresses appetite, which leads to initial weight loss. Why is weight later regained? One possibility is that serotonin receptors become desensitized over time, and hence appetite returns to pretreatment levels. The results of nine trials in obese patients (average BMI of 35.5) show weight loss of 10.4 pounds at 6 months, but only 6.9 pounds at 12 months. Common adverse effects include agitation, insomnia, and sexual dysfunction (eg, decreased libido, anorgasmia, impotence). Use late in pregnancy can produce a withdrawal syndrome in the neonate. Daily doses used for weight loss are much higher
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Pharmacology for(eg, Nursing Edition sexual dysfunction decreasedCare, libido, 7th anorgasmia, impotence). Use late in pregnancy can produce a withdrawal syndrome in the neonate. Daily doses used for weight loss are much higher than those used for depression (60 mg vs. 20 mg). The basic pharmacology of fluoxetine is presented in Chapter 32. 82.4.4
Topiramate and Zonisamide Topiramate and zonisamide are antiseizure drugs that, when used for epilepsy, produce weight loss as an adverse effect. Because of this effect, both have been studied for treatment of obesity. The basic pharmacology of these drugs is presented in Chapter 24.
82.4.4.1
Topiramate. When tested in obese patients, topiramate [Topamax] produced a 6% to 8% reduction in weight. Two mechanisms are involved: appetite suppression and, possibly, increased expenditure of energy. Unfortunately, many patients experienced unacceptable side effects, including memory impairment, difficulty concentrating, visual problems, fatigue, insomnia, and numbness and tingling in the limbs. The ACP guidelines conclude there are insufficient data to recommend this drug.
82.4.4.2
Zonisamide. Information on using zonisamide [Zonegran] for weight loss is limited. However, in one trial, the drug did produce dramatic results: In patients with a mean BMI of 36.3 at baseline, mean weight loss was 13 pounds after 16 weeks, and 20 pounds after an additional 16 weeks. Side effects include somnolence, dizziness, and cognitive problems (eg, confusion, impaired concentration, and speech abnormalities). As with topiramate, the ACP guidelines conclude there are insufficient data to recommend this drug.
82.4.5
Dexfenfluramine and Fenfluramine Dexfenfluramine [Redux] and fenfluramine [Pondimin]—two highly effective appetite suppressants—can damage valves of the heart. Accordingly, in 1997, they were voluntarily withdrawn from the market. Prior to being withdrawn, fenfluramine was the “fen” in the widely used combination known as “fen-phen” (fenfluramine plus phentermine). For more information on fenfluramine, dexfenfluramine, and “fen-phen,” refer to the fifth edition of this text.
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Pharmacology for Nursing Care, 7th Edition on fenfluramine, dexfenfluramine, and “fen-phen,” refer to the fifth edition of this text.
967
82.5
968
INVESTIGATIONAL WEIGHT-LOSS DRUGS
82.5.1
Rimonabant Rimonabant [Acomplia] is highly effective for promoting weight loss, but also carries a high risk of depression. The drug has a unique mechanism of action: selective blockade of cannabinoid receptors, the same receptors that marijuana works through. By blocking cannabinoid receptors, rimonabant produces multiple beneficial effects: It works in the brain to reduce food intake and nicotine craving, and it works in the periphery to decrease insulin resistance, improve glucose tolerance, reduce triglyceride levels, and increase HDL cholesterol (good cholesterol). In one study, obese subjects who took rimonabant for 1 year lost a mean of 14.7 pounds, and also had a significant decrease in waist circumference. In addition, the drug increased HDL cholesterol levels, reduced triglyceride levels, and increased levels of adiponectin, a cardioprotective molecule. Unfortunately, even though rimonabant improves these risk factors for coronary artery disease (CAD), the drug does not slow CAD progression, as shown in the Strategy to Reduce Atherosclerosis Development Involving Administration of Rimonabant—The Intravascular Ultrasound Study (STRADIVARIUS). Compared with patients taking a placebo, those taking rimonabant experienced greater weight loss along with improvements in lipid profile and in levels of C-reactive protein and glycated hemoglobin. However, there was no decrease in the volume of coronary artery atheromas. Furthermore, there was an alarmingly high rate of depression (44%). Given that obese people are already prone to depression, it would seem imprudent to treat them with a drug that further increases the risk—especially since rimonabant does not slow progression of CAD. In 2007, an FDA panel recommended unanimously against approving the drug, primarily because of concerns about depression and other psychiatric effects. Rimonabant was approved in Europe for treating obesity in 2006.
82.5.2
Leptin In 1994, Jeffrey Friedman of Rockefeller University announced the discovery of leptin, a hormone the helps regulate appetite and energy metabolism. In addition, leptin participates in sexual development. The name leptin derives from leptos, the Greek word for thin. Mice and humans that lack the gene for leptin are obese. For this reason, leptin is also known as the antiobesity hormone. The physiology of leptin is only partly understood. The hormone is released by adipocytes (fat cells) when they fill with fat. Leptin then acts in the hypothalamus to reduce appetite, increase physical activity, and increase fat metabolism. These actions serve to halt further fat accumulation. Hence, the leptin system behaves like a typical feedback loop: When fat storage climbs too high, leptin is released and suppresses further storage; when fat storage falls too low, leptin release is suppressed, allowing more fat to accumulate. The evolutionary purpose of this
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Pharmacology Nursing 7th Edition climbs too high,for leptin is releasedCare, and suppresses further storage; when fat storage falls too low, leptin release is suppressed, allowing more fat to accumulate. The evolutionary purpose of this system is unknown, although there are two obvious possibilities: it may serve to protect against storing too much fat, or it may serve to ensure storage of sufficient fat. Genetic deficiency of leptin causes extreme obesity. Congenital deficiency is characterized by hyperphagia (overeating), excessive weight gain early in life, and severe obesity. In addition, sexual development is delayed. In 1999, researchers from England described the effects of leptin deficiency and leptin replacement therapy in a young girl. The child had a normal weight at birth, but began gaining excessive weight after 4 months. She was constantly hungry (despite hyperphagia), demanded food continuously, and expressed great discontent when food was denied. By age 6, she weighed 125 pounds and needed leg liposuction to improve mobility. By age 9, she weighed 208 pounds. At that time, she began daily subQ injections of leptin. Within a week, her appetite subsided. After 1 year, she had lost 36 pounds, almost all of it fat. Interestingly, she also showed signs of early puberty. (As noted, leptin stimulates sexual development.) This was the first report that leptin replacement is effective in a leptin-deficient person. Can exogenous leptin help obese people lose weight? Yes—but only if they are like the girl just described. That is, for leptin to work, patients must be unable to make leptin themselves. Unfortunately, the vast majority of obese people have no problem making leptin. In fact, their leptin levels are usually high—not low, as might be expected. High levels suggest leptin resistance. Possible causes include failure to produce enough leptin receptors or production of receptors that are faulty. When tested in such people, leptin did not induce significant loss of weight. 82.6
CALORIE-SAVING FOODS
82.6.1
Sugar Substitvutes
82.6.1.1
Calorie-Free Sweeteners Five non-nutritive sweeteners are available: saccharin [Sweet 'N Low], aspartame [NutraSweet, Equal], sucralose [Splenda], acesulfame [Sunett, Sweet One], and neotame (no trade name yet). Their calorie content is negligible. As indicated in Table 81-3, all five are much sweeter than sucrose (table sugar), when compared ounce-for-ounce. With the exception of aspartame, which is unstable at high heat, all can be used for cooking. These sweeteners are present in literally thousands of commercial food products, including soft drinks, alcoholic beverages, canned goods, baked goods, candies, and various desserts. For people trying to lose pounds or keep them off, switching to foods made with these sweeteners may help.
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Pharmacology for Nursing Care, them off, switching to foods made with7th theseEdition sweeteners may help. TABLE 81-3 Sugar Substitutes Generic Name
Trade Name
Relative
Heat Sweetness* Stability Comments
Calorie-Free Products Saccharin
Sweet ‘N Low
Aspartame
Sucralose
300
Good
Bitter aftertaste. High doses cause bladder cancer in rats, but there is no evidence of cancer in humans. OK for cooking.
NutraSweet, 180 Equal
Poor
No aftertaste. Made of two amino acids: aspartate and phenylalanine. Phenylalanine makes it dangerous for phenylketonurics. Because of poor heat stability, it is not good for cooking.
Splenda
600
Very good
No aftertaste. The only low-calorie sweetener derived from sucrose. Very heat stable, and hence excellent for cooking.
Acesulfame Sunett, Sweet One
200
Good
No aftertaste. Derived from acetoacetic acid. OK for cooking.
Neotame
8000
Good
No aftertaste. OK for cooking.
1
Good
An isomer of fructose with 38% of the calories of sucrose. No aftertaste. OK for cooking.
Reduced-Calorie Product Tagatose
*
Slimsweet, Nutratose
Intensity of sweetness relative to sucrose (eg, saccharin is 300 times sweeter than sucrose).
Calorie-free sweeteners have been used extensively for years, and have proved very safe. At very high doses, saccharin can cause bladder cancer in rats. However, at the doses consumed in the diet, there is no evidence that it causes cancer in humans. Aspartame contains phenylalanine, and hence can harm people with phenylketonuria. All of these sweeteners are safe for diabetes patients. There is no evidence to support rumors that aspartame contributes to multiple sclerosis, systemic lupus erythematosus, Alzheimer's disease, and other disorders. 82.6.1.2
Reduced-Calorie Sweetener: Tagatose Tagatose [Slimsweet, Nutratose], an isomer of fructose, is a naturally occurring sugar with properties much like those of sucrose—but with only 38% of the calories. Tagatose tastes like sucrose and, unlike saccharin, has no bitter aftertaste. When used for cooking and baking, tagatose behaves the same as sucrose. Tagatose received FDA approval in October 2001.
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Pharmacology forthe Nursing Care, Tagatose 7th Edition tagatose behaves same as sucrose. received FDA approval in October 2001. 82.6.2
Olestra, a Fat Substitute Olestra [Olean] is a nonabsorbable, calorie-free fat substitute used to make potato chips, corn chips, crackers, and other snack foods. Olestra cannot be broken down by pancreatic enzymes, and hence cannot be absorbed. As a result, it provides no dietary fat or calories. Olestra is very well tolerated. Two randomized, double-blind trials failed to support anecdotal reports of olestra-induced GI symptoms. In one trial, subjects were given a large bag of potato chips—fried in olestra or a traditional fat—to eat while watching a movie. Later, 563 subjects were interviewed. The result? Olestra produced virtually no increase in gas, diarrhea, or abdominal cramping—although the participants did rate the olestra chips as less tasty (5.6 vs. 6.4 on a 9-point scale). In the second study, 3181 subjects ate traditional potato chips or olestra potato chips over 6 weeks. Again, olestra caused no increase in GI symptoms (heartburn, nausea, vomiting, gas, bloating, cramping, frequency of bowel movements, or loose stools). Olestra can reduce the absorption of fat-soluble vitamins (A, D, E, and K). When these vitamins are ingested at the same time as olestra, they can dissolve in the olestra, and then pass through the intestine without being absorbed. To compensate for this action, snack foods made with olestra are fortified with fat-soluble vitamins. Hence, there is no risk of vitamin deficiency.
82.6.2.1
KEY POINTS ▪ Obesity increases the risk of morbidity and mortality. ▪ Obesity is a chronic disease that requires lifelong treatment. ▪ The body mass index (BMI) is a measure of body fat content. ▪ A BMI of 25 to 29.9 indicates overweight, and a BMI of 30 or more indicates obesity. ▪ Waist circumference (WC) is an index of abdominal fat. Accumulation of abdominal fat poses a greater risk to health than accumulation of fat in the hips and thighs. ▪ Obesity-related health risk is determined by the degree of obesity, excessive abdominal fat, and the presence of obesity-related diseases (eg, type 2 diabetes, sleep apnea) and cardiovascular risk factors (eg, smoking, hypertension, high LDL cholesterol). ▪ Weight reduction reduces morbidity and probably mortality. ▪ Weight reduction can be accomplished with diet therapy, physical activity, behavior therapy, drug therapy, and surgery.
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Pharmacology fordrug Nursing Care, 7th Edition therapy, therapy, and surgery. ▪ Antiobesity drugs should be used only as adjuncts to a comprehensive weight-loss program that includes exercise, behavior modification, and a reduced-calorie diet. ▪ Antiobesity drugs are indicated for patients with a BMI of 30 or more (in the absence of other risk factors) or 27 or more (in the presence of other risk factors). ▪ Most patients regain lost weight when antiobesity drugs are discontinued. Hence, to remain effective, these drugs must be taken indefinitely. ▪ Only two drugs—sibutramine and orlistat—are approved for long-term therapy of obesity. ▪ Sibutramine promotes weight loss by suppressing appetite. The underlying mechanism is blockade of NE and 5-HT reuptake. ▪ Sibutramine can elevate blood pressure and heart rate, and hence must be used with caution in patients with hypertension or a history of dysrhythmias. ▪ Sibutramine poses a risk of serotonin syndrome, and hence must not be combined with other serotonergic drugs. Among these are selective serotonin reuptake inhibitors (eg, fluoxetine [Prozac]), serotonin agonists used for migraine (eg, sumatriptan [Imitrex]), and lithium. ▪ By blocking reuptake of norepinephrine, sibutramine can increase the risk of hypertensive crisis in patients taking MAOIs. At least 2 weeks should separate use of these drugs. ▪ Orlistat promotes weight loss by decreasing absorption of dietary fat. The underlying mechanism is inhibition of gastric and pancreatic lipases. ▪ Orlistat frequently causes GI symptoms (oily spotting, fecal urgency, oily stools, and fecal incontinence). These symptoms, which are a direct result of reduced fat absorption, can be minimized by reducing fat intake, and by taking the bulk-forming laxative psyllium [Metamucil, others]. ▪ Orlistat can reduce absorption of fat-soluble vitamins (vitamins A, D, E, and K). To avoid deficiency, patients should take a daily multivitamin supplement.
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83
CHAPTER 82 Basic Principles of Antimicrobial Therapy With this chapter we begin our study of drugs used to treat infectious diseases. These drugs are given to about 30% of all hospitalized patients, and constitute one of our most widely used groups of medicines. Modern antimicrobial agents had their debut in the 1930s and 1940s, and have greatly reduced morbidity and mortality from infection. As newer drugs are introduced, our ability to fight infections increases even more. However, despite impressive advances, continued progress is needed. Why? Because there are organisms that respond poorly to available drugs; there are effective drugs whose use is limited by toxicity; and there is, because of evolving microbial resistance, the constant threat that currently effective antibiotics will be rendered useless. In this introductory chapter, we focus on two principal themes. The first is microbial susceptibility to drugs, with special emphasis on resistance. The second is clinical usage of antimicrobials. Topics addressed include criteria for drug selection, host factors that modify drug use, use of antimicrobial combinations, and use of antimicrobial agents for prophylaxis. Before going further, we need to consider three terms: chemotherapy, antibiotic, and antimicrobial agent. Although we often think of chemotherapy as the use of drugs to kill or suppress cancer cells, this term was first defined as the use of chemicals against invading organisms (eg, bacteria, viruses, fungi). Today, the word is applied to the treatment of both cancer and infection. Hence, not only do we speak of cancer chemotherapy, we also speak of chemotherapy of infectious diseases. In common practice, the terms antibiotic and antimicrobial drug are used interchangeably, as they are in this book. However, be aware that the formal definitions of these words are not identical. Strictly speaking, an antibiotic is a chemical that is produced by one microbe and has the ability to harm other microbes. Under this definition, only those compounds that are actually made by microorganisms qualify as antibiotics. Drugs such as the sulfonamides, which are produced in the laboratory, would not be considered antibiotics under the strict definition. In contrast, an antimicrobial drug is defined as any agent, natural or synthetic, that has the ability to kill or suppress microorganisms. Under this definition, no distinction is made between compounds produced by microbes and those made by chemists. From the perspective of therapeutics, there is no benefit to distinguishing between drugs made by microorganisms and drugs made by chemists. Hence, the current practice is to use the terms antibiotic and antimicrobial drug interchangeably.
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Pharmacology for Nursing Care, 7th Edition antibiotic and antimicrobial drug interchangeably. 83.1
SELECTIVE TOXICITY
83.1.1
What Is Selective Toxicity? The term selective toxicity is defined as the ability of a drug to injure a target cell or target organism without injuring other cells or organisms that are in intimate contact with the target. As applied to antimicrobial drugs, selective toxicity indicates the ability of an antibiotic to kill or suppress microbial pathogens without causing injury to the host. Selective toxicity is the property that makes antibiotics valuable. If it weren't for selective toxicity—that is, if antibiotics were as harmful to the host as they are to infecting organisms—these drugs would have no therapeutic utility.
83.1.2
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How Is Selective Toxicity Achieved? How can a drug be highly toxic to microbes but harmless to the host? The answer lies with differences in the cellular chemistry of mammals and microbes. There are biochemical processes critical to microbial well-being that do not take place in mammalian cells. Hence, drugs that selectively interfere with these unique microbial processes can cause serious injury to microorganisms while leaving mammalian cells intact. Three examples of how we achieve selective toxicity are discussed below.
83.1.2.1
Disruption of the Bacterial Cell Wall. Unlike mammalian cells, bacteria are encased in a rigid cell wall. The protoplasm within this wall has a high concentration of solutes, making osmotic pressure within the bacterium high. If it were not for the cell wall, bacteria would absorb water, swell, and then burst. Several families of drugs (eg, penicillins, cephalosporins) weaken the cell wall and thereby promote bacterial lysis. Because mammalian cells have no cell wall, drugs directed at this structure do not affect us.
83.1.2.2
Inhibition of an Enzyme Unique to Bacteria. The sulfonamides represent antibiotics that are selectively toxic because they inhibit an enzyme critical to bacterial survival but not to our survival. Specifically, sulfonamides inhibit an enzyme needed to make folic acid, a compound required by all cells, both mammalian and bacterial. If we need folic acid, why don't sulfonamides hurt us? Because we can use folic acid from dietary sources. In contrast, bacteria must synthesize folic acid themselves (because, unlike us, they can't take up folic acid from the environment). Hence, to meet their needs, bacteria first take up para-aminobenzoic acid (PABA), a precursor of folic acid, and then convert the PABA into
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Pharmacology Nursing 7th Edition can't take up for folic acid from theCare, environment). Hence, to meet their needs, bacteria first take up para-aminobenzoic acid (PABA), a precursor of folic acid, and then convert the PABA into folic acid. Sulfonamides block this conversion. Since mammalian cells do not make their own folic acid, sulfonamide toxicity is limited to microbes. 83.1.2.3
Disruption of Bacterial Protein Synthesis. In bacteria as in mammalian cells, protein synthesis is done by ribosomes. However, bacterial and mammalian ribosomes are not identical, and hence we can make drugs that disrupt function of one but not the other. As a result, we can impair protein synthesis in bacteria while leaving mammalian protein synthesis untouched.
83.2
CLASSIFICATION OF ANTIMICROBIAL DRUGS Various schemes are employed to classify antimicrobial drugs. The two schemes most suited to our objectives are considered below.
83.2.1
Classification by Susceptible Organism Antibiotics differ widely in their antimicrobial activity. Some agents, called narrow-spectrum antibiotics, are active against only a few species of microorganisms. In contrast, broad-spectrum antibiotics are active against a wide variety of microbes. As discussed below, narrow-spectrum drugs are generally preferred to broad-spectrum drugs. Table 82-1 classifies the major antimicrobial drugs according to susceptible organisms. The table shows three major groups: antibacterial drugs, antifungal drugs, and antiviral drugs. In addition, the table subdivides the antibacterial drugs into narrow-spectrum and broad-spectrum agents, and indicates the principal classes of bacteria against which they are active.
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Pharmacology for Nursing Edition indicates the principal classes of Care, bacteria 7th against which they are active. TABLE 82-1 Classification of Antimicrobial Drugs by Susceptible Organisms ANTIBACTERIAL DRUGS Narrow Spectrum Gram-Positive Cocci and Gram-Positive Bacilli Penicillin G and V Penicillinase-resistant penicillins: methicillin, nafcillin Vancomycin Erythromycin Clindamycin Gram-Negative Aerobes Aminoglycosides: gentamicin, others Cephalosporins (first and second generations) Mycobacterium tuberculosis Isoniazid Rifampin Ethambutol Pyrazinamide Broad Spectrum Gram-Positive Cocci and Gram-Negative Bacilli Broad-spectrum penicillins: ampicillin, others Extended-spectrum penicillins: carbenicillin, others Cephalosporins (third generation) Tetracyclines: tetracycline, others Carbapenems: imipenem, others Trimethoprim
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Pharmacology for Nursing Care, 7th Edition Trimethoprim Sulfonamides: sulfisoxazole, others Fluoroquinolones: ciprofloxacin, others ANTIVIRAL DRUGS Drugs for HIV Infection Reverse transcriptase inhibitors: zidovudine, others Protease inhibitors: ritonavir, others Fusion inhibitors: enfuvirtide Integrase inhibitors: raltegravir CCR5 antagonists: maraviroc Drugs for Influenza Adamantanes: amantadine, others Neuraminidase inhibitors: oseltamivir, others Other Antiviral Drugs Acyclovir Ribavirin Interferon alfa ANTIFUNGAL DRUGS Polyene antibiotics: amphotericin B, others Azoles: itraconazole, others Echinocandins: caspofungin, others 83.2.2
Classification by Mechanism of Action The antimicrobial drugs fall into seven major groups based on mechanism of action. This classification is summarized in Table 82-2. Properties of the seven major classes are discussed briefly below. • Drugs that inhibit bacterial cell wall synthesis or activate enzymes that disrupt the cell wall —These drugs (eg, penicillins, cephalosporins) weaken the cell wall and thereby promote bacterial lysis and death.
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Pharmacology bacterial for lysis Nursing and death. Care, 7th Edition
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TABLE 82-2 Classification of Antimicrobial Drugs by Mechanism of Action Drug Class
Representative Antibiotics
Inhibitors of cell wall synthesis
Penicillins
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Cephalosporins Imipenem Vancomycin Caspofungin Drugs that disrupt the cell membrane
Amphotericin B Daptomycin Itraconazole
Bactericidal inhibitors of protein synthesis
Aminoglycosides
Bacteriostatic inhibitors of protein synthesis
Clindamycin Erythromycin Linezolid Tetracyclines
Drugs that interfere with synthesis or integrity of bacterial DNA and RNA
Fluoroquinolones Metronidazole Rifampin
Antimetabolites
Flucytosine Sulfonamides Trimethoprim
Drugs that suppress viral replication Viral DNA polymerase inhibitors
Acyclovir Ganciclovir
HIV reverse transcriptase inhibitors
Zidovudine Lamivudine
HIV protease inhibitors
CHAPTER 82 Basic Principles of Antimicrobial Therapy
Ritonavir
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Pharmacology for Nursing Care, 7th Edition HIV protease inhibitors
Lamivudine Ritonavir Saquinavir
HIV fusion inhibitors
Enfuvirtide
HIV integrase inhibitors
Raltegravir
HIV CCR5 antagonists
Maraviroc
Influenza neuraminidase inhibitors
Oseltamivir Zanamivir
• Drugs that increase cell membrane permeability—Drugs in this group (eg, amphotericin B) increase the permeability of cell membranes, causing leakage of intracellular material. • Drugs that cause lethal inhibition of bacterial protein synthesis—The aminoglycosides (eg, gentamicin) are the only drugs in this group. We do not know why inhibition of protein synthesis by these agents results in cell death. • Drugs that cause nonlethal inhibition of protein synthesis—Like the aminoglycosides, these drugs (eg, tetracyclines) inhibit bacterial protein synthesis. However, in contrast to the aminoglycosides, these agents only slow microbial growth; they do not kill bacteria at clinically achievable concentrations. • Drugs that inhibit bacterial synthesis of DNA and RNA or disrupt DNA function—These drugs inhibit synthesis of DNA or RNA by binding directly to nucleic acids or by interacting with enzymes required for nucleic acid synthesis. They may also bind with DNA and disrupt its function. Members of this group include rifampin, metronidazole, and the fluoroquinolones (eg, ciprofloxacin). • Antimetabolites—These drugs disrupt specific biochemical reactions. The result is either a decrease in the synthesis of essential cell constituents or synthesis of nonfunctional analogs of normal metabolites. Examples of antimetabolites include trimethoprim and the sulfonamides. • Drugs that suppress viral replication—Most of these drugs inhibit specific enzymes—DNA polymerase, reverse trans-criptase, protease, integrase, or neuraminidase—required for viral replication and infectivity. One agent—enfuvirtide—inhibits viral entry into host cells. When considering the antibacterial drugs, it is useful to distinguish between agents that are bactericidal and agents that are bacteriostatic. Bactericidal drugs are directly lethal to bacteria at clinically achievable concentrations. In contrast, bacteriostatic drugs can slow bacterial growth but do not cause cell death. When a bacteriostatic drug is used, elimination of bacteria must
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Pharmacology for Nursing Care, 7th Edition clinically achievable concentrations. In contrast, bacteriostatic drugs can slow bacterial growth but do not cause cell death. When a bacteriostatic drug is used, elimination of bacteria must ultimately be accomplished by host defenses (ie, the immune system working in concert with phagocytic cells). 83.3
ACQUIRED RESISTANCE TO ANTIMICROBIAL DRUGS Over time, an organism that had once been highly responsive to an antibiotic may become less susceptible, or it may lose drug sensitivity entirely. In some cases, resistance to several drugs develops. Acquired resistance is of great concern in that it can render currently effective drugs useless, thereby creating a clinical crisis and a constant need for new antimicrobial agents. Organisms for which drug resistance is now a serious clinical problem include Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, and Klebsiella pneumoniae (Table 82-3). One of these resistant bacteria—methicillinresistant Staphylococcus aureus—is discussed at length in Chapter 83 (see Box 83-1). In the discussion that follows, we examine the mechanisms by which microbial drug resistance is acquired and the measures by which emergence of resistance can be delayed. As you read this section, keep in mind that it is the microbe that becomes drug resistant, not the patient.
83.3.1
Microbial Mechanisms of Drug Resistance Microbes have four basic mechanisms for resisting drugs. They can (1) decrease the concentration of a drug at its site of action, (2) inactivate a drug, (3) alter the structure of drug target molecules, and (4) produce a drug antagonist.
83.3.1.1
Reduction of Drug Concentration at Its Site of Action. For most antimicrobial drugs, the site of action is intracellular. Accordingly, if a bug can reduce the intracellular concentration of a drug, it can resist harm. Two basic mechanisms are involved. First, microbes can cease active uptake of certain drugs—tetracyclines and gentamicin, for example. Second, microbes can increase active export of certain drugs—tetracyclines, fluoroquinolones, and macrolides, for example.
83.3.1.2
Drug Inactivation. Microbes can resist harm by producing drug-metabolizing enzymes. For example, many bacteria are now resistant to penicillin G because of increased production of penicillinase, an enzyme that inactivates penicillin. Through production of enzymes, some bacteria can inactivate several different kinds of antibiotics.
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Pharmacology forkinds Nursing Care, 7th Edition several different of antibiotics. 83.3.1.3
Alteration of Drug Target Molecules.
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Most antibiotics, like most other drugs, must interact with target molecules (receptors) to produce their effects. Hence, if the structure of the target molecule is altered, resistance can result. For example, some bacteria are now resistant to streptomycin because of structural changes in bacterial ribosomes, the sites at which streptomycin acts to inhibit protein synthesis.
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TABLE 82-3 Drugs for Some Highly Resistant Bacteria Bacterium
Resistant to
Preferred Treatment
Enterococcus faecalis Beta-lactamase Vancomycin + streptomycin or gentamicin negative
Penicillin G or ampicillin
Beta-lactamase Penicillin producing
Vancomycin, ampicillin/ sulbactam
Enterococcus faecium
Vancomycin, streptomycin, gentamicin
Penicillin G or ampicillin
Vancomycin, streptomycin, gentamicin, penicillin G, ampicillin
Linezolid, quinupristin/ dalfopristin
Staphylococcus
Methicillin
Vancomycin
Methicillin, vancomycin
Possibly: linezolid, quinupristin/dalfopristin, very high doses of vancomycin
Staphylococcus epidermidis
Methicillin
Vancomycin
Methicillin, vancomycin, and other glycopeptides
Quinupristin/dalfopristin
Streptococcus pneumoniae
Penicillin G (MIC 0.1–1 mcg/mL)
Ceftriaxone, cefotaxime
Penicillin G (MIC 2 mcg/mL or higher)
Vancomycin ± rifampin
Penicillin G, erythromycin, tetracycline, chloramphenicol, TMP/SMZ
Vancomycin ± rifampin
Ceftazidime, third-generation cephalosporins
Imipenem/cilastatin, meropenem, a fluoroquinolone
aureus*
Klebsiella pneumoniae
MIC = minimum inhibitory concentration, TMP/SMZ = trimethoprim/sulfamethoxazole.
*
Methicillin-resistant Staphylococcus aureus is discussed at length in Chapter 83 (Box 83-1).
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Pharmacology for Nursing Care, 7th Edition 83.3.1.4
Antagonist Production. In rare cases, a microbe can synthesize a compound that antagonizes drug actions. For example, by acquiring the ability to synthesize increased quantities of PABA, some bacteria have developed resistance to sulfonamides.
83.3.2
Mechanisms by Which Resistance Is Acquired How do microbes acquire mechanisms of resistance? Ultimately, all of the alterations in structure and function discussed above result from changes in the microbial genome. These genetic changes may result either from spontaneous mutation or from acquisition of DNA from an external source. One important mechanism of DNA acquisition is conjugation with other bacteria.
83.3.2.1
Spontaneous Mutation. Spontaneous mutations produce random changes in a microbe's DNA. The result is a gradual increase in resistance. Low-level resistance develops first. With additional mutations, resistance becomes greater. As a rule, spontaneous mutations confer resistance to only one drug.
83.3.2.2
Conjugation. Conjugation is a process by which extrachromosomal DNA is transferred from one bacterium to another. In order to transfer resistance by conjugation, the donor organism must possess two unique DNA segments, one that codes for the mechanisms of drug resistance and one that codes for the “sexual” apparatus required for DNA transfer. Together, these two DNA segments constitute an R factor (resistance factor). Conjugation takes place primarily among gram-negative bacteria. Genetic material may be transferred between members of the same species or between members of different species. Because transfer of R factors is not species specific, it is possible for pathogenic bacteria to acquire R factors from the normal flora of the body. Because R factors are becoming common in normal flora, the possibility of transferring resistance from normal flora to pathogens is a significant clinical concern. In contrast to spontaneous mutation, conjugation frequently confers multiple drug resistance. This can be achieved, for example, by transferring DNA that codes for several different drugmetabolizing enzymes. Hence, in a single event, a drug-sensitive bacterium can become highly drug resistant.
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Pharmacology drug resistant.for Nursing Care, 7th Edition 83.3.3
Relationships Between Antibiotic Use and Emergence of Drug-Resistant Microbes Use of antibiotics promotes the emergence of drug-resistant microbes. Please note, however, that although antibiotics promote drug resistance, they are not mutagenic and do not directly cause the genetic changes that underlie reduced drug sensitivity. Spontaneous mutation and conjugation are random events whose incidence is independent of drug use. Drugs simply make conditions favorable for overgrowth of microbes that have already acquired mechanisms for resistance.
83.3.3.1
How Do Antibiotics Promote Resistance? To answer this question, we need to recall two aspects of microbial ecology: (1) microbes secrete compounds that are toxic to other microbes, and (2) microbes within a given ecologic niche (eg, large intestine, urogenital tract, skin) compete with one another for available nutrients. Under drug-free conditions, the various microbes in a given niche keep one another in check. Furthermore, if none of these organisms is drug resistant, introduction of antibiotics will be equally detrimental to all members of the population, and therefore will not promote the growth of any individual. However, if a drug-resistant organism is present, antibiotics will create selection pressure favoring its growth. How? By killing off sensitive organisms, the drug will eliminate the toxins they produce, and will thereby facilitate survival of the microbe that is drug resistant. Also, elimination of sensitive organisms will remove competition for available nutrients, thereby making conditions even more favorable for the resistant microbe to flourish. Hence, although drug resistance is of no benefit to an organism when there are no antibiotics present, when antibiotics are introduced, they create selection pressure favoring overgrowth of microbes that are resistant.
83.3.3.2
973 974
Which Antibiotics Promote Resistance? All antimicrobial drugs promote the emergence of drug-resistant organisms. However, some agents are more likely to promote resistance than others. Because broad-spectrum antibiotics kill more competing organisms than do narrow-spectrum drugs, broad-spectrum agents do the most to facilitate emergence of resistance.
83.3.3.3
Does the Amount of Antibiotic Use Influence the Emergence of Resistance? You bet! The more that antibiotics are used, the faster drug-resistant organisms will emerge. Not only do antibiotics promote emergence of resistant pathogens, they also promote overgrowth of normal flora that possess mechanisms for resistance. Because drug use can increase resistance in
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Pharmacology for Nursing Care, 7th Edition only do antibiotics promote emergence of resistant pathogens, they also promote overgrowth of normal flora that possess mechanisms for resistance. Because drug use can increase resistance in normal flora, and because normal flora can transfer resistance to pathogens, every effort should be made to avoid use of antibiotics by individuals who don't actually need them (ie, individuals who don't have a treatable infection). Because all antibiotic use will further the emergence of resistance, there can be no excuse for casual or indiscriminate dispensing of these drugs. 83.3.3.4
Nosocomial Infections. Because hospitals are sites of intensive antibiotic use, resident organisms can be extremely drug resistant. As a result, nosocomial infections (defined as infections acquired in hospitals) are among the most difficult to treat. According to the Centers for Disease Control and Prevention (CDC), about 1.7 million patients acquire an infection while hospitalized each year, resulting in 99,000 deaths. Measures to delay emergence of resistant organisms in hospitals are discussed below.
83.3.4
Suprainfection (Superinfection) Suprainfection is simply a special example of the emergence of drug resistance. A suprainfection is defined as a new infection that appears during the course of treatment for a primary infection. New infections develop when antibiotics eliminate the inhibitory influence of normal flora, thereby allowing a second infectious agent to flourish. Because broad-spectrum antibiotics kill off more normal flora than do narrow-spectrum drugs, suprainfections are more likely in patients receiving broad-spectrum agents. Because suprainfections are caused by drug-resistant microbes, these infections are often difficult to treat. It should be noted that, in most texts, suprainfections are referred to as superinfections; this term may have been chosen to reflect the difficulties of treatment.
83.3.5
Delaying the Emergence of Resistance in Hospitals In the Spring of 2002, the CDC launched its Campaign to Prevent Antimicrobial Resistance. The campaign is directed primarily at hospitals, which are major breeding grounds for resistant pathogens. As shown in Figure 82-1, the campaign
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Pharmacology for Nursing Care, 7th Edition pathogens. As shown in Figure 82-1, the campaign Figure 82-1 Pocket card from the CDC's Campaign to Prevent Antimicrobial Resistance.
consists of 12 action steps that fall under four major headings: CHAPTER 82 Basic Principles of Antimicrobial Therapy
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Pharmacology for Nursing Care, 7th Edition consists of 12 action steps that fall under four major headings: • Prevent infection • Diagnose and treat infection effectively • Use antimicrobials wisely • Prevent transmission The 12 steps are discussed briefly below. You can get more information online at www.cdc.gov/ drugresistance. Because the CDC campaign is limited to antibiotic use by humans, there is a major cause of resistance that it doesn't address: Feeding thousands of tons of antibiotics to livestock to promote growth. This important and contentious topic is discussed in Box 82-1. 83.3.5.1
Step 1. Vaccinate. By preventing infection, vaccination reduces the need to use antimicrobial drugs, and thereby helps prevent emergence of resistance. Accordingly, the CDC recommends predischarge vaccination of all at-risk patients, especially against two respiratory infections: influenza and pneumococcal pneumonia. In addition, all healthcare personnel who have patient care duties should receive a flu shot annually.
83.3.5.2
Step 2. Get the catheters out. Catheters and other invasive devices are the leading exogenous cause of nosocomial infections. Infections can occur in association with IV catheters, arterial catheters, urinary tract catheters, endotracheal tubes, and other devices. Every year, an estimated 250,000 Americans develop bacteremia related to use of central ve-nous catheters alone; the cost of treatment ranges from $35,000 to $56,000 per patient. To help prevent these infections, catheters should be used only when essential, and should be removed as soon as they are no longer needed.
83.3.5.2.1 83.3.5.2.1.1
974 975
BOX 82-1 Special Interest Topic ANTIBIOTICS IN ANIMAL FEED: DYING FOR A BIG MAC AND CHICKEN MCNUGGETS Drug-resistant infection resulting from use of antibiotics in agriculture is a global public health concern. Antibiotics are employed extensively in the livestock and poultry industries. Not surprisingly, this practice has created a large reservoir of drug-resistant
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Pharmacology for Nursing Care, 7th Edition health concern. Antibiotics are employed extensively in the livestock and poultry industries. Not surprisingly, this practice has created a large reservoir of drug-resistant bacteria, some of which now infect humans. In addition to being a direct detriment to health, these infections pose an even larger threat: passage of resistance genes to normal intestinal flora, and then from normal flora to other human pathogens. The amount of antibiotics given to food animals is staggering. According to estimates made by the Union for Concerned Scientists, of the 14,800 tons of antibiotics produced in the United States each year, nearly 90% (13,300 tons) goes to animals. Even more surprisingly, of the antibiotics that animals receive, only 7.5% (1000 tons) is given to treat infection. The vast majority—12,300 tons—is mixed with feed to promote growth. Both uses encourage the emergence of resistance. Of the two agricultural uses—growth promotion and treatment of infection—growth promotion is by far the more controversial. Few authorities would argue that we shouldn't give animals antibiotics to treat infection. In contrast, there are strong arguments against giving antibiotics to promote growth. The doses employed for growth promotion are much lower than those used for infection, and hence are more likely to encourage emergence of resistance. Moreover, since growth can be promoted by other means, giving antibiotics for this purpose is unnecessary. Which antibiotics are employed in agriculture? Essentially all of the antibiotics used in humans are also used in animals—including fluoroquinolones and third-generation cephalosporins, agents that are among the most effective we have. Because all antibiotics are being used, we are hastening the day when all will be useless. The story of virginiamycin and Synercid illustrates the potentially serious consequences of giving antibiotics to farm animals. Virginiamycin is a mixture of two streptogramins. For 30 years, the drug has been used to promote animal growth. In 1999, a mixture of two similar streptogramins—quinupristin and dalfopristin, sold as Synercid—was approved for medical use in the United States. Synercid is an extremely important drug because it can kill vancomycin-resistant Enterococcus faecium, a dangerous pathogenic strain that is resistant to all other antibiotics. Unfortunately, agricultural use of virginiamycin is likely to shorten Synercid's useful life: A study of chickens that were fed virginiamycin indicates that 50% of the birds carried Synercid-resistant E. faecium. Sooner or later, these birds will pass these resistant pathogens on to humans—if they haven't already. How can we reduce agriculture-related resistance? Clearly, if we want to delay emergence of resistance, and thereby extend the useful life of our antibiotics, we must limit agricultural use of these drugs. To this end, the World Health Organization has
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Pharmacology for Nursing 7thuseful Edition of resistance, and therebyCare, extend the life of our antibiotics, we must limit agricultural use of these drugs. To this end, the World Health Organization has recommended that all antibiotics used by humans be banned from use to promote growth in animals. Fifteen countries in the European Union have banned four widely used antibiotics, including virginiamycin, from use as growth promoters. In Denmark, use of antibiotics in animal feed has stopped entirely—with no apparent detriment to either animal health or the incomes of producers. Furthermore, within a few years after these drugs were discontinued, rates of antibiotic resistance among farm animals dropped dramatically. For example, resistance to avoparcin dropped from 73% to 5% in less than 5 years. In the United States, public health and agriculture officials have discussed and debated the issue for more than 25 years, but no legislation has been enacted. A major stumbling block has been the inability to quantify the problem. That is, although there is universal agreement that giving antibiotics to animals represents a threat to public health, we lack sufficient data to determine just how big that threat is. Hopefully, Congress and the Food and Drug Administration (FDA) will take appropriate action before the threat has grown too large to overcome. Although restrictive rules are not yet in place, they may be forthcoming: In 2002, the FDA proposed a draft “guidance” on antibiotic use in animals. If adopted, the guidance would require manufacturers of agricultural antibiotics to assess the ability of new drugs to promote emergence of pathogens resistant to antibiotics used in humans; drugs that did so could be kept off the market. In addition, the guidance proposes to review the impact of drugs already in use. Important among these are virginiamycin, penicillins, fluoroquinolones, tetracyclines, and third-generation cephalosporins. In 2005, the FDA took a big step forward: For the first time, they banned the agricultural use of a specific drug. The FDA ruling, which took effect September 12, 2005, banned the use of enrofloxacin [Baytril] in chickens and turkeys. (Enrofloxacin is a fluoroquinolone similar to ciprofloxacin [Cipro].) The ban was based on concerns that widespread use of enrofloxacin in poultry was promoting resistance to ciprofloxacin and other fluoroquinolones in humans. This case is important in that it sets a precedent for FDA action against other animal antibiotics. Note: Use of antibiotics by vegetable and fruit growers is just as widespread as in animal husbandry, and probably just as detrimental to public health—but that's another story.
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Pharmacology for Nursing Care, 7th Edition 83.3.5.3
Step 3. Target the pathogen. Proper antimicrobial therapy requires that we choose drugs that are active against the causative organism. To do so, we must determine both the identity and drug sensitivity of the pathogen. This important issue is discussed in depth later under Selection of Antibiotics.
83.3.5.4
Step 4. Access the experts. Not surprisingly, input from an infectious disease expert can improve patient outcomes, decrease treatment costs, and shorten the time to discharge. Expert assistance can be especially helpful for (1) patients with serious infections, (2) patients receiving complex antimi-crobial regimens, (3) patients who fail to respond as expected, and (4) patients with a complicated underlying illness.
83.3.5.5
975 976
Step 5. Practice antimicrobial control. To facilitate antimicrobial control, institutions are encouraged to implement procedures and programs that can help clinicians use antimicrobial drugs more wisely. Perhaps the most effective option is to implement a computerized support system designed to help clinicians select antimicrobial regimens. Other effective measures include use of standardized antimicrobial order forms, providing interactive education for prescribers, giving individual prescribers critical feedback on their choices, and establishing a multidisciplinary system to evaluate drug utilization.
83.3.5.6
Step 6. Use local data. Drug susceptibility of microbes varies over time and according to locale, patient population, and hospital unit. To facilitate drug selection, institutions often compile data on drug susceptibility into an “antibiogram,” which provides an overview of common local pathogens and their current pattern of drug sensitivity. Clinicians use the antibiogram to guide initial drug selection while awaiting patient-specific data on drug susceptibility from the microbiology lab.
83.3.5.7
Step 7. Treat infection, not contamination. Contamination of culture samples can lead to false-positive results on bacteriologic tests, and hence can lead to unneeded treatment with antimicrobial drugs. Studies indicate, in fact, that contamination is a major cause of unnecessary antimicrobial use. To decrease contamination, clinicians should simply use approved procedures to obtain and process all culture samples. For example, to prevent contamination when drawing blood, clinicians can decontaminate the skin
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Pharmacology forsimply Nursing Care, procedures 7th Edition clinicians should use approved to obtain and process all culture samples. For example, to prevent contamination when drawing blood, clinicians can decontaminate the skin with tincture of iodine. 83.3.5.8
Step 8. Treat infection, not colonization. A small, localized colony of bacteria does not constitute an infection. However, for two reasons, colonization is a concern. First, in patients who do not have an active infection, treatment because of colonization would be an unnecessary use of antibiotics. Second, in patients who do have an active infection, wrongly attributing the infection to colonizing bacteria could lead to treatment with drugs that are inactive against the real cause. To avoid both problems, it is essential that we differentiate between bacteria that are simply colonizing a region and those that are causing an actual infection.
83.3.5.9
Step 9. Know when to say “no” to vanco. “Vanco” (ie, vancomycin) is a drug of last resort against several important pathogens, including methicillin-resistant Staph. aureus (MRSA) and multidrug-resistant Streptococcus pneumoniae. To delay emergence of vancomycin-resistant organisms, we must use the drug only when clearly necessary. Guidelines from the CDC spell out situations in which using vancomycin is deemed appropriate and situations in which using the drug should be discouraged.
83.3.5.10
Step 10. Stop treatment when infection is cured or unlikely. Common sense dictates that we administer antibiotics only when they are actually needed: If the patient doesn't have an infection, we shouldn't use these drugs. When an infection has been cured, antibiotics should be discontinued. Similarly, if antibiotics were started before culture results were available, and if the culture comes back negative, then the antibiotics should be stopped.
83.3.5.11
Step 11. Isolate the pathogen. By using standard infection control procedures, such as proper containment and disposal of contagious body fluids, we can isolate the pathogen, and can thereby reduce the risk of transferring resistant organisms from one patient to another.
83.3.5.12
Step 12. Break the chain of contagion. This step could also be titled Wash your hands! All too often, bacteria are transferred from patient to patient on the hands of physicians, nurses, and other hospital workers. Fortunately, this transfer can be stopped by following a simple rule: Wash your hands before and after touching any patient. Unfortunately, at least 50% of the time, clinicians fail to do so. The issue
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Pharmacology forbeNursing 7th Edition this transfer can stopped by Care, following a simple rule: Wash your hands before and after touching any patient. Unfortunately, at least 50% of the time, clinicians fail to do so. The issue of hand hygiene is discussed at length in Chapter 95 (Antiseptics and Disinfectants). 83.4
SELECTION OF ANTIBIOTICS When treating infection, the therapeutic objective is to produce maximal antimicrobial effects while causing minimal harm to the host. To achieve this goal, we must select the most appropriate antibiotic for the individual patient. When choosing an antibiotic, three principal factors must be considered: (1) the identity of the infecting organism, (2) drug sensitivity of the infecting organism, and (3) host factors, such as the site of infection and the status of host defenses. For any given infection, several drugs may be effective. However, for most infections, there is usually one drug that is superior to the alternatives (Table 82-4). This drug of first choice may be preferred for several reasons, such as greater efficacy, lower toxicity, or more narrow spectrum. Whenever possible, the drug of first choice should be employed. Alternative agents should be used only when the first-choice drug is inappropriate. Conditions that might rule out a first-choice agent include (1) allergy to the drug of choice, (2) inability of the drug of choice to penetrate to the site of infection, and (3) unusual susceptibility of the patient to toxicity of the first-choice drug.
83.4.1
Empiric Therapy Prior to Completion of Laboratory Tests Optimal antimicrobial therapy requires identification of the infecting organism and determination of its drug sensitivity. However, when the patient has a severe infection, we may have to initiate treatment before test results are available. Under these conditions, drug selection must be based on clinical evaluation and knowledge of which microbes are most likely to cause infection at a particular site. If necessary, a broad-spectrum agent can be used for initial treatment. Once the identity and drug sensitivity of the infecting organism have been determined, we can switch to a more selective antibiotic. When conditions demand that we start therapy in the absence of laboratory data, it is essential that samples of exudates and body fluids be obtained for culture prior to initiation of treatment; if antibiotics are present at the time of sampling, they can suppress microbial growth in culture, and can thereby confound identification.
83.4.2
Identifying the Infecting Organism The first rule of antimicrobial therapy is to match the drug with the bug. Hence, whenever possible, the infecting organism should be identified prior to initiation of therapy. If treatment is begun in the absence of a definitive diagnosis, positive identification should be established as soon as possible, so as to permit adjustment of the regimen to better conform with the drug sensitivity of the infecting organism.
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Pharmacology for Nursing Care, 7th Edition sensitivity of the infecting organism. TABLE 82-4 Antibacterial Drugs of Choice Organism
Drug of First Choice
Some Alternative Drugs
Gram-Positive Cocci Enterococcus* Endocarditis and other Penicillin G or ampicillin with severe infections either gentamicin or streptomycin
Vancomycin with either gentamicin or streptomycin, quinupristin/dalfopristin, linezolid, daptomycin
Uncomplicated urinary Ampicillin, amoxicillin tract infection
Nitrofurantoin, a fluoroquinolone, fosfomycin
Staphylococcus aureus or epidermidis*
Penicillinase producing A penicillinase-resistant penicillin
A cephalosporin, vancomycin, imipenem, linezolid, clindamycin, daptomycin, a fluoroquinolone
Methicillin resistant
Linezolid, quinupristin/dalfopristin, daptomycin, tigecycline, doxycycline, trimethoprim/sulfamethoxazole, a fluoroquinolone
Vancomycin with or without gentamicin with or without rifampin
Streptococcus pyogenes Penicillin G, penicillin V (group A) and groups C and G
Clindamycin, vancomycin, erythromycin, clarithromycin, azithromycin, daptomycin, linezolid, a cephalosporin
Streptococcus, group B
Penicillin G or ampicillin
A cephalosporin, vancomycin, erythromycin, daptomycin
Streptococcus viridans group
Penicillin G with or without gentamicin
A cephalosporin, vancomycin
Streptococcus bovis
Penicillin G
A cephalosporin, vancomycin
Streptococcus, anaerobic
Penicillin G
Clindamycin, a cephalosporin, vancomycin
Streptococcus
Penicillin G, penicillin V, amoxicillin
A cephalosporin, erythromycin, azithromycin, clarithromycin, levofloxacin, gemifloxacin, moxifloxacin, meropenem, imipenem, ertapenem, trimethoprim/sulfamethoxazole, clindamycin, a tetracycline, vancomycin
pneumoniae*
(pneumococcus)
Gram-Negative Cocci Neisseria gonorrhoeae (gonococcus)
See Chapter 94, Table 94-1
Neisseria meningitides
Penicillin G
Cefotaxime, ceftriaxone, ceftizoxime,
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Pharmacology (gonococcus) for Nursing Care, 7th Edition Neisseria meningitides (meningococcus)
Penicillin G
Cefotaxime, ceftriaxone, ceftizoxime, chloramphenicol, a sulfonamide, a fluoroquinolone
Gram-Positive Bacilli Bacillus anthracis (anthrax)
See Chapter 109
Clostridium difficile
Metronidazole
Vancomycin (PO)
Clostridium perfringens
Penicillin G, clindamycin
Metronidazole, chloramphenicol, imipenem, meropenem, ertapenem
Clostridium tetani
Metronidazole
Penicillin G, doxycycline
Corynebacterium diphtheriae
Erythromycin
Penicillin G
Listeria monocytogenes
Ampicillin with or without gentamicin
Trimethoprim/sulfamethoxazole
Campylobacter jejuni
Erythromycin, azithromycin
A fluoroquinolone, gentamicin, a tetracycline
Enterobacter
Imipenem, meropenem, cefepime
Trimethoprim/sulfamethoxazole, gentamicin, tobramycin, amikacin, ciprofloxacin, cefotaxime, ticarcillin/clavulanic acid, piperacillin/tazobactam, aztreonam, ceftizoxime, ceftazidime, tigecycline
Escherichia coli
Cefotaxime, ceftazidime, cefepime, ceftriaxone
Ampicillin with or without gentamicin, ticarcillin/clavulanic acid, trimethoprim/ sulfamethoxazole, imipenem, meropenem, others
Klebsiella pneumoniae*
Cefotaxime, ceftriaxone, cefepime, ceftazidime
Imipenem, meropenem, ertapenem, gentamicin, tobramycin, amikacin, others
Enteric Gram-Negative Bacilli
Proteus, indole positive Cefotaxime, ceftriaxone, (including Providencia cefepime, ceftazidime rettgeri and Morganella morganii)
Imipenem, meropenem, ertapenem, gentamicin, a fluoroquinolone, trimethoprim/ sulfamethoxazole, others
Proteus mirabilis
Ampicillin
A cephalosporin, ticarcillin, trimethoprim/ sulfamethoxazole, imipenem, meropenem, ertapenem, gentamicin, others
Salmonella typhi
Ceftriaxone, a fluoroquinolone
Trimethoprim/sulfamethoxazole, ampicillin, amoxicillin, chloramphenicol, azithromycin
Other Salmonella
Ceftriaxone, cefotaxime, a fluoroquinolone
Trimethoprim/sulfamethoxazole, chloramphenicol, ampicillin, amoxicillin
Serratia
Imipenem, meropenem
Gentamicin, amikacin, cefotaxime, a
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Pharmacology for Nursing Care, 7th Editionchloramphenicol, ampicillin, amoxicillin fluoroquinolone Serratia
Imipenem, meropenem
Gentamicin, amikacin, cefotaxime, a fluoroquinolone, trimethoprim/ sulfamethoxazole, aztreonam, others
Shigella
A fluoroquinolone
Trimethoprim/sulfamethoxazole, ampicillin, ceftriaxone, azithromycin
Yersinia enterocolitica
Trimethoprim/sulfamethoxazole A fluoroquinolone, gentamicin, tobramycin, amikacin, cefotaxime
Other Gram-Negative Bacilli Acinetobacter
Imipenem, meropenem
An aminoglycoside, trimethoprim/ sulfamethoxazole, doxycycline, ciprofloxacin, ceftazidime, ticarcillin/clavulanic acid, piperacillin/tazobactam
Bacteroides
Metronidazole
Imipenem, ertapenem, meropenem, amoxicillin/clavulanic acid, ticarcillin/ clavulanic acid, piperacillin/tazobactam, ampicillin/sulbactam, chloramphenicol
Bordetella pertussis (whooping cough)
Azithromycin, clarithromycin, erythromycin
Trimethoprim/sulfamethoxazole
Brucella (brucellosis)
A tetracycline plus rifampin
A tetracycline plus either gentamicin or streptomycin, trimethoprim/sulfamethoxazole with or without gentamicin, chloramphenicol with or without streptomycin, ciprofloxacin plus rifampin
Calymmatobacterium granulomatis
Trimethoprim/sulfamethoxazole Doxycycline or ciprofloxacin
Francisella tularensis (tularemia)
See Chapter 109
Gardnerella vaginalis
Metronidazole (PO)
Topical clindamycin or metronidazole, clindamycin (PO)
Haemophilus ducreyi (chancroid)
Azithromycin, ceftriaxone
Ciprofloxacin, erythromycin
Haemophilus influenzae Meningitis, epiglottitis, Cefotaxime, ceftriaxone arthritis, and other serious infections
Cefuroxime, chloramphenicol, meropenem
Upper respiratory Trimethoprim/sulfamethoxazole Cefuroxime, amoxicillin/clavulanic acid, a infection and bronchitis fluoroquinolone, others Helicobacter pylori
Clarithromycin plus amoxicillin
Tetracycline plus metronidazole plus bismuth
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Pharmacology for Nursing Care, 7th Editionfluoroquinolone, others infection and bronchitis Helicobacter pylori
Clarithromycin plus amoxicillin plus esomeprazole (a proton pump inhibitor)
Tetracycline plus metronidazole plus bismuth subsalicylate plus esomeprazole (a proton pump inhibitor)
Legionella species
Azithromycin, a Doxycycline with or without rifampin, fluoroquinolone with or without trimethoprim/sulfamethoxazole, erythromycin rifampin
Pasteurella multocida
Penicillin G
Doxycycline, a second- or third-generation cephalosporin, amoxicillin/clavulanic acid, ampicillin/sulbactam
Urinary tract infection
Ciprofloxacin
Levofloxacin, piperacillin/tazobactam, ceftazidime, cefepime, imipenem, meropenem, gentamicin, tobramycin, amikacin, aztreonam
Other infections
Piperacillin/tazobactam (or ticarcillin/clavulanic acid) with or without tobramycin, gentamicin, or amikacin
Ceftazidime, ciprofloxacin, imipenem, meropenem, aztreonam, or cefepime, either one with or without tobramycin, gentamicin, or amikacin
Pseudomonas aeruginosa
Spirillum minus (rat bite Penicillin G fever)
Doxycycline, streptomycin
Streptobacillus moniliformis (rat bite fever)
Penicillin G
Doxycycline, streptomycin
Vibrio cholerae (cholera)
A tetracycline
Trimethoprim/sulfamethoxazole, a fluoroquinolone
Yersinia pestis (plague)
See Chapter 109
Mycobacteria Mycobacterium avium complex
See Chapter 89
Mycobacterium leprae (leprosy)
See Chapter 89
Mycobacterium tuberculosis
See Chapter 89
Actinomycetes Actinomycetes israelii
Penicillin G
Doxycycline, erythromycin, clindamycin
Nocardia
Trimethoprim/sulfamethoxazole Sulfisoxazole, imipenem, meropenem, amikacin, a tetracycline, linezolid, ceftriaxone, cycloserine
Chlamydiae
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Pharmacology for Nursing Care, 7th Editioncycloserine Chlamydiae Chlamydia psittaci
Doxycycline
Chlamydia trachomatis
See Chapter 94, Table 94-1
Chloramphenicol
Mycoplasma Mycoplasma pneumoniae
Erythromycin, clarithromycin, azithromycin, a tetracycline
Ureaplasma urealyticum Azithromycin
A fluoroquinolone A tetracycline, clarithromycin, erythromycin, ofloxacin
Rickettsia Rocky Mountain Doxycycline spotted fever, endemic typhus (murine), trench fever, typhus, scrub typhus, Q fever
Chloramphenicol, a fluoroquinolone
Spirochetes Borrelia burgdorferi (Lyme disease)
Doxycycline, amoxicillin, cefuroxime
Ceftriaxone, cefotaxime, penicillin G, azithromycin, clarithromycin
Borrelia recurrentis (relapsing fever)
A tetracycline
Penicillin G, erythromycin
Leptospira
Penicillin G
Doxycycline, ceftriaxone
Treponema pallidum (syphilis)
Penicillin G
Doxycycline, ceftriaxone
Treponema pertenue (yaws)
Penicillin G
Doxycycline
*
Drugs for highly resistant strains are listed in Table 82-3.
The quickest, simplest, and most versatile technique for identifying microorganisms is microscopic examination of a Gram-stained preparation. Samples for examination can be obtained from pus, sputum, urine, blood, and other body fluids. The most useful samples are direct aspirates from the site of infection. In some cases, only a small number of infecting organisms will be present. Under these conditions, positive identification may require that the microbes be grown out in culture. As stressed above, material for culture should be obtained prior to initiating treatment. Furthermore, the samples should be taken in a fashion that minimizes contamination with normal body flora. Also, the samples should not be exposed to low temperature, antiseptics, or oxygen.
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Pharmacology forshould Nursing Care, 7th Also, the samples not be exposed to lowEdition temperature, antiseptics, or oxygen. 83.4.3
Determining Drug Susceptibility Because of the emergence of drug-resistant organisms, testing for drug sensitivity is common. However, sensitivity testing is not always needed. Rather, testing is indicated only when the infecting organism is one in which resistance is likely. Hence, for microbes such as the group A streptococci, which have remained highly susceptible to penicillin G, sensitivity testing is unnecessary. In contrast, when resistance is common, as it is with Staph. aureus and the gramnegative bacilli, tests for drug sensitivity should be performed.
83.4.3.1
Disk-Diffusion Test. The most widely used method for assessing drug sensitivity is the disk-diffusion test, also known as the Kirby-Bauer test. This test is performed by inoculating an agar plate with the infecting organism and then placing on that plate several small disks, each of which is impregnated with a different antibiotic. Because of diffusion, an antibiotic-containing zone becomes established around each disk. As the bacteria proliferate, growth will be inhibited around the disks that contain an antibiotic to which the bacteria are sensitive. The degree of drug sensitivity is proportional to the size of the bacteria-free zone. Hence, by measuring the diameter of these zones, we can determine the drugs to which the organism is more susceptible, as well as those to which it is highly resistant.
83.4.3.2
Broth Dilution Procedure. In this procedure, bacteria are grown in a series of tubes containing different concentrations of an antibiotic. The advantage of this method over the disk-diffusion test is that it provides a more precise measure of drug sensitivity. With the broth dilution procedure, we can establish close estimates of two clinically useful values: (1) the minimum inhibitory concentration (MIC), defined as the lowest concentration of antibiotic that produces complete inhibition of bacterial growth (but does not kill bacteria); and (2) the minimum bactericidal concentration (MBC), defined as the lowest concentration of drug that produces a 99.9% decline in the number of bacterial colonies (indicating bacterial kill). Because of the quantitative information provided, broth dilution procedures are especially useful for guiding therapy of infections that are unusually difficult to treat.
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Pharmacology for Nursing Care, 7th Edition unusually difficult to treat. 83.5
HOST FACTORS THAT MODIFY DRUG CHOICE, ROUTE OF ADMINISTRATION, OR DOSAGE In addition to matching the drug with the bug and determining the drug sensitivity of an infecting organism, we must consider host factors when prescribing an antimicrobial drug. Two host factors —host defenses and the site of infection—are unique to the selection of antibiotics. Other host factors, such as age, pregnancy, and previous drug reactions, are the same factors that must be considered when choosing any other drug.
83.5.1
Host Defenses Host defenses consist primarily of the immune system and phagocytic cells (macrophages, neutrophils). Without the contribution of these defenses, successful antimicrobial therapy would be rare. In most cases, the drugs we use do not cure infection on their own. Rather, they work in concert with host defense systems to subdue infection. Accordingly, the usual objective of antibiotic treatment is not outright kill of infecting organisms. Rather, the goal is to suppress microbial growth to the point at which the balance is tipped in favor of the host. Underscoring the critical role of host defenses is the grim fact that people whose defenses are impaired, such as those with AIDS and those undergoing cancer chemotherapy, frequently die from infections that drugs alone are unable to control. When treating the immunocompromised host, our only hope lies with drugs that are rapidly bactericidal, and even these may prove inadequate.
83.5.2
979 980
Site of Infection To be effective, an antibiotic must be present at the site of infection in a concentration greater than the MIC. At some sites, drug penetration may be hampered, making it difficult to achieve the MIC. For example, drug access can be impeded in meningitis (because of the blood-brain barrier), endocarditis (because bacterial vegetations in the heart are difficult to penetrate), and infected abscesses (because of poor vascularity and the presence of pus and other material). When treating meningitis, two approaches may be used: (1) we can select a drug that readily crosses the bloodbrain barrier, and (2) we can inject an antibiotic directly into the subarachnoid space. When pus and other fluids hinder drug access, surgical drainage is indicated. Foreign materials (eg, cardiac pacemakers, prosthetic joints and heart valves, synthetic vascular shunts) present a special local problem. Phagocytes react to these objects and attempt to destroy them. Because of this behavior, the phagocytes are less able to attack bacteria, thereby allowing microbes to flourish. Treatment of these infections often results in failure or relapse. In many cases, the infection can be eliminated only by removing the foreign material.
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Pharmacology for can Nursing Care, Editionthe foreign material. cases, the infection be eliminated only7th by removing 83.5.3
Other Host Factors
83.5.3.1
Age. Infants and the elderly are highly vulnerable to drug toxicity. In the elderly, heightened drug sensitivity is due in large part to reduced rates of drug metabolism and drug excretion, which can result in accumulation of antibiotics to toxic levels. Multiple factors contribute to antibiotic sensitivity in infants. Because of poorly developed kidney and liver function, neonates eliminate drugs slowly. To avoid drug accumulation, many antibiotics must be used in low dosage. The very young are also subject to special toxicities. For example, use of sulfonamides in newborns can produce kernicterus, a severe neurologic disorder caused by displacement of bilirubin from plasma proteins (see Chapter 87). The tetracyclines provide another example of toxicity unique to the young: These antibiotics bind to developing teeth, causing discoloration.
83.5.3.2
Pregnancy and Lactation. Antimicrobial drugs can cross the placenta, posing a risk to the developing fetus. For example, when gentamicin is used during pregnancy, irrever-sible hearing loss may result. Also, tetracyclines can stain immature teeth. Antibiotic use during pregnancy may pose a risk to the expectant mother. It has been shown, for example, that during pregnancy there is an increased incidence of toxicity from tetracycline, characterized by hepatic necrosis, pancreatitis, renal damage, and, in extreme cases, death. Antibiotics can enter breast milk, possibly affecting the nursing infant. Sulfonamides, for example, can reach levels in milk that are sufficient to cause kernicterus in nursing newborns. As a general guideline, antibiotics and all other drugs should be avoided by women who are breast-feeding.
83.5.3.3
Previous Allergic Reaction. Severe allergic reactions are more common with the penicillins than with any other family of drugs. As a rule, patients with a history of allergy to the penicillins should not receive them again. The exception is treatment of a life-threatening infection for which no suitable alternative is available. In addition to the penicillins, other antibiotics (sulfonamides, trimethoprim, erythromycin) are associated with a high incidence of allergic responses. However, severe reactions to these agents are rare.
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Pharmacology for agents Nursing Care, 7th Edition reactions to these are rare. 83.5.3.4
Genetic Factors. As with other drugs, responses to antibiotics can be influenced by the patient's genetic heritage. For example, some antibiotics (eg, sulfonamides, nalidixic acid) can cause hemolysis in patients who, because of their genetic makeup, have red blood cells that are deficient in glucose6phosphate dehydrogenase. Clearly, people with this deficiency should not be given antibiotics that are likely to induce red cell lysis. Genetic factors can also affect rates of metabolism. For example, hepatic inactivation of isoniazid is rapid in some people and slow in others. If the dosage is not adjusted accordingly, isoniazid may accumulate to toxic levels in the slow metabolizers, and may fail to achieve therapeutic levels in the rapid metabolizers.
83.6
DOSAGE SIZE AND DURATION OF TREATMENT Success requires that the antibiotic be present at the site of infection in an effective concentration for a sufficient time. Dosages should be adjusted to produce drug concentrations that are equal to or greater than the MIC for the infection being treated. Drug levels 4 to 8 times the MIC are often desirable. Duration of therapy depends on a number of variables, including the status of host defenses, the site of the infection, and the identity of the infecting organism. It is imperative that antibiotics not be discontinued prematurely. Accordingly, patients should be instructed to take their medication for the entire prescribed course, even though symptoms may subside before the full course has been completed. Early withdrawal is a common cause of recurrent infection, and the organisms responsible for relapse are likely to be more drug resistant than those present when therapy began.
83.7
THERAPY WITH ANTIBIOTIC COMBINATIONS Therapy with a combination of antimicrobial agents is indicated only in specific situations. Under these well-defined conditions, use of multiple drugs may be lifesaving. However, it should be stressed that, although antibiotic combinations do have a valuable therapeutic role, routine use of two or more antibiotics should be discouraged. When an infection is caused by a single, identified microbe, treatment with just one drug is usually most appropriate.
83.7.1
981
Antimicrobial Effects of Antibiotic Combinations When two antibiotics are used together, the result may be additive, potentiative, or, in certain cases, antagonistic. An additive response is one in which the antimicrobial effect of the combination is equal to the sum of the effects of the two drugs alone. A potentiative interaction
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Pharmacology for An Nursing Care, 7th cases, antagonistic. additive response is oneEdition in which the antimicrobial effect of the combination is equal to the sum of the effects of the two drugs alone. A potentiative interaction (also called a synergistic interaction) is one in which the effect of the combination is greater than the sum of the effects of the individual agents. A classic example of potentiation is produced by trimethoprim plus sulfamethoxazole, drugs that inhibit sequential steps in the synthesis of tetrahydrofolic acid (see Chapter 87). In certain cases, a combination of two antibiotics may be less effective than one of the agents by itself, indicting antagonism between the drugs. Antagonism is most likely when a bacteriostatic agent (eg, tetracycline) is combined with a bactericidal drug (eg, penicillin). Antagonism occurs because bactericidal drugs are usually effective only against organisms that are actively growing. Hence, when bacterial growth has been suppressed by a bacteriostatic drug, the effects of a bactericidal agent can be reduced. If host defenses are intact, antagonism between two antibiotics may have little clinical significance. However, if host defenses are compromised, the consequences can be dire. 83.7.2
Indications for Antibiotic Combinations
83.7.2.1
Initial Therapy of Severe Infection. The most common indication for use of multiple antibiotics is initial therapy of severe infection of unknown etiology, especially in the neutropenic host. Until the infecting organism has been identified, wide antimicrobial coverage is appropriate. Just how broad the coverage should be depends on the clinician's skill in narrowing the field of potential pathogens. Once the identity of the infecting microbe is known, drug selection can be adjusted accordingly. As discussed above, samples for culture should be obtained before drug therapy starts.
83.7.2.2
Mixed Infections. An infection may be caused by more than one microbe. Multiple infecting organisms are common in brain abscesses, pelvic infections, and infections resulting from perforation of abdominal organs. When the infecting microbes differ from one another in drug susceptibility, treatment with more than one antibiotic is required.
83.7.2.3
Prevention of Resistance. Although use of multiple antibiotics is usually associated with promoting drug resistance, there is one infectious disease—tuberculosis—in which drug combinations are employed for the specific purpose of suppressing the emergence of resistant bacteria. Just why tuberculosis differs from other infections in this regard is discussed in Chapter 89.
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Pharmacology for Nursing 7this Edition differs from other infections inCare, this regard discussed in Chapter 89. 83.7.2.4
Decreased Toxicity. In some situations, an antibiotic combination can reduce toxicity to the host. For example, by combining flucytosine with amphotericin B in the treatment of fungal meningitis, the dosage of amphotericin B can be reduced, thereby decreasing the risk of amphotericin-induced damage to the kidneys.
83.7.2.5
Enhanced Antibacterial Action. In specific infections, a combination of antibiotics can have greater antibacterial action than a single agent. This is true of the combined use of penicillin plus an aminoglycoside in the treatment of enterococcal endocarditis. Penicillin acts to weaken the bacterial cell wall; the aminoglycoside acts to suppress protein synthesis. The combination has enhanced antibacterial action because, by weakening the cell wall, penicillin facilitates penetration of the aminoglycoside to its intracellular site of action.
83.7.3
Disadvantages of Antibiotic Combinations Use of multiple antibiotics has several drawbacks, including (1) increased risk of toxic and allergic reactions, (2) possible antagonism of antimicrobial effects, (3) increased risk of suprainfection, (4) selection of drug-resistant bacteria, and (5) increased cost. Accordingly, antimicrobial combinations should be employed only when clearly indicated.
83.8
PROPHYLACTIC USE OF ANTIMICROBIAL DRUGS Estimates indicate that between 30% and 50% of the antibiotics used in the United States are administered for prophylaxis. That is, these agents are given to prevent infection rather than to treat an established infection. Much of this prophylactic use is uncalled for. However, in certain situations, antimicrobial prophylaxis is both appropriate and effective. Whenever prophylaxis is attempted, the benefits must be weighed against the risks of toxicity, allergic reactions, suprainfection, and selection of drug-resistant organisms. Generally approved indications for prophylaxis are discussed below.
83.8.1
Surgery. Prophylactic use of antibiotics can decrease the incidence of infection in certain kinds of surgery. Procedures in which prophylactic efficacy has been documented include cardiac surgery, peripheral vascular surgery, orthopedic surgery, and surgery on the GI tract (stomach, duodenum, colon, rectum, and appendix). Prophylaxis is also beneficial for women undergoing a hysterectomy or an emergency cesarean section. In “dirty” surgery (operations performed on
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Pharmacology forappendix). NursingProphylaxis Care, 7th Edition colon, rectum, and is also beneficial for women undergoing a hysterectomy or an emergency cesarean section. In “dirty” surgery (operations performed on perforated abdominal organs, compound fractures, or lacerations from animal bites), the risk of infection is nearly 100%. Hence, for these operations, use of antibiotics is considered treatment, not prophylaxis. When antibiotics are given for prophylaxis, they should be administered before the surgery. If the procedure is unusually long, re-administration during surgery may be indicated. As a rule, postoperative antibiotics are unnecessary. For most operations, a first-generation cephalosporin (eg, cefazolin) will suffice. 83.8.2
Bacterial Endocarditis. Individuals with congenital or valvular heart disease and those with prosthetic heart valves are unusually susceptible to bacterial endocarditis. For these people, endocarditis can develop following certain dental and medical procedures that dislodge bacteria into the bloodstream. Hence, prior to undergoing such procedures, these patients may need prophylactic antimicrobial medication. However, according to guidelines released by the American Heart Association in 2007, antibiotic prophylaxis is less necessary than previously believed, and hence should be done much less often than in the past.
83.8.3
Neutropenia. Severe neutropenia puts individuals at high risk of infection. There is some evidence that the incidence of bacterial infection may be reduced through antibiotic prophylaxis. However, prophylaxis may increase the risk of infection with fungi: By killing normal flora, whose presence helps suppress fungal growth, antibiotics can encourage fungal invasion.
83.8.4
981 982
Other Indications for Antimicrobial Prophylaxis. For young women with recurrent urinary tract infection, prophylaxis with trimethoprim/ sulfamethoxazole may be helpful. Amantadine (an antiviral agent) may be employed for prophylaxis against type A influenza. For individuals who have had severe rheumatic endocarditis, lifelong prophylaxis with penicillin may be needed. Antimicrobial prophylaxis is indicated following exposure to organisms responsible for sexually transmitted diseases (eg, syphilis, gonorrhea).
83.9
MISUSES OF ANTIMICROBIAL DRUGS Throughout this chapter, we have focused on the proper use of antimicrobial medications. In this section, we consider important ways in which these drugs are misused. The data in Table 82-5 illustrate how common misuse can be.
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Pharmacology for Nursing 7th Edition illustrate how common misuse canCare, be. 83.9.1
Attempted Treatment of Untreatable Infection. The majority of viral infections—including mumps, chickenpox, and the common cold—do not respond to currently available drugs. Hence, when drug therapy of these disorders is attempted, patients are exposed to all the risks of drug use without receiving any benefits. Acute infections of the upper respiratory tract are a particular concern. When these infections are treated with antibiotics, only 1 patient out of 4000 is likely to benefit. However, the risks remain high: 1 in 4 patients will get diarrhea, 1 in 50 will get a rash, and 1 in 1000 will need to visit an emergency department, usually because of a severe allergic reaction.
83.9.2
Treatment of Fever of Unknown Origin. Although fever can be a sign of infection, it can also signify other diseases, including hepatitis, arthritis, and cancer. Unless the cause of a fever is a proven infection, antibiotics should not be employed. Why? Because (1) if the fever is not due to an infection, antibiotics would not only be inappropriate, they would expose the patient to unnecessary toxicity and delay correct diagnosis of the fever's cause; and (2) if the fever is caused by infection, antibiotics could hamper later attempts to identify the infecting organism. The only situation in which fever, by itself, constitutes a legitimate indication for antibiotic use is when fever occurs in the severely immunocompromised host. Since fever may indicate infection, and since infection can be lethal to the immunocompromised patient, these patients should be given antibiotics when fever occurs—even if fever is the only indication that an infection may be present.
83.9.3
Improper Dosage. Like all other medications, antibiotics must be used in the right dosage. If the dosage is too low, the patient will be exposed to a risk of adverse effects without benefit of antibacterial effects. If the dosage is too high, the risks of suprainfection and adverse effects become unnecessarily high.
83.9.4
Treatment in the Absence of Adequate Bacteriologic Information. As stressed earlier, proper antimicrobial therapy requires information on the identity and drug sensitivity of the infecting organism. Except in life-threatening situations, therapy should not be undertaken in the absence of bacteriologic information. This important guideline is often ignored.
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Pharmacology forabsence Nursing Care, 7th EditionThis important guideline is often ignored. undertaken in the of bacteriologic information. 83.9.5
Omission of Surgical Drainage. Antibiotics may have limited efficacy in the presence of foreign material, necrotic tissue, or pus. Hence, when appropriate, surgical drainage and cleansing should be performed to promote antimicrobial effects.
83...
MONITORING ANTIMICROBIAL THERAPY Antimicrobial therapy is assessed by monitoring clinical responses and laboratory results. The frequency of monitoring is directly proportional to the severity of infection. Important clinical indicators of success are reduction of fever and resolution of signs and symptoms related to the affected organ system (eg, improvement of breath sounds in patients with pneumonia). Various laboratory tests are used to monitor treatment. Serum drug levels may be monitored for two reasons: to ensure that levels are sufficient for antimicrobial effects and to avoid toxicity from excessive levels. Success of therapy is indicated by the disappearance of infectious organisms from post-treatment cultures. Cultures may become sterile within hours of the onset of treatment (as may happen with urinary tract infections), or they may not become sterile for weeks (as may happen with tuberculosis).
TABLE 82-5 Examples of Inappropriate Antibiotic Prescriptions Type of Prescriptions Percent Infection per Year Inappropriate Comment
83.10.1
Common 18 million cold
100
Antibiotics are ineffective against the common cold.
Bronchitis 16 million
80
Antibiotics are ineffective against bronchitis, except in a few infections or in patients with chronic severe lung disease.
Sore throat
13 million
50
Antibiotics should be used only in patients with confirmed strep infection.
Sinusitis
13 million
50
Most cases are viral, not bacterial. In the absence of facial pain or swelling, antibiotics should be withheld for about 10 days to see if symptoms improve without drugs.
982 983
KEY POINTS ▪ In antimicrobial therapy, the term selective toxicity refers to the ability of a drug to injure invading microbes without injuring cells of the host.
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Pharmacology Nursing Care, 7th invadingfor microbes without injuring cellsEdition of the host. ▪ Narrow-spectrum antibiotics are active against only a few microorganisms, whereas broad-spectrum antibiotics are active against a wide array of microbes. ▪ Bactericidal drugs kill bacteria, whereas bacteriostatic drugs only suppress growth. ▪ Emergence of resistance to antibiotics is a major concern in antimicrobial therapy. ▪ An important method by which bacteria acquire resistance is conjugation, a process in which DNA coding for drug resistance is transferred from one bacterium to another. ▪ Antibiotics do not cause the genetic changes that underlie resistance. Rather, antibiotics promote emergence of drug-resistant organisms by creating selection pressures that favor them. ▪ Broad-spectrum antibiotics promote the emergence of resistance more than do narrowspectrum antibiotics. ▪ In the hospital, we can delay the emergence of antibiotic resistance in four basic ways: (1) preventing infection, (2) diagnosing and treating infection effectively, (3) using antimicrobial drugs wisely, and (4) preventing patient-to-patient transmission. ▪ Use of antibiotics to promote growth in livestock is a major force for promoting emergence of resistance. ▪ Effective antimicrobial therapy requires that we determine both the identity and drug sensitivity of the infecting organism. ▪ The minimum inhibitory concentration (MIC) of an antibiotic is defined as the lowest concentration needed to completely suppress bacterial growth. ▪ The minimum bactericidal concentration (MBC) is defined as the concentration that decreases the number of bacterial colonies by 99.9%. ▪ Host defenses—the immune system and phagocytic cells—are essential to the success of antimicrobial therapy. ▪ Patients should complete the prescribed course of antibiotic treatment, even though symptoms may abate before the full course is over. ▪ Although combinations of antibiotics should generally be avoided, they are appropriate in some situations, including (1) initial treatment of severe infections, (2) infection with more than one organism, (3) treatment of tuberculosis, and (4) treatment of an infection in
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Pharmacology for Nursing 7th Edition some situations, includingCare, (1) initial treatment of severe infections, (2) infection with more than one organism, (3) treatment of tuberculosis, and (4) treatment of an infection in which combination therapy can greatly enhance antibacterial effects. ▪ Appropriate indications for prophylactic antimicrobial treatment include (1) certain surgeries, (2) neutropenia, (3) recurrent urinary tract infections, and (4) patients at risk of bacterial endocarditis (eg, those with prosthetic heart valves or congenital heart disease). ▪ Important misuses of antibiotics include (1) treatment of untreatable infections (eg, the common cold and most other viral infections), (2) treatment of fever of unknown origin (except in the immunocompromised host), (3) treatment in the absence of adequate bacteriologic information, and (4) treatment in the absence of appropriate surgical drainage.
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Pharmacology for Nursing Care, 7th Edition 984
84
CHAPTER 83 Drugs That Weaken the Bacterial Cell Wall I: Penicillins
84.1
INTRODUCTION TO THE PENICILLINS The penicillins are practically ideal antibiotics. Why? Because they are active against a variety of bacteria and their direct toxicity is low. Allergic reactions are the principal adverse effect. Owing to their safety and efficacy, the penicillins are widely prescribed. Because they have a beta-lactam ring in their structure (Fig. 83-1), the penicillins are known as betalactam antibiotics. The beta-lactam family also includes the cephalosporins, aztreonam, imipenem, meropenem, and ertapenem (see Chapter 84). All of the beta-lactam antibiotics share the same mechanism of action: disruption of the bacterial cell wall.
84.1.1
Mechanism of Action To understand the actions of the penicillins, we must first understand the structure and function of the bacterial cell wall—a rigid, permeable, mesh-like structure that lies outside the cytoplasmic membrane. Inside the cytoplasmic membrane, osmotic pressure is very high. Hence, were it not for the rigid cell wall, which prevents expansion, bacteria would take up water, swell, and then burst. Penicillins weaken the cell wall, causing bacteria to take up excessive amounts of water and rupture. As a result, penicillins are generally bactericidal. However, it is important to note that penicillins are active only against bacteria that are undergoing growth and division (see below). Penicillins weaken the cell wall by two actions: (1) inhibition of transpeptidases and (2) disinhibition (activation) of autolysins. Transpeptidases are enzymes critical to cell wall synthesis. Specifically, they catalyze the formation of cross-bridges between the peptidoglycan polymer strands that form the cell wall, and thereby give the cell wall its strength (Fig. 83-2). Autolysins are bacterial enzymes that cleave bonds in the cell wall. Bacteria employ these enzymes to break down segments of the cell wall to permit growth and division. By simultaneously inhibiting transpeptidases and activating autolysins, the penicillins (1) disrupt synthesis of the cell wall and (2) promote its active destruction. These combined actions result in cell lysis and death. The molecular targets of the penicillins (transpeptidases, autolysins, other bacterial enzymes) are known collectively as penicillin-binding proteins (PBPs). These molecules are so named because penicillins must bind to them to produce antibacterial effects. As indicated in Figure 83-3, PBPs are located on the outer surface of the cytoplasmic membrane. More than eight different PBPs have been identified. Of these, PBP1 and PBP3 are most critical to penicillin's antibacterial effects. Bacteria express PBPs only during growth and division. Accordingly, since PBPs must be
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Pharmacology for Nursing Care, have been identified. Of these, PBP1 and 7th PBP3Edition are most critical to penicillin's antibacterial effects. Bacteria express PBPs only during growth and division. Accordingly, since PBPs must be present for penicillins to work, these drugs work only when bacteria are growing. Since mammalian cells lack a cell wall, and since penicillins act specifically on enzymes that affect cell wall integrity, the penicillins have virtually no direct effects on cells of the host. As a result, the penicillins are among our safest antibiotics. 84.1.2
Mechanisms of Bacterial Resistance Bacterial resistance to penicillins is determined primarily by three factors: (1) inability of penicillins to reach their targets (PBPs), (2) inactivation of penicillins by bacterial enzymes, and (3) production of PBPs that have a low affinity for penicillins.
84.1.2.1
The Gram-Negative Cell Envelope All bacteria are surrounded by a cell envelope. However, the cell envelope of gram-negative organisms differs from that of gram-positive organisms. Because of this difference, some penicillins are ineffective against gram-negative bacteria. As indicated in Figure 83-3, the cell envelope of gram-positive bacteria has only two layers: the cytoplasmic membrane plus a relatively thick cell wall. Despite its thickness, the cell wall can be readily penetrated by penicillins, giving them easy access to PBPs on the cytoplasmic membrane. As a result, penicillins are generally very active against gram-positive organisms.
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Pharmacology for Nursing Care, 7th Edition membrane. As a result, penicillins are generally very active against gram-positive organisms. Figure 83-1 Structural formulas of representative penicillins. The unique structure of individual penicillins is determined by the side chain coupled to the penicillin nucleus at the position labeled R. This side chain influences acid stability, pharmacokinetic properties, penicillinase resistance, and ability to bind specific penicillin-binding proteins.
CHAPTER 83 Drugs That Weaken the Bacterial Cell Wall I: Penicillins
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Pharmacology for Nursing Care, 7th Edition The gram-negative cell envelope has three layers: the cytoplasmic membrane, a relatively thin cell wall, and an additional outer membrane (see Fig. 83-3). Like the grampositive cell wall, the gram-negative cell wall can be easily penetrated by penicillins. The outer membrane, however, is difficult to penetrate. As a result, only certain penicillins (eg, ampicillin) are able to cross it and thereby reach PBPs on the cytoplasmic membrane. 84.1.2.2
Penicillinases (Beta-Lactamases) Beta-lactamases are enzymes that cleave the beta-lactam ring, and thereby render penicillins and other beta-lactam antibiotics inactive (Fig. 83-4). Bacteria produce a large variety of betalactamases; some are specific for penicillins, some are specific for other beta-lactam antibiotics (eg, cephalosporins), and some act on several kinds of beta-lactam antibiotics. Beta-lactamases that act selectively on penicillins are known as penicillinases.
Figure 83-2 Inhibition of transpeptidase by penicillins. The bacterial cell wall is composed of long strands of a peptidoglycan polymer. As depicted, transpeptidase enzymes create cross-bridges between the peptidoglycan strands, giving the cell wall added strength. By inhibiting transpeptidases, penicillins prevent cross-bridge synthesis and thereby weaken the cell wall.
Penicillinases are synthesized by gram-positive and gram-negative bacteria. Gram-positive organisms produce large amounts of these enzymes, and then export them into the surrounding medium. In contrast, gram-negative bacteria produce penicillinases in relatively small amounts,
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Pharmacology for Nursing Care, 7thenzymes, Edition organisms produce large amounts of these and then export them into the surrounding medium. In contrast, gram-negative bacteria produce penicillinases in relatively small amounts, and, rather than exporting them to the environment, secrete them into the periplasmic space (see Fig. 83-3). The genes that code for beta-lactamases are located on chromosomes and on plasmids (extrachromosomal DNA). The genes on plasmids may be transferred from one bacterium to another, thereby promoting the spread of penicillin resistance. Transfer of resistance is of special importance with Staphylococcus aureus. When penicillin was first introduced in the early 1940s, all strains of Staph. aureus were sensitive. However, by 1960, as many as 80% of Staph. aureus isolates in hospitals displayed penicillin resistance. Fortunately, a penicillin derivative (methicillin) that has resistance to the actions of betalactamases was introduced at this time. To date, no known strains of Staph. aureus produce beta-lactamases capable of inactivating methicillin or related penicillinase-resistant penicillins (although some strains are resistant to these drugs for other reasons). 84.1.2.3
Altered Penicillin-Binding Proteins Certain bacterial strains, known collectively as methicillin-resistant Staphylococcus aureus (MRSA), have a unique mechanism of resistance: production of PBPs with a low affinity for penicillins and all other beta-lactam antibiotics. How did MRSA develop this ability? By acquiring genes that code for low-affinity PBPs from other bacteria.
84.1.3
Chemistry All of the penicillins are derived from a common nucleus: 6-aminopenicillanic acid. As shown in Figure 83-1, this nucleus contains a beta-lactam ring joined to a second ring. The beta-lactam ring is essential for antibacterial actions. Properties of individual penicillins are determined by additions made to the basic nucleus, primarily at the site labeled R. These modifications determine (1) affinity for PBPs, (2) resistance to penicillinases, (3) ability to penetrate the gramnegative cell envelope, (4) resistance to stomach acid, and (5) pharmacokinetic properties.
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Pharmacology for Nursing Care, Edition envelope, (4) resistance to stomach acid, 7th and (5) pharmacokinetic properties.
985
Figure 83-3 The bacterial cell envelope. Note that the gramnegative cell envelope has an outer membrane, whereas the gram-positive envelope does not. The outer membrane of the gram-negative cell envelope prevents certain penicillins from reaching their target molecules. (PBP = penicillin-binding protein [transpeptidases and other penicillin target molecules], • = beta-lactamases.)
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Pharmacology for Nursing Care, 7th Edition Figure 83-4 The effect of beta-lactamase on the penicillin nucleus.
84.1.4
Classification The most useful classification of penicillins is based on antimicrobial spectrum. When classified this way, the penicillins fall into four major groups: (1) narrow-spectrum penicillins that are penicillinase sensitive, (2) narrow-spectrum penicillins that are penicillinase resistant
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Pharmacology for Nursing 7th Edition this way, the penicillins fall into Care, four major groups: (1) narrow-spectrum penicillins that are penicillinase sensitive, (2) narrow-spectrum penicillins that are penicillinase resistant (antistaphylococcal penicillins), (3) broad-spectrum penicillins (aminopenicillins), and (4) extended-spectrum penicillins (antipseudomonal penicillins). Table 83-1 lists the members of each group and their principal target organisms. 84.2
PROPERTIES OF INDIVIDUAL PENICILLINS
84.2.1
Penicillin G Penicillin G (benzylpenicillin) was the first penicillin available and will serve as our prototype for the penicillin family. This drug is often referred to simply as penicillin. Penicillin G is bactericidal to a number of gram-positive bacteria as well as to some gram-negative bacteria. Despite the introduction of newer antibiotics, penicillin G remains a drug of choice for many infections. Its structure is shown in Figure 83-1.
84.2.1.1
Antimicrobial Spectrum Penicillin G is active against most gram-positive bacteria (except penicillinase-producing staphylococci), gram-negative cocci (Neisseria meningitidis and non–penicillinase-producing strains of Neisseria gonorrhoeae), anaerobic bacteria, and spirochetes (including Treponema pallidum). With few exceptions, gram-negative bacilli are resistant. Although many organisms respond to penicillin G, the drug is considered a narrow-spectrum agent (compared with other members of the penicillin family).
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Pharmacology forpenicillin Nursing Care, 7th Edition members of the family).
986 987
TABLE 83-1 Classification of the Penicillins Penicillin Class
Drug
Clinically Useful Antimicrobial Spectrum
Narrow-spectrum penicillins: Penicillin G penicillinase sensitive Penicillin V
Streptococcus species, Neisseria species, many anaerobes, spirochetes, others
Narrow-spectrum penicillins: Methicillin* penicillinase resistant (antistaphylococcal Nafcillin penicillins) Oxacillin
Staphylococcus aureus
Cloxacillin* Dicloxacillin Broad-spectrum penicillins (aminopenicillins)
Ampicillin Amoxicillin
Haemophilus influenzae, Escherichia coli, Proteus mirabilis, enterococci, Neisseria gonorrhoeae
Bacampicillin* Extended-spectrum Carbenicillin penicillins (antipseudomonal indanyl* penicillins) Ticarcillin
Same as broad-spectrum penicillins plus Pseudomonas aeruginosa, Enterobacter species, Proteus (indole positive), Bacteroides fragilis, many Klebsiella
Mezlocillin* Piperacillin
* 84.2.1.2
No longer used in the United States.
Therapeutic Uses Penicillin G is a drug of first choice for infections caused by sensitive gram-positive cocci. Important among these are pneumonia and meningitis caused by Streptococcus pneumoniae (pneumococcus), pharyngitis caused by Streptococcus pyogenes, and infectious endocarditis caused by Streptococcus viridans. Penicillin is also the preferred drug for those few strains of Staph. aureus that do not produce penicillinase. Penicillin is a preferred agent for infections caused by several gram-positive bacilli, specifically, gas gangrene (caused by Clostridium perfringens), tetanus (caused by Clostridium tetani), and anthrax (caused by Bacillus anthracis).
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Pharmacology forbyNursing Care, 7th Edition anthrax (caused Bacillus anthracis). Penicillin is the drug of first choice for meningitis caused by N. meningitidis (meningococcus). Although once the drug of choice for gonorrhea (caused by N. gonorrhoeae), penicillin has been replaced by ceftriaxone as the primary treatment. Penicillin is now limited to infections caused by non–penicillinase-producing strains of N. gonorrhoeae. Penicillin is the drug of choice for syphilis, an infection caused by the spirochete T. pallidum. In addition to treating active infections, penicillin G has important prophylactic applications. The drug is used to prevent syphilis in sexual partners of individuals who have this infection. Benzathine penicillin G (administered monthly for life) is employed for prophylaxis against recurrent attacks of rheumatic fever; treatment is recommended for patients with a history of recurrent rheumatic fever and for those with clear evidence of rheumatic heart disease. Penicillin is also employed for prophylaxis of bacterial endocarditis; candidates include individuals with (1) prosthetic heart valves, (2) most congenital heart diseases, (3) acquired valvular heart disease, (4) mitral valve prolapse, and (5) previous history of bacterial endocarditis. For prevention of endocarditis, penicillin is administered prior to dental procedures and other procedures that are likely to produce temporary bacteremia. 84.2.1.3
Pharmacokinetics
84.2.1.3.1
Absorption. Penicillin G is available as three salts: (1) potassium penicillin G, (2) procaine penicillin G, and (3) benzathine penicillin G. These salts differ with respect to route of administration and time course of action. With all three forms, the salt dissociates to release penicillin G, the active component.
84.2.1.3.1.1
Oral. Oral administration is obsolete. Penicillin G is unstable in acid, and the majority of an oral dose is destroyed in the stomach.
84.2.1.3.1.2
Intramuscular. All forms of penicillin may be administered IM. However, it is important to note that the different salts are absorbed at very different rates. As indicated in Figure 83-5, absorption of potassium penicillin G is rapid; blood levels peak about 15 minutes after injection. In contrast, the procaine and benzathine salts are absorbed slowly, and hence are considered repository preparations. When benzathine penicillin is injected IM, penicillin G is absorbed
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Pharmacology Nursing 7th Edition contrast, for the procaine and Care, benzathine salts are absorbed slowly, and hence are considered repository preparations. When benzathine penicillin is injected IM, penicillin G is absorbed for weeks, producing blood levels that are persistent but very low (see Fig. 83-5). Consequently, this preparation is useful only against highly sensitive organisms (eg, T. pallidum, the bacterium that causes syphilis). 84.2.1.3.1.3
Intravenous. When high blood levels are needed rapidly, penicillin can be administered IV. Only the potassium salt should be used by this route. Owing to poor water solubility, procaine and benzathine salts must never be administered IV.
84.2.1.3.2
Distribution. Penicillin distributes well to most tissues and body fluids. In the absence of inflammation, penetration of the meninges and into fluids of joints and the eye is poor. However, in the presence of inflammation, entry into cerebrospinal fluid, joints, and the eye is enhanced, permitting treatment of infections caused by susceptible organisms.
84.2.1.3.3
Metabolism and Excretion. Penicillin undergoes minimal metabolism, and hence is eliminated by the kidneys, primarily as the unchanged drug. Renal excretion is accomplished mainly (90%) by active tubular secretion; the remaining 10% results from glomerular filtration. In older children and adults, the half-life is very short (about 30 minutes). Renal impairment causes the half-life to increase dramatically, and may necessitate a reduction in dosage. In patients at high risk of toxicity (those with renal impairment, the acutely ill, the elderly, the very young), kidney function should be monitored. Renal excretion of penicillin can be delayed with probenecid, a compound that competes with penicillin for active tubular transport. In the past, when penicillin was both scarce and expensive, probenecid was employed routinely to prolong antibacterial effects. However, since penicillin is now available in abundance at low cost, concurrent use of probenecid is seldom indicated.
84.2.1.4
Side Effects and Toxicities Penicillin G is the least toxic of all antibiotics, and among the safest of all medications. Allergic reactions, the principal concern with penicillin, are discussed separately below. Other reactions include pain at sites of IM injection, prolonged (but reversible) sensory and motor dysfunction
CHAPTER 83 Drugs That Weaken the Bacterial Cell Wall I: Penicillins
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Pharmacology Nursing 7th Edition reactions, thefor principal concernCare, with penicillin, are discussed separately below. Other reactions include pain at sites of IM injection, prolonged (but reversible) sensory and motor dysfunction following accidental injection into a peripheral nerve, and neurotoxicity (sei
Figure 83-5 Blood levels of penicillin G following IM injection of three different penicillin G salts.
987 988
(Adapted from Pratt WB, Fekety R: The Antimicrobial Drugs. New York: Oxford University Press, 1986.) zures, confusion, hallucinations) if blood levels are too high. Inadvertent intra-arterial injection can produce severe reactions—gangrene, necrosis, sloughing of tissue—and must be avoided. Certain adverse effects may be caused by compounds coadministered with penicillin. For example, the procaine component of procaine penicillin G may cause bizarre behavioral effects when procaine penicillin is given in large doses. When large IV doses of potassium penicillin G are administered rapidly, hyperkalemia can result, possibly causing dysrhythmias and even cardiac arrest.
CHAPTER 83 Drugs That Weaken the Bacterial Cell Wall I: Penicillins
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Pharmacology cardiac arrest.for Nursing Care, 7th Edition 84.2.1.5 84.2.1.5.1
Penicillin Allergy General Considerations. Penicillins are the most common cause of drug allergy. Between 0.4% and 7% of patients who receive penicillins experience an allergic reaction. Severity can range from a minor rash to life-threatening anaphylaxis. As with most allergic reactions, there is no direct relationship between the size of the dose and the intensity of the response. Although prior exposure to penicillins is required for an allergic reaction, responses may occur in the absence of prior penicillin use. How can this be? Because patients may have been exposed to penicillins produced by fungi or to penicillins present in foods of animal origin. Because of cross sensitivity, patients allergic to one penicillin should be considered allergic to all penicillins. In addition, a few patients (about 1%) display cross sensitivity to cephalosporins. If at all possible, patients with penicillin allergy should not be treated with any member of the penicillin family. Use of cephalosporins depends on the intensity of allergic response: If the penicillin allergy is mild, use of cephalosporins is probably safe; however, if the allergy is severe, cephalosporins should be avoided. Individuals allergic to penicillin should be encouraged to wear a Medic Alert bracelet to alert healthcare personnel to their condition.
84.2.1.5.2
Types of Allergic Reactions. Penicillin reactions are classified as immediate, accelerated, and late. Immediate reactions occur 2 to 30 minutes after drug administration; accelerated reactions occur within 1 to 72 hours; and late reactions occur within days to weeks. Anaphylaxis (laryngeal edema, bronchoconstriction, severe hypotension) is an immediate hypersensitivity reaction, and the reaction of greatest concern. Anaphylactic reactions occur more frequently with penicillins than with any other drugs. However, even with penicillins, the incidence of anaphylaxis is extremely low (the estimated incidence is between 0.004% and 0.04%). Nonetheless, when these reactions do occur, the risk of mortality is high (about 10%). The primary treatment is epinephrine (subQ, IM, or IV) plus respiratory support. To ensure prompt treatment if anaphylaxis should develop, patients should remain in the prescriber's office for at least 30 minutes after drug injection (ie, until the risk of an anaphylactic reaction has passed).
CHAPTER 83 Drugs That Weaken the Bacterial Cell Wall I: Penicillins
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Pharmacology has passed).for Nursing Care, 7th Edition 84.2.1.5.3
Development of Penicillin Allergy. Before discussing penicillin allergy further, we need to review development of allergy to small molecules as a class. Small molecules, such as penicillin and most other drugs, are unable to induce antibody formation directly. Therefore, in order to promote antibody formation, the small molecule must first bond covalently to a larger molecule (usually a protein). In these combinations, the small molecule is referred to as a hapten. The haptenprotein combination constitutes the complete antigen that stimulates antibody formation. The hapten that stimulates production of penicillin antibodies is rarely intact penicillin itself. Rather, compounds formed from the degradation of penicillin are the actual cause. As a result, most “penicillin antibodies” are not directed at penicillin itself. Rather, they are directed at various penicillin degradation products.
84.2.1.5.4
988 989
Skin Tests for Penicillin Allergy. Allergy to penicillin can decrease over time. Hence, an intense allergic reaction in the past does not necessarily mean that an intense reaction will occur again. In patients with a history of penicillin allergy, skin tests can be employed to assess the current risk. These tests are performed by injecting a tiny amount of allergen intradermally and observing for an allergic response. Two reagents can be employed to assess penicillin allergy. One of these, benzylpenicilloylpolylysine [Pre-Pen], tests primarily for delayed hypersensitivity. This reagent is referred to as a major antigenic determinant, a term indicating that the antibodies for which this reagent tests are relatively common. Benzylpenicilloyl-polylysine is a large polymeric molecule that is poorly absorbed. Hence, even in patients with severe penicillin allergy, a skin test carries little risk of a systemic reaction. The second reagent, known as the minor determinant mixture (MDM), detects antibodies that mediate immediate allergic responses (eg, anaphylaxis). The term minor indicates that the antibodies being tested for are relatively uncommon and not that the allergic response mediated by these antibodies is of minor significance. It is important to note that skin testing with MDM can be dangerous: In patients with severe penicillin allergy, the skin test itself can precipitate an anaphylactic reaction. Accordingly, the test should be performed only if epinephrine and facilities for respiratory support are immediately available.
CHAPTER 83 Drugs That Weaken the Bacterial Cell Wall I: Penicillins
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Pharmacology 7thsupport Edition epinephrinefor and Nursing facilities forCare, respiratory are immediately available. For two reasons, penicillin itself is rarely employed for skin tests. First, skin testing with penicillin can elicit an anaphylactic reaction in highly sensitized individuals. Second, use of penicillin can produce a false-negative result. This second point is paradoxical and requires explanation. Recall that most antibodies that mediate penicillin allergy are directed against degradation products of penicillin, and not against penicillin itself. Nonetheless, intact penicillin is able to bind to the active site of these antibodies—but that binding will not trigger an immune response. As a result, when small amounts of degradation products are formed following intradermal injection of penicillin, the presence of large amounts of intact penicillin can compete with those products for antibody-binding sites, thereby preventing the degradation products from triggering an allergic reaction. 84.2.1.5.5
Management of Patients with a History of Penicillin Allergy. All patients who are candidates for penicillin therapy should be asked if they have penicillin allergy. For patients who answer “yes,” the general rule is to avoid penicillins. If the allergy is mild, a cephalosporin is often an appropriate alternative. However, if there is a history of anaphylaxis or some other severe allergic reaction, it is prudent to avoid cephalosporins as well (because there is about a 1% risk of cross sensitivity to cephalosporins). When a cephalosporin is indicated, an oral cephalosporin is preferred (because the risk of a severe reaction is lower than with parenteral therapy). For many infections, vancomycin, erythromycin, and clindamycin are effective and safe alternatives for patients with penicillin allergy. Rarely, a patient with a history of anaphylaxis may have a life-threatening infection (eg, enterococcal endocarditis) for which alternatives to penicillins are ineffective. In these cases, the potential benefits of penicillin therapy outweigh the risks, and treatment should be instituted. To minimize the chances of an anaphylactic reaction, penicillin should be administered according to a desensitization schedule. In this procedure, an initial small dose is followed at 60-minute intervals by progressively larger doses until the full therapeutic dose has been achieved. It should be noted that the desensitization procedure is not without risk. Accordingly, epinephrine and facilities for respiratory support should be immediately available.
CHAPTER 83 Drugs That Weaken the Bacterial Cell Wall I: Penicillins
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Pharmacology available. for Nursing Care, 7th Edition 84.2.1.6 84.2.1.6.1
Drug Interactions Aminoglycosides. For some infections, penicillins are used in combination with an aminoglycoside (eg, gentamicin). By weakening the cell wall, the penicillin facilitates access of the aminoglycoside to its intracellular site of action, thereby increasing bactericidal effects. Unfortunately, when penicillins are present in high concentrations, they interact chemically with aminoglycosides and thereby inactivate the aminoglycoside. Accordingly, penicillins and aminoglycosides should never be mixed in the same IV solution. Rather, they should be administered separately. Once a penicillin has been diluted in body fluids, the potential for inactivating the aminoglycoside is minimal.
84.2.1.6.2
Probenecid. As noted, probenecid can delay renal excretion of penicillin, thereby prolonging antibacterial effects.
84.2.1.6.3
Bacteriostatic Antibiotics. Since penicillins are most effective against actively growing bacteria, concurrent use of a bacteriostatic antibiotic (eg, tetracycline) could, in theory, reduce the bactericidal effects of the penicillin. However, the clinical significance of such interactions is not known. Nonetheless, combined use of penicillin and bacteriostatic agents is generally avoided.
84.2.1.7 84.2.1.7.1
Preparations, Dosage, and Administration Preparations and Routes of Administration. Penicillin G is available as three different salts (potassium, procaine, and benzathine). These salts differ with respect to routes of administration: potassium penicillin G [Pfizerpen] is administered IM, IV, and by local infusion (eg, intrapleural); and benzathine penicillin G [Bicillin L-A, Permapen], procaine penicillin G [Wycillin], and a combination product [Bicillin C-R], composed of benzathine penicillin G plus procaine penicillin G, are all administered IM. Check to ensure that the penicillin salt to be administered is appropriate for the intended route.
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Pharmacology Nursing Care, 7th Edition the intendedfor route. 84.2.1.7.2
Dosage. Dosage of penicillin G is prescribed in units (1 unit equals 0.6 mg). Dosage ranges are summarized in Table 83-2. For any particular patient, the specific dosage will depend on the type and severity of infection. Dosage should be reduced in patients with severe renal impairment.
84.2.1.7.3
Administration. Solutions for parenteral administration should be prepared according to the manufacturer's instructions. During IM administration, take care to avoid inadvertent injection into an artery or peripheral nerve.
84.2.2
Penicillin V Penicillin V [Veetids], also known as penicillin VK, is similar to penicillin G in most respects. The principal difference is acid stability: penicillin V is stable in stomach acid, whereas penicillin G is not. Because of its acid stability, penicillin V has replaced penicillin G for oral therapy. Penicillin V may be taken with meals. Dosages are summarized in Table 83-2.
84.2.3
Penicillinase-Resistant Penicillins (Antistaphylococcal Penicillins) By altering the penicillin side chain, pharmaceutical chemists have created a group of penicillins that are highly resistant to inactivation by beta-lactamases. In the United States, three such drugs are available: nafcillin, oxacillin, and dicloxacillin. These agents have a very narrow antimicrobial spectrum and are used only against penicillinase-producing strains of staphylococcus (Staph. aureus and Staph. epidermidis). Since most strains of staphylococci produce penicillinase, the penicillinase-resistant penicillins are drugs of choice for the majority of staphylococcal infections. It should be noted that these agents should not be used against infections caused by non– penicillinase-producing staphylococci, since they are less active than penicillin G against these bacteria.
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Pharmacology for Nursing Care, 7th Edition bacteria. TABLE 83-2 Dosages for Penicillin Total Daily Dosagea
Generic Name
Trade Name
Usual Routes
Dosing Interval (hr)
Adults
Children
Narrow-Spectrum Penicillins: Penicillinase-Sensitive Penicillin G
Bicillin C-R, Bicillin L- IM, IV A,
4
1.2–2.4 million
unitsb
100,000–250,000 units/kgb
Permapen, Pfizerpen, Wycillin Penicillin V
Veetids
PO
4–6
0.5–2 gm
25–50 mg/kg
Narrow-Spectrum Penicillins: Penicillinase-Resistant (Antistaphylococcal Penicillins) Nafcillin
IV
4–6
2–12 gm
100–200 mg/kg
Oxacillin
IV
4–6
2–12 gm
100–200 mg/kg
Dicloxacillin
PO
6
1–4 gm
12.5–25 mg/kg
PO
6–8
2–4 gm
50–100 mg/kg
IV
6–8
2–12 gm
10–200 mg/kg 300 mg/kgc
Broad-Spectrum Penicillins (Aminopenicillins) Ampicillin
Principen
Ampicillin/sulbactam
Unasyn
IV
6
4–8 gmc
Amoxicillin
Amoxil, DisperMox,
PO
8
0.75–1.5 gm 20–40 mg/kg
PO
8
250–500
20–40 mg/kgd
Augmentin ES-600
PO
12
—
90 mg/kg
Augmentin XR
PO
12
4000 mg
—
Moxatag, Trimox Amoxicillin/clavulanate Augmentin
mgd
Extended-Spectrum Penicillins (Antipseudomonal Penicillins) Ticarcillin
Ticar
IV
4–6
200–300 mg/kg
200–300 mg/kg
Ticarcillin/clavulanate
Timentin
IV
4–6
200–300
200 mg/kge
Piperacillin
IV
4–6
12–24 gm
200–300 mg/kg
Piperacillin/tazobactam Zosyn
IV
4–6
12 gmf
80–100 mg/kgf
CHAPTER 83 Drugs That Weaken the Bacterial Cell Wall I: Penicillins
mg/kge
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Pharmacology for Nursing Care, 7th Edition a
Doses vary widely, depending upon the type and severity of infection; doses and dosing intervals presented here may not be appropriate for all patients.
b
10,000 units = 6 mg.
c
Dose based on ampicillin content.
d
Dose based on amoxicillin content.
e
Dose based on ticarcillin content.
f
Dose based on piperacillin content.
An increasing clinical problem is the emergence of staphylococcal strains referred to as methicillin-resistant Staphylococcus aureus (MRSA), a term used to indicate lack of susceptibility to methicillin (an obsolete penicillinase-resistant penicillin) and all other penicillinase-resistant penicillins. Resistance appears to result from production of PBPs to which the penicillinaseresistant penicillins cannot bind. Currently, vancomycin (alone or combined with rifampin) is the treatment of choice. Infection with MRSA is discussed further in Box 83-1. 84.2.3.1
Nafcillin Nafcillin is usually administered IV. Intramuscular use is rare. Absorption from the GI tract is erratic and incomplete, and hence oral formulations have been discontinued. Dosage is summarized in Table 83-2.
84.2.3.2
Oxacillin and Dicloxacillin These drugs are similar in structure and pharmacokinetic properties: both are acid stable and available for oral administration. Oxacillin may also be administered IV. Oral dosing with both may be done with meals. Dosages are summarized in Table 83-2.
84.2.3.3
Methicillin Methicillin, the oldest penicillinase-resistant penicillin, is no longer available in the United States. In addition to causing allergic reactions typical of all penicillins, methicillin may produce interstitial nephritis, an adverse effect that is usually reversible but sometimes progresses to complete renal failure.
84.2.4
Broad-Spectrum Penicillins (Aminopenicillins) Only two broad-spectrum penicillins are available: ampicillin and amoxicillin. Both have the same antimicrobial spectrum as penicillin G, plus increased activity against certain gram-negative bacilli, including Haemophilus influenzae, Escherichia coli, Salmonella, and Shigella. This
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Pharmacology for Nursing Care, 7thincreased Edition antimicrobial spectrum as penicillin G, plus activity against certain gram-negative bacilli, including Haemophilus influenzae, Escherichia coli, Salmonella, and Shigella. This broadened spectrum is due in large part to an increased ability to penetrate the gram-negative cell envelope. Both drugs are readily inactivated by beta-lactamases, and hence are ineffective against most infections caused by Staph. aureus. 84.2.4.1
Ampicillin Ampicillin [Principen] was the first broad-spectrum penicillin in clinical use. The drug is useful against infections caused by Enterococcus faecalis, Proteus mirabilis, E. coli, Salmonella, Shigella, and H. influenzae. The most common side effects are rash and diarrhea, both of which occur more frequently with ampicillin than with any other penicillin. Administration may be oral or IV. It should be noted, however, that for oral therapy, amoxicillin is preferred (see below). Dosages for patients with normal kidney function are summarized in Table 83-2. For patients with renal impairment, dosage should be reduced.
84.2.4.1.1 84.2.4.1.1.1
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BOX 83-1 Special Interest Topic METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS Staphylococcus aureus is a gram-positive bacterium that often colonizes the skin and nostrils of healthy people. Infection usually involves the skin and soft tissues, causing abscesses, boils, cellulitis, and impetigo. However, more serious infections can also develop, including infections of the lungs and bloodstream, which can be fatal. Like other pathogens, Staph. aureus has developed resistance over the years. When penicillins were introduced in the 1940s, all strains of Staph. aureus were susceptible. However, penicillin-resistant strains quickly emerged, owing to bacterial production of penicillinases. In 1959, this resistance was overcome with methicillin, the first penicillinase-resistant penicillin. Unfortunately, by 1968, strains resistant to methicillin had emerged. These highly resistant bacteria, known as methicillin-resistant Staph. aureus (MRSA), are resistant not only to methicillin (now obsolete), but to all penicillins and all cephalosporins as well. The basis of MRSA resistance is acquisition of genes that code for penicillin-binding proteins that have very low affinity for penicillins and cephalosporins. Resistant strains were initially limited to healthcare facilities, but are now found in the community as well. In the United States, MRSA is a serious public health problem—and it's getting worse. Between 2000 and 2005, hospital stays for MRSA infection tripled, rising from 128,500 to 368,800. In 2005, MRSA caused an estimated 94,360 severe (ie, invasive) infections,
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Pharmacology Betweenfor 2000Nursing and 2005, Care, hospital 7th stays Edition for MRSA infection tripled, rising from 128,500 to 368,800. In 2005, MRSA caused an estimated 94,360 severe (ie, invasive) infections, resulting in 18,650 deaths—6150 more than were caused by HIV/AIDS. Not only does MRSA increase mortality, it increases costs: Treating hospitalized patients runs about $35,000, compared with $14,000 for patients with methicillin-sensitive infections. Fortunately, although MRSA infection is becoming more common and more invasive, it still remains treatable. There are two distinct types of MRSA, referred to as hospital-associated MRSA (HAMRSA) and community-associated MRSA (CA-MRSA). Of the two, HA-MRSA is more prevalent (85% vs. 15%) and emerged earlier (1968 vs. 1981). Also, HA-MRSA infection is generally more serious and harder to treat. Molecular typing indicates that HA-MRSA and CA-MRSA are genetically distinct strains, known as USA100 and USA300, respectively. 84.2.4.1.1....
Hospital-Associated MRSA Methicillin resistance in Staph. aureus was first reported in isolates from hospitalized patients. The year was 1968. Since then, the prevalence of HA-MRSA among hospitalized patients has steadily climbed, reaching 2% of all Staph. aureus infections in 1974, 22% in 1995, and 63% in 2004. The prevalence of HA-MRSA in invasive infections (eg, bacteremia) is even higher, accounting for 85% of all invasive Staph. aureus infections. Although many infections with HA-MRSA surface in the community, nearly all occur in people who had been exposed to a healthcare facility within the prior year, indicating that acquisition of the infection probably occurred in a healthcare setting—not out in the community. Transmission of HA-MRSA is usually through person-to-person contact, very often between healthcare workers and patients. Risk factors for acquiring HA-MRSA include old age, recent surgery or hospitalization, dialysis, treatment in an ICU, prolonged antibiotic therapy, an indwelling catheter, and residence in a long-term care facility. How do we treat HA-MRSA infection? Because most strains are multidrug resistant, many antibiotics are ineffective, including beta-lactam agents, tetracyclines, clindamycin, and trimethoprim/sulfamethoxazole. Fortunately, most isolates remain highly sensitive to IV vancomycin, the current treatment of choice. Alternatives include linezolid, daptomycin, tigecycline, and quinupristin/dalfopristin.
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Pharmacology fordaptomycin, Nursing tigecycline, Care, 7thandEdition linezolid, quinupristin/dalfopristin. 84.2.4.1.1....
Community-Associated MRSA Infection with CA-MRSA, first reported in 1981, is caused by staphylococcal strains that are genetically distinct from HA-MRSA. For example, most strains of CA-MRSA carry a gene for Panton-Valentine leukocidin (a cytotoxin that causes necrosis), whereas HA-MRSA strains do not. Many people are now asymptomatic carriers of CA-MRSA. In fact, between 20% and 30% of the population is colonized, typically on the skin and in the nostrils. Infection with CA-MRSA is generally less dangerous than with HA-MRSA, but more dangerous than with methicillin-sensitive Staph. aureus. In most cases, CA-MRSA causes mild infections of the skin and soft tissues, manifesting as boils, impetigo, and so forth. However, CA-MRSA can also cause more serious infections, including necrotizing fasciitis, severe necrotizing pneumonia, and severe sepsis. Fortunately, these invasive infections are relatively rare. On the other hand, infections of the skin and soft tissues are now common, with CA-MRSA accounting for more than 50% of the Staph. aureus isolates from these sites. How is CA-MRSA transmitted? And who is vulnerable? Transmission is by skin-toskin contact, and by contact with contaminated objects, including frequently touched surfaces, sports equipment, and personal items (eg, razors). In contrast to HA-MRSA infection, CA-MRSA infection is seen primarily in young, healthy people with no recent exposure to healthcare facilities. Individuals at risk include athletes in contact sports (eg, wrestling), men who have sex with men, and people who live in close quarters, such as family members, day care clients, prison inmates, military personal, and college students. Several measures can reduce the risk of CA-MRSA transmission. Topping the list is good hand hygiene—washing with soap and water or applying an alcohol-based sanitizer. Other measures include showering after contact sports, cleaning frequently touched surfaces, keeping infected sites covered, and not sharing towels and personal items. Treatment depends on infection severity. For boils, small abscesses, and other superficial infections, surgical drainage may be all that is needed. For more serious infections, drugs may be indicated. Preferred agents are trimethoprim/ sulfamethoxazole, minocycline, doxycycline, and clindamycin. Alternative drugs— vancomycin, daptomycin, and linezolid—should be reserved for severe infections and treatment failures. To eradicate the carrier state, intranasal application of a topical
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Pharmacology for Nursing Care, 7th Edition be reserved for severe infections and vancomycin, daptomycin, and linezolid—should treatment failures. To eradicate the carrier state, intranasal application of a topical antibiotic—mupirocin or retapamulin—can be effective. Like HA-MRSA, CA-MRSA will not respond to beta-lactam antibiotics. As discussed below, ampicillin is also available in a fixed-dose combination with sulbactam, an inhibitor of bacterial beta-lactamase. The combination is sold as Unasyn. 84.2.4.2
Amoxicillin Amoxicillin [Amoxil, DisperMox, Moxatag, Trimox] is similar to ampicillin in structure and actions. The two drugs differ primarily in acid stability, amoxicillin being the more acid resistant. Hence, when the two are administered orally in equivalent doses, blood levels of amoxicillin are greater. Accordingly, when oral therapy is indicated, amoxicillin is preferred. Amoxicillin produces less diarrhea than ampicillin, perhaps because less amoxicillin remains unabsorbed in the intestine. As discussed below, amoxicillin is also available in fixed-dose combinations with clavulanic acid, an inhibitor of bacterial beta-lactamases. The combination is marketed as Augmentin. Amoxicillin, by itself, is one of our most frequently prescribed antibiotics.
84.2.5
Extended-Spectrum Penicillins (Antipseudomonal Penicillins) Two extended-spectrum penicillins are available: ticarcillin and piperacillin; a third drug— carbenicillin indanyl [Geocillin]—has been withdrawn. The antimicrobial spectrum of these drugs includes organisms that are susceptible to the aminopenicillins plus Pseudomonas aeruginosa, Enterobacter species, Proteus (indole positive), Bacteroides fragilis, and many Klebsiella. Both extended-spectrum penicillins are susceptible to beta-lactamases, and hence are ineffective against most strains of Staph. aureus. The extended-spectrum penicillins are used primarily for infections with P. aeruginosa. These infections often occur in the immunocompromised host and can be very difficult to eradicate. To increase killing of Pseudomonas, an antipseudomonal aminoglycoside (gentamicin, tobramycin, amikacin, netilmicin) is almost always added to the regimen. When these combinations are employed, the penicillin and the aminoglycoside should not be mixed in the same IV solution. Why? Because high concentrations of penicillins can inactivate aminoglycosides.
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Pharmacology Care, 7th Edition Why? Because for high Nursing concentrations of penicillins can inactivate aminoglycosides. 84.2.5.1 84.2.5.1.1
Ticarcillin Antimicrobial Spectrum and Therapeutic Use. Ticarcillin [Ticar] has one of the broadest antimicrobial spectra of all penicillins. However, like other extended-spectrum penicillins, the drug is susceptible to destruction by penicillinase. The primary indication for ticarcillin is infection with P. aeruginosa. When used against Pseudomonas, ticarcillin is usually combined with an aminoglycoside.
84.2.5.1.2
Adverse Effects. In addition to promoting the allergic reactions typical of all penicillins, ticarcillin can cause unique effects. Since the drug is administered as the disodium salt, and since large IV doses are often required, symptoms of sodium overload (eg, congestive heart failure) may develop. Also, ticarcillin interferes with platelet function and can thereby promote bleeding.
84.2.5.1.3
Preparations and Administration. Ticarcillin [Ticar] is unstable in acid, and hence must be given parenterally (almost always IV). When ticarcillin is used in combination with an aminoglycoside, the two drugs should be administered separately. As discussed below, ticarcillin is available in a fixed-dose combination with clavulanic acid, a beta-lactamase inhibitor. The combination [Timentin] is administered IV. Dosages for patients with normal kidney function are summarized in Table 83-2. Dosages must be reduced in patients with renal impairment.
84.2.5.2
Piperacillin Piperacillin has a broad antimicrobial spectrum. However, like other extended-spectrum penicillins, the drug is penicillinase sensitive. Piperacillin is highly active against P. aeruginosa, its principal target. Like ticarcillin, piperacillin can cause bleeding secondary to disrupting platelet function. The drug is acid labile and hence must be administered parenterally, usually IV. The risk of sodium overload is much less than with IV ticarcillin. When piperacillin is used in combination with an aminoglycoside, it should not be mixed in the same IV solution. Dosages for patients with normal kidney function are shown in Table 83-2. Dosage should be reduced in patients with renal impairment. As discussed below, piperacillin is also available in a
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Pharmacology for Nursing Care, 7th Edition Dosages for patients with normal kidney function are shown in Table 83-2. Dosage should be reduced in patients with renal impairment. As discussed below, piperacillin is also available in a fixed-dose combination with tazobactam, a beta-lactamase inhibitor. The combination is marketed as Zosyn. 84.2.6
Penicillins Combined with a Beta-Lactamase Inhibitor As their name indicates, beta-lactamase inhibitors are drugs that inhibit bacterial beta-lactamases. By combining a beta-lactamase inhibitor with a penicillinase-sensitive penicillin, we can extend the antimicrobial spectrum of the penicillin. In the United States, three beta-lactamase inhibitors are used: clavulanic acid, tazobactam, and sulbactam. These drugs are not available alone. Rather, they are available only in fixed-dose combinations with a penicillin. Four such combination products are available: • Ampicillin/sulbactam [Unasyn] • Amoxicillin/clavulanic acid [Augmentin] • Ticarcillin/clavulanic acid [Timentin] • Piperacillin/tazobactam [Zosyn] Because beta-lactamase inhibitors have minimal toxicity, any adverse effects that occur with the combination products are due to the penicillin. Routes of administration and dosages are summarized in Table 83-2.
84.2.6.1
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KEY POINTS ▪ Penicillins weaken the bacterial cell wall, causing lysis and death. ▪ Some bacteria resist penicillins by producing penicillinases (beta-lactamases), enzymes that inactivate penicillins. ▪ Gram-negative bacteria are resistant to penicillins that cannot penetrate the gramnegative cell envelope. ▪ Penicillins are the safest antibiotics available. ▪ The principal adverse effect of penicillins is allergic reaction, which can range in intensity from rash to lifethreatening anaphylaxis.
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Pharmacology forfrom Nursing Care, 7th anaphylaxis. Edition intensity rash to lifethreatening ▪ Patients allergic to one penicillin should be considered cross-allergic to all other penicillins. In addition, they have about a 1% chance of cross-allergy to cephalosporins. ▪ Vancomycin, erythromycin, and clindamycin are safe and effective alternatives to penicillins for patients with penicillin allergy. ▪ Penicillins are normally eliminated rapidly by the kidney, but can accumulate to harmful levels if renal function is severely impaired. ▪ The principal differences among the penicillins relate to antibacterial spectrum, stability in stomach acid, and duration of action. ▪ Penicillin G has a narrow antibacterial spectrum and is unstable in stomach acid. ▪ Benzathine penicillin G is released very slowly following IM injection, and thereby produces prolonged antibacterial effects. ▪ The penicillinase-resistant penicillins (eg, nafcillin) are used primarily against penicillinase-producing strains of Staph. aureus. ▪ In contrast to penicillin G, the broad-spectrum penicillins, such as ampicillin and amoxicillin, have useful activity against gram-negative bacilli. ▪ Extended-spectrum penicillins, such as ticarcillin, are useful against P. aeruginosa. ▪ Beta-lactamase inhibitors, such as clavulanic acid, are combined with certain penicillins to increase their activity against beta-lactamase–producing bacteria. ▪ Penicillins should not be combined with aminoglycosides (eg, gentamicin) in the same IV solution. 84.2.6.2 84.2.6.2.1
Summary of Major Nursing Implications* PENICILLINS Amoxicillin Ampicillin
CHAPTER 83 Drugs That Weaken the Bacterial Cell Wall I: Penicillins
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Pharmacology for Nursing Care, 7th Edition Ampicillin Dicloxacillin Nafcillin Oxacillin Penicillin G Penicillin V Piperacillin Ticarcillin Except where indicated otherwise, the implications summarized below apply to all members of the penicillin family. 84.2.6.2... 84.2.6.2...
Preadministration Assessment Therapeutic Goal Treatment of infections caused by sensitive bacteria.
84.2.6.2...
Baseline Data The prescriber may order tests to identify the infecting organism and its drug sensitivity. Take samples for microbiologic culture prior to starting treatment. In patients with a history of penicillin allergy, a skin test may be performed to determine current allergic status.
84.2.6.2...
Identifying High-Risk Patients Penicillins should be used with extreme caution, if at all, in patients with a history of severe allergic reactions to penicillins, cephalosporins, or carbapenems.
CHAPTER 83 Drugs That Weaken the Bacterial Cell Wall I: Penicillins
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Pharmacology Nursing 7th Edition severefor allergic reactionsCare, to penicillins, cephalosporins, or carbapenems. 84.2.6.2... 84.2.6.2...
Implementation: Administration Routes Penicillins are administered orally, IM, and IV. Routes for individual agents are summarized in Table 83-2. Before giving a penicillin, make sure the preparation is appropriate for the intended route.
84.2.6.2...
Dosage Doses for penicillin G are prescribed in units (1 unit equals 0.6 mg). Doses for all other penicillins are prescribed by weight. Dosages for individual penicillins are summarized in Table 83-2.
84.2.6.2...
Administration During IM injection, aspirate to avoid injection into an artery. Take care to avoid injection into a nerve. Instruct the patient to take oral penicillins with a full glass of water 1 hour before meals or 2 hours after. Penicillin V, amoxicillin, and amoxicillin/clavulanic acid may be taken with meals.
993 994
Instruct the patient to complete the prescribed course of treatment, even though symptoms may abate before the full course is over. 84.2.6.2... 84.2.6.2...
Ongoing Evaluation and Interventions Evaluating Therapeutic Effects Monitor the patient for indications of antimicrobial effects (eg, reduction in fever, pain, or inflammation; improved appetite or sense of well-being).
84.2.6.2...
Monitoring Kidney Function Renal impairment can cause penicillins to accumulate to toxic levels, and hence monitoring kidney function can help avoid injury. Measuring intake and output is especially helpful in patients with kidney disease, acutely ill patients, and the very old and very young. Notify the prescriber if a significant change in intake/output ratio
CHAPTER 83 Drugs That Weaken the Bacterial Cell Wall I: Penicillins
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Pharmacology for helpful Nursing Care,with 7th Edition especially in patients kidney disease, acutely ill patients, and the very old and very young. Notify the prescriber if a significant change in intake/output ratio develops. 84.2.6.2... 84.2.6.2...
Minimizing Adverse Effects Allergic Reactions. Penicillin allergy is common. Very rarely, life-threatening anaphylaxis occurs. Interview the patient for a history of penicillin allergy. For patients with prior allergic responses, a skin test may be ordered to assess current allergy status. Exercise caution: The skin test itself can cause a severe reaction. When skin tests are performed, epinephrine and facilities for respiratory support should be immediately available. Advise patients with penicillin allergy to wear some form of identification (eg, Medic Alert bracelet) to alert emergency healthcare personnel. Instruct outpatients to report any signs of an allergic response (eg, skin rash, itching, hives). Whenever a parenteral penicillin is used, keep the patient under observation for at least 30 minutes. If anaphylaxis occurs, treatment consists of epinephrine (subQ, IM, or IV) plus respiratory support. As a rule, patients with a history of penicillin allergy should not receive penicillins again. If previous reactions have been mild, a cephalosporin (preferably oral) may be an appropriate alternative. However, if severe immediate reactions have occurred, cephalosporins should be avoided too. Rarely, a patient with a history of anaphylaxis nonetheless requires penicillin. To minimize the risk of a severe reaction, administer penicillin according to a desensitization schedule. Be aware, however, that the procedure does not guarantee that anaphylaxis will not occur. Accordingly, have epinephrine and facilities for respiratory support immediately available.
CHAPTER 83 Drugs That Weaken the Bacterial Cell Wall I: Penicillins
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Pharmacology for Nursing Care, 7th Edition respiratory support immediately available. 84.2.6.2...
Sodium Loading. High IV doses of ticarcillin can produce sodium overload. Exercise caution in patients under sodium restriction (eg, cardiac patients, those with hypertension). Monitor electrolytes and cardiac status.
84.2.6.2...
Hyperkalemia. High doses of IV potassium penicillin G may cause hyperkalemia, possibly resulting in dysrhythmias or cardiac arrest. Monitor electrolyte and cardiac status.
84.2.6.2...
Effects Resulting from Incorrect Injection. Take care to avoid intra-arterial injection or injection into peripheral nerves, because serious injury can result.
84.2.6.2...
Minimizing Adverse Interactions
84.2.6.2...
Aminoglycosides. When present in high concentration, penicillins can inactivate aminoglycosides (eg, gentamicin). Do not mix penicillins and aminoglycosides in the same IV solution. *
Patient education information is highlighted as blue text.
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Pharmacology for Nursing Care, 7th Edition 85
CHAPTER 84 Drugs That Weaken the Bacterial Cell Wall II: Cephalosporins, Carbapenems, Vancomycin, Aztreonam, Teicoplanin, and Fosfomycin
995
Like the penicillins, the drugs discussed in this chapter are inhibitors of cell wall synthesis. By disrupting the cell wall, these drugs produce bacterial lysis and death. Much of the chapter focuses on the cephalosporins, our most widely used antibacterial drugs. With only three exceptions— vancomycin, teicoplanin, and fosfomycin—the drugs addressed here are beta-lactam drugs. 85.1
CEPHALOSPORINS The cephalosporins are beta-lactam antibiotics similar in structure and actions to the penicillins. These drugs are bactericidal, often resistant to beta-lactamases, and active against a broad spectrum of pathogens. Their toxicity is low. Because of these attributes, the cephalosporins are popular therapeutic agents and constitute our most widely used group of antibiotics. Hospitals in the United States spend more on cephalosporins than on all other antibiotics combined.
85.1.1
Chemistry All cephalosporins are derived from the same nucleus. As shown in Figure 84-1, this nucleus contains a betalactam ring fused to a second ring. The beta-lactam ring is required for antibacterial activity. Unique properties of individual cephalosporins are determined by additions made to the nucleus at the sites labeled R1 and R2.
85.1.2
Mechanism of Action The cephalosporins are bactericidal drugs with a mechanism like that of the penicillins. These agents bind to penicillinbinding proteins (PBPs) and thereby (1) disrupt cell wall synthesis and (2) activate autolysins (enzymes that cleave bonds in the cell wall). The resultant damage to the cell wall causes death by lysis. Like the penicillins, cephalosporins are most effective against cells undergoing active growth and division.
85.1.3
Resistance The principal cause of cephalosporin resistance is production of beta-lactamases, enzymes that cleave the beta-lactam ring, and thereby render these drugs inactive. Beta-lactamases that act on cephalosporins are sometimes referred to as cephalosporinases. Some of the beta-lactamases that
CHAPTER 84 Drugs That Weaken the Bacterial Cell Wall II: Cephalosporins, Carbapenems, Vancomycin, Aztreonam, Teicoplanin, and Fosfomycin
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Pharmacology for Nursing Care, render 7th Edition cleave the beta-lactam ring, and thereby these drugs inactive. Beta-lactamases that act on cephalosporins are sometimes referred to as cephalosporinases. Some of the beta-lactamases that act on cephalosporins can also cleave the beta-lactam ring of penicillins. Not all cephalosporins are equally susceptible to betalactamases. Most first-generation cephalosporins are destroyed by beta-lactamases; second-generation cephalosporins are less sensitive to destruction; and third- and fourth-generation cephalosporins are highly resistant. In some cases, bacterial resistance results from producing altered PBPs that have a low affinity for cephalosporins. Methicillin-resistant staphylococci produce these unusual PBPs and are resistant to cephalosporins as a result. 85.1.4
Classification and Antimicrobial Spectra The cephalosporins can be grouped into four “generations” based on the order of their introduction to clinical use. The generations differ significantly with respect to antimicrobial spectrum and susceptibility to beta-lactamases. In general, as we progress from first-generation agents to fourth-generation agents, there is (1) increasing activity against gram-negative bacteria and anaerobes, (2) increasing resistance to destruction by beta-lactamases, and (3) increasing ability to reach the cerebrospinal fluid (CSF). These differences are summarized in Table 84-1.
85.1.4.1
First Generation. First-generation cephalosporins, represented by cephalexin, are highly active against grampositive bacteria. These drugs are the most active of all cephalosporins against staphylococci and nonenterococcal streptococci. However, staphylococci that are resistant to methicillin-like drugs are also resistant to first-generation cephalosporins (and to most other cephalosporins as well). The first-generation agents have only modest activity against gram-negative bacteria and do not reach effective concentrations in CSF.
85.1.4.2
Second Generation. Second-generation cephalosporins (eg, cefoxitin) have enhanced activity against gram-negative bacteria. The increase is due to a combination of factors: (1) increased affinity for PBPs of gram-negative bacteria, (2) increased ability to penetrate the gram-negative cell envelope, and
CHAPTER 84 Drugs That Weaken the Bacterial Cell Wall II: Cephalosporins, Carbapenems, Vancomycin, Aztreonam, Teicoplanin, and Fosfomycin
995
Page 2 of 32
Pharmacology for Nursing Care,ability 7th Edition gram-negative bacteria, (2) increased to penetrate the gram-negative cell envelope, and Figure 84-1 Structural formulas of representative cephalosporins. The unique structure and pharmacologic properties of individual cephalosporins are determined by additions made to the cephalosporin nucleus at the positions labeled R1 and R2.
995 997
(3) increased resistance to beta-lactamases produced by gram-negative organisms. However, CHAPTER 84 Drugs That Weaken the Bacterial Cell Page 3 of 32 Wall II: Cephalosporins, Carbapenems, Vancomycin, Aztreonam, Teicoplanin, and Fosfomycin
Pharmacology for Nursing Care, 7th Edition (3) increased resistance to beta-lactamases produced by gram-negative organisms. However, none of the second-generation agents is active against Pseudomonas aeruginosa. These drugs do not reach effective concentrations in CSF.
TABLE 84-1 Major Differences Between Cephalosporin Generations Activity Against GramNegative Bacteria
Resistance to Beta-Lactamases
Distribution to Cerebrospinal Fluid
Low
Low
Poor
Second generation (eg, Higher cefoxitin)
Higher
Poor
Third generation (eg, cefotaxime)
Higher
Higher
Good
Fourth generation (cefepime)
Highest
Highest
Good
Class First generation (eg, cephalexin)
85.1.4.3
Third Generation. Third-generation cephalosporins (eg, cefotaxime) have a broad spectrum of antimicrobial activity. Because of increased resistance to beta-lactamases, these drugs are considerably more active against gram-negative aerobes than are the first- and second-generation agents. Some third-generation cephalosporins (eg, ceftazidime) have important activity against P. aeruginosa. Others (eg, cefixime) lack such activity. In contrast to first- and second-generation cephalosporins, the third-generation agents reach clinically effective concentrations in CSF.
85.1.4.4
Fourth Generation. Cefepime, the only fourth-generation cephalosporin, is highly resistant to beta-lactamases and has a very broad antibacterial spectrum. Activity against P. aeruginosa equals that of ceftazidime. Penetration to CSF is good.
CHAPTER 84 Drugs That Weaken the Bacterial Cell Wall II: Cephalosporins, Carbapenems, Vancomycin, Aztreonam, Teicoplanin, and Fosfomycin
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Pharmacology for Nursing Care, 7th Edition ceftazidime. Penetration to CSF is good. 85.1.5
Pharmacokinetics
85.1.5.1
Absorption. Because of poor absorption from the GI tract, many cephalosporins must be administered parenterally (IM or IV). Of the 18 cephalosporins used in the United States, only 10 can be administered by mouth (Table 84-2). Of these, only one—cefuroxime—can be administered orally and by injection.
85.1.5.2
Distribution. Cephalosporins distribute well to most body fluids and tissues. Therapeutic concentrations are achieved in pleural, pericardial, and peritoneal fluids. However, concentrations in ocular fluids are generally low. Penetration to the CSF by first- and second-generation drugs is unreliable, and hence these drugs should not be used for bacterial meningitis. In contrast, CSF levels achieved with third- and fourth-generation drugs are generally sufficient for bactericidal effects.
85.1.5.3
Elimination. Practically all cephalosporins are eliminated by the kidney; excretion is by a combination of glomerular filtration and active tubular secretion. Probenecid can decrease tubular secretion of some cephalosporins, thereby prolonging their effects. In patients with renal insufficiency, dosages of most cephalosporins must be reduced (to prevent accumulation to toxic levels). One cephalosporin—ceftriaxone—is eliminated largely by the liver. Consequently, dosage reduction is unnecessary in patients with renal impairment.
85.1.6
Adverse Effects Cephalosporins are generally well tolerated and constitute one of our safest groups of antimicrobial drugs. Serious adverse effects are rare.
85.1.6.1
Allergic Reactions. Hypersensitivity reactions are the most frequent adverse events. Maculopapular rash that develops several days after the onset of treatment is most common. Severe, immediate reactions (eg, bronchospasm, anaphylaxis) are rare. If, during the course of treatment, signs of
CHAPTER 84 Drugs That Weaken the Bacterial Cell Wall II: Cephalosporins, Carbapenems, Vancomycin, Aztreonam, Teicoplanin, and Fosfomycin
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Pharmacology fordays Nursing Edition develops several after theCare, onset of7th treatment is most common. Severe, immediate reactions (eg, bronchospasm, anaphylaxis) are rare. If, during the course of treatment, signs of allergy appear (eg, urticaria, rash, hypotension, difficulty in breathing), the cephalosporin should be discontinued immediately. Anaphylaxis is treated with respiratory support and parenteral epinephrine. Patients with a history of cephalosporin allergy should not be given these drugs. Because of structural similarities between penicillins and cephalosporins, a few patients allergic to one type of drug may experience cross-reactivity with the other. In clinical practice, the incidence of cross-reactivity has been low: Only 1% of penicillin-allergic patients experience an allergic reaction if given a cephalosporin. For patients with mild penicillin allergy, cephalosporins can be used with minimal concern. However, because of the potential for fatal anaphylaxis, cephalosporins should not be given to patients with a history of severe reactions to penicillins.
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Pharmacology for Nursing Care, 7th Edition reactions to penicillins. TABLE 84-2 Pharmacokinetic Properties of the Cephalosporins Half-Life (hr)
Class
Drug
First Generation
Cefadroxil
PO
Renal
1.2–1.3
20–25
Cefazolin
IM, IV
Renal
1.5–2.2
24–50
Cephalexin
PO
Renal
0.4–1
10–20
Cefaclor
PO
Renal
0.6–0.9
2–3
Cefotetan
IM, IV
Renal
3–4.5
13–35
Cefoxitin
IM, IV
Renal
0.7–1
13–22
Cefprozil
PO
Renal
1.3
5–6
Cefuroxime
PO, IM, IV
Renal
1–1.9
15–22
Cefdinir
PO
Renal
1.7
16
Cefditoren
PO
Renal
1.6
—
Cefixime
PO
Renal
3–4
11.5
Cefotaxime
IM, IV
Renal
0.9–1.4
3–11
Cefpodoxime PO
Renal
2–3
9.8
Ceftazidime
IM, IV
Renal
1.9–2
—
Ceftibuten
PO
Renal
2
Increased
Ceftizoxime
IM, IV
Renal
1.1–2.3
30
Ceftriaxone
IM, IV
Hepatic
5.8–8.7
15.7
Cefepime
IM, IV
Renal
2
Increased
Second Generation
Third Generation
Fourth Generation 85.1.6.2
Major Route of Elimination
Normal Renal Function
Severe Renal Impairment
Routes of Administration
997 998
Bleeding. One cephalosporin—cefotetan—causes bleeding tendencies. The mechanism is reduction of prothrombin levels through interference with vitamin K metabolism.
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Pharmacology for Nursing Care, 7th prothrombin levels through interference withEdition vitamin K metabolism. Several measures can reduce the risk of hemorrhage. During prolonged treatment, patients should be monitored for prothrombin time, bleeding time, or both. Parenteral vitamin K can correct an abnormal prothrombin time. Patients should be observed for signs of bleeding, and, if bleeding develops, the cephalosporin should be withdrawn. Caution should be exercised during concurrent use of anticoagulants or thrombolytic agents. Because of their antiplatelet effects, aspirin and other nonsteroidal anti-inflammatory drugs should be used with care. Caution is needed in patients with a history of bleeding disorders. 85.1.6.3
Thrombophlebitis. Thrombophlebitis may develop during IV infusion. This reaction can be minimized by rotating the infusion site and by administering cephalosporins slowly and in dilute solution. Patients should be observed for phlebitis. If it develops, the infusion site should be changed.
85.1.6.4
Other Adverse Effects. Cephalosporins may cause pain at sites of IM injection; patients should be forewarned. Rarely, cephalosporins may be the cause of antibiotic-associated pseudomembranous colitis due to overgrowth with Clostridium difficile. If this suprainfection develops, the cephalosporin should be discontinued and, if necessary, oral vancomycin or metronidazole should be given. With one cephalosporin—cefditoren—there are two unique concerns. First, the drug contains a milk protein (sodium caseinate), and hence should be avoided by patients with milk-protein hypersensitivity (as opposed to lactose intolerance). Second, cefditoren is excreted in combination with carnitine, and hence can cause carnitine loss. Accordingly, the drug is contraindicated for patients with existing carnitine deficiency or conditions that predispose to carnitine deficiency.
85.1.7
Drug Interactions
85.1.7.1
Probenecid. Probenecid delays renal excretion of some cephalosporins and can thereby prolong their effects. This is the same interaction that occurs between probenecid and the penicillins.
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Pharmacology for Care, Edition effects. This is theNursing same interaction that7th occurs between probenecid and the penicillins. 85.1.7.2
Alcohol. One cephalosporin—cefotetan—can induce a state of alcohol intolerance. If a patient taking this drug were to ingest alcohol, a disulfiram-like reaction could occur. (As discussed in Chapter 38, the disulfiram effect is brought on by accumulation of acetaldehyde and can be extremely dangerous.) Accordingly, patients using cefotetan must not consume alcohol in any form.
85.1.7.3
Drugs That Promote Bleeding. As noted, cefotetan promotes bleeding. Caution is needed if this drug is combined with other agents that promote bleeding (anticoagulants, thrombolytics, nonsteroidal anti-inflammatory drugs and other antiplatelet agents).
85.1.7.4
Calcium and Ceftriaxone. Combining calcium with ceftriaxone can form potentially fatal precipitates. In neonates, the combination of IV calcium and IV ceftriaxone has caused death from depositing precipitates in the lungs and kidneys. Serious reactions in older patients have not been reported. Nonetheless, for all patients, the following rules apply: • Don't reconstitute powdered ceftriaxone with calcium-containing diluents (eg, Ringer's solution). • Don't mix reconstituted ceftriaxone with calcium-containing solutions. • Don't give IV ceftriaxone and IV calcium by the same route or different routes within 48 hours of each other. • If the patient must receive ceftriaxone and calcium, use oral calcium or IM ceftriaxone.
85.1.8
Therapeutic Uses The therapeutic role of the cephalosporins is continually evolving as new agents are introduced and more experience is gained with older ones. Only general recommendations are considered here.
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Pharmacology for Nursing Care, 7th Edition here. The cephalosporins are broad-spectrum, bactericidal drugs with a high therapeutic index. They have been employed widely and successfully against a variety of infections. Cephalosporins can be useful alternatives for patients with mild penicillin allergy. The four generations of cephalosporins differ significantly in their applications. With one important exception—the use of first-generation agents for infections caused by sensitive staphylococci—the first- and second-generation cephalosporins are rarely drugs of choice for active infections. In most cases, equally effective and less expensive alternatives are available. In contrast, the third-generation agents have qualities that make them the preferred therapy for several infections. The role of fourth-generation agents is yet to be established. 85.1.8.1
First-Generation Cephalosporins. When a cephalosporin is indicated for a gram-positive infection, a first-generation drug should be used; these agents are the most active of the cephalosporins against gram-positive organisms and are less expensive than other cephalosporins. First-generation agents are frequently employed as alternatives to penicillins to treat infections caused by staphylococci or streptococci (except enterococci) in patients with penicillin allergy. However, it is important to note that cephalosporins should be given only to patients with a history of mild penicillin allergy—not those who have experienced a severe, immediate hypersensitivity reaction. The first-generation agents have been employed widely for prophylaxis against infection in surgical patients. First-generation agents are preferred to second- or third-generation cephalosporins for surgical prophylaxis. Why? Because they are as effective as the newer drugs, are less expensive, and have a more narrow antimicrobial spectrum.
85.1.8.2
Second-Generation Cephalosporins. Specific indications for second-generation cephalosporins are limited. Cefuroxime, a prototype for the group, has been used with success against pneumonia caused by Haemophilus influenzae, Klebsiella, pneumococci, and staphylococci. Oral cefuroxime is useful for otitis, sinusitis, and respiratory tract infections. Cefoxitin is useful for abdominal and pelvic infections.
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Pharmacology infections. for Nursing Care, 7th Edition 85.1.8.3
Third-Generation Cephalosporins. Because they are highly active against gram-negative organisms, and because they penetrate to the CSF, third-generation cephalosporins are drugs of choice for meningitis caused by enteric, gram-negative bacilli. Ceftazidime is of special utility for treating meningitis caused by P. aeruginosa. Nosocomial infections caused by gram-negative bacilli, which are often resistant to first- and second-generation cephalosporins (and most other commonly used antibiotics), are appropriate indications for the third-generation drugs. Two third-generation agents— ceftriaxone and cefotaxime—are drugs of choice for infections caused by Neisseria gonorrhoeae (gonorrhea), H. influenzae, Proteus, Salmonella, Klebsiella, and Serratia; these drugs are also effective against meningitis caused by Streptococcus pneumoniae, a grampositive bacterium. The third-generation cephalosporins should not be used routinely. Rather, they should be given only when conditions demand, so as to delay emergence of resistance.
85.1.9
Drug Selection Eighteen cephalosporins are currently employed in the United States, and selection among them can be a challenge. Within each generation, the similarities among cephalosporins are more pronounced than the differences. Hence, aside from cost, there is frequently no rational basis for choosing one drug over another. However, there are some differences between cephalosporins, and these differences may render one agent preferable to another for treating a specific infection in a specific host. The differences that do exist can be grouped into three main categories: (1) antimicrobial spectrum, (2) adverse effects, and (3) pharmacokinetics (eg, route of administration, penetration to the CSF, time course, mode of elimination). Drug selection based on these differences is discussed below.
85.1.9.1
998 999
Antimicrobial Spectrum. A prime rule of antimicrobial therapy is to match the drug with the bug: The drug should be active against known or suspected pathogens, but its spectrum should be no broader than required. When a cephalosporin is appropriate, we should select from among those drugs known to have good activity against the causative pathogen. The third- and fourth-generation agents, with their very broad antimicrobial spectra, should be avoided in situations where a
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Pharmacology for Nursing Care,the7th Edition known to have good activity against causative pathogen. The third- and fourth-generation agents, with their very broad antimicrobial spectra, should be avoided in situations where a narrower spectrum, first- or second-generation drug would suffice. For some infections, one cephalosporin may be decidedly more effective than all others, and should be selected on this basis. For example, ceftazidime (a third-generation drug) is the most effective of all cephalosporins against P. aeruginosa and is clearly the preferred cephalosporin for treating infections caused by this microbe. 85.1.9.2
Adverse Effects. Although most cephalosporins produce the same spectrum of adverse effects, a few can cause unique reactions. In particular, cefotetan can cause bleeding tendencies and intolerance to alcohol. When an equally effective alternative is available, it would be prudent to avoid these drugs.
85.1.9.3
Pharmacokinetics. Four pharmacokinetic properties are of interest: (1) route of administration, (2) duration of action, (3) distribution to CSF, and (4) route of elimination. The relationship of these properties to drug selection is discussed below.
85.1.9.3.1
Route of Administration. Ten cephalosporins can be administered orally. These drugs may be preferred for mild to moderate infections in patients who can't tolerate parenteral agents.
85.1.9.3.2
Duration of Action. In patients with normal renal function, the half-lives of the cephalosporins range from about 30 minutes to 9 hours (see Table 84-2). Because they require fewer doses per day, drugs with a long half-life are frequently preferred. Cephalosporins with the longest half-lives in each generation are as follows: first generation, cefazolin (1.5 to 2 hours); second generation, cefotetan (3 to 4.5 hours); and third generation, ceftriaxone (6 to 9 hours).
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Pharmacology Nursing Care, 7th Edition cefotetan (3for to 4.5 hours); and third generation, ceftriaxone (6 to 9 hours). 85.1.9.3.3
Distribution to CSF. Only the third- and fourth-generation agents achieve CSF concentrations sufficient for bactericidal effects. Hence, for meningitis caused by susceptible organisms, these drugs are preferred over first- and second-generation agents.
85.1.9.3.4
Route of Elimination. Most cephalosporins are eliminated by the kidneys and, if dosage is not carefully adjusted, may accumulate to toxic levels in patients with renal impairment. Only one agent— ceftriaxone—is eliminated primarily by nonrenal routes, and hence can be used with relative safety in patients with bad kidneys.
85.1.10
Dosage and Administration
85.1.10.1
Routes. Many cephalosporins cannot be absorbed from the GI tract and must therefore be administered parenterally (IM or IV). As shown in Table 84-2, only 10 cephalosporins can be given orally. One drug—cefuroxime—can be administered both orally and by injection.
85.1.10.2
Dosage. Dosages are summarized in Table 84-3. For most cephalosporins (ceftriaxone excepted), dosage should be reduced in patients with significant renal impairment.
85.1.10.3
Administration. Oral. If oral cephalosporins produce nausea, administration with food can reduce the response. Oral suspensions should be stored cold.
85.1.10.3.1
Intramuscular. Intramuscular injections should be made deep into a large muscle. Intramuscular injection of cephalosporins is frequently painful; the patient should be forewarned. The injection site should be checked for induration, tenderness, and redness, and the prescriber informed if these occur.
CHAPTER 84 Drugs That Weaken the Bacterial Cell Wall II: Cephalosporins, Carbapenems, Vancomycin, Aztreonam, Teicoplanin, and Fosfomycin
999 1000
Page 13 of 32
Pharmacology these occur.for Nursing Care, 7th Edition TABLE 84-3 Cephalosporin Dosages Total Daily Dosage*
Trade Name
Route
Dosing Interval (hr)
Adults (gm)
Children (mg/ kg)
Cefadroxil
Duricef
PO
12, 24
1–2
30
Cefazolin
generic only
IM, IV
6, 8
2–12
80–160
Cephalexin
Keflex
PO
6
1–4
25–50
Cefaclor
Ceclor, Raniclor
PO
8
0.75–1.5
20–40
Cefotetan
Cefotan
IM, IV
12
2–6
—
Cefoxitin
Mefoxin
IM, IV
4, 8
3–12
80–160
Cefprozil
Cefzil
PO
12, 24
0.5–1
30
Cefuroxime
Ceftin
PO
12
0.5–1
250–500
Zinacef
IM, IV
8
2.25–9
50–100
Cefdinir
Omnicef
PO
12, 24
0.6
14
Cefditoren
Spectracef
PO
12
0.4–0.8
—
Cefixime
Suprax
PO
24
0.4
8
Cefotaxime
Claforan
IM, IV
4, 8
2–12
100–200
Cefpodoxime
Vantin
PO
12
0.2–0.4
10
Ceftazidime
Ceptaz, Fortaz, IM, IV Tazicef, Tazidime
8, 12
0.5–6
90–150
Ceftibuten
Cedax
PO
24
0.4
9
Ceftizoxime
Cefizox
IM, IV
6, 12
2–12
150–200
Ceftriaxone
Rocephin
IM, IV
12, 24
1–4
50–100
Drug First Generation
Second Generation
Third Generation
CHAPTER 84 Drugs That Weaken the Bacterial Cell Wall II: Cephalosporins, Carbapenems, Vancomycin, Aztreonam, Teicoplanin, and Fosfomycin
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Pharmacology for Nursing Care, Ceftizoxime Cefizox IM, IV7th Edition 6, 12 Ceftriaxone
2–12
150–200
Rocephin
IM, IV
12, 24
1–4
50–100
Maxipime
IM, IV
12
1–2
100
Fourth Generation Cefepime
* 85.1.10.3.2
With the exception of ceftriaxone, cephalosporins require a reduction of dosage for patients with severe renal impairment.
Intravenous. For IV therapy, cephalosporins may be administered by three techniques: (1) bolus injection, (2) slow injection (over 3 to 5 minutes), and (3) continuous infusion. The prescriber's order should state which method to use. If there is uncertainty as to method, clarification should be requested. Solutions for parenteral administration should be prepared according to the manufacturer's recommendations.
85.2
CARBAPENEMS Carbapenems are beta-lactam antibiotics that have very broad antimicrobial spectra—although none is active against methicillin-resistant Staphylococcus aureus. Four carbapenems are available: imipenem, meropenem, ertapenem, and doripenem. With all four, administration is parenteral. To delay emergence of resistance, these drugs should be reserved for patients who cannot be treated with more narrow-spectrum drugs.
85.2.1
Imipenem Imipenem [Primaxin], a beta-lactam antibiotic (Fig. 84-2), has an extremely broad antimicrobial spectrum—broader, in fact, than nearly all other antimicrobial drugs. As a result, imipenem may be of special use for treating mixed infections in which anaerobes, Staph. aureus, and gramnegative bacilli may all be involved. Imipenem is supplied in fixed-dose combinations with cilastatin, a compound that inhibits destruction of imipenem by renal enzymes.
85.2.1.1
Mechanism of Action. Imipenem binds to two PBPs (PBP1 and PBP2), causing weakening of the bacterial cell wall with subsequent lysis and death. Antimicrobial effects are enhanced by the drug's resistance to practically all beta-lactamases, and by its ability to penetrate the gram-negative cell envelope.
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Pharmacology Nursing Care, 7th Edition practically allfor beta-lactamases, and by its ability to penetrate the gram-negative cell envelope. 85.2.1.2
Antimicrobial Spectrum. Imipenem is active against most bacterial pathogens, including organisms resistant to other antibiotics. The drug is highly active against grampositive cocci and most gram-negative cocci and bacilli. In addition, imipenem is the most effective beta-lactam antibiotic for use against anaerobic bacteria.
85.2.1.3
Pharmacokinetics. Imipenem is not absorbed from the GI tract and hence must be given parenterally (IV or IM). The drug is well distributed to body fluids and tissues. Imipenem penetrates the meninges to produce therapeutic concentrations in CSF. Elimination is primarily renal. When employed alone, imipenem is inactivated by dipeptidase, an enzyme present in the kidney. As a result, drug levels in urine are low. To increase urinary concentrations, imipenem is administered in combination with cilastatin, a dipeptidase inhibitor. When the combination is used, about 70% of imipenem is excreted unchanged in the urine. The elimination half-life is about 1 hour.
85.2.1.4
Adverse Effects. Imipenem is generally well tolerated. Gastrointestinal effects (nausea, vomiting, diarrhea) are most common. Hypersensitivity reactions (rashes, pruritus, drug fever) have occurred, and patients allergic to other beta-lactam antibiotics may be cross-allergic with imipenem. Suprainfections with bacteria or fungi develop in about 4% of patients. Rarely, seizures have occurred.
85.2.1.5
Therapeutic Use. Because of its broad spectrum and low toxicity, imipenem is used widely. The drug has proved
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Pharmacology Nursing Edition Because of itsfor broad spectrum Care, and low 7th toxicity, imipenem is used widely. The drug has proved Figure 84-2 Miscellaneous beta-lactam antibiotics.
effective for serious infections caused by gram-positive cocci, gram-negative cocci, gramCHAPTER 84 Drugs That Weaken the Bacterial Cell Page 17 of 32 Wall II: Cephalosporins, Carbapenems, Vancomycin, Aztreonam, Teicoplanin, and Fosfomycin
Pharmacology for Nursing Care, 7th Edition effective for serious infections caused by gram-positive cocci, gram-negative cocci, gramnegative bacilli, and anaerobic bacteria. This broad antimicrobial spectrum gives imipenem special utility for chemotherapy of mixed infections (eg, simultaneous infection with aerobic and anaerobic bacteria). When imipenem has been given alone to treat infection with P. aeruginosa, resistant organisms have emerged. Consequently, imipenem should be combined with another anti–pseudomonal drug for use against this microbe. 85.2.1.6
Preparations, Dosage, and Administration. Imipenem is formulated in 1:1 fixed-dose combinations with cilastatin. The combination products are marketed under the trade name Primaxin. Two formulations are available: Primaxin I.V. and Primaxin I.M., for intravenous and intramuscular use, respectively. These products are supplied in powdered form and must be reconstituted in accord with the manufacturer's instructions. The usual adult dosage (based on imipenem content) is 250 to 500 mg every 6 hours. Dosage should be reduced in patients with renal impairment.
85.2.2
Other Carbapenems
85.2.2.1 85.2.2.1.1
Meropenem Actions and Uses. Meropenem [Merrem IV] is a beta-lactam antibiotic similar in structure and actions to imipenem. Meropenem is active against most clinically important gram-positive and gramnegative aerobes and anaerobes. Approved indications are (1) bacterial meningitis in children age 3 months or older, (2) complicated intra-abdominal infections in children and adults, and (3) skin and skin structure infections in children and adults. Meropenem may prove especially useful for nosocomial infections caused by organisms resistant to other antibiotics.
85.2.2.1.2
Pharmacokinetics. Meropenem is administered IV and distributes to all body fluids and tissues. The drug has a plasma half-life of 1 hour and is eliminated primarily unchanged in the urine. In contrast to imipenem, mer–openem is not degraded by renal dipeptidases, and hence is not combined with cilastatin.
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Pharmacology for Nursing Care, 7th Edition with cilastatin. 85.2.2.1.3
Adverse Effects. Like other beta-lactam antibiotics, meropenem is generally well tolerated. Principal adverse effects are rashes, diarrhea, nausea, and vomiting. As with imipenem, seizures occur rarely. The risk of seizures is highest in patients with central nervous system (CNS) disorders (eg, brain lesions, history of seizures) and bacterial meningitis.
85.2.2.1.4
1000 1001
Preparations, Dosage, and Administration. Meropenem [Merrem IV] is supplied in powdered form to be reconstituted for IV administration. Depending on the volume employed, the drug may be (1) infused over 15 to 30 minutes or (2) injected as a bolus over 3 to 5 minutes. The dosage for adults is 1 gm every 8 hours. The dosage for pediatric patients is 20 mg/kg every 8 hours (for intra-abdominal infections) and 40 mg/kg every 8 hours (for bacterial meningitis). Adult and pediatric dosages must be reduced for patients with significant renal impairment (creatinine clearance less than 50 mL/min).
85.2.2.2 85.2.2.2.1
Ertapenem Actions and Uses. Like other carbapenems, ertapenem [Invanz] weakens the bacterial cell wall, and thereby causes cell lysis and death. Also like other carbapenems, ertapenem is highly resistant to beta-lactamases, and hence has a very broad antimicrobial spectrum—but less broad than that of imipenem or meropenem. Ertapenem is active against most gram-positive bacteria and most anaerobes. However, in contrast to imipenem and meropenem, the drug has little or no activity against P. aeruginosa or Acinetobacter species. In addition, ertapenem has minimal activity against pneumococci that are highly resistant to penicillin, and has no activity against methicillin-resistant staphylococci, Enterococcus faecium, Enterococcus faecalis, or atypical respiratory tract pathogens, including Chlamydia species, Legionella species, and Mycoplasma pneumoniae. Ertapenem is indicated for parenteral therapy of acute pelvic infections, community-acquired pneumonia, prophylaxis following elective colorectal surgery, and complicated infections of the urinary tract, abdomen, and skin and skin structures.
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Pharmacology structures. for Nursing Care, 7th Edition 85.2.2.2.2
Pharmacokinetics. Ertapenem may be administered by IM injection or IV infusion. Absorption following IM injection is complete. In the blood, ertapenem is highly bound to plasma proteins. The drug undergoes some hydrolysis of the beta-lactam ring prior to excretion in the urine (80%) and feces (10%). Its half-life is approximately 4 hours (compared with only 1 hour for imipenem or meropenem).
85.2.2.2.3
Adverse Effects. Like other carbapenems, ertapenem is generally well tolerated. In clinical trials, the most common adverse effects were diarrhea (10.3%), nausea (8%), infused-vein complications (7.1%), headache (5.6%), vomiting (3.7%), and edema (3.4%). In addition, CNS effects (agitation, confusion, disorientation, decreased mental acuity, somnolence, stupor) were reported in 5.1% of patients. Like imipenem and meropenem, ertapenem can cause seizures, but the incidence is relatively low (0.5%).
85.2.2.2.4
Preparations, Dosage, and Administration. Ertapenem [Invanz] is available as a powder to be reconstituted for IM or IV administration. For IV therapy, the drug is infused over 30 minutes, and should not be mixed with other drugs or with diluents that contain dextrose. The dosage (IM or IV) for adults and children 13 years and older is 1 gm once daily (for patients with good kidney function) or 500 mg once daily (for patients with significant renal impairment). The dosage for children ages 3 months to 12 years is 15 mg/kg twice daily (for children with good renal function); dosages for children with impaired renal function have not been established. For adults and children, the duration of treatment is 3 to 14 days, depending on the infection being treated.
85.2.2.3 85.2.2.3.1
Doripenem Actions and Uses. Doripenem [Doribax], approved in 2007, is active against a broad spectrum of gram-positive, gram-negative, and anaerobic bacteria. Activity against P. aeruginosa is greater than with other carbapenems. Cell kill results from disrupting cell wall synthesis. Doripenem has two approved indications: complicated intra-abdominal infections and complicated urinary tract infections. To delay emergence of resistance, the drug should be reserved for seriously ill
CHAPTER 84 Drugs That Weaken the Bacterial Cell Wall II: Cephalosporins, Carbapenems, Vancomycin, Aztreonam, Teicoplanin, and Fosfomycin
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Pharmacology for Nursing Care,intra-abdominal 7th Editioninfections and complicated urinary tract approved indications: complicated infections. To delay emergence of resistance, the drug should be reserved for seriously ill patients with mixed infections or infection with multidrug-resistant, gram-negative bacteria or Pseudomonas. 85.2.2.3.2
Pharmacokinetics. Doripenem is administered by IV infusion. Binding to plasma proteins is low, and hepatic metabolism is minimal. Elimination is by renal excretion, primarily as unchanged drug. In patients with normal renal function, the half-life is about 1 hour. In patients with renal impairment, the half-life is longer, and hence these people require a reduced dosage to avoid accumulation of the drug to dangerous levels.
85.2.2.3.3
Adverse Effects and Interactions. Like other carbapenems, doripenem is generally well tolerated. The most common side effects are headache (4% to 16%), nausea (4% to 12%), diarrhea (6% to 11%), rash (up to 3%), and injection-site phlebitis (4% to 8%). In contrast to other carbapenems, doripenem does not cause seizures. However, like other carbapenems, doripenem can reduce levels of valproic acid, and may thereby cause loss of seizure control.
85.2.2.3.4
Preparations, Dosage, and Administration. Doripenem [Doribax] is supplied as a powder (500 mg) to be reconstituted in a total of 110 mL of normal saline or sterile water (to make 250 mg/55 mL). All doses are administered by IV infusion over a 1-hour span. Dosage depends on renal function as follows: normal renal function, 500 mg every 8 hours; creatinine clearance 30 to 50 mL/min, 250 mg every 8 hours; and creatinine clearance 11 to 29 mL/min, 250 mg every 12 hours.
85.3
OTHER INHIBITORS OF CELL WALL SYNTHESIS
85.3.1
Vancomycin Vancomycin [Vancocin, Vancoled] is a potentially toxic drug used only for serious infections. Principal indications are antibiotic-associated pseudomembranous colitis (caused by C. difficile), infection with MRSA and treatment of serious infections with susceptible organisms in patients allergic to penicillins. Unlike most other drugs discussed in this chapter, vancomycin does not contain a beta-lactam ring.
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Pharmacology for Nursing Care, 7th Edition contain a beta-lactam ring. 85.3.1.1
Mechanism of Action. Like the beta-lactam antibiotics, vancomycin inhibits cell wall synthesis and thereby promotes bacterial lysis and death. However, in contrast to the beta-lactams, vancomycin does not interact with PBPs. Instead, it disrupts the cell wall by binding to molecules that serve as precursors for cell wall biosynthesis.
85.3.1.2
Antimicrobial Spectrum. Vancomycin is active only against gram-positive bacteria. The drug is especially active against Staph. aureus and Staphylococcus epidermidis, including strains of both species that are methicillin resistant. Other susceptible organisms include streptococci, penicillin-resistant pneumococci, and C. difficile.
85.3.1.3
Pharmacokinetics. Absorption from the GI tract is poor. Hence, for most infections, vancomycin is given parenterally (by slow IV infusion). Oral administration is employed only for infections of the intestine. Vancomycin is well distributed to most body fluids and tissues. Although it enters the CSF, levels may be insufficient to treat meningitis. Hence, if meningeal infection fails to respond to IV therapy, concurrent intrathecal administration may be required. Vancomycin is eliminated unchanged by the kidneys. In patients with renal impairment, dosage must be reduced.
85.3.1.4
Therapeutic Use. Vancomycin should be reserved for serious infections. This agent is the drug of choice for infections caused by MRSA or Staph. epidermidis; most strains of these bacteria remain vancomycin sensitive. The drug is also employed as an alternative to penicillins and cephalosporins to treat severe infections (eg, staphylococcal and streptococcal endocarditis) in patients allergic to beta-lactam antibiotics. Until recently, oral vancomycin was considered the treatment of choice for antibioticassociated pseudomembranous colitis caused by suprainfection with C. difficile. However, to delay emergence of resistance to vancomycin, metronidazole is now tried first. Vancomycin is
CHAPTER 84 Drugs That Weaken the Bacterial Cell Wall II: Cephalosporins, Carbapenems, Vancomycin, Aztreonam, Teicoplanin, and Fosfomycin
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Pharmacology for Nursing Care, 7th Edition associated pseudomembranous colitis caused by suprainfection with C. difficile. However, to delay emergence of resistance to vancomycin, metronidazole is now tried first. Vancomycin is used only in severely ill patients who have not responded to metronidazole. 85.3.1.5
Adverse Effects. The most serious adverse effect is ototoxicity. Although hearing impairment is often reversible, permanent impairment can occur. Ototoxicity is most likely when plasma levels of vancomycin exceed 30 mcg/mL. The risk of hearing loss is increased by high dosage, prolonged treatment, renal impairment, and concurrent use of other ototoxic drugs (eg, aminoglycosides, ethacrynic acid). Rapid infusion of vancomycin can cause a constellation of disturbing effects—flushing, rash, pruritus, urticaria, tachycardia, and hypotension—known collectively as red man syndrome, red person syndrome, or simply red neck. These effects, which may result from release of histamine, can usually be avoided by infusing vancomycin slowly (over 60 minutes or more). Thrombophlebitis is common. The reaction can be minimized by administering vancomycin in dilute solution and by changing the infusion site frequently. Rarely, vancomycin causes immune-mediated thrombocytopenia, a condition in which platelets are lost and spontaneous bleeding results. The underlying mechanism is development of unusual antibodies that bind to platelets—but only if the platelets first bind with vancomycin (forming a vancomycin-platelet complex). The resulting antibody-vancomycin-platelet complexes are then removed from the circulation by macrophages. Patients allergic to penicillins do not show cross-reactivity with vancomycin. Accordingly, vancomycin is an alternative to penicillins in patients allergic to them.
85.3.1.6
Preparations, Dosage, and Administration. For systemic infection, vancomycin is administered by intermittent infusion over 60 minutes or more. The usual adult dosage is 2 gm/day administered in divided doses at 12- or 24-hour intervals. The dosage for children is 44 mg/kg/day administered in divided doses at 6- or 12hour intervals. In patients with renal impairment, dosages must be reduced. Serum drug levels should be monitored to ensure that dosage is appropriate. Blood for measuring peak drug levels should be drawn 1.5 to 2.5 hours after completing the IV infusion. Peak levels of 30 to 40 mcg/ mL are generally acceptable.
CHAPTER 84 Drugs That Weaken the Bacterial Cell Wall II: Cephalosporins, Carbapenems, Vancomycin, Aztreonam, Teicoplanin, and Fosfomycin
1001 1002
Page 23 of 32
Pharmacology for acceptable. Nursing Care, 7th Edition mL are generally For antibiotic-associated pseudomembranous colitis, vancomycin is given orally. The adult dosage is 125 to 500 mg every 6 hours. The dosage for children is 11 mg/kg every 6 hours. Because vancomycin is not absorbed from the GI tract, there is no need to decrease oral doses in patients with renal impairment. 85.3.2
Aztreonam
85.3.2.1
Chemistry. Aztreonam [Azactam] belongs to a relatively new class of beta-lactam antibiotics known as monobactams. These agents contain a beta-lactam ring, but the ring is not fused with a second ring. The structure of aztreonam is shown in Figure 84-2.
85.3.2.2
Mechanism of Action. Aztreonam binds to PBP3. Hence, like most beta-lactam antibiotics, the drug inhibits bacterial cell wall synthesis, and thereby promotes cell lysis and death. The drug does not bind to PBPs produced by anaerobes or gram-positive bacteria.
85.3.2.3
Antimicrobial Spectrum and Therapeutic Use. Aztreonam has a narrow antimicrobial spectrum, being active only against gram-negative aerobic bacteria. Susceptible organisms include Neisseria species, H. influenzae, P. aeruginosa, and Enterobacteriaceae (eg, Escherichia coli, Klebsiella, Proteus, Serratia, Salmonella, Shigella). Aztreonam is highly resistant to beta-lactamases, and therefore is active against many gram-negative aerobes that produce them. The drug is not active against grampositive bacteria and anaerobes.
85.3.2.4
Pharmacokinetics. Aztreonam is not absorbed from the GI tract and hence must be administered parenterally (IM or IV). Once in the blood, the drug distributes widely to most body fluids and tissues. Therapeutic concentrations can be achieved in the CSF. Aztreonam is eliminated by the kidneys, primarily unchanged.
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Pharmacology for Nursing kidneys, primarily unchanged. Care, 7th Edition 85.3.2.5
Adverse Effects. Aztreonam is generally well tolerated. Adverse effects are like those of other beta-lactam antibiotics. The most common effects are pain and thrombophlebitis at the site of injection. Because aztreonam differs greatly in structure from penicillins and cephalosporins, there is little cross-allergenicity with them. Hence, it appears that aztreonam is safe for patients with allergies to other beta-lactam antibiotics.
85.3.2.6
Preparations, Dosage, and Administration. Aztreonam [Azactam] is supplied in powdered form to be reconstituted for IM or IV administration. The usual adult dosage is 1 to 2 gm every 8 to 12 hours. Dosage should be reduced in patients with renal impairment.
85.3.3
Teicoplanin
85.3.3.1
Chemistry and Actions. Teicoplanin [Targocid] is similar in structure and actions to vancomycin. Both drugs disrupt cell wall synthesis to cause lysis and death, and both are active only against gram-positive bacteria. Sensitive organisms include MRSA, enterococci, and C. difficile. Like vancomycin— and unlike most other drugs discussed in the chapter—teicoplanin does not have a beta-lactam ring.
85.3.3.2
Pharmacokinetics. The kinetics of teicoplanin are much like those of vancomycin—except that teicoplanin can be administered IM as well as IV. Neither drug is absorbed from the GI tract, so oral administration is reserved for infection of the intestine. Following parenteral administration, teicoplanin is well distributed to tissues and most body fluids, but not to the CSF. Teicoplanin has a long half-life (up to 100 hours) and is eliminated intact by the kidneys.
85.3.3.3
Therapeutic Use. Teicoplanin is not approved in the United States, although it is approved in Japan and Europe. The drug has been used with success against an array of infections. Potential applications include osteomyelitis and endocarditis caused by methicillin-resistant staphylococci,
CHAPTER 84 Drugs That Weaken the Bacterial Cell Wall II: Cephalosporins, Carbapenems, Vancomycin, Aztreonam, Teicoplanin, and Fosfomycin
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Pharmacology Care,against 7th Edition The drug has for beenNursing used with success an array of infections. Potential applications include osteomyelitis and endocarditis caused by methicillin-resistant staphylococci, streptococci, and enterococci. Combining the drug with gentamicin can increase bactericidal effects. Teicoplanin represents a safe and effective alternative to vancomycin, and offers several advantages, namely (1) the option of IM administration, (2) shorter infusion time with IV administration (30 vs. 60 minutes), (3) once-a-day dosing, and (4) the absence of serious adverse effects, including infusion-related reactions. 85.3.3.4
Adverse Effects. Teicoplanin is largely devoid of adverse effects. In contrast to vancomycin, teicoplanin does not promote histamine release, and hence does not cause infusion-related reactions (eg, flushing, tachycardia, hypotension). Ototoxicity may occur but is rare. Not surprisingly, patients allergic to beta-lactam antibiotics are not cross-allergic to teicoplanin.
85.3.3.5
Dosage and Administration. Teicoplanin may be given parenterally or orally. Parenteral administration is done by IM injection, IV injection, or 30-minute IV infusion. For parenteral therapy, the usual adult dosage is 6 mg/kg initially followed by 3 mg/kg every 24 hours. Dosage should be reduced in patients with renal impairment. As noted, oral therapy is used only for intestinal infections.
85.3.4
Fosfomycin Fosfomycin [Monurol] is a unique antibiotic approved for single-dose therapy of women who have uncomplicated urinary tract infections (ie, acute cystitis) caused by E. coli or Enterococcus faecalis. The drug kills bacteria by disrupting synthesis of the peptidoglycan polymer strands that compose the cell wall. (As discussed in Chapter 83, penicillins kill bacteria in part by preventing cross-linking of peptidoglycan strands.) The most common adverse effects are diarrhea (10.4%), headache (10.3%), vaginitis (7.6%), and nausea (5.2%). Fosfomycin may also cause abdominal pain, rhinitis, drowsiness, dizziness, and rash.
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Pharmacology for Nursing Care, 7th Edition rash. Fosfomycin is supplied as a water-soluble powder in single-dose, 3-gm packets. Dosing may be done with or without food. Symptoms of cystitis should improve in 2 to 3 days. If symptoms fail to improve, additional doses will not help—but will increase the risk of side effects. 85.3.4.1
KEY POINTS ▪ Cephalosporins are beta-lactam antibiotics that weaken the bacterial cell wall, causing lysis and death. ▪ The major cause of cephalosporin resistance is production of beta-lactamases. ▪ Cephalosporins can be grouped into four “generations.” As we progress from first- to fourth-generation drugs, there is (1) increasing activity against gram-negative bacteria, (2) increasing resistance to destruction by betalactamases, and (3) increasing ability to reach the CSF. ▪ Except for ceftriaxone, all cephalosporins are eliminated by the kidneys, and therefore must be given in reduced dosage to patients with renal impairment. ▪ The most common adverse effects of cephalosporins are allergic reactions. Patients allergic to penicillins have about a 1% risk of cross-reactivity with cephalosporins. ▪ One cephalosporins—cefotetan—can cause bleeding tendencies and disulfiram-like reactions. ▪ Imipenem, a beta-lactam antibiotic, has an antimicrobial spectrum that is broader than that of practically all other antimicrobial drugs. ▪ Vancomycin is an important but potentially toxic drug generally reserved for (1) antibiotic-associated pseudomembranous colitis (caused by C. difficile), (2) infections with MRSA, and (3) serious infections by susceptible organisms in patients allergic to penicillins.
CHAPTER 84 Drugs That Weaken the Bacterial Cell Wall II: Cephalosporins, Carbapenems, Vancomycin, Aztreonam, Teicoplanin, and Fosfomycin
1002
Page 27 of 32
Pharmacology for Nursing Care, 7th Edition 85.3.4.2 85.3.4.2.1
Summary of Major Nursing
1002 1003
Implications*
CEPHALOSPORINS Cefaclor
Cefoxitin
Cefadroxil
Cefpodoxime
Cefazolin
Cefprozil
Cefdinir
Ceftazidime
Cefditoren
Ceftibuten
Cefepime
Ceftizoxime
Cefixime
Ceftriaxone
Cefotaxime Cefuroxime Cefotetan
Cephalexin
Except where indicated, the implications summarized below apply to all members of the cephalosporin family. 85.3.4.2... 85.3.4.2...
Preadministration Assessment Therapeutic Goal Treatment of infections caused by susceptible organisms.
85.3.4.2...
Baseline Data The prescriber may order tests to determine the identity and drug sensitivity of the infecting organism. Take samples for culture prior to initiating treatment.
85.3.4.2...
Identifying High-Risk Patients Cephalosporins are contraindicated for patients with a history of allergic reactions to cephalosporins or of severe allergic reactions to penicillins.
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Pharmacology for Nursing Care, 7threactions Edition cephalosporins or of severe allergic to penicillins. 85.3.4.2... 85.3.4.2...
Implementation: Administration Routes Ten cephalosporins are given parenterally (IM or IV), 10 are given orally, and 1— cefuroxime—is given orally and parenterally (see Table 84-3).
85.3.4.2...
Dosage Dosages are summarized in Table 84-3. Dosages for all cephalosporins—except ceftriaxone—should be reduced in patients with significant renal impairment.
85.3.4.2... 85.3.4.2...
Administration Oral. Advise patients to take oral cephalosporins with food if gastric upset occurs. Instruct patients to refrigerate oral suspensions. Instruct patients to complete the prescribed course of therapy even though symptoms may abate before the full course is over.
85.3.4.2...
Intramuscular. Make IM injections deep into a large muscle. Intramuscular injections are frequently painful; forewarn the patient. Check the injection site for induration, tenderness, and redness—and notify the prescriber if these occur.
85.3.4.2...
Intravenous. Techniques for IV administration are bolus injection, slow injection (over 3 to 5 minutes), and continuous infusion. The prescriber's order should specify which method to use; request clarification if the order is unclear.
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Pharmacology fortoNursing Care, 7th Edition method use; request clarification if the order is unclear. 85.3.4.2... 85.3.4.2...
Ongoing Evaluation and Interventions Evaluating Therapeutic Effects Monitor for indications of antimicrobial effects (eg, reduction in fever, pain, or inflammation; improved appetite or sense of well-being).
85.3.4.2... 85.3.4.2...
Minimizing Adverse Effects Allergic Reactions. Hypersensitivity reactions are relatively common. Rarely, life-threatening anaphylaxis occurs. Avoid cephalosporins in patients with a history of cephalosporin allergy or severe penicillin allergy. If penicillin allergy is mild, cephalosporins can be used with relative safety. Instruct the patient to report any signs of allergy (eg, skin rash, itching, hives). If anaphylaxis occurs, administer parenteral epinephrine and provide respiratory support.
85.3.4.2...
Bleeding. Cefotetan can promote bleeding. Monitor prothrombin time, bleeding time, or both. Parenteral vitamin K can correct abnormal prothrombin time. Observe patients for signs of bleeding and, if bleeding develops, discontinue the drug. Exercise caution in patients with a history of bleeding disorders and in patients receiving drugs that can interfere with hemostasis (anticoagulants; thrombolytics; antiplatelet drugs, including aspirin and other nonsteroidal anti-inflammatory drugs).
85.3.4.2...
Thrombophlebitis. Intravenous cephalosporins may cause thrombophlebitis. To minimize this reaction, rotate the injection site and inject cephalosporins slowly and in dilute solution. Observe the patient for phlebitis and change the infusion site if phlebitis develops.
85.3.4.2...
Antibiotic-Associated Pseudomembranous Colitis (AAPMC). AAPMC may develop, especially with use of broad-spectrum cephalosporins. Notify the prescriber if diarrhea occurs (a possible indication of colitis). If AAPMC is diagnosed, discontinue the cephalosporin. Oral vancomycin or metronidazole may
CHAPTER 84 Drugs That Weaken the Bacterial Cell Wall II: Cephalosporins, Carbapenems, Vancomycin, Aztreonam, Teicoplanin, and Fosfomycin
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Pharmacology for Nursing Care, 7th Edition the prescriber if diarrhea occurs (a possible indication of colitis). If AAPMC is diagnosed, discontinue the cephalosporin. Oral vancomycin or metronidazole may be needed. 85.3.4.2...
Milk-Protein Hypersensitivity. Cefditoren tablets contain sodium caseinate, a milk protein. Do not give cefditoren to patients with milk-protein allergy. (The drug is safe in patients with lactose intolerance.)
85.3.4.2...
Carnitine Deficiency. Cefditoren is excreted in combination with carnitine, and can thereby lower carnitine levels. Do not give cefditoren to patients with pre-existing carnitine deficiency or conditions that predispose to carnitine deficiency.
85.3.4.2...
Minimizing Adverse Interactions
85.3.4.2...
Alcohol. Cefotetan can cause alcohol intolerance. A serious disulfiram-like reaction may occur if alcohol is consumed. Inform patients about alcohol intolerance and warn them not to drink alcoholic beverages.
85.3.4.2...
Drugs That Promote Bleeding. Drugs that interfere with hemostasis—anticoagulants, thrombolytics, and antiplatelet drugs (including aspirin and other nonsteroidal anti-inflammatory drugs)—can intensify bleeding tendencies caused by cefotetan. Do not combine these drugs.
85.3.4.2...
1003 1004
Calcium and Ceftriaxone. Combining calcium with ceftriaxone can form potentially fatal precipitates. To avoid harm, don't reconstitute powdered ceftriaxone with calcium-containing diluents; don't mix reconstituted ceftriaxone with calcium-containing solutions; and don't give IV ceftriaxone and IV calcium by the same or different routes within 48 hours of each other. *
Patient education information is highlighted as blue text.
CHAPTER 84 Drugs That Weaken the Bacterial Cell Wall II: Cephalosporins, Carbapenems, Vancomycin, Aztreonam, Teicoplanin, and Fosfomycin
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Pharmacology Nursing Care, 7th Edition eachfor other. *
Patient education information is highlighted as blue text.
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Pharmacology for Nursing Care, 7th Edition 86
CHAPTER 85 Bacteriostatic Inhibitors of Protein Synthesis: Tetracyclines, Macrolides, and Others
1005
All of the drugs discussed in this chapter inhibit bacterial protein synthesis. Unlike the aminoglycosides, whose effects on protein synthesis produce microbial death, the drugs considered here are usually bacteriostatic. That is, they suppress bacterial growth and replication but do not produce outright kill. In general, the drugs presented here are second-line agents, used primarily for infections resistant to first-line agents. 86.1
TETRACYCLINES The tetracyclines are broad-spectrum antibiotics. Four members of the family are available for systemic therapy in the United States. All four—tetracycline, demeclocycline, doxycycline, and minocycline—are similar in structure, antimicrobial actions, and adverse effects. Principal differences among them are pharmacokinetic. Because the similarities among these drugs are more pronounced than their differences, we will discuss the tetracyclines as a group, rather than focusing on a prototype. Unique properties of individual tetracyclines are indicated as appropriate.
86.1.1
Mechanism of Action The tetracyclines suppress bacterial growth by inhibiting protein synthesis. These drugs bind to the 30S ribosomal subunit, and thereby inhibit binding of transfer RNA to the messenger RNA– ribosome complex.* As a result, addition of amino acids to the growing peptide chain is prevented. At the concentrations achieved clinically, the tetracyclines are bacteriostatic.
Selective toxicity of the tetracyclines results from their poor ability to cross mammalian cell membranes. In order to influence protein synthesis, tetracyclines must first gain access to the cell interior. These drugs enter bacteria by way of an energy-dependent transport system. Mammalian cells lack this transport system, and hence do not actively accumulate the drug. Consequently, although tetracyclines are inherently capable of inhibiting protein synthesis in mammalian cells, their levels within host cells remain too low to be harmful. * 86.1.2
Figure 86-2 in Chapter 86 depicts the role of the 30S ribosomal subunit in bacterial protein synthesis.
Microbial Resistance Bacterial resistance results from reduced drug accumulation, increased drug inactivation, and decreased access of drug to ribosomes (owing to the presence of ribosome protection proteins). Regarding reduced accumulation, two mechanisms are involved: (1) decreased uptake and (2)
CHAPTER 85 Bacteriostatic Inhibitors of Protein Synthesis: Tetracyclines, Macrolides, and Others
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Pharmacology for Nursing Care,(owing 7th to Edition decreased access of drug to ribosomes the presence of ribosome protection proteins). Regarding reduced accumulation, two mechanisms are involved: (1) decreased uptake and (2) increased ability to actively extrude tetracyclines. 86.1.3
Antimicrobial Spectrum The tetracyclines are broad-spectrum antibiotics, active against a wide variety of gram-positive and gram-negative bacteria. Sensitive organisms include Rickettsia, spirochetes, Brucella, Chlamydia, Mycoplasma, Helicobacter pylori, Borrelia burgdorferi, Bacillus anthracis, and Vibrio cholerae.
86.1.4
Therapeutic Uses
86.1.4.1
Treatment of Infectious Diseases. Extensive use of tetracyclines has resulted in increasing bacterial resistance. Because of resistance, and because antibiotics with greater selectivity and less toxicity are now available, use of tetracyclines has declined. Today, tetracyclines are rarely drugs of first choice. Disorders for which they are first-line drugs include (1) rickettsial diseases (eg, Rocky Mountain spotted fever, typhus fever, Q fever); (2) infections caused by Chlamydia trachomatis (trachoma, lymphogranuloma venereum, urethritis, cervicitis); (3) brucellosis; (4) cholera; (5) pneumonia caused by Mycoplasma pneumoniae; (6) Lyme disease; (7) anthrax; and (8) gastric infection with H. pylori.
86.1.4.2
Treatment of Acne. Tetracyclines are used topically and orally for severe acne vulgaris. Beneficial effects derive from suppressing the growth and metabolic activity of Propionibacterium acnes, an organism that secretes inflammatory chemicals. Oral doses for acne are relatively low. As a result, adverse effects are minimal. Treatment of acne is discussed further in Chapter 104 (Drugs for the Skin).
CHAPTER 85 Bacteriostatic Inhibitors of Protein Synthesis: Tetracyclines, Macrolides, and Others
1005
Page 2 of 43
Pharmacology the Skin). for Nursing Care, 7th Edition
1005 1006
TABLE 85-1 Pharmacokinetic Properties of the Tetracyclines Half-Life
Class
Drug
Percent of Effect of Lipid Oral Dose Food on Route of Normal Anuric Solubility Absorbed Absorption Elimination (hr) (hr)
Short Acting
Tetracycline
Low
60–80
Decrease
Renal
8
57–108*
Intermediate Demeclocycline Moderate 60–80 Acting
Decrease
Renal
12
40–60*
Long Acting
* 86.1.4.3
Doxycycline
High
90–100
No change
Hepatic
18
12–22
Minocycline
High
90–100
No change
Hepatic
16
11–23
Do not use in patients with renal impairment because the drug could accumulate to toxic levels.
Peptic Ulcer Disease. Helicobacter pylori, a bacterium that lives in the stomach, is a major contributing factor to peptic ulcer disease. Tetracyclines, in combination with metronidazole and bismuth subsalicylate, are a treatment of choice for eradicating this bug. The role of H. pylori in ulcer formation is discussed in Chapter 77 (Drugs for Peptic Ulcer Disease).
86.1.4.4
Periodontal Disease. Two tetracyclines—doxycycline and minocycline—are used for periodontal disease. Doxycycline is used orally and topically, whereas minocycline is only used topically.
86.1.4.4.1
Oral Therapy. Benefits of oral doxycycline [Periostat] result from inhibiting collagenase, an enzyme that destroys connective tissue in the gums. The small doses employed— 20 mg twice daily—are too low to harm bacteria.
86.1.4.4.2
Topical Therapy. Topical minocycline [Arestin] and doxy–cycline [Atridox] are employed as adjuncts to scaling and root planing. The objective is to reduce pocket depth and bleeding in adults with periodontitis. Benefits derive from suppressing bacterial growth. Both products are applied
CHAPTER 85 Bacteriostatic Inhibitors of Protein Synthesis: Tetracyclines, Macrolides, and Others
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Pharmacology 7th scaling andfor root Nursing planing. TheCare, objective is toEdition reduce pocket depth and bleeding in adults with periodontitis. Benefits derive from suppressing bacterial growth. Both products are applied directly to the site of periodontal disease. 86.1.4.5
Rheumatoid Arthritis Minocycline can reduce symptoms in patients with rheumatoid arthritis, suggesting a possible infectious component to the disease.
86.1.5
Pharmacokinetics Individual tetracyclines differ significantly in their pharmacokinetic properties. Of particular significance are differences in half-life and route of elimination. Also important is the degree to which food decreases absorption. The pharmacokinetic properties of individual tetracyclines are summarized in Table 85-1.
86.1.5.1
Duration of Action. The tetracyclines can be divided into three groups: short acting, intermediate acting, and long acting (see Table 85-1). These differences are related to differences in lipid solubility: The only short-acting tetracycline (tetracycline) has relatively low lipid solubility, whereas the longacting agents (doxycycline, minocycline) have relatively high lipid solubility.
86.1.5.2
Absorption. All of the tetracyclines are orally effective, although the extent of absorption differs among individual agents (see Table 85-1). Absorption of the short- and intermediate-acting tetracyclines is reduced by food; in contrast, absorption of the long-acting agents is not. The tetracyclines form insoluble chelates with calcium, iron, magnesium, aluminum, and zinc. The result is decreased absorption. Accordingly, tetracyclines should not be administered together with (1) calcium supplements, (2) milk products (because they contain calcium), (3) iron supplements, (4) magnesium-containing laxatives, and (5) most antacids (because they contain magnesium, aluminum, or both).
86.1.5.3
Distribution. Tetracyclines are widely distributed to most tissues and body fluids. However, penetration to the cerebrospinal fluid (CSF) is poor, and hence levels in the CSF are too low to treat meningeal infections. Tetracyclines readily cross the placenta and enter the fetal circulation.
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Pharmacology for Nursing Care, 7thcross Edition meningeal infections. Tetracyclines readily the placenta and enter the fetal circulation. 86.1.5.4
Elimination. Tetracyclines are eliminated by the kidneys and liver. All tetracyclines are excreted by the liver into the bile. After the bile enters the intestine, most tetracyclines are reabsorbed. Ultimate elimination of short- and intermediate-acting tetracyclines—tetracycline and demeclocycline—is in the urine, largely as the unchanged drug (see Table 85-1). Because these agents undergo renal excretion, they can accumulate to toxic levels if the kidneys fail. Consequently, tetracycline and demeclocycline should not be given to patients with renal failure. Long-acting tetracyclines are eliminated by the liver, primarily as metabolites. Because these agents are excreted by the liver, their half-lives are unaffected by kidney dysfunction. Accordingly, the long-acting agents (doxycycline and minocycline) are drugs of choice for tetracycline-responsive infections in patients with renal impairment.
86.1.6
Adverse Effects
86.1.6.1
Gastrointestinal Irritation. Tetracyclines irritate the GI tract. As a result, oral therapy is frequently associated with epigastric burning, cramps, nausea, vomiting, and diarrhea. These reactions can be reduced by giving tetracyclines with meals—although food may decrease absorption. Occasionally, tetracyclines cause esophageal ulceration. Risk can be minimized by avoiding dosing at bedtime. Because diarrhea may result from suprainfection of the bowel (in addition to nonspecific irritation), it is important that the cause of diarrhea be determined.
86.1.6.2
Effects on Bones and Teeth. Tetracyclines bind to calcium in developing teeth, resulting in yellow or brown discoloration; hypoplasia of the enamel may also occur. The intensity of tooth discoloration is related to the total cumulative dose: Staining is darker with prolonged and repeated treatment. When taken after the fourth month of gestation, tetracyclines can cause staining of deciduous teeth. However, use during pregnancy will not affect permanent teeth. Discoloration of permanent teeth occurs when tetracyclines are taken by patients ages 4 months to 8 years, the interval during which tooth enamel is being formed. Accordingly, these drugs should be avoided by children under 8 years old. The risk of tooth discoloration with doxycycline may be less than with other tetracyclines.
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Pharmacology for Nursing Care, 7th Edition with other tetracyclines. Tetracyclines can suppress long-bone growth in premature infants. This effect is reversible upon discontinuation of treatment. 86.1.6.3
Suprainfection. As discussed in Chapter 82, a suprainfection is an overgrowth with drug-resistant microbes, which occurs secondary to suppression of drug-sensitive organisms. Because the tetracyclines are broad-spectrum agents, and therefore can decrease viability of a wide variety of microbes, the risk of suprainfection is greater than with antibiotics that have a more narrow spectrum. Suprainfection of the bowel with staphylococci or with Clostridium difficile produces severe diarrhea and can be life threatening. The infection caused by C. difficile is known as antibioticassociated pseudomembranous colitis (AAPMC). Patients should notify the prescriber if significant diarrhea occurs, so that the possibility of bacterial suprainfection can be evaluated. If a diagnosis of suprainfection with staphylococci or C. difficile is made, tetracyclines should be discontinued immediately. Treatment consists of oral vancomycin or metronidazole plus vigorous fluid and electrolyte replacement. Overgrowth with fungi (commonly Candida albicans) may occur in the mouth, pharynx, vagina, and bowel. Symptoms include vaginal or anal itching; inflammatory lesions of the anogenital region; and a black, furry appearance of the tongue. Suprainfection with Candida can be managed by discontinuing tetracyclines. When this is not possible, antifungal therapy is indicated.
86.1.6.4
Hepatotoxicity. Tetracyclines can cause fatty infiltration of the liver. Hepatotoxicity manifests clinically as lethargy and jaundice. Rarely, the condition progresses to massive liver failure. Liver damage is most likely when tetracyclines are administered intravenously in high doses (greater than 2 gm/day). Pregnant and postpartum women with kidney disease are at especially high risk.
86.1.6.5
Renal Toxicity. Tetracyclines may exacerbate renal impairment in patients with pre-existing kidney disease. Because most tetracyclines are excreted by the kidneys, these agents should not be given to patients with renal impairment. Exceptions to this rule are doxycycline and perhaps minocycline, because both are eliminated primarily by the liver.
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Pharmacology Nursing 7th Edition minocycline, for because both are Care, eliminated primarily by the liver. 86.1.6.6
Photosensitivity. All tetracyclines can increase the sensitivity of the skin to ultraviolet light. The most common result is exaggerated sunburn. Advise patients to avoid prolonged exposure to sunlight, wear protective clothing, and apply a sunscreen to exposed skin.
86.1.6.7
Other Adverse Effects. Vestibular toxicity—manifesting as dizziness, lightheadedness, and unsteadiness—has occurred with minocycline. Rarely, tetracyclines have produced pseudotumor cerebri (a benign elevation in intracranial pressure). In a few patients, demeclocycline has produced nephrogenic diabetes insipidus, a syndrome characterized by thirst, increased frequency of urination, and unusual weakness or tiredness. Because of their irritant properties, tetracyclines can cause pain at sites of IM injection and thrombophlebitis when administered intravenously.
86.1.7
Drug and Food Interactions As noted, tetracyclines can form nonabsorbable chelates with certain metal ions (calcium, iron, magnesium, aluminum, zinc). Substances that contain these ions include milk products, calcium supplements, iron supplements, magnesium-containing laxatives, and most antacids. If a tetracycline is administered with these agents, its absorption will be decreased. To minimize interference with absorption, tetracyclines should be administered at least 2 hours before or 2 hours after ingestion of chelating agents.
86.1.8
Dosage and Administration
86.1.8.1
Administration. For systemic therapy, tetracyclines may be administered orally, intravenously, and by IM injection. Oral administration is preferred, and all tetracyclines are available in oral formulations. As a rule, oral tetracyclines should be taken on an empty stomach (1 hour before meals or 2 hours after) and with a full glass of water. An interval of at least 2 hours should separate tetracycline ingestion and ingestion of products that can chelate these drugs (eg, milk, calcium or iron supplements, antacids). Three tetracyclines can be given IV (Table 85-2), but this route should be employed only when oral therapy cannot be tolerated or has proved inadequate. Intramuscular injection is extremely painful and used rarely. In addition to their systemic use, two agents—doxycycline and minocycline—are available in formulations for topical therapy of periodontal disease (see above).
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Pharmacology Nursing Care, 7th Edition formulations for for topical therapy of periodontal disease (see above). 86.1.8.2
Dosage. Dosage is determined by the nature and intensity of the infection. Typical systemic doses for adults and children are summarized in Table 85-2.
86.1.9
Summary of Major Precautions Two tetracyclines—tetracycline and demeclocycline—are eliminated primarily in the urine, and hence will accumulate to toxic levels in patients with kidney disease. Accordingly, patients with kidney disease should not use these drugs. Tetracyclines can cause discoloration of deciduous and permanent teeth. Tooth discoloration can be avoided by withholding these drugs from pregnant women and from children under 8 years of age. Diarrhea may indicate a potentially life-threatening suprainfection of the bowel. Advise patients to notify the prescriber if diarrhea occurs. High-dose IV therapy has been associated with severe liver damage, particularly in pregnant and postpartum women with kidney disease. As a rule, these women should not receive tetracyclines.
86.1.10
Summary of Unique Properties of Individual Tetracyclines
86.1.10.1
Tetracycline. Tetracycline hydrochloride [Sumycin] is the least expensive and most widely used member of the family. When employed systemically, the drug has the indications, pharmacokinetics, adverse effects, and drug interactions described for the tetracyclines as a group. Like most tetracyclines, tetracycline hydrochloride should not be administered with food, and is contraindicated for patients with kidney dysfunction. This agent and all other tetracyclines should not be given to pregnant women or to children less than 8 years old.
86.1.10.2
Demeclocycline. Demeclocycline [Declomycin] shares the actions, indications, and adverse effects described above for the tetracyclines as a group. Because of its intermediate duration of action, demeclocycline can be administered at dosing intervals that are longer than those used for tetracycline.
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Pharmacology tetracycline. for Nursing Care, 7th Edition Demeclocycline is unique among the tetracyclines in that it stimulates urine flow. This side effect can lead to excessive urination, thirst, and tiredness. Interestingly, because of its effect on renal function, demeclocycline has been employed therapeutically to promote urine production in patients suffering from the syndrome of inappropriate (excessive) secretion of antidiuretic hormone. 86.1.10.3
Doxycycline. Doxycycline [Vibramycin, others] is a long-acting agent that shares the actions and adverse effects described for the tetracyclines as a group. Because of its extended half-life, doxycycline can be administered once daily. Absorption of oral doxycycline is greater than that of tetracycline, and is not diminished by food or milk, and hence the drug may be administered with meals. Doxycycline is eliminated primarily by nonrenal mechanisms. As a result, it is safe for patients with renal failure. Doxycycline is a first-line drug for Lyme disease, anthrax, chlamydial infections (urethritis, cervicitis, and lymphogranuloma venereum), and sexually acquired proctitis (in combination with ceftriaxone). A topical formulation [Atridox] is used for periodontal disease, as is a low-dose oral formulation [Periostat]. Another low-dose oral formulation [Oracea] is used for acne (see Chapter 104).
CHAPTER 85 Bacteriostatic Inhibitors of Protein Synthesis: Tetracyclines, Macrolides, and Others
1007 1008
Page 9 of 43
Pharmacology for Nursing Care, 7thChapter Edition formulation [Oracea] is used for acne (see 104). TABLE 85-2 Tetracyclines: Routes of Administration, Dosing Interval, and Dosage Total Daily Dose
Class
Drug
Trade Name
Short Acting
Tetracycline
Sumycin
PO
6
1000–2000
25–50
IVb
12
500–1000
10–20
IMc
12
300
15–25
(mg/kg)a
Intermediate Acting
Demeclocycline Declomycin
PO
12
600
6–12
Long Acting
Doxycycline
PO
24
100d
2.2e
IVb
24
100–200f
2.2–4.4g
PO
12
200h
4i
IVb
12
200h
4i
Minocycline
86.1.10.4
Adult (mg)
Pediatric
Usual Dosing Route Interval (hr)
Vibramycin, others
Minocin, Dynacin
a
Doses presented are for children over the age of 8 years; use in children below this age may cause permanent staining of teeth.
b
The intravenous route is used only if oral therapy cannot be tolerated or is inadequate.
c
Intramuscular injection is extremely painful and used only rarely.
d
First-day regimen is 100 mg initially, followed by 100 mg 12 hours later.
e
First-day regimen is 2.2 mg/kg initially, followed by 2.2 mg/kg 12 hours later.
f
First-day regimen is 200 mg in one or two slow infusions (1 to 4 hours).
g
First-day regimen is 4.4 mg/kg in one or two slow infusions (1 to 4 hours).
h
First-day regimen is 200 mg initially, followed by 100 mg 12 hours later.
i
First-day regimen is 4 mg/kg initially, followed by 2 mg/kg 12 hours later.
Minocycline. Minocycline [Minocin, Dynacin] is a long-acting agent similar to doxycycline. Like doxycycline, minocycline can be taken with food, and is safe for patients with kidney disease. The drug is unique among the tetracyclines in that it can damage the vestibular system, causing
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Pharmacology Nursing Care, Edition doxycycline, for minocycline can be taken 7th with food, and is safe for patients with kidney disease. The drug is unique among the tetracyclines in that it can damage the vestibular system, causing unsteadiness, lightheadedness, and dizziness. This toxicity limits its use. Minocycline is expensive, costing significantly more than tetracycline. In addition to fighting systemic infection, minocycline can reduce symptoms of arthritis (see Chapter 72), and is available in an extended-release formulation [Solodyn] for acne, and a topical formulation [Arestin] for periodontal disease. 86.2
MACROLIDES The macrolides are broad-spectrum antibiotics that inhibit bacterial protein synthesis. Why are they called macrolides? Because they are very big molecules. Erythromycin is the oldest member of the family. All of the newer macrolides—azithromycin, clarithromycin, dirithromycin, and troleandomycin—are derivatives of erythromycin.
86.2.1
Erythromycin Erythromycin has a relatively broad antimicrobial spectrum and is a preferred or alternative treatment for a number of infections. The drug is one of our safest antibiotics and will serve as our prototype for the macrolide family.
86.2.1.1
Mechanism of Action Antibacterial effects result from inhibition of protein synthesis: Erythromycin binds to the 50S ribosomal subunit and thereby blocks addition of new amino acids to the growing peptide chain. The drug is usually bacteriostatic, but can be bactericidal against highly susceptible organisms, or when present in high concentration. Erythromycin is selectively toxic to bacteria because ribosomes in the cytoplasm of mammalian cells do not bind the drug. Also, in contrast to chloramphenicol (see below), erythromycin cannot cross the mitochondrial membrane, and therefore does not inhibit protein synthesis in host mitochondria.
86.2.1.2
Acquired Resistance Bacteria can become resistant by two mechanisms: (1) production of a pump that exports the drug and (2) modification (by methylation) of target ribosomes so that binding of erythromycin is impaired.
86.2.1.3
Antimicrobial Spectrum Erythromycin has an antibacterial spectrum similar to that of penicillin. The drug is active against most gram-positive bacteria as well as some gram-negative bacteria. Bacterial sensitivity is determined in large part by the ability of erythromycin to gain access to the cell
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Pharmacology Nursing Care, 7thasEdition against most for gram-positive bacteria as well some gram-negative bacteria. Bacterial sensitivity is determined in large part by the ability of erythromycin to gain access to the cell interior. 86.2.1.4
Therapeutic Uses Erythromycin is a commonly used antibiotic. The drug is a treatment of first choice for several infections and may be used as an alternative to penicillin G in patients with penicillin allergy. Erythromycin is a preferred treatment for pneumonia caused by Legionella pneumophila (legionnaires' disease). Erythromycin is considered the drug of first choice for individuals infected with Bordetella pertussis, the causative agent of whooping cough. Because symptoms are caused by a toxin produced by B. pertussis, erythromycin does little to alter the course of the disease. However, by eliminating B. pertussis from the nasopharynx, treatment does lower infectivity. Corynebacterium diphtheriae is highly sensitive to erythromycin. Accordingly, erythromycin is the treatment of choice for acute diphtheria and eliminating the diphtheria carrier state. Several infections respond equally well to erythromycin and tetracyclines. Both are drugs of first choice for certain chlamydial infections (urethritis, cervicitis) and for pneumonia caused by M. pneumoniae.
1008 1009
Erythromycin may be employed as an alternative to penicillin G in patients with penicillin allergy. The drug is used most frequently as a substitute for penicillin to treat respiratory tract infections caused by Streptococcus pneumoniae and by group A Streptococcus pyogenes. Erythromycin can also be employed as an alternative to penicillin for preventing recurrences of rheumatic fever and bacterial endocarditis. 86.2.1.5 86.2.1.5.1
Pharmacokinetics Absorption and Bioavailability. Erythromycin for oral administration is available in three forms: erythromycin base and two derivatives of the base: erythromycin stearate and erythromycin ethylsuccinate. The base is unstable in stomach acid, and its absorption can be variable; the derivatives were synthesized to improve bioavailability. Bioavailability has also been enhanced by use of acid-resistant coatings, which protect erythromycin while in the stomach and then dissolve in the duodenum, thereby permitting absorption from the small intestine. As a rule, food decreases the absorption of erythromycin base and erythromycin stearate, whereas absorption of erythromycin ethylsuccinate is not affected. Only erythromycin base is biologically active;
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Pharmacology forofNursing Care, 7therythromycin Edition stearate, whereas absorption of the absorption erythromycin base and erythromycin ethylsuccinate is not affected. Only erythromycin base is biologically active; the derivatives must be converted to the base (either in the intestine or following absorption) in order to work. When used properly (ie, when dosage is correct and the effects of food are accounted for), all of the oral erythromycins produce equivalent responses. In addition to its oral forms, erythromycin is available as erythromycin lactobionate for IV use. Intravenous dosing produces drug levels that are higher than those achieved with oral dosing. 86.2.1.5.2
Distribution. Erythromycin readily distributes to most tissues and body fluids. Penetration to the CSF, however, is poor. Erythromycin crosses the placenta, but adverse effects on the fetus have not been observed.
86.2.1.5.3
Elimination. Erythromycin is eliminated primarily by hepatic mechanisms, including metabolism by CYP3A4 (the 3A4 isozyme of cytochrome P450). Erythromycin is concentrated in the liver and then excreted in the bile. A small amount (10% to 15%) is excreted unchanged in the urine.
86.2.1.6
Adverse Effects Erythromycin is generally free of serious toxicity and is considered one of our safest antibiotics. However, the drug does carry a very small risk of sudden cardiac death.
86.2.1.6.1
Gastrointestinal Effects. Gastrointestinal disturbances (epigastric pain, nausea, vomiting, diarrhea) are the most common adverse effects. These can be reduced by administering erythromycin with meals. However, this should be done only when using erythromycin products whose absorption is unaffected by food (erythromycin estolate, erythromycin ethylsuccinate, certain entericcoated formulations of erythromycin base). Patients who experience persistent or severe GI reactions should notify the prescriber.
86.2.1.6.2
QT Prolongation and Sudden Cardiac Death. A study published in 2004 has raised concerns about cardiotoxicity, especially when erythromycin is combined with drugs that can raise its plasma level. When present in high concentrations, erythromycin can prolong the QT interval, thereby posing a risk of torsades
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Pharmacology foris Nursing Care, Edition erythromycin combined with drugs7th that can raise its plasma level. When present in high concentrations, erythromycin can prolong the QT interval, thereby posing a risk of torsades de pointes, a potentially fatal ventricular dysrhythmia. Sudden death can result. The 2004 study revealed that, when erythromycin is combined with a CYP3A4 inhibitor, there is a fivefold increase in the risk of sudden cardiac death—or 6 extra deaths for every 100,000 patients using the drug. To minimize risk, erythromycin should be avoided by patients with congenital QT prolongation and by those taking class IA or class III antidysrhythmic drugs. Also, the drug should be avoided by patients taking CYP3A4 inhibitors, including certain calcium channel blockers (ver–apamil and diltiazem), azole antifungal drugs (eg, ketoco– nazole, itraconazole), HIV protease inhibitors (eg, ritonavir, saquinavir), and nefazodone (an antidepressant). 86.2.1.6.3
Other Adverse Effects. By killing off sensitive gut flora, erythromycin can promote suprainfection of the bowel. Thrombophlebitis can occur with IV administration; this reaction can be minimized by infusing the drug slowly in dilute solution. Transient hearing loss occurs rarely with highdose therapy. There is evidence that erythromycin may cause hypertrophic pyloric stenosis in infants, especially those under 2 weeks of age.
86.2.1.7
Drug Interactions Erythromycin can increase the plasma levels and half-lives of several drugs, thereby posing a risk of toxicity. The mechanism is inhibition of hepatic P450 drug-metabolizing enzymes. Elevated levels are a concern with theophylline (used for asthma), carbamazepine (used for seizures and bipolar disorder), and warfarin (an anticoagulant). Accordingly, when these agents are combined with erythromycin, the patient should be monitored closely for signs of toxicity. Erythromycin prevents binding of chloramphenicol and clindamycin to bacterial ribosomes, thereby antagonizing the effects of these antibiotics. Accordingly, concurrent use of erythromycin with these two drugs is not recommended. As noted, erythromycin should not be combined with drugs that can inhibit erythromycin metabolism. Among these are verapamil, diltiazem, HIV protease inhibitors, and azole antifungal drugs.
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Pharmacology for Nursing Care, 7th Edition antifungal drugs. 86.2.1.8 86.2.1.8.1
Preparations, Dosage, and Administration Preparations. For treating systemic infections, erythromycin is available in oral and IV formulations. All preparations have the same indications, antimicrobial spectrum, and adverse effects. Erythromycin is also available in topical formulations [Eryderm, others] to treat acne (see Chapter 104).
86.2.1.8.2
Oral Dosage and Administration. Oral erythromycin should be administered on an empty stomach and with a full glass of water. If necessary, some preparations (erythromycin ethylsuccinate, certain enteric-coated preparations of erythromycin base) can be administered with food to decrease GI reactions. The usual adult dosage for erythromycin base and erythromycin stearate is 250 to 500 mg every 6 hours; the adult dosage for erythromycin ethylsuccinate is 400 to 800 mg every 6 hours. The usual pediatric dosage for all oral erythromycins is 7.5 to 12.5 mg/kg every 6 hours. Trade names for oral erythromycins are Ery-Tab, PCE Dispertab, and Erythromycin Filmtabs (for erythromycin base) and E.E.S. and EryPed (for erythromycin ethylsuccinate). Erythromycin stearate is available only as a generic product.
86.2.1.8.3
Intravenous Dosage and Administration. Intravenous administration is reserved for severe infections and is used rarely. Continuous infusion is preferred to intermittent dosing. Only erythromycin lactobionate [Erythrocin Lactobionate] is given IV. The usual adult dosage is 1 to 4 gm daily. The usual pediatric dosage is 15 to 50 mg/kg/day. Erythromycin should be infused slowly and in dilute solution (to minimize the risk of thrombophlebitis). For instruction on preparation and storage of IV solutions, consult the manufacturer's literature.
86.2.2
Other Macrolides All of the macrolides are similar to erythromycin with respect to mechanism of action, antimicrobial spectrum, and resistance. Major differences among these drugs are pharmacokinetic.
CHAPTER 85 Bacteriostatic Inhibitors of Protein Synthesis: Tetracyclines, Macrolides, and Others
1009
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Pharmacology for Nursing Care, 7th Edition pharmacokinetic.
1009
86.2.2.1
1010
86.2.2.1.1
Clarithromycin Actions and Therapeutic Uses. Like erythromycin, clarithromycin [Biaxin, Biaxin XL] binds the 50S subunit of bacterial ribosomes, causing inhibition of protein synthesis. The drug is approved for respiratory tract infections, uncomplicated infections of the skin and skin structures, and prevention of disseminated Mycobacterium avium complex infections in patients with advanced HIV infection. It is also used for H. pylori infection and as a substitute for penicillin G in penicillin-allergic patients.
86.2.2.1.2
Pharmacokinetics. Clarithromycin is available in three oral formulations: standard tablets, extended-release tablets, and granules. The standard tablets and granules are well absorbed, even in the presence of food. In contrast, the extended-release tablets are absorbed poorly if food is absent. Following absorption, clarithromycin is widely distributed and readily penetrates cells. Elimination is by hepatic metabolism and renal excretion. A reduction in dosage may be needed for patients with severe renal impairment.
86.2.2.1.3
Adverse Effects and Interactions. Clarithromycin is well tolerated and does not produce the intense nausea seen with erythromycin. The most common reactions (3%) have been diarrhea, nausea, and distorted taste—all described as mild to moderate. In clinical trials, only 3% of patients withdrew because of side effects, compared with 20% of those taking erythromycin. High doses of clarithromycin have caused fetal abnormalities in laboratory animals; possible effects on the human fetus are unknown. Like erythromycin, clarithromycin may prolong the QT interval, and hence may pose a risk of serious dysrhythmias. Like erythromycin, clarithromycin can inhibit hepatic metabolism of other drugs, and can thereby elevate their levels. Affected drugs include warfarin, carbamazepine, and theophylline; dosages of these drugs may need to be reduced.
86.2.2.1.4
Preparations, Dosage, and Administration. Clarithromycin is available in standard tablets (250 and 500 mg), sold as Biaxin; extendedrelease tablets (500 mg), sold as Biaxin XL; and granules for oral suspension (25 and 50 mg/mL), sold as Biaxin. With the standard tablets and granules, the recommended dosage is 250 or 500 mg every 12 hours for 7 to 14 days; the exact dosage size and duration
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Pharmacology for Nursing Care, Edition and 50 mg/mL), sold as Biaxin. With7th the standard tablets and granules, the recommended dosage is 250 or 500 mg every 12 hours for 7 to 14 days; the exact dosage size and duration depend on the infection being treated. With the extended-release tablets, the recommended dosage is 500 mg once a day for 7 to 14 days. The standard tablets and granules may be taken without regard to meals, but the extended-release tablets should be taken with food. 86.2.2.2 86.2.2.2.1
Azithromycin Actions and Therapeutic Uses. Like erythromycin, azithromycin [Zithromax, Zmax] binds the 50S subunit of bacterial ribosomes, causing inhibition of protein synthesis. The drug is used for respiratory tract infections, cholera, chancroid, otitis media, uncomplicated infections of the skin and skin structures, disseminated M. avium complex disease, and infections caused by Chlamydia trachomatis, for which it is a drug of choice. It may also be used as a substitute for penicillin G in penicillin-allergic patients.
86.2.2.2.2
Pharmacokinetics. Absorption of azithromycin is increased by food, and hence dosing may be done with meals. Following absorption, azithromycin is widely distributed to tissues and becomes concentrated in cells. Elimination is via the bile, as both metabolites and parent drug.
86.2.2.2.3
Adverse Effects and Interactions. Like clarithromycin, azithromycin is well tolerated and does not produce the intense nausea seen with erythromycin. The most common reactions are diarrhea (5%), and nausea and abdominal pain (3%). In one clinical trial, only 0.7% of patients withdrew because of side effects. Aluminum- and magnesium-containing antacids reduce the rate (but not the extent) of absorption. In contrast to erythromycin and clarithromycin, azithromycin does not inhibit the metabolism of other drugs.
86.2.2.2.4
Preparations, Dosage, and Administration. Oral, Immediate Release. Azithromycin [Zithromax] is available in two immediate-release oral formulations: tablets (250, 500, and 600 mg) and a suspension (20 and 40 mg/mL). The usual dosing schedule is 500 mg once on the first day, followed by 250 mg once daily on the following 4 days. Dosing may be done with or without food, but not with aluminum- or magnesium-containing antacids.
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Pharmacology for Nursing Care, 7th Edition magnesium-containing antacids. 86.2.2.2.4.1
Oral, Extended Release. Extended-release azithromycin [Zmax] is formulated as a powder composed of extendedrelease microspheres, designed to dissolve in the small intestine. The rationale is to reduce GI upset. The powder, sold in 2-gm, single-dose bottles, must be suspended in 60 mL of water before ingestion. Dosing is done just once a day.
86.2.2.2.4.2
Intravenous. Azithromycin is supplied as powder (500 mg) to be reconstituted for IV infusion. The usual dosage is 500 mg infused slowly (over 60 minutes or more) on 2 or more days. Intravenous therapy is followed by oral therapy. A complete course of treatment takes 7 days.
86.2.2.3 86.2.2.3.1
Dirithromycin Actions and Therapeutic Uses. Dirithromycin [Dynabac] is similar to erythromycin with respect to mechanism of action, antimicrobial spectrum, and clinical effects. Approved indications include bronchitis caused by Strep. pneumoniae (but not Haemophilus influenzae); community-acquired pneumonia caused by pneumococci, M. pneumoniae, or L. pneumophila; and skin and soft tissue infections caused by Staphylococcus aureus. In 2009, dirithromycin was withdrawn from the United States market.
86.2.2.3.2
Pharmacokinetics. Following oral administration, dirithromycin is absorbed from the GI tract and converted by nonenzymatic hydrolysis into erythromycylamine, an active metabolite. The drug reaches high concentrations in tissues, although serum concentrations may be low. Dirithromycin and its metabolite are eliminated slowly in the bile, with a half-life of 40 hours. Because of this extended half-life, once-daily dosing is sufficient.
86.2.2.3.3
Adverse Effects and Interactions. As with erythromycin, nausea and abdominal pain are common; the reported incidence is about 10%, but the actual incidence may be higher. In contrast to erythromycin and clarithromycin, dirithromycin does not inhibit the metabolism of other drugs.
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Pharmacology for dirithromycin Nursing Care, 7th Edition clarithromycin, does not inhibit the metabolism of other drugs. 86.2.2.3.4
Dosage and Administration. The usual dosage is 500 mg once daily for 7 to 14 days. Dirithromycin should be taken with meals or within 1 hour after eating. Food does not reduce absorption.
86.2.2.4
Troleandomycin Troleandomycin [Tao], the newest macrolide, is no longer available in the United States. Like other macrolides, the drug suppresses bacterial growth by inhibiting protein synthesis. At this time, troleandomycin has only two approved indications: pneumococcal pneumonia and upper respiratory tract infections caused by group A beta-hemolytic streptococci. Some patients have developed jaundice while taking the drug. Accordingly, liver function should be monitored. Troleandomycin inhibits cytochrome P450, and hence can suppress metabolism of other drugs, causing their levels to rise. The usual adult dosage is 250 to 500 mg 4 times a day for 10 days.
86.3
OTHER BACTERIOSTATIC INHIBITORS OF PROTEIN SYNTHESIS
86.3.1
Clindamycin Clindamycin [Cleocin] can promote severe antibiotic-associated pseudomembranous colitis, a condition that can be fatal. Because of the risk of colitis, indications for clindamycin are limited. Currently, systemic use is indicated only for certain anaerobic infections located outside the central nervous system (CNS).
86.3.1.1
Mechanism of Action Clindamycin binds to the 50S subunit of bacterial ribosomes and thereby inhibits protein synthesis. The site at which clindamycin binds overlaps the binding sites for erythromycin and chloramphenicol. As a result, these agents may antagonize each other's effects. Accordingly, there are no indications for concurrent use of clindamycin with these other antibiotics.
86.3.1.2
Antimicrobial Spectrum Clindamycin is active against most anaerobic bacteria (gram positive and gram negative) and most gram-positive aerobes. Gram-negative aerobes are generally resistant. Susceptible anaerobes include Bacteroides fragilis, Fusobacterium, Clostridium perfringens, and anaerobic streptococci. Clindamycin is usually bacteriostatic. However, it can be bactericidal if the target organism is especially sensitive. Resistance can be a significant problem with B. fragilis.
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Pharmacology for Nursing Care, 7th can Edition organism is especially sensitive. Resistance be a significant problem with B. fragilis. 86.3.1.3
Therapeutic Use Because of its efficacy against gram-positive cocci, clindamycin has been used widely as an alternative to penicillin. The drug is employed primarily for anaerobic infections outside the CNS (it doesn't cross the blood-brain barrier). Clindamycin is the drug of choice for severe group A streptococcal infection and for gas gangrene (an infection caused by C. perfringens), owing to its ability to rapidly suppress synthesis of bacterial toxins. In addition, clindamycin is a preferred drug for abdominal and pelvic infections caused by B. fragilis.
86.3.1.4 86.3.1.4.1
1010 1011
Pharmacokinetics Absorption and Distribution. Clindamycin may be administered orally, IM, or IV. Absorption from the GI tract is nearly complete and not affected by food. The drug is widely distributed to most body fluids and tissues, including synovial fluid and bone. However, penetration to the CSF is poor.
86.3.1.4.2
Elimination. Clindamycin undergoes hepatic metabolism to active and inactive products, which are then excreted in the urine and bile. Only 10% of the drug is eliminated unchanged by the kidneys. The half-life is approximately 3 hours. In patients with substantial reductions in liver function or kidney function, the half-life increases slightly, but adjustments in dosage are not needed. However, in patients with combined hepatic and renal disease, the half-life increases significantly, and hence the drug may accumulate to toxic levels if dosage is not reduced.
86.3.1.5 86.3.1.5.1
Adverse Effects Antibiotic-Associated Pseudomembranous Colitis. AAPMC is the most severe toxicity. The cause is suprainfection of the bowel with C. difficile, an anaerobic gram-positive bacillus. AAPMC is characterized by profuse, watery diarrhea (10 to 20 watery stools per day), abdominal pain, fever, and leukocytosis. Stools often contain mucus and blood. Symptoms usually begin during the first week of treatment, but may develop as long as 4 to 6 weeks after clindamycin withdrawal. Left untreated, the condition can be fatal. AAPMC occurs with parenteral and oral therapy. Because of the risk of colitis, patients should be instructed to report significant diarrhea (more than five watery stools per day). If suprainfection with C. difficile is diagnosed, clindamycin should be discontinued and the patient given oral vancomycin or metronidazole, which are drugs of
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Pharmacology for IfNursing Care, Edition stools per day). suprainfection with7th C. difficile is diagnosed, clindamycin should be discontinued and the patient given oral vancomycin or metronidazole, which are drugs of choice for eliminating C. difficile from the bowel. Diarrhea usually ceases 3 to 5 days after starting vancomycin. Vigorous replacement therapy with fluids and electrolytes is usually indicated. Drugs that decrease bowel motility (eg, opioids, anticholinergics) may worsen symptoms and should not be used. 86.3.1.5.2
Other Adverse Effects. Diarrhea (unrelated to AAPMC) is relatively common. Hypersensitivity reactions (especially rashes) occur frequently. Hepatotoxicity and blood dyscrasias (agranulocytosis, leukopenia, thrombocytopenia) develop rarely. Rapid IV administration can cause electrocardiographic changes, hypotension, and cardiac arrest.
86.3.1.6 86.3.1.6.1
Preparations, Dosage, and Administration Preparations. Clindamycin is available as clindamycin hydrochloride and clindamycin palmitate for oral dosing, and as clindamycin phosphate for IM, IV, or topical (vaginal) dosing. Clindamycin hydrochloride [Cleocin] is supplied in capsules (75, 150, and 300 mg). Clindamycin palmitate [Cleocin Pediatric] is supplied in flavored granules, which are reconstituted with fluid to make an oral solution containing 15 mg of clindamycin per milliliter. Clindamycin phosphate [Cleocin, Cleocin Phosphate, others] is supplied in solution (150 mg/mL) for parenteral therapy, and in a 2% cream and 100-mg suppositories for intravaginal dosing.
86.3.1.6.2
Oral Dosage and Administration. For clindamycin hydrochloride, the adult dosage range is 150 to 450 mg every 6 hours; the pediatric dosage range is 8 to 20 mg/kg daily in three or four divided doses. For clindamycin palmitate, adult and pediatric dosages range from 8 to 25 mg/kg/day administered in three or four divided doses. Oral clindamycin should be taken with a full glass of water. The drug may be administered with meals.
86.3.1.6.3
Parenteral Dosage and Administration. For parenteral (IM or IV) therapy, clindamycin phosphate is employed. Intramuscular and IV dosages are the same. The usual adult dosage is 0.6 to 3.6 gm/day administered in three or four divided doses. The usual pediatric dosage is 15 to 40 mg/kg/day in three or four divided doses.
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Pharmacology for Nursing Care, 7th Edition doses. 86.3.1.6.4
Intravaginal Administration. Intravaginal clindamycin (suppositories or cream) is indicated for bacterial vaginosis. The suppositories are approved only for nonpregnant women; the cream can be used by pregnant women, but only during the second and third trimesters. Women using clindamycin cream should apply 1 applicatorful (5 gm containing 100 mg clindamycin) nightly for 7 days (if pregnant) or for 3 to 7 days (if nonpregnant). Women using clindamycin suppositories should insert 1 suppository (100 mg) on three consecutive evenings.
86.3.2
Linezolid Linezolid [Zyvox] is the first member of a new class of antibiotics, the oxazolidinones. The drug is important because it has activity against multidrug-resistant gram-positive pathogens, including vancomycin-resistant enterococci (VRE) and methicillin-resistant Staph. aureus (MRSA). For treatment of MRSA, the drug is at least as effective as vancomycin. To delay the emergence of resistance, linezolid should generally be reserved for infections caused by VRE or MRSA, even though it has additional approved uses.
86.3.2.1
Mechanism, Resistance, and Antimicrobial Spectrum Linezolid is a bacteriostatic inhibitor of protein synthesis. The drug binds to the 23S portion of the 50S ribosomal subunit, and thereby blocks formation of the initiation complex. No other antibiotic works quite this way. As a result, cross-resistance with other agents is unlikely. In clinical trials, development of resistance to linezolid was rare, and occurred only in association with prolonged treatment of VRE infections and the presence of a prosthetic implant or undrained abscess. Linezolid is active primarily against aerobic and facultative gram-positive bacteria. Susceptible pathogens include Enterococcus faecium (vancomycin-sensitive and vancomycin-resistant strains), Enterococcus faecalis (vancomycinresistant strains), Staph. aureus (methicillinsensitive and methicillin-resistant strains), Staphylococcus epidermidis (including methicillinresistant strains), and Strep. pneumoniae (penicillin-sensitive and penicillin-resistant strains). Linezolid is not active against gram-negative bacteria, which readily export the drug.
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Pharmacology foractive Nursing 7th Edition Linezolid is not against Care, gram-negative bacteria, which readily export the drug. 86.3.2.2
Pharmacokinetics Oral linezolid is rapidly and completely absorbed. Food decreases the rate of absorption but not the extent. Linezolid is eliminated by hepatic metabolism and renal excretion. Its half-life is about 5 hours.
86.3.2.3
Adverse Effects Linezolid is generally well tolerated. The most common side effects are diarrhea (5.3%), nausea (3.5%), and headache (2.7%). Linezolid oral suspension contains phenylalanine, and hence must not be used by patients with phenylketonuria. Linezolid can cause reversible myelosuppression, manifesting as anemia, leukopenia, thrombocytopenia, or even pancytopenia. Risk is related to duration of use. Complete blood counts should be done weekly. Special caution is needed in patients with pre-existing myelosuppression, those taking other myelosuppressive drugs, and those receiving linezolid for more than 2 weeks. If existing myelosuppression worsens or new myelosuppression develops, discontinuing linezolid should be considered. Rarely, prolonged therapy has been associated with neuropathy. Patients taking the drug for more than 5 months have developed reversible optic neuropathy and irreversible peripheral neuropathy.
86.3.2.4
1011 1012
Drug Interactions Linezolid is a weak inhibitor of monoamine oxidase (MAO), and hence poses a risk of hypertensive crisis. As discussed in Chapter 32, MAO inhibitors can cause severe hypertension if combined with indirect-acting sympathomimetics (eg, ephedrine, pseudoephedrine, methylphenidate, cocaine) or with foods that contain large amounts of tyramine. Accordingly, patients using linezolid should be warned to avoid these agents. In theory, combining linezolid with a selective serotonin reuptake inhibitor (eg, fluoxetine [Prozac]) can increase the risk of serotonin syndrome (because inhibition of MAO increases the serotonin content of CNS neurons). However, serotonin syndrome has not been reported.
86.3.2.5
Preparations, Dosage, and Administration Linezolid is available in three formulations: (1) 600-mg tablets, (2) a powder for reconstitution to a 20-mg/mL oral suspension, and (3) a 2-mg/mL intravenous solution supplied in 100-, and 300-mL single-use bags. Oral linezolid can be taken with or without food. Intravenous
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Pharmacology for Nursing Care, Edition to a 20-mg/mL oral suspension, and (3)7th a 2-mg/mL intravenous solution supplied in 100-, and 300-mL single-use bags. Oral linezolid can be taken with or without food. Intravenous linezolid is infused over 30 to 120 minutes, and should not be combined with additives or other drugs. Adult dosages for specific infections are as follows: • VRE infections—600 mg PO or IV every 12 hours for 14 to 28 days • Pneumonia (nosocomial or community acquired)—600 mg PO or IV every 12 hours for 10 to 14 days • Complicated skin and skin structure infections (including MRSA infections)—same as pneumonia • Uncomplicated skin and skin structure infections—400 mg PO every 12 hours for 10 to 14 days 86.3.3
Telithromycin
86.3.3.1
Therapeutic Use. Telithromycin [Ketek], a close relative of erythromycin and other macrolides, is the first representative of a new class of antibiotics, the ketolides. Antibacterial activity is similar to that of the macrolides, with one important exception: telithromycin has significant activity against strains of Strep. pneumoniae that are penicillin and macrolide resistant. The Food and Drug Administration (FDA) initially approved the drug for three indications, but has since withdrawn approval for two of them. Currently, the only approved indication is communityacquired pneumonia (CAP) caused by Strep. pneumoniae (including multidrug-resistant isolates [MDRSP]), H. influenzae, M. catarrhalis, Chlamydia pneumoniae, or Mycoplasma pneumoniae. Unfortunately, although telithromycin is an effective antibiotic, it carries a significant risk of adverse effects (especially severe liver injury) and drug interactions. As a result, it should be reserved for infections caused by MDRSP that cannot be treated with other agents.
86.3.3.2
Mechanism of Action. Like the macrolides, telithromycin binds to the 50S ribosomal subunit, and thereby inhibits bacterial protein synthesis. However, in contrast to the macrolides, telithromycin has properties that give it activity against bacteria that are macrolide resistant. Among respiratory tract pathogens, macrolide resistance occurs by two mechanisms: (1) removal of the macrolide with export pumps and (2) modification (by methylation) of the bacterial ribosome in a way that decreases macrolide binding. Because telithromycin differs in structure from the macrolides,
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Pharmacology Care, Edition export pumpsfor and Nursing (2) modification (by 7th methylation) of the bacterial ribosome in a way that decreases macrolide binding. Because telithromycin differs in structure from the macrolides, the drug is less subject to removal by bacterial export pumps, and can bind strongly to bacterial ribosomes even if they are methylated. 86.3.3.3
Pharmacokinetics. Telithromycin undergoes rapid but incomplete absorption following oral administration. Bioavailability is about 57%, both in the presence and absence of food. Once in the blood, telithromycin becomes concentrated in white cells. About 70% of absorbed drug is metabolized in the liver—half by CYP3A4 (the 3A4 isozyme of cytochrome P450) and half by P450independent pathways. Excretion of parent drug and metabolites occurs in the urine and feces. The half-life is 10 hours.
86.3.3.4
Adverse Effects. Although telithromycin is generally well tolerated, the drug can cause serious adverse effects, especially injury to the liver (see below). As a result, the drug should be used only when absolutely necessary. In clinical trials, most adverse effects were mild to moderate. Furthermore, the rate of discontinuation because of adverse effects was nearly the same as with patients taking a comparator antibiotic (4.4% vs. 4.3%). The most common adverse effects are gastrointestinal disturbances, including diarrhea (10% vs. 8% with a comparator antibiotic), nausea (7% vs. 4.1%), vomiting (2.4% vs. 1.4%), and loose stools (2.1% vs. 1.4%). Telithromycin can cause severe liver injury (fulminant hepatitis, hepatic necrosis) and acute hepatic failure. Liver transplants have been required and deaths have occurred. Liver damage can develop early in telithromycin treatment and can progress rapidly. Patients should be monitored for signs of hepatitis (eg, jaundice, fatigue, abdominal pain, dark urine). If liver injury is diagnosed, telithromycin should be discontinued and never used again. In patients with myasthenia gravis, telithromycin can make muscle weakness much worse, sometimes within hours of taking the first dose. Some patients have died from respiratory failure. Accordingly, telithromycin is contraindicated for patients with this disorder. About 1% of patients experience visual disturbances, including blurred vision, double vision, and difficulty focusing. Females and patients under 40 years old are at highest risk. These disturbances usually develop after the first or second dose, and can persist for several hours. Symptoms may or may not recur with subsequent doses.
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Pharmacology fororNursing Care, 7th Edition Symptoms may may not recur with subsequent doses. Like erythromycin and clarithromycin, telithromycin can prolong the QT interval, and hence may pose a risk of adverse cardiac events. However, QT prolongation was not observed in clinical trials, and there have been no reports of torsades de pointes or other ventricular dysrhythmias. Nonetheless, telithromycin should be avoided by patients with congenital QT prolongation and by those taking class IA or class III antidysrhythmics. 86.3.3.5
Drug Interactions. Telithromycin is both a substrate for and inhibitor of CYP3A4, and hence has the potential for numerous drug interactions. Because telithromycin is a substrate for CYP3A4, agents that inhibit the enzyme (eg, itraconazole, ketoconazole) can elevate telithromycin levels. Conversely, agents that induce CYP3A4 (eg, rifampin, phenytoin, carbamazepine, phenobarbital) can decrease telithromycin levels, possibly resulting in therapeutic failure. By inhibiting CYP3A4, telithromycin can increase levels of many drugs that are substrates for the enzyme, thereby posing a risk of toxicity. Two such substrates—cisapride [Propulsid] and pimozide [Orap]—are contraindicated for use with telithromycin. Similarly, use of three statintype cholesterollowering agents—simvastatin [Zocor], lovastatin [Mevacor], and atorvastatin [Lipitor]—should be interrupted during telithromycin therapy. However, use of two other statins—pravastatin [Pravachol] and fluvastatin [Lescol]—may continue. Telithromycin is likely to increase levels of ergotamine and dihydroergotamine (ergot alkaloids used for migraine), and may thereby cause severe peripheral vasospasm. Accordingly, use of these alkaloids must be avoided. Telithromycin increases peak levels of digoxin [Lanoxin] by 73%. Accordingly, digoxin levels and side effects should be monitored closely. Other CYP3A4 substrates whose levels can be increased include midazolam [Versed], ritonavir [Norvir], sirolimus [Rapamune], and tacrolimus [Prograf]. Finally, telithromycin can increase levels of metoprolol [Lopressor], a substrate for CYP2D6. Patients with heart failure who are using metoprolol should be monitored closely.
86.3.3.6
Preparations, Dosage, and Administration. Telithromycin [Ketek] is available in 300 and 400 mg tablets for oral dosing, with or without food. The dosage for CAP is 800 mg once a day for 7 to 10 days. A dosage reduction may be needed for patients with severe renal impairment, but not for patients with mild to moderate renal impairment or those with hepatic impairment.
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Pharmacology for orNursing Edition renal impairment those withCare, hepatic 7th impairment. 86.3.4
Dalfopristin/Quinupristin Dalfopristin and quinupristin are the first members of a new class of antibiotics known as streptogramins. The two drugs are available in a fixed-dose combination (70 parts dalfopristin/30 parts quinupristin) under the trade name Synercid.
86.3.4.1
Mechanism of Action. Dalfopristin and quinupristin inhibit bacterial protein synthesis. When used separately, dalfopristin and quinupristin are bacteriostatic. However, in combination they are bactericidal.
86.3.4.2
Therapeutic Use. The principal indication for dalfopristin/quinupristin is vancomycin-resistant E. faecium. (The drugs are not active against E. faecalis.) To delay emergence of resistance, dalfopristin/ quinupristin should be reserved for infections that have not responded to vancomycin. Other indications include MRSA, methicillin-resistant Staph. epidermidis, and drugresistant Strep. pneumoniae. Dalfopristin/quinupristin is safe for patients who are allergic to penicillins and cephalosporins.
86.3.4.3
Adverse Effects Hepatotoxicity is the major concern. Blood should be tested for liver enzymes and bilirubin at least twice during the first week of therapy and weekly thereafter. About 50% of patients develop infusionrelated thrombophlebitis. When this occurs, administration must be switched to a central venous line. Other adverse effects include joint and muscle pain, rash, pruritus, vomiting, and diarrhea.
86.3.4.4
1012 1013
Drug Interactions. Dalfopristin and quinupristin inhibit hepatic drug-metabolizing enzymes, specifically CYP3A4. Accordingly, the combination is likely to inhibit the metabolism of many other drugs, including cyclosporine, tacrolimus, and cisapride.
86.3.4.5
Preparations, Dosage, and Administration. Dalfopristin/quinupristin [Synercid] is supplied as a powder in 500-mg vials to be reconstituted for IV administration. The usual dosage is 7.5 mg/kg infused slowly (over 1 hour) 2 or 3 times a day. To minimize venous irritation, flush the vein with 0.5% dextrose after the infusion. If irritation occurs despite flushing, the drug should be infused through a central venous line.
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Pharmacology for Nursing Care,flush 7ththe Edition a day. To minimize venous irritation, vein with 0.5% dextrose after the infusion. If irritation occurs despite flushing, the drug should be infused through a central venous line. Because dalfopristin and quinupristin are eliminated by hepatic metabolism, dosage should be reduced in patients with liver impairment. 86.3.5
Chloramphenicol Chloramphenicol [Chloromycetin] is a broad-spectrum antibiotic with the potential for causing fatal aplastic anemia and other blood dyscrasias. Because of the risk of severe blood disorders, use of chloramphenicol is limited to serious infections for which less toxic drugs are not effective.
86.3.5.1
Mechanism of Action Chloramphenicol inhibits bacterial protein synthesis. The drug binds reversibly to the 50S subunit of bacterial ribosomes and thereby prevents addition of new amino acids to the growing peptide chain. Chloramphenicol is usually bacteriostatic, but can be bactericidal against highly susceptible organisms or when its concentration is high. Since most protein synthesis in mammalian cells is carried out in the cytoplasm employing ribosomes that are insensitive to chloramphenicol, toxic effects are restricted largely to bacteria. However, because the ribosomes of mammalian mitochondria are very similar to those of bacteria, chloramphenicol can decrease mitochondrial protein synthesis in the host. This action may underlie certain adverse effects (eg, dose-dependent bone marrow suppression, gray syndrome in infants).
86.3.5.2
Antimicrobial Spectrum Chloramphenicol is active against a broad spectrum of bacteria. A large number of grampositive and gram-negative aerobic organisms are sensitive. Among these are Salmonella typhi, H. influenzae, Neisseria meningitidis, and Strep. pneumoniae. Most anaerobic bacteria (eg, B. fragilis) are also susceptible. In addition, chloramphenicol is active against rickettsiae, chlamydiae, mycoplasmas, and treponemes.
86.3.5.3
Resistance Resistance among gram-negative bacteria results from acquisition of an R factor that codes for acetyltransferase, an enzyme that inactivates chloramphenicol. This same R factor also codes for resistance to tetracyclines, and frequently confers resistance to penicillins too.
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Pharmacology Nursing and Care, 7th Edition for resistancefor to tetracyclines, frequently confers resistance to penicillins too. 86.3.5.4
Pharmacokinetics Chloramphenicol is available in two forms: chloramphenicol base (administered PO), and chloramphenicol succinate (administered IV). Chloramphenicol base is active as administered. In contrast, chloramphenicol succinate is a prodrug that must be hydrolyzed to free chloramphenicol before it can act.
86.3.5.4.1
Availability of Active Drug. Chloramphenicol base is absorbed rapidly following oral administration, and bioavailability is high (between 75% and 90%). In contrast, when the drug is administered IV as chloramphenicol succinate, conversion to the active form (free chloramphenicol) is variable and incomplete. Production of active drug is especially erratic in newborns, infants, and young children.
86.3.5.4.2
Distribution. Chloramphenicol is highly lipid soluble and widely distributed to body tissues and fluids. Therapeutic concentrations are readily achieved in the CSF, and drug levels in the brain may be as much as 9 times those in plasma. As a result, chloramphenicol is of special value for treating meningitis and brain abscesses caused by susceptible bacteria. The drug crosses the placenta and is secreted in breast milk.
86.3.5.4.3
Metabolism and Excretion. Chloramphenicol is eliminated primarily by hepatic metabolism. Inactive metabolites are excreted in the urine. In patients with liver dysfunction, the half-life is prolonged and accumulation can occur. Accordingly, dosage should be reduced. Because the kidneys serve only to excrete inactive metabolites, there is no need for dosage reduction in patients with renal dysfunction. In neonates, hepatic metabolism is not fully developed and hence the halflife of chloramphenicol is prolonged.
86.3.5.4.4
Monitoring Chloramphenicol Serum Levels. Because chloramphenicol has a low therapeutic index, and because serum levels of the drug can vary substantially among patients, monitoring drug levels is frequently indicated. Monitoring is especially important for neonates, infants, and young children because chloramphenicol levels in these patients can be highly variable. For most infections, effective therapy is achieved with peak serum drug levels of 10 to 20 mcg/mL and trough levels of 5 to 10 mcg/mL. The risk of dose-dependent bone marrow suppression is significantly
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Pharmacology for Nursing Edition therapy is achieved with peakCare, serum 7th drug levels of 10 to 20 mcg/mL and trough levels of 5 to 10 mcg/mL. The risk of dose-dependent bone marrow suppression is significantly increased when peak levels rise above 25 mcg/mL. 86.3.5.5
Therapeutic Use When first introduced, chloramphenicol was employed widely. However, use dropped sharply when its ability to cause fatal aplastic anemia became evident. Today, chloramphenicol is indicated only for life-threatening infections for which safer drugs are ineffective or contraindicated.
86.3.5.6
Adverse Effects The most important adverse effects are gray syndrome and toxicities related to the blood. Because of these toxicities, indications for chloramphenicol are limited.
86.3.5.6.1
Gray Syndrome. Gray syndrome, originally known as gray baby syndrome, is a potentially fatal toxicity observed most commonly in newborns. Initial symptoms are vomiting, abdominal distention, cyanosis, and gray discoloration of the skin. These may be followed by vasomotor collapse and death. The syndrome results from accumulation of chloramphenicol to high levels. Newborns are especially vulnerable to gray syndrome because (1) hepatic function is insufficient to detoxify chloramphenicol and (2) renal function is insufficient to excrete active drug. Although gray syndrome is usually observed in neonates, it can occur in older children and adults if dosage is excessive. If drug use is discontinued immediately when early symptoms appear, the syndrome is usually reversible. The risk of gray syndrome in infants can be reduced by using low doses and by monitoring chloramphenicol levels in serum.
86.3.5.6.2
Reversible Bone Marrow Suppression. Chloramphenicol can produce dose-related suppression of the bone marrow, resulting in anemia, and sometimes leukopenia and thrombocytopenia. Marrow suppression is dose related, occurring most commonly when plasma drug levels exceed 25 mcg/mL. The cause of bone marrow suppression appears to be inhibition of protein synthesis in host mitochondria. To promote early detection of bone marrow suppression, complete blood counts should be performed prior to therapy and every 2 days thereafter. Advise patients to notify the physician if signs of blood disorders develop (eg, sore throat, fever, unusual bleeding or bruising). Chloramphenicol should be withdrawn if evidence of bone marrow suppression is detected. Suppression of bone marrow usually reverses within 1 to 3 weeks
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Pharmacology Nursing Care, 7thshould Edition bleeding orfor bruising). Chloramphenicol be withdrawn if evidence of bone marrow suppression is detected. Suppression of bone marrow usually reverses within 1 to 3 weeks following drug withdrawal. The anemia associated with toxic bone marrow suppression is not related to aplastic anemia (discussed next). 86.3.5.6.3
Aplastic Anemia. Rarely, chloramphenicol produces aplastic anemia, a condition characterized by pancytopenia and bone marrow aplasia. The reaction is usually fatal. Aplastic anemia develops in 1 of 35,000 patients, and is not related to dosage. As a rule, the reaction develops weeks or months after termination of treatment. Aplastic anemia can occur with oral, IV, or even topical (ophthalmic) use of the drug. The mechanism underlying aplastic anemia has not been determined, but toxicity may result from a genetic predisposition. Unfortunately, aplastic anemia cannot be predicted by monitoring the blood.
86.3.5.6.4
Other Adverse Effects. Gastrointestinal effects (vomiting, diarrhea, glossitis) occur occasionally. Herxheimer reactions have occurred during treatment of typhoid fever. Neurologic effects (peripheral neuropathy, optic neuritis, confusion, delirium) develop rarely, usually in association with prolonged treatment. Other rare toxicities include suprainfection of the bowel, allergic reactions, and fever.
86.3.5.7
Drug Interactions Chloramphenicol can inhibit hepatic drug-metabolizing enzymes, thereby prolonging the halflives of other drugs. Agents that may be affected include phenytoin (an anticonvulsant), warfarin (an anticoagulant), and two oral hypoglycemics: tolbutamide and chlorpropamide. If any of these drugs are taken concurrently with chloramphenicol, their dosages should be reduced.
86.3.5.8 86.3.5.8.1
Preparations, Dosage, and Administration General Considerations Regarding Route and Dosage. For treatment of systemic infections, chloramphenicol is administered IV. The oral formulation is no longer available. As a rule, the dosing objective is to produce peak chloramphenicol plasma levels that range between 10 and 20 mcg/mL.
CHAPTER 85 Bacteriostatic Inhibitors of Protein Synthesis: Tetracyclines, Macrolides, and Others
1013
Page 31 of 43
Pharmacology between 10for and Nursing 20 mcg/mL.Care, 7th Edition
1013
86.3.5.8.2
1014
Preparations. For intravenous therapy, chloramphenicol is available in powdered form as chloramphenicol sodium succinate [Chloromycetin Sodium Succinate], which must be reconstituted to a 100mg/mL solution.
86.3.5.8.3
Dosage and Administration. The usual IV dosage for adults and children is 12.5 to 25 mg/kg every 6 hours. For infants 7 days old or younger, the usual dosage is 25 mg/kg once a day. For infants more than 7 days old, the recommended dosage is 25 mg/kg every 12 hours. Dosage should be reduced for patients with liver dysfunction.
86.3.6
Spectinomycin
86.3.6.1
Mechanism of Action and Antimicrobial Spectrum. Spectinomycin [Trobicin] binds to the 30S ribosomal subunit and thereby suppresses bacterial protein synthesis. The drug is active against a number of gram-negative bacteria. Resistance develops frequently.
86.3.6.2
Therapeutic Use. Because resistant organisms emerge rapidly, use of spectinomycin is limited. Its principal indication is anogenital gonorrhea in patients who cannot tolerate preferred drugs (eg, ceftriaxone, cefixime).
86.3.6.3
Pharmacokinetics. Spectinomycin is administered by IM injection. (The drug is not absorbed from the GI tract.) Most of each dose is excreted unchanged in the urine. The plasma half-life is approximately 2 hours.
86.3.6.4
Adverse Effects. Spectinomycin is generally well tolerated. Adverse effects seen occasionally include soreness at the site of injection, dizziness, nausea, urticaria, pruritus, chills, fever, and insomnia.
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Pharmacology for Nursing Care, 7th Edition at the site of injection, dizziness, nausea, urticaria, pruritus, chills, fever, and insomnia. 86.3.6.5
Preparations, Dosage, and Administration. Spectinomycin [Trobicin] is supplied as a sterile powder together with sufficient diluent to produce a 400-mg/mL solution. For treatment of uncomplicated gonorrhea of the rectum or genitalia, the usual adult dose is 2 gm administered as a single IM (intragluteal) injection. For children weighing less than 45 kg, a single injection of 40 mg/kg is given. For disseminated gonococcal infection, the adult dosage is 2 gm twice a day for 3 days.
86.3.7
Tigecycline Tigecycline [Tygacil], approved in 2005, is the first representative of a new class of antibiotics, the glycylcyclines. The drug is a tetracycline derivative designed to overcome drug resistance. Tigecycline is active against a broad spectrum of bacteria, including many drug-resistant strains. Adverse effects may be similar to those of the tetracyclines.
86.3.7.1
Mechanism of Action and Resistance. Tigecycline is a bacteriostatic inhibitor of protein synthesis. Like the tetracyclines, tigecycline binds to the 30S ribosomal subunit and thereby inhibits binding of transfer RNA to the messenger RNA–ribosome complex. As a result, addition of amino acids to the growing peptide chain is stopped. Bacterial resistance to tigecycline is much less than with the tetracyclines. Why? First, because bacteria are unable to extrude tigecycline. Second, they cannot block binding of tigecycline to ribosomes.
86.3.7.2
Antimicrobial Spectrum. Tigecycline is a broad-spectrum antibiotic with activity against gram-positive and gramnegative bacteria, including many strains that are drug resistant. Susceptible gram-positive organisms include Staph. aureus (vancomycin sensitive, methicillin sensitive, and methicillin resistant), vancomycin-resistant enterococci, penicillin-resistant Strep. pneumoniae, C. perfringens, and C. difficile. Susceptible gram-negative organisms include Acinetobacter baumanii, Stenotrophomonas maltophilia, B. fragilis, Escherichia coli, and Enterobacter species. Of note, tigecycline is not active against Pseudomonas aeruginosa or Proteus species.
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Pharmacology fortigecycline NursingisCare, 7th Edition species. Of note, not active against Pseudomonas aeruginosa or Proteus species. 86.3.7.3
Therapeutic Use. Tigecycline is approved for treating complicated intra-abdominal infections and complicated skin infections that need broad empiric coverage. To delay emergence of resistance, tigecycline should be used only when other drugs are considered likely to fail.
86.3.7.4
Pharmacokinetics. Tigecycline is administered IV and undergoes moderate binding to plasma proteins (about 80%). Very little of the drug is metabolized. Excretion occurs in the bile (59%) and urine (33%), mainly as unchanged drug. The plasma half-life is 42 hours.
86.3.7.5
Adverse Effects. Because tigecycline is a tetracycline analog, adverse effects may be like those of the tetracyclines. In clinical trials, the most common reactions were nausea (30%) and vomiting (20%). Like the tetracyclines, tigecycline may pose a risk of pseudotumor cerebri (a benign elevation of intracranial pressure) and may increase sensitivity to ultraviolet light (thereby increasing the risk of sunburn). Tigecycline may stain developing teeth, and hence should not be used by children under 8 years old. Being a broadspectrum antibiotic, tigecycline may pose a risk of suprainfection, including antibiotic-associated pseudomembranous colitis. Tigecycline is in FDA Pregnancy Risk Category D, and hence should be avoided by pregnant women.
86.3.7.6
Drug Interactions. Drug interactions appear minimal. Tigecycline does not affect the cytochrome P450 system, and hence will not alter the kinetics of drugs metabolized by P450. Similarly, because tigecycline undergoes very little metabolism, drugs that alter P450 activity should not alter the kinetics of tigecycline. Tigecycline can delay the clearance of warfarin (an anticoagulant). Accordingly, if the drugs are used concurrently, coagulation status should be monitored.
86.3.7.7
Preparations, Dosage, and Administration. Tigecycline [Tygacil] is supplied as a lyophilized powder in single-dose 50-mg vials, to be reconstituted for IV infusion. The powder should be dissolved in 5.3 mL of sodium chloride injection or 5% dextrose injection, to produce a 10-mg/mL solution. This concentrated solution is then added to a 100-mL IV bag for infusion over 30 to 60 minutes. For adults, treatment consists of a 100-mg initial dose followed by 50 mg every 12 hours for 5 to 14 days. No adjustment in dosage is needed for patients with renal impairment or with mild to moderate hepatic impairment. For patients with severe hepatic impairment, the initial dose is unchanged,
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Pharmacology Nursing 7thwith Edition adjustment infor dosage is neededCare, for patients renal impairment or with mild to moderate hepatic impairment. For patients with severe hepatic impairment, the initial dose is unchanged, but maintenance dosing should be reduced to 25 mg every 12 hours. 86.3.8
Retapamulin and Mupirocin Retapamulin and mupirocin are new topical antibiotics. Both drugs are indicated for impetigo; mupirocin is also indicated for clearing the nostrils of methicillin-resistant Staph. aureus (MRSA). For impetigo therapy, retapamulin is more convenient than mupirocin, but generic mupirocin is cheaper.
86.3.8.1
Retapamulin Retapamulin [Altabax] is the first representative of a new class of antibiotics, the pleuromutalins. The drug binds the 50S bacterial ribosomal subunit, and thereby inhibits protein synthesis. However, the 50S binding site is different from that of other antibiotics, and hence cross-resistance with other antibiotics is not expected. Retapamulin is bacteriostatic at therapeutic concentrations. At this time, the drug is approved only for topical therapy of impetigo caused by Strep. pyogenes or methicillin-susceptible Staph. aureus. However, in vitro data indicate that the drug may be effective against methicillin- and mupirocin-resistant Staph. aureus. Significant resistance among Staph. aureus has not be observed, and is considered unlikely. The principal adverse effect is local irritation, which only 2% of users experience. Systemic toxicity does not occur, owing to minimal absorption from topical sites. Retapamulin is available as a 1% ointment in 5-, 10-, and 15-gm tubes. Application is done twice daily for 5 days.
86.3.8.2
Mupirocin Mupirocin [Bactroban, Bactroban Nasal] is a topical antibiotic with two indications: (1) impetigo caused by Staph. aureus, Strep. pyogenes, or betahemolytic streptococci; and (2) elimination of nasal colonization by MRSA. Mupirocin has a unique mechanism: The drug binds with bacterial isoleucyl transfer-RNA synthetase, and thereby blocks protein synthesis. The drug is bactericidal at therapeutic concentrations. Resistance has developed owing to production of a modified form of isoleucyl transfer-RNA synthetase, but cross-resistance with other antibiotics has not been seen. Adverse effects depend on the application site. With application to the skin, local irritation can occur, but systemic effects occur rarely, if at all. (Absorption from intact skin is minimal, and any absorbed drug undergoes rapid conversion to inactive products.) With intranasal application, the most common side effects are headache (9%), rhinitis (6%), upper respiratory
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Pharmacology Care, 7th Edition any absorbedfor drugNursing undergoes rapid conversion to inactive products.) With intranasal application, the most common side effects are headache (9%), rhinitis (6%), upper respiratory congestion (5%), and pharyngitis (4%). Mupirocin is available as a 2% cream and a 2% ointment. For impetigo, the cream or ointment is applied 3 times a day for 10 to 12 days. To eradicate MRSA nasal colonization, the ointment is applied twice daily for 5 days. 86.3.8.2.1
1014 1015
KEY POINTS ▪ Tetracyclines are broad-spectrum, bacteriostatic antibiotics that inhibit bacterial protein synthesis. ▪ Tetracyclines are first-choice drugs for just a few infections, including those caused by Chlamydia trachomatis, rickettsia (eg, Rocky Mountain spotted fever), H. pylori (ie, peptic ulcer disease), B. anthracis (anthrax), Borrelia burgdorferi (Lyme disease), and M. pneumoniae. ▪ Tetracyclines form insoluble chelates with calcium, iron, magnesium, aluminum, and zinc. Accordingly, they must not be administered with calcium supplements, milk products, iron supplements, magnesium-containing laxatives, and most antacids. ▪ Tetracycline and demeclocycline should not be given to patients with renal failure. ▪ Tetracyclines can stain developing teeth, and therefore should not be given to pregnant women or children under 8 years old. ▪ Because they are broad-spectrum antibiotics, tetracyclines can cause suprainfections, especially antibioticassociated pseudomembranous colitis (AAPMC) and overgrowth of the mouth, pharynx, vagina, or bowel with Candida albicans. ▪ High doses of tetracyclines can cause severe liver damage, especially in pregnant and postpartum women who have renal impairment. ▪ Erythromycin, the prototype of the macrolide antibiotics, is a bacteriostatic drug that inhibits bacterial protein synthesis. ▪ Erythromycin has an antimicrobial spectrum similar to that of penicillin G, and hence can be used in place of penicillin G in patients with penicillin allergy.
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Pharmacology for Edition hence canNursing be used in Care, place of 7th penicillin G in patients with penicillin allergy. ▪ Erythromycin is generally very safe. However, combined use of erythromycin with inhibitors of CYP3A4 increases the risk of QT prolongation and sudden cardiac death. ▪ Clindamycin is used primarily as an alternative to penicillin for serious grampositive anaerobic infections. ▪ Clindamycin causes a high incidence of AAPMC. ▪ Linezolid is important because it can suppress multidrug-resistant gram-positive pathogens, including vancomycin-resistant enterococci (VRE) and methicillinresistant Staph. aureus (MRSA). 86.3.8.2.2 86.3.8.2.2.1
Summary of Major Nursing Implications* TETRACYCLINES Demeclocycline Doxycycline Minocycline Tetracycline Except where stated otherwise, the implications summarized below pertain to all tetracyclines.
86.3.8.2.2.... 86.3.8.2.2....
Preadministration Assessment Therapeutic Goal Treatment of tetracycline-sensitive infections, acne, and periodontal disease.
86.3.8.2.2....
Identifying High-Risk Patients Tetracyclines are contraindicated in pregnant women and children under 8 years of age.
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Pharmacology age.for Nursing Care, 7th Edition Tetracycline and demeclocycline must be used with great caution in patients with significant renal impairment. 86.3.8.2.2.... 86.3.8.2.2.... 86.3.8.2.2....
Implementation: Administration Routes Systemic. All tetracyclines are used systemically. Specific routes for individual agents are shown in Table 85-2.
86.3.8.2.2....
Topical. Doxycycline and minocycline are used topically to treat periodontal disease.
86.3.8.2.2.... 86.3.8.2.2....
Administration Oral. Advise patients to take oral tetracyclines on an empty stomach (1 hour before meals or 2 hours after) and with a full glass of water. Doxycycline and minocycline may be taken with food. Absorption of tetracyclines is reduced by certain chelating agents: milk products, calcium supplements, iron supplements, magnesium-containing laxatives, and most antacids. Instruct patients to allow at least 2 hours between ingestion of tetracyclines and these chelators. Instruct patients to complete the prescribed course of treatment, even though symptoms may abate before the full course is over.
86.3.8.2.2....
Parenteral. Intravenous administration is performed only when oral administration is ineffective or cannot be tolerated. Intramuscular injection is painful and used rarely.
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Pharmacologyrarely. for Nursing Care, 7th Edition 86.3.8.2.2....
Ongoing Evaluation and Interventions
86.3.8.2.2....
Minimizing Adverse Effects
86.3.8.2.2....
Gastrointestinal Irritation. Inform patients that GI distress (epigastric burning, cramps, nausea, vomiting, diarrhea) can be reduced by taking tetracyclines with meals, although absorption may be reduced.
86.3.8.2.2....
Effects on Teeth. Tetracyclines can discolor developing teeth. To prevent this, avoid tetracyclines in pregnant women and children under 8 years of age.
86.3.8.2.2....
Suprainfection. Tetracyclines can promote bacterial suprainfection of the bowel, resulting in severe diarrhea. Instruct patients to notify the prescriber if significant diarrhea develops. If suprainfection is diagnosed, discontinue tetracyclines immediately; treatment consists of oral vancomycin or metronidazole, plus fluid and electrolyte replacement. Fungal overgrowth may occur in the mouth, pharynx, vagina, and bowel. Inform patients about symptoms of fungal infection (vaginal or anal itching; inflammatory lesions of the anogenital region; black, furry appearance of the tongue), and advise them to notify the prescriber if these occur. Suprainfection caused by Candida can be managed by discontinuing the tetracycline or by giving an antifungal drug.
86.3.8.2.2....
1015 1016
Hepatotoxicity. Tetracyclines can cause fatty infiltration of the liver, resulting in jaundice and, rarely, massive liver failure. The risk of liver injury can be reduced by avoiding high-dose IV therapy and by withholding tetracyclines from pregnant and postpartum women who have kidney disease.
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Pharmacologypostpartum for Nursing 7th Edition womenCare, who have kidney disease. 86.3.8.2.2....
Renal Toxicity. Tetracyclines can exacerbate pre-existing renal impairment. Tetracycline and demeclocycline should not be used by patients with kidney disease.
86.3.8.2.2....
Photosensitivity. Tetracyclines can increase the sensitivity of the skin to ultraviolet light, thereby increasing the risk of sunburn. Advise patients to avoid prolonged exposure to sunlight, wear protective clothing, and apply a sunscreen to exposed skin.
86.3.8.2.2.2
ERYTHROMYCIN The implications summarized below apply to all forms of erythromycin, except where noted otherwise.
86.3.8.2.2.... 86.3.8.2.2....
Preadministration Assessment Therapeutic Goal Erythromycin is indicated for legionnaires' disease, whooping cough, diphtheria, chancroid, chlamydial infections, and other infections caused by erythromycinsensitive organisms. The drug is also used as a substitute for penicillin G in penicillin-allergic patients.
86.3.8.2.2....
Identifying High-Risk Patients All forms of erythromycin should be avoided by patients with QT prolongation and by those taking inhibitors of CYP3A4.
86.3.8.2.2.... 86.3.8.2.2.... 86.3.8.2.2....
Implementation: Administration Routes Oral. Erythromycin base, erythromycin ethylsuccinate, and erythromycin stearate.
86.3.8.2.2....
Intravenous. Erythromycin lactobionate.
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PharmacologyErythromycin for Nursing Care, 7th Edition lactobionate. 86.3.8.2.2.... 86.3.8.2.2....
Administration Oral. Advise patients to take oral preparations on an empty stomach (1 hour before meals or 2 hours after) and with a full glass of water. However, if GI upset occurs, administration may be done with meals. Inform patients using erythromycin ethylsuccinate and enteric-coated formulations of erythromycin base that they make take these drugs without regard to meals. Instruct patients to complete the prescribed course of treatment, even though symptoms may abate before the full course is over.
86.3.8.2.2....
Intravenous. Administer by slow infusion and in dilute solution to minimize thrombophlebitis.
86.3.8.2.2....
Ongoing Evaluation and Interventions
86.3.8.2.2....
Minimizing Adverse Effects
86.3.8.2.2....
Gastrointestinal Effects. Gastrointestinal disturbances (epigastric pain, nausea, vomiting, diarrhea) can be reduced by administering erythromycin with meals. Advise patients to notify the prescriber if GI reactions are severe or persistent.
86.3.8.2.2....
QT Prolongation and Sudden Cardiac Death. High levels of erythromycin can prolong the QT interval, thereby posing a risk of a potentially fatal cardiac dysrhythmia. Avoid erythromycin in patients with preexisting QT prolongation, and in those taking drugs that can increase erythromycin levels.
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Pharmacologylevels. for Nursing Care, 7th Edition 86.3.8.2.2....
Minimizing Adverse Interactions Erythromycin can increase the half-lives and plasma levels of several drugs. When erythromycin is combined with theophylline, carbamazepine, or warfarin, patients should be monitored closely for toxicity. Erythromycin can antagonize the antibacterial actions of clindamycin and chloramphenicol. Concurrent use of erythromycin with these agents is not recommended. Drugs that inhibit CYP3A4 (eg, verapamil, diltiazem, HIV protease inhibitors, azole antifungal drugs) can increase erythromycin levels, thereby posing a risk of QT prolongation and sudden cardiac death. People using these drugs should not use erythromycin.
86.3.8.2.2.3 86.3.8.2.2.... 86.3.8.2.2....
CLINDAMYCIN Preadministration Assessment Therapeutic Goal Treatment of anaerobic infections outside the CNS.
86.3.8.2.2.... 86.3.8.2.2....
Implementation: Administration Routes Oral, IM, IV, intravaginal.
86.3.8.2.2....
Administration Instruct patients to take oral clindamycin with a full glass of water. Instruct patients to complete the prescribed course of treatment, even though symptoms may abate before the full course is over.
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Pharmacology for Nursing Care, Edition symptoms may abate before7th the full course is over. 86.3.8.2.2....
Ongoing Evaluation and Interventions
86.3.8.2.2....
Minimizing Adverse Effects
86.3.8.2.2....
Antibiotic-Associated Pseudomembranous Colitis. Clindamycin can promote AAPMC, a potentially fatal suprainfection. Prominent symptoms are profuse watery diarrhea, abdominal pain, fever, and leukocytosis. Stools often contain mucus and blood. Instruct patients to report significant diarrhea (more than five watery stools per day). If AAPMC is diagnosed, discontinue clindamycin. Treat with oral vancomycin or metronidazole and vigorous replacement of fluids and electrolytes. Drugs that decrease bowel motility (eg, opioids, anticholinergics) may worsen symptoms and should be avoided. *
Patient education information is highlighted as blue text.
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Pharmacology for Nursing Care, 7th Edition 87
CHAPTER 86 Aminoglycosides: Bactericidal Inhibitors of Protein Synthesis
1017
The aminoglycosides are narrow-spectrum antibiotics, used primarily against aerobic gram-negative bacilli. These drugs disrupt protein synthesis, resulting in rapid bacterial death. The aminoglycosides can cause serious injury to the inner ear and kidney. Because of these toxicities, indications for these drugs are limited. All of the aminoglycosides carry multiple positive charges. As a result, the drugs are not absorbed from the GI tract, and hence must be administered parenterally to treat systemic infections. In the United States, seven aminoglycosides are approved for clinical use. The agents employed most commonly are gentamicin, tobramycin, and amikacin. 87.1
BASIC PHARMACOLOGY OF THE AMINOGLYCOSIDES
87.1.1
Chemistry The aminoglycosides are composed of two or more amino sugars connected by a glycoside linkage, hence the family name. At physiologic pH, these drugs are highly polar polycations (ie, they carry several positive charges), and therefore cannot readily cross membranes. As a result, aminoglycosides are not absorbed from the GI tract, do not enter the cerebrospinal fluid, and are rapidly excreted by the kidneys. Structural formulas for the three major aminoglycosides are shown in Figure 86-1.
87.1.2
Mechanism of Action The aminoglycosides disrupt bacterial protein synthesis. As indicated in Figure 86-2, these drugs bind to the 30S ribosomal subunit, and thereby cause (1) inhibition of protein synthesis, (2) premature termination of protein synthesis, and (3) production of abnormal proteins (secondary to misreading of the genetic code). The aminoglycosides are bactericidal. Cell kill is concentration dependent. Hence, the higher the concentration, the more rapidly the infection will clear. Of note, bactericidal activity persists for several hours after serum levels have dropped below the minimal bactericidal concentration, a phenomenon known as the postantibiotic effect. Bacterial kill appears to result from production of abnormal proteins rather than from simple inhibition of protein synthesis. Studies suggest that abnormal proteins become inserted in the bacterial cell membrane, causing it to leak. The resultant loss of cell contents causes death. Inhibition of protein synthesis per se does not seem the likely cause of bacterial death. Why? Because complete blockade of protein synthesis by other antibiotics (eg, tetracyclines,
CHAPTER 86 Aminoglycosides: Bactericidal Inhibitors of Protein Synthesis
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Pharmacology for Nursing Edition Inhibition of protein synthesis perCare, se does7th not seem the likely cause of bacterial death. Why? Because complete blockade of protein synthesis by other antibiotics (eg, tetracyclines, chloramphenicol) is usually bacteriostatic—not bactericidal. 87.1.3
Microbial Resistance The principal cause for bacterial resistance is production of enzymes that can inactivate aminoglycosides. Among gram-negative bacteria, the genetic information needed to synthesize these enzymes is acquired through transfer of R factors. To date, more than 20 different aminoglycosideinactivating enzymes have been identified. Since each of the aminoglycosides can be modified by more than one of these enzymes, and since each enzyme can act on more than one aminoglycoside, patterns of bacterial resistance can be complex. Of all the aminoglycosides, amikacin is least susceptible to inactivation by bacterial enzymes. As a result, resistance to amikacin is uncommon. To minimize emergence of resistant bacteria, amikacin should be reserved for infections that are unresponsive to other aminoglycosides.
87.1.4
Antimicrobial Spectrum Bactericidal effects of the aminoglycosides are limited almost exclusively to aerobic gramnegative bacilli. Sensitive organisms include Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, Proteus mirabilis, and Pseudomonas aeruginosa. Aminoglycosides are inactive against most gram-positive bacteria. Aminoglycosides cannot kill anaerobes. To produce antibacterial effects, aminoglycosides must be transported across the bacterial cell membrane, a process that is oxygen dependent. Since, by definition, anaerobic organisms live in the absence of oxygen, these microbes cannot take up aminoglycosides, and hence are resistant. For the same reason, aminoglycosides are inactive against facultative bacteria when these organisms are living under anaerobic conditions.
87.1.5
Therapeutic Use
87.1.5.1
Parenteral Therapy. The principal use for parenteral aminoglycosides is treatment of serious infections due to aerobic gram-negative bacilli. Primary target organisms are
CHAPTER 86 Aminoglycosides: Bactericidal Inhibitors of Protein Synthesis
1017
Page 2 of 20
Pharmacology for Nursing aerobic gram-negative bacilli. Care, Primary7th targetEdition organisms are
1017
Figure 86-1 Structural formulas of the major aminoglycosides.
1018
Pseudomonas aeruginosa and the Enterobacteriaceae (eg, E. coli, Klebsiella, Serratia, Proteus mirabilis). One aminoglycoside—gentamicin—is now commonly used in combination with either vancomycin or a beta-lactam antibiotic to treat serious infections with certain gram-positive cocci, specifically Enterococcus species, some streptococci, and Staphylococcus aureus. The aminoglycosides used most commonly for parenteral therapy are gentamicin, tobramycin, and amikacin. Selection among the three depends in large part on patterns of resistance in a given community or hospital. In settings where resistance to aminoglycosides is uncommon, either gentamicin or tobramycin is usually preferred. Of the two, gentamicin is less expensive and may be selected on this basis. Organisms resistant to both gentamicin and tobramycin are usually sensitive to amikacin. Accordingly, in settings where resistance to gentamicin and tobramycin is common, amikacin may be preferred for initial therapy.
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Pharmacology Nursing Care, 7th Edition tobramycin isfor common, amikacin may be preferred for initial therapy. 87.1.5.2
Oral Therapy. Aminoglycosides are not absorbed from the GI tract, and hence oral therapy is used only for local effects within the intestine. In patients anticipating elective colorectal surgery, oral aminoglycosides have been given prophylactically to suppress bacterial growth in the bowel. One aminoglycoside—paromomycin—is used to treat intestinal amebiasis.
87.1.5.3
Topical Therapy. Neomycin is available in formulations for application to the eyes, ears, and skin. Topical preparations of gentamicin and tobramycin are used to treat conjunctivitis caused by susceptible gram-negative bacilli.
87.1.6
Pharmacokinetics All of the aminoglycosides have similar pharmacokinetic profiles. Pharmacokinetic properties of the principal aminoglycosides are summarized in Table 86-1.
87.1.6.1
Absorption. Because they are polycations, the aminoglycosides cross membranes poorly. As a result, very little (about 1%) of an oral dose is absorbed. Hence, for treatment of systemic infections, aminoglycosides must be given parenterally (IM or IV). Absorption following application to the intact skin is minimal. However, when used for wound irrigation, aminoglycosides may be absorbed in amounts sufficient to produce systemic toxicity.
87.1.6.2
Distribution. Distribution of aminoglycosides is limited largely to extracellular fluid. Entry into the cerebrospinal fluid is insufficient to treat meningitis in adults. Aminoglycosides bind tightly to renal tissue, achieving levels in the kidney up to 50 times higher than levels in serum. These high levels are responsible for nephrotoxicity (see below). Aminoglycosides penetrate readily to the perilymph and endolymph of the inner ear, and can thereby cause ototoxicity (see below). Aminoglycosides can cross the placenta and may be toxic to the fetus.
87.1.6.3
Elimination. The aminoglycosides are eliminated primarily by the kidney. These drugs are not metabolized. In patients with normal renal function, half-lives of the aminoglycosides range from 2 to 3 hours. However, because elimination is almost exclusively renal, half-lives increase
CHAPTER 86 Aminoglycosides: Bactericidal Inhibitors of Protein Synthesis
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Pharmacology fornormal Nursing Care, half-lives 7th Edition In patients with renal function, of the aminoglycosides range from 2 to 3 hours. However, because elimination is almost exclusively renal, half-lives increase dramatically in patients with renal impairment (see Table 86-1). Accordingly, to avoid serious toxicity, we must reduce dosage size or increase the dosing interval in patients with kidney disease. 87.1.6.4
Interpatient Variation. Different patients receiving the same aminoglycoside dosage (in milligrams per kilogram of body weight) can achieve widely different serum levels of drug. This interpatient variation is caused by several factors,
Figure 86-2 Mechanism of action of aminoglycosides.A, Protein synthesis begins with binding of the 50S and 30S ribosomal subunits to messenger RNA (mRNA), followed by attachment of the first amino acid of the new protein to the 50S subunit. As the ribosome moves down the mRNA strand, additional amino acids are added to the growing peptide chain. When the new protein is complete, it separates from the ribosome and the ribosomal subunits separate from the mRNA. B, Aminoglycosides bind to the 30S ribosomal subunit and can thereby (1) block initiation, (2) terminate synthesis before the new protein is complete, and (3) cause misreading of the genetic code, which causes synthesis of faulty proteins.
1018 1019
including age, percent body fat, and pathophysiology (eg, renal impairment, fever, edema, CHAPTER 86 Aminoglycosides: Bactericidal Page 5 of 20 Inhibitors of Protein Synthesis
Pharmacology for Nursing Care, 7th Edition including age, percent body fat, and pathophysiology (eg, renal impairment, fever, edema, dehydration). Because of variability among patients, aminoglycoside dosage must be individualized. As dramatic evidence of this need, in one clinical study it was observed that, in order to produce equivalent serum drug levels, the doses required ranged from as little as 0.5 mg/kg in one patient to a high of 25.8 mg/kg in another—a difference of more than 50-fold. 87.1.7
Adverse Effects The aminoglycosides can produce serious toxicity, especially to the inner ear and kidney. The inner ear and kidney are vulnerable because aminoglycosides become concentrated within cells of these structures.
87.1.7.1
Ototoxicity. All aminoglycosides can accumulate within the inner ear, causing cellular injury that can impair both hearing and balance. Impairment of hearing is caused by damage to sensory hair cells in the cochlea. Disruption of balance is caused by damage to sensory hair cells of the vestibular apparatus.
1019 1020
TABLE 86-1 Dosages and Pharmacokinetics of Systemic Aminoglycosides Total Daily
Half-Life in Adults (hr)
Dose (mg/kg)a,b
Generic Name
Trade Name
Amikacin
Amikin
Therapeutic (Peak)
Adults Children Normal Anuric Levelc,d (mcg/mL) 15
Safe Trough
Levele,f (mcg/mL)
15
2–3
24–60
15–30
Less than 5–10
Gentamicin generic
3–5h
6–7.5h
2
24–60
4–10i
Less than
Tobramycin generic
3–6
6–7.5
2–2.5
24–60
4–10
Less than
onlyg
onlyj,k
a
1–2j 1–2j
The total daily dose may be administered as one large dose each day, or as two or three divided doses given at equally spaced intervals around-the-clock.
CHAPTER 86 Aminoglycosides: Bactericidal Inhibitors of Protein Synthesis
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Pharmacology for Nursing Care, 7th Edition b
Because of interpatient variability, standard doses cannot be relied upon to produce appropriate serum drug levels, and hence dosage should be adjusted on the basis of serum drug measurements.
c
Measured 30 minutes after IM injection or a 30-minute IV infusion.
d
The peak values presented refer to levels obtained when the total daily dosage is given in divided doses, rather than as a single large daily dose.
e
Measured just prior to the next dose.
f
To minimize ototoxicity, drug levels should drop below the listed values between doses.
g
Formerly available as Garamycin.
h
When gentamicin is combined with either vancomycin or a beta-lactam antibiotic to treat certain gram-positive infections, the total daily dose is much lower (eg, about 1 mg/kg for adults).
i
These peak values apply when gentamicin is used to treat gram-negative infections, not when gentamicin is combined with vancomycin or a beta-lactam antibiotic to treat gram-positive infections.
j
For severe infections, the trough may be less than 2-4 mcg/mL.
k
Formerly available as Nebcin.
The risk of ototoxicity is related primarily to excessive trough levels* of drug—rather than to excessive peak levels. Why? Because, when trough levels remain persistently elevated, aminoglycosides are unable to diffuse out of inner ear cells, and hence the cells are exposed to the drug continuously for an extended time. It is this prolonged exposure, rather than brief exposure to high levels, that underlies cellular injury. In addition to high trough levels, the risk of ototoxicity is increased by (1) renal impairment (which can cause accumulation of aminoglycosides); (2) concurrent use of ethacrynic acid (a drug that has ototoxic properties of its own); and (3) administering aminoglycosides in excessive doses or for more than 10 days. Patients should be monitored for ototoxicity. The first sign of impending cochlear damage is high-pitched tinnitus (ringing in the ears). As injury to cochlear hair cells proceeds, hearing in the high-frequency range begins to decline. Loss of low-frequency hearing develops with continued drug use. Because the initial decline in high-frequency hearing is subtle, audiometric testing is needed to detect it. The first sign of impending vestibular damage is headache, which may last for 1 or 2 days. After that, nausea, unsteadiness, dizziness, and vertigo begin to appear. Patients should be informed about the symptoms of vestibular and cochlear damage
CHAPTER 86 Aminoglycosides: Bactericidal Inhibitors of Protein Synthesis
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Pharmacology 7thunsteadiness, Edition dizziness, and vertigo begin to may last for 1for or 2Nursing days. After Care, that, nausea, appear. Patients should be informed about the symptoms of vestibular and cochlear damage and instructed to report them. Ototoxicity is largely irreversible. Accordingly, if permanent injury is to be avoided, aminoglycosides should be withdrawn at the first sign of damage (ie, tinnitus, persistent headache, or both). The risk of ototoxicity can be minimized in several ways. Dosages should be adjusted so that trough serum drug levels do not exceed recommended values. (Aminoglycosides diffuse out of the endolymph and perilymph during the trough time, thereby decreasing exposure of sensory hair cells.) Special care should be taken to ensure safe trough levels in patients with renal impairment. When possible, aminoglycosides should be used for no more than 10 days. Concurrent use of ethacrynic acid should be avoided. * 87.1.7.2
The trough serum level is defined as the lowest level between doses, and occurs just prior to administering the next dose.
Nephrotoxicity. Aminoglycosides can injure cells of the proximal renal tubules. These drugs are taken up by tubular cells and achieve high intracellular concentrations. Nephrotoxicity correlates with the total cumulative dose of aminoglycosides and with high trough levels. High peak levels do not seem to increase toxicity. Aminoglycoside-induced nephrotoxicity usually manifests as acute tubular necrosis. Prominent symptoms are proteinuria, casts in the urine, production of dilute urine, and elevations in serum creatinine and blood urea nitrogen (BUN). Serum creatinine and BUN should be monitored. The risk of nephrotoxicity is especially high in the elderly, in patients with pre-existing kidney disease, and in patients receiving other nephrotoxic drugs (eg, amphotericin B, cephalothin, cyclosporine). Fortunately, cells of the proximal tubule readily regenerate. As a result, injury to the kidney usually reverses following cessation of aminoglycoside use.* The most significant consequence of renal damage is accumulation of aminoglycosides themselves, which can lead to ototoxicity and even more kidney damage. *
87.1.7.3
If interstitial fibrosis or renal tubular nercrosis develop, damage to the kidney may be permanent.
Neuromuscular Blockade. Aminoglycosides can inhibit neuromuscular transmission, causing flaccid paralysis and potentially fatal respiratory depression. Most episodes of neuromuscular blockade have occurred following intraperitoneal or intrapleural instillation of aminoglycosides. However, neuromuscular blockade has also occurred with IV, IM, and oral administration. The risk of
CHAPTER 86 Aminoglycosides: Bactericidal Inhibitors of Protein Synthesis
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Pharmacology for Nursing Care, 7th Edition occurred following intraperitoneal or intrapleural instillation of aminoglycosides. However, neuromuscular blockade has also occurred with IV, IM, and oral administration. The risk of paralysis is increased by concurrent use of neuromuscular blocking agents and general anesthetics. Myasthenia gravis is an additional risk. Neuromuscular blockade can be reversed with calcium; IV infusion of a calcium salt (eg, calcium gluconate) is the treatment of choice. Because of increased prescriber awareness, aminoglycoside-induced neuromuscular blockade is now rare. 87.1.7.4
Other Adverse Effects. Hypersensitivity reactions (eg, rash, pruritus, urticaria) occur occasionally. Blood dyscrasias (neutropenia, agranulocytosis, aplastic anemia) are rare. Streptomycin has been associated with neurologic disorders (optic nerve dysfunction, peripheral neuritis, paresthesias of the face and hands). Oral neomycin has caused suprainfection of the bowel and intestinal malabsorption. Topical neomycin can cause contact dermatitis.
87.1.8
1021
Drug Interactions
87.1.8.1
1020
Penicillins. Penicillins and aminoglycosides are frequently employed in combination to enhance bacterial kill. The combination is effective because penicillins disrupt the cell wall, and thereby facilitate access of aminoglycosides to their site of action. Unfortunately, when present in high concentrations, penicillins can inactivate aminoglycosides by direct chemical interaction. Therefore, penicillins and aminoglycosides should not be mixed together in the same IV solution. (Inactivation is not likely to occur once the drugs are in the body, because drug concentrations are usually too low for significant chemical interaction.)
87.1.8.2
Cephalosporins and Vancomycin. Like the penicillins, cephalosporins and vancomycin weaken the bacterial cell wall, and can thereby act in concert with aminoglycosides to enhance bacterial kill.
87.1.8.3
Ototoxic Drugs. The risk of injury to the inner ear is significantly increased by concurrent use of ethacrynic acid, a loop diuretic that has ototoxic actions of its own. Combining aminoglycosides with two other loop diuretics—furosemide and bumetanide—appears to cause no more ototoxicity than aminoglycosides alone.
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Pharmacology foralone. Nursing Care, 7th Edition aminoglycosides 87.1.8.4
Nephrotoxic Drugs. The risk of renal damage is increased by concurrent therapy with other nephrotoxic agents. Additive or potentiative nephrotoxicity can occur with amphotericin B, cephalosporins, polymyxins, vancomycin, and cyclosporine, as well as with aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs).
87.1.8.5
Skeletal Muscle Relaxants. Aminoglycosides can intensify neuromuscular blockade induced by pancuronium and other skeletal muscle relaxants. If aminoglycosides are used with these agents, caution must be exercised to avoid respiratory arrest.
87.1.9
Dosing Schedules Systemic aminoglycosides may be administered as a single large dose each day, or as two or three smaller doses. Traditionally, these drugs have been administered in divided doses, given at equally spaced intervals around-the-clock (eg, every 8 hours). Today, however, it is common to administer the total daily dose all at once, rather than dividing it up. Several studies have shown that once-daily doses are just as effective as divided doses, and may be safer. Because once-daily dosing is both safe and effective, and because it's easier and cheaper than giving divided doses, once-daily dosing has become the preferred schedule. Keep in mind, however, that this schedule is not appropriate for some patients, including neonates and women who are pregnant. How can it be that giving one large daily dose is just as safe and effective as giving divided doses? The answer lies in the hypothetical data for gentamicin levels plotted in Figure 86-3. As indicated, when we give one large dose (4.5 mg/kg) once a day, we achieve a very high peak plasma level—much higher than when we give the same daily total in the form of three smaller doses (1.5 mg/kg) every 8 hours. Because of this high peak concentration, and because aminoglycosides exhibit a postantibiotic effect (see Mechanism of Action above), bacterial kill using a single daily dose is just as great as when we use divided doses—even though, with oncedaily dosing, plasma drug levels are subtherapeutic for a prolonged time between doses. This prolonged period of low drug levels also explains why once-daily dosing is very safe: Because levels
CHAPTER 86 Aminoglycosides: Bactericidal Inhibitors of Protein Synthesis
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Pharmacology for Nursing Care, 7th Edition levels Figure 86-3 Plasma gentamicin levels produced with once-daily doses versus divided doses. The curves depict plasma levels of gentamicin produced with (1) a single large dose administered once a day versus (2) the same daily total given as three smaller doses spaced 8 hours apart. Plasma levels with both regimens are high enough to produce good bactericidal effects. The shaded area indicates levels that are low enough to permit washout of the drug from vulnerable cells in the inner ear. Note that, with once-daily dosing, levels are in the washout range for over 12 hours, versus a total of only 6 hours when divided doses are used. As a result, ototoxicity is lower with the once-a-day schedule.
are low for a long time, aminoglycosides are able to wash out from vulnerable cells, thereby
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Pharmacology for Nursing Care, 7th Edition are low for a long time, aminoglycosides are able to wash out from vulnerable cells, thereby reducing injury. In contrast, when we use divided doses, the time during which drug levels are low enough to permit washout is quite short, and hence the risk of toxicity is high. 87.1.10
Monitoring Serum Drug Levels Monitoring serum drug levels provides the best basis for adjusting aminoglycoside dosage. To produce bacterial kill, peak levels must be sufficiently high. To minimize ototoxicity, trough levels must be sufficiently low. Therapeutic levels and trough levels for the major systemic aminoglycosides are listed in Table 86-1. How monitoring is done depends on the dosing schedule employed (ie, once-daily dosing or use of divided doses). When once-daily dosing is employed, we only need to measure trough levels. As a rule, there is no need to measure peak levels. Why? Because, when the entire daily dose is given at once, high peak levels are guaranteed. (They're typically 3 to 4 times those achieved with divided doses.) In contrast, when divided doses are employed, we need to measure both the peak and the trough. When drawing blood samples for aminoglycoside levels, timing is important. Samples for peak levels should be taken 30 minutes after giving an IM injection or after completing a 30-minute IV infusion. Sampling for trough levels depends on the dosing schedule. For patients receiving divided doses, trough samples should be taken just prior to the next dose. For patients receiving once-daily doses, a single sample can be drawn 1 hour before the next dose. The value should be very low, preferably close to zero.
87.2
1022
PROPERTIES OF INDIVIDUAL AMINOGLYCOSIDES
87.2.1
1021
Gentamicin
87.2.1.1
Therapeutic Use Gentamicin (formerly available as Garamycin) is used primarily to treat serious infections caused by aerobic gram-negative bacilli. Primary targets are Pseudomonas aeruginosa and the Enterobacteriaceae (eg, E. coli, Klebsiella, Serratia, Proteus mirabilis). In hospitals where resistance is not a problem, gentamicin is often the preferred aminoglycoside for use against these bacteria. Why? Because gentamicin is cheaper than the alternatives (tobramycin and amikacin). Unfortunately, resistance to gentamicin is increasing, and crossresistance to tobramycin is common. For infections that are resistant to gentamicin and tobramycin, amikacin is usually effective.
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Pharmacology for Nursing amikacin is usually effective. Care, 7th Edition In addition to its use against gram-negative bacilli, gentamicin can be combined with vancomycin, a cephalosporin, or a penicillin to treat serious infections caused by certain grampositive cocci, namely, Enterococcus species, some streptococci, and Staphylococcus aureus. 87.2.1.2
Adverse Effects and Interactions Like all other aminoglycosides, gentamicin is toxic to the kidney and inner ear. Caution must be exercised when combining gentamicin with other nephrotoxic or ototoxic drugs. Gentamicin is inactivated by penicillins and should not be mixed with these drugs in the same IV solution.
87.2.1.3
Preparations, Dosage, and Administration
87.2.1.3.1 87.2.1.3.1.1
Treatment of Gram-Negative Infections. Intravenous and Intramuscular. Gentamicin sulfate (formerly available as Garamycin) is supplied in solution (0.8, 0.9, 1, 1.2, 1.4, 1.6, 10 and 40 mg/mL) for IM and IV administration. The dosage for both routes is the same. For adults, the traditional dosing scheme consists of a loading dose (2 mg/kg) followed by doses of 1 to 1.7 mg/kg every 8 hours—for a total of 3 to approximately 5 mg/ kg/day. When once-daily dosing is employed, the dosage is 5 mg/kg every 24 hours; no loading dose is needed. For children, the traditional maintenance dosage is 2 to 2.5 mg/kg every 8 hours. In patients with renal impairment, the total daily dosage should be reduced. Duration of treatment is usually 7 to 10 days. Because of substantial interpatient variation, it is desirable to monitor serum drug levels and to adjust dosage accordingly. Peak levels should range between 4 and 10 mcg/mL (for traditional dosing) or between 16 and 24 mcg/mL (for once-daily dosing). The trough should not exceed 2 mcg/mL. For IV administration, gentamicin should be diluted in either 0.9 sodium chloride injection or 5% dextrose and infused over 30 minutes or longer. The drug should not be mixed with penicillins in the same IV solution.
87.2.1.3.1.2
Intrathecal. Intrathecal therapy is done with a 2-mg/mL solution devoid of preservatives. The usual dosage for children under 3 months old is 1 to 2 mg once daily. The usual dosage for adults is 4 to 8 mg once daily. For all patients, treatment should continue for 1 day after samples
CHAPTER 86 Aminoglycosides: Bactericidal Inhibitors of Protein Synthesis
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Pharmacology for Nursing dosage for children under 3Care, months7th old isEdition 1 to 2 mg once daily. The usual dosage for adults is 4 to 8 mg once daily. For all patients, treatment should continue for 1 day after samples of cerebrospinal fluid become negative for the infecting organism. 87.2.1.3.2
Treatment of Gram-Positive Infections. As noted, gentamicin may be combined with vancomycin, a penicillin, or a cephalosporin to treat serious infections caused by Enterococcus species, certain streptococci, and S. aureus. When gentamicin is used in this way, dosages are much lower than when the drug is used against gram-negative infections. For combination therapy, a typical dosage for adults is 1 mg/kg/day, compared with 3 to 5 mg/kg/day when the drug is used by itself.
87.2.2
Tobramycin
87.2.2.1
Uses, Adverse Effects, and Interactions. Tobramycin (formerly available as Nebcin) is similar to gentamicin with respect to uses, adverse effects, and interactions. The drug is more active than gentamicin against Pseudomonas aeruginosa, but less active against enterococci and Serratia. Inhaled tobramycin is used for patients with cystic fibrosis (see Chapter 106). Like all other aminoglycosides, tobramycin can injure the inner ear and kidney. If possible, concurrent therapy with other ototoxic or nephrotoxic drugs should be avoided.
87.2.2.2 87.2.2.2.1
Preparations, Dosage, and Administration. Intravenous and Intramuscular. Tobramycin sulfate (formerly available as Nebcin) is supplied in solution (0.8, 1.2, 10 and 40 mg/mL) for IM and IV administration. Dosages and serum levels are the same as those given for gentamicin. Ideally, dosages should be individualized to produce peak and trough levels within the ranges indicated in Table 86-1. In patients with renal impairment, the total daily dosage should be reduced. For IV administration, the drug should be diluted in either 0.9% sodium chloride injection or 5% dextrose and infused over 30 minutes or more. Tobramycin should not be mixed with penicillins in the same IV solution. Duration of treatment is usually 7 to 10 days.
87.2.2.2.2
Nebulization. For patients with cystic fibrosis, tobramycin [TOBI] is available in solution (300 mg/5 mL) for use in a nebulizer. The dosage is 300 mg twice daily administered in a repeating cycle consisting of 28 days of drug use followed by 28 days off. Cystic fibrosis is discussed in
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Pharmacology Nursing Care, 7thmg Edition for use in afor nebulizer. The dosage is 300 twice daily administered in a repeating cycle consisting of 28 days of drug use followed by 28 days off. Cystic fibrosis is discussed in Chapter 106. 87.2.3
Amikacin
87.2.3.1
Uses, Adverse Effects, and Interactions. Amikacin [Amikin] has two outstanding features: (1) of all the aminoglycosides, amikacin is active against the broadest spectrum of gram-negative bacilli; and (2) of all the aminoglycosides, amikacin is the least vulnerable to inactivation by bacterial enzymes. Because most aminoglycoside-inactivating enzymes do not affect amikacin, the incidence of bacterial resistance to this agent is lower than with other major aminoglycosides (gentamicin and tobramycin). In hospitals where resistance to gentamicin and tobramycin is common, amikacin is the preferred agent for initial treatment of infections caused by aerobic gramnegative bacilli. However, in settings where resistance to the other aminoglycosides is infrequent, amikacin should be reserved for infections of proven aminoglycoside resistance. Why? Because this practice will delay emergence of organisms resistant to amikacin. Like all other aminoglycosides, amikacin is toxic to the kidney and inner ear. Caution should be exercised if amikacin is used in combination with other ototoxic or nephrotoxic drugs.
87.2.3.2
Preparations, Dosage, and Administration. Amikacin sulfate [Amikin] is available in solution (50, 100, and 250 mg/mL) for IM and IV administration. For IV use, amikacin should be diluted in 0.9% sodium chloride injection or 5% dextrose; infusion time should be 30 to 60 minutes in adults and 1 to 2 hours in infants. The recommended dosage for adults and children is 15 mg/kg/day administered either (1) as a single daily dose or (2) in equally divided doses at 8- or 12-hour intervals. In patients with renal impairment, dosage should be reduced or the dosing interval increased. Dosage adjustments should be based on measurements of serum drug levels. As a rule, duration of treatment should not exceed 10 days.
87.2.4
Other Aminoglycosides
87.2.4.1
Neomycin Neomycin is more ototoxic and nephrotoxic than any other aminoglycoside. As a result, neomycin is not used parenterally. Instead, the drug is employed for topical treatment of infections of the eye, ear, and skin. Neomycin is also administered orally to suppress bowel flora prior to surgery of the intestine. Because aminoglycosides are not absorbed from the GI tract, oral administration constitutes a local (nonsystemic) use of the drug. Oral neomycin can
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Pharmacology Nursing Care,Because 7th Edition flora prior to for surgery of the intestine. aminoglycosides are not absorbed from the GI tract, oral administration constitutes a local (nonsystemic) use of the drug. Oral neomycin can cause suprainfection of the bowel as well as an intestinal malabsorption syndrome. 87.2.4.2
Kanamycin Kanamycin [Kantrex] is an older aminoglycoside to which bacterial resistance is common. The drug is still active against some gram-negative bacilli, but Serratia and Pseudomonas aeruginosa are resistant. Because of resistance, systemic use of the drug has sharply declined; gentamicin, tobramycin, and amikacin are preferred. Like neomycin, kanamycin is employed to suppress bacterial flora of the bowel prior to elective colorectal surgery. Kanamycin is supplied in capsules for oral use and in solution for IM and IV use.
87.2.4.3
1022 1023
Streptomycin Streptomycin, discovered in 1943, was the first aminoglycoside drug. Although once employed widely, streptomycin has been largely replaced by safer or more effective medications. As discussed in Chapter 89, streptomycin can be used in combination with other drugs to treat tuberculosis, but newer and safer agents (rifampin, isoniazid, ethambutol) are generally preferred. Streptomycin is also indicated for several uncommon infections (plague, tularemia, glanders, brucellosis). When combined with ampicillin or penicillin G, streptomycin may be used for enterococcal endocarditis.
87.2.4.4
Paromomycin Paromomycin [Humatin] is an aminoglycoside employed only for local effects within the intestine. The drug is approved for oral therapy of intestinal amebiasis, and has been used investigationally against other intestinal parasites. The dosage for amebiasis in adults and children is 8 to 12 mg/kg 3 times daily for 5 to 10 days. Principal adverse effects are nausea, cramps, and diarrhea. Paromomycin is supplied in 250-mg capsules.
87.2.4.4.1
KEY POINTS ▪ Aminoglycosides are narrow-spectrum antibiotics, used primarily against aerobic gram-negative bacilli. ▪ Aminoglycosides disrupt protein synthesis and cause rapid bacterial death.
CHAPTER 86 Aminoglycosides: Bactericidal Inhibitors of Protein Synthesis
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Pharmacology for Nursing Care, 7thsynthesis Edition ▪ Aminoglycosides disrupt protein and cause rapid bacterial death. ▪ Aminoglycosides are highly polar polycations. As a result, they are not absorbed from the GI tract, do not cross the blood-brain barrier, and are excreted rapidly by the kidney. ▪ Aminoglycosides can cause irreversible injury to sensory cells of the inner ear, resulting in hearing loss and disturbed balance. ▪ The risk of ototoxicity is related primarily to persistently elevated trough drug levels, rather than to excessive peak levels. ▪ Aminoglycosides are nephrotoxic, but renal injury is usually reversible. ▪ The risk of nephrotoxicity is related to the total cumulative dose, not to elevated trough levels. ▪ Because the same aminoglycoside dose can produce very different plasma levels in different patients, monitoring serum levels is common. Peak levels must be high enough to cause bacterial kill; trough levels must be low enough to minimize toxicity. 87.2.4.4.2 87.2.4.4.2.1
Summary of Major Nursing Implications* AMINOGLYCOSIDES Amikacin Gentamicin Kanamycin Neomycin Paromomycin Tobramycin Except where noted, the implications summarized below apply to all aminoglycosides.
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Pharmacology for Nursing Care, 7thsummarized Edition below apply to all aminoglycosides. Except where noted, the implications 87.2.4.4.2.... 87.2.4.4.2.... 87.2.4.4.2....
Preadministration Assessment Therapeutic Goal Parenteral Therapy. Treatment of serious infections caused by gram-negative aerobic bacilli. One aminoglycoside—gentamicin—is also used (in combination with vancomycin or a beta-lactam antibiotic) to treat serious infections caused by certain gram-positive cocci, namely Enterococcus species, some streptococci, and S. aureus.
87.2.4.4.2....
Oral Therapy. Suppression of bowel flora prior to elective colorectal surgery.
87.2.4.4.2....
Topical Therapy. Treatment of local infections of the eyes, ears, and skin.
87.2.4.4.2....
Identifying High-Risk Patients Aminoglycosides must be used with caution in patients with renal impairment, preexisting hearing impairment, and myasthenia gravis, and in patients receiving ototoxic drugs (especially ethacrynic acid), nephrotoxic drugs (eg, amphotericin B, cephalosporins, vancomycin, cyclosporine, NSAIDs), and neuromuscular blocking agents.
87.2.4.4.2.... 87.2.4.4.2.... 87.2.4.4.2....
Implementation: Administration Routes Intramuscular and Intravenous. Gentamicin, tobramycin, amikacin, kanamycin.
87.2.4.4.2....
Oral. Neomycin, paromomycin.
CHAPTER 86 Aminoglycosides: Bactericidal Inhibitors of Protein Synthesis
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PharmacologyNeomycin, for Nursing Care, 7th Edition paromomycin. 87.2.4.4.2....
Topical. Neomycin, tobramycin.
87.2.4.4.2....
Dosing Schedule Aminoglycosides may be given as one large dose each day, or in two or three divided doses administered at equally spaced intervals around-the-clock.
87.2.4.4.2....
Administration Aminoglycosides must be given parenterally (IV, IM) to treat systemic infections. Intravenous infusions should be done slowly (over 30 minutes or more). Do not mix aminoglycosides and penicillins in the same IV solution.
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When possible, adjust the dosage on the basis of plasma drug levels. When using divided daily doses, draw blood samples for measuring peak levels 1 hour after IM injection and 30 minutes after completing an IV infusion. When using a single daily dose, measuring peak levels is unnecessary. Draw samples for trough levels just prior to the next dose (when using divided daily doses) or 1 hour before the next dose (when using a single daily dose). In patients with renal impairment, the dosage should be reduced or the dosing interval increased. 87.2.4.4.2.... 87.2.4.4.2....
Ongoing Evaluation and Interventions Monitoring Summary Monitor aminoglycoside levels (peaks and troughs), inner ear function (hearing and balance), creatinine clearance, BUN, and urine output.
87.2.4.4.2.... 87.2.4.4.2....
Minimizing Adverse Effects Ototoxicity. Aminoglycosides can damage the inner ear, causing irreversible impairment of hearing and balance. Monitor for ototoxicity, using audiometry in high-risk patients. Instruct patients to report symptoms of ototoxicity (tinnitus, highfrequency hearing loss, persistent headache, nausea, unsteadiness, dizziness,
CHAPTER 86 Aminoglycosides: Bactericidal Inhibitors of Protein Synthesis
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Pharmacologypatients. for Nursing Care, to 7th Edition Instruct patients report symptoms of ototoxicity (tinnitus, highfrequency hearing loss, persistent headache, nausea, unsteadiness, dizziness, vertigo). If ototoxicity is detected, aminoglycosides should be withdrawn. 87.2.4.4.2....
Nephrotoxicity. Aminoglycosides can cause reversible acute tubular necrosis. To evaluate renal injury, monitor serum creatinine and BUN. If oliguria or anuria develops, withhold the aminoglycoside and notify the prescriber.
87.2.4.4.2....
Neuromuscular Blockade. Aminoglycosides can inhibit neuromuscular transmission, causing potentially fatal respiratory depression. Carefully observe patients with myasthenia gravis and patients receiving skeletal muscle relaxants or general anesthetics. Aminoglycoside-induced neuromuscular blockade can be reversed with IV calcium gluconate.
87.2.4.4.2....
Minimizing Adverse Interactions
87.2.4.4.2....
Penicillins. Aminoglycosides can be inactivated by high concentrations of penicillins. Never mix penicillins and aminoglycosides in the same IV solution.
87.2.4.4.2....
Ototoxic and Nephrotoxic Drugs. Exercise caution when using aminoglycosides in combination with other nephrotoxic or ototoxic drugs. Increased nephrotoxicity may occur with amphotericin B, cephalosporins, polymyxins, vancomycin, cyclosporine, and NSAIDs. Increased ototoxicity may occur with ethacrynic acid.
87.2.4.4.2....
Skeletal Muscle Relaxants. Aminoglycosides can intensify neuromuscular blockade induced by pancuronium and other skeletal muscle relaxants. When aminoglycosides are used concurrently with these agents, exercise caution to avoid respiratory arrest. *
Patient education information is highlighted as blue text.
CHAPTER 86 Aminoglycosides: Bactericidal Inhibitors of Protein Synthesis
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Pharmacology for Nursing Care, 7th Edition 1025
88
CHAPTER 87 Sulfonamides and Trimethoprim The sulfonamides and trimethoprim are broad-spectrum antimicrobials that have closely related mechanisms: They all disrupt the synthesis of tetrahydrofolic acid. In approaching these drugs, we begin with the sulfonamides, followed by trimethoprim, and then conclude with trimethoprim/ sulfamethoxazole, an important fixed-dose combination.
88.1
SULFONAMIDES Sulfonamides were the first drugs available for systemic treatment of bacterial infections. Their introduction and subsequent widespread use produced a sharp decline in morbidity and mortality from susceptible infections. Until the penicillins became generally available, sulfonamides remained the mainstay of antibacterial chemotherapy. With the advent of newer antimicrobial drugs, use of sulfonamides has greatly declined. Today, only a few remain on the market. Nonetheless, the sulfonamides still have important uses, primarily against urinary tract infections. With the introduction of trimethoprim/sulfamethoxazole in the 1970s, indications for the sulfonamides have expanded.
88.1.1
Basic Pharmacology Similarities among the sulfonamides are more striking than the differences. Accordingly, rather than focusing on a representative prototype, we discuss the sulfonamides as a group.
88.1.1.1
Chemistry The general structural formula for the sulfonamides is shown in Fig. 87-1. As you can see, sulfonamides are structural analogs of para-aminobenzoic acid (PABA). The antimicrobial actions of sulfonamides are based on this similarity. Individual sulfonamides vary greatly with respect to solubility in water. Older sulfonamides had low solubility, and hence they often crystallized out in the urine, causing injury to the kidneys. The sulfonamides in current use are much more soluble, and hence the risk of renal damage is low.
88.1.1.2
Mechanism of Action Sulfonamides suppress bacterial growth by inhibiting synthesis of folic acid (folate), a compound required by all cells to synthesize DNA, RNA, and proteins. The steps in folate synthesis are shown in Fig. 87-2. As indicated, sulfonamides block the step in which PABA is combined with pteridine to form dihydropteroic acid. Because of their structural similarity to PABA, sulfonamides act as competitive inhibitors of this reaction. Sulfonamides are usually
CHAPTER 87 Sulfonamides and Trimethoprim
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Pharmacology for Nursing Care, 7th Edition combined with pteridine to form dihydropteroic acid. Because of their structural similarity to PABA, sulfonamides act as competitive inhibitors of this reaction. Sulfonamides are usually bacteriostatic. Hence, host defenses are essential for a complete elimination of infection. If all cells require folate, why don't sulfonamides harm us? The answer lies in how bacteria and mammalian cells acquire folic acid. Bacteria are unable to take up folate from their environment, and hence must synthesize folic acid from precursors. It is this process that sulfonamides disrupt. In contrast, mammalian cells do not manufacture their own folate. Rather, they simply take up folic acid obtained from the diet, using a specialized transport system for uptake. Because mammalian cells use preformed folic acid rather than synthesizing it, sulfonamides are harmless to us. 88.1.1.3
Microbial Resistance Many bacterial species have developed resistance to sulfonamides, thereby decreasing the utility of these drugs. Resistance is especially high among gonococci, meningococci, streptococci, and shigellae. Resistance may be acquired by spontaneous mutation or by transfer of R factors. Principal resistance mechanisms are (1) synthesis of PABA in amounts sufficient to overcome sulfonamide-mediated inhibition of dihydropteroate synthetase, (2) alteration in the structure of dihydropteroate synthetase such that binding and inhibition by sulfonamides is reduced, and (3) reduced sulfonamide uptake.
88.1.1.4
Antimicrobial Spectrum The sulfonamides are active against a broad spectrum of microbes. Susceptible organisms include gram-positive cocci (including methicillin-resistant Staphylococcus aureus), gramnegative bacilli, Listeria monocytogenes, actinomycetes (eg, Nocardia), chlamydiae (eg, Chlamydia trachomatis), some protozoa (eg, Toxoplasma, plasmodia, Isospora belli), and two fungi: Pneumocystis jiroveci (formerly thought to be Pneumocystis carinii) and Paracoccidioides brasiliensis.
88.1.1.5
Therapeutic Uses Although the sulfonamides were once employed widely, their applications are now limited. Two factors explain why: (1) introduction of bactericidal antibiotics that are less toxic than the sulfonamides, and (2) development of sulfonamide resistance. Today, urinary tract infection is the principal indication for these drugs.
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Pharmacology Nursing Care, the principal for indication for these drugs.7th Edition 88.1.1.5.1
Urinary Tract Infections. Sulfonamides are often preferred drugs for acute infections of the urinary tract. About 90% of these infections are due to Escherichia coli, a bacterium that is usually sulfonamide sensitive. Of the sulfonamides available, sulfamethoxazole (in combination with
Figure 87-1 Structural relationships among sulfonamides, PABA, and folic acid.
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trimethoprim) is generally favored. Sulfamethoxazole has good solubility in urine and achieves effective concentrations within the urinary tract. Urinary tract infections and their treatment are the topic of Chapter 88.
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Pharmacology for Care, treatment are theNursing topic of Chapter 88.7th Edition 88.1.1.5.2
Other Uses. Sulfonamides are useful drugs for nocardiosis (infection with Nocardia asteroides), listeria, paracoccidioidomycosis, and infection with Pneumocystis jiroveci. In addition, sulfonamides are alternatives to doxycycline and erythromycin for infections caused by C. trachomatis (trachoma, inclusion conjunctivitis, urethritis, lymphogranuloma venereum). Sulfonamides are used in conjunction with pyrimethamine to treat two protozoal infections: toxoplasmosis and malaria caused by chloroquine-resistant Plasmodium falciparum. Topical sulfonamides are used to treat superficial infections of the eye and to suppress bacterial colonization in burn patients. One sulfonamide—sulfasalazine—is used to treat ulcerative colitis. However, benefits in this disorder do not result from inhibiting microbial growth. Ulcerative colitis is discussed in Chapter 79.
88.1.1.6 88.1.1.6.1
Pharmacokinetics Absorption. Sulfonamides are well absorbed following oral administration. When applied topically to the skin or mucous membranes, these drugs may be absorbed in amounts sufficient to cause systemic effects.
88.1.1.6.2
Distribution. Sulfonamides are well distributed to all tissues. Concentrations in pleural, peritoneal, ocular, and similar body fluids may be as much as 80% of the concentration in blood. Sulfonamides readily cross the placenta, and levels achieved in the fetus are sufficient to produce antimicrobial effects and toxicity.
88.1.1.6.3
Metabolism. Sulfonamides are metabolized in the liver, principally by acetylation. Acetylated derivatives lack antimicrobial activity, but are just as toxic as the parent compounds. Acetylation may decrease sulfonamide solubility, thereby increasing the risk of renal damage from crystal formation.
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Pharmacology formation. for Nursing Care, 7th Edition 88.1.1.6.4
Excretion. Sulfonamides are excreted primarily by the kidneys. Hence, the rate of renal excretion is the principal determinant of their half-lives.
88.1.1.7
Adverse Effects Sulfonamides can cause multiple adverse effects. Prominent among these are hypersensitivity reactions, blood dyscrasias, and kernicterus, which occurs in newborn infants. Renal damage from crystalluria was a problem with older sulfonamides but is of minimal concern with the drugs used today.
Figure 87-2 Sites of action of sulfonamides and trimethoprim. Sulfonamides and trimethoprim inhibit sequential steps in the synthesis of tetrahydrofolic acid (FAH4). In the absence of FAH4, bacteria are unable to synthesize DNA, RNA, and proteins.
CHAPTER 87 Sulfonamides and Trimethoprim
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Pharmacology for Nursing Care, 7th Edition 88.1.1.7.1
Hypersensitivity Reactions. Sulfonamides can induce a variety of hypersensitivity reactions. Mild reactions—rash, drug fever, photosensitivity—are relatively common. To minimize photosensitivity reactions, patients should avoid prolonged exposure to sunlight, wear protective clothing, and apply a sunscreen to exposed skin. Hypersensitivity reactions are especially frequent with topical sulfonamides. As a result, these preparations are no longer employed routinely. Rather, they are reserved for ophthalmic infections, burns, and bacterial vaginosis caused by Gardnerella vaginalis and a mixed population of anaerobic bacteria. The most severe hypersensitivity response to sulfonamides is Stevens-Johnson syndrome, a rare reaction with a mortality rate of about 25%. Symptoms include widespread lesions of the skin and mucous membranes, combined with fever, malaise, and toxemia. The reaction is most likely with long-acting sulfonamides, which are now banned in the United States. Short-acting sulfonamides may also induce the syndrome, but the incidence is low. To minimize the risk of severe reactions, sulfonamides should be discontinued immediately if skin rash of any sort is observed. In addition, sulfonamides should not be given to patients with a history of hypersensitivity to sulfonamide antibiotics or to chemically related drugs, including thiazide diuretics, loop diuretics, and sulfonylurea-type oral hypoglycemics (eg, tolbutamide).
88.1.1.7.2
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Hematologic Effects. Sulfonamides can cause hemolytic anemia in patients whose red blood cells have a genetically determined deficiency in glucose-6-phosphate dehydrogenase (G6PD). This inherited trait is most common among African Americans and people of Mediterranean origin. Rarely, hemolysis occurs in the absence of G6PD deficiency. Red cell lysis can produce fever, pallor, and jaundice; patients should be observed for these signs. In addition to hemolytic anemia, sulfonamides can cause agranulocytosis, leukopenia, thrombocytopenia, and, very rarely, aplastic anemia. When sulfonamides are used for a long time, periodic blood tests should be obtained.
88.1.1.7.3
Kernicterus. Kernicterus is a disorder in newborns caused by deposition of bilirubin in the brain. Bilirubin is neurotoxic and can cause severe neurologic deficits and even death. Under normal conditions, infants are not vulnerable to kernicterus. Why? Because any bilirubin present in their blood is tightly bound to plasma proteins, and therefore is not free to enter the central
CHAPTER 87 Sulfonamides and Trimethoprim
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Pharmacology Nursing Care, 7th EditionWhy? Because any bilirubin present in conditions,for infants are not vulnerable to kernicterus. their blood is tightly bound to plasma proteins, and therefore is not free to enter the central nervous system (CNS). Sulfonamides promote kernicterus by displacing bilirubin from plasma proteins. Since the blood-brain barrier of infants is poorly developed, the newly freed bilirubin has easy access to sites within the brain. Because of the risk of kernicterus, sulfonamides should not be administered to infants under the age of 2 months. In addition, sulfonamides should not be given to pregnant women near term or to mothers who are breast-feeding. 88.1.1.7.4
Renal Damage from Crystalluria. Because of their low solubility, older sulfonamides tended to come out of solution in the urine, forming crystalline aggregates in the kidneys, ureters, and bladder. These aggregates caused irritation and obstruction, sometimes resulting in anuria and even death. Renal damage is uncommon with today's sulfonamides, owing to their increased water solubility. To minimize the risk of renal damage, adults should maintain a daily urine output of 1200 mL. This can be accomplished by consuming 8 to 10 glasses of water each day. Because the solubility of sulfonamides is highest at elevated pH, alkalinization of the urine (eg, with sodium bicarbonate) can further decrease the chances of crystalluria.
88.1.1.8 88.1.1.8.1
Drug Interactions Metabolism-Related Interactions. Sulfonamides can intensify the effects of warfarin, phenytoin, and sulfonylurea-type oral hypoglycemics (eg, glipizide, glyburide). The principal mechanism is inhibition of hepatic metabolism. When combined with sulfonamides, these drugs may require a reduction in dosage to prevent toxicity.
88.1.1.8.2
Allergy-Inducing Drugs. People who are hypersensitive to sulfonamide antibiotics are likely to be hypersensitive to all other drugs that contain a sulfonamide moiety (eg, thiazide diuretics, loop diuretics, sulfonylurea-type oral hypoglycemics). This cross-reactivity appears to reflect a general predisposition to drug allergy, rather than a specific cross-reactivity with sulfonamides. Hence sulfonamide-allergic patients may also display hypersensitivity to penicillins and possibly other drugs.
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Pharmacology fordrugs. Nursing Care, 7th Edition possibly other 88.1.2
Sulfonamide Preparations The sulfonamides fall into two major categories: (1) systemic sulfonamides and (2) topical sulfonamides. The systemic agents are used more often.
88.1.2.1
Systemic Sulfonamides In the past, we had three groups of systemic sulfonamides: short acting, intermediate acting, and long acting. Today, the long-acting agents are no longer available, owing to a high risk of Stevens-Johnson syndrome. The remaining two groups—short acting and intermediate acting —differ primarily with regard to dosing interval, which is much shorter for the shortacting drugs. Except where noted, the adverse effects and drug interactions of individual sulfonamides are the same as those discussed above.
88.1.2.1.1
Sulfamethoxazole. Sulfamethoxazole is the only intermediate-acting sulfonamide available. Because its effects are moderately prolonged, dosing can be done less often than with the short-acting agents. The risk of renal damage from crystalluria can be reduced by maintaining adequate hydration. Sulfamethoxazole is not available for use by itself—but is available in combination with trimethoprim (see below).
88.1.2.1.2
Sulfisoxazole. Sulfisoxazole is a short-acting sulfonamide. Prior to the introduction of trimethoprim/ sulfamethoxazole, sulfisoxazole was the preferred sulfonamide for urinary tract infections. The drug is just as effective as other sulfonamides and less expensive. Moreover, owing to its high water solubility, sulfisoxazole poses a minimal risk of crystalluria. Because high plasma concentrations of sulfisoxazole can be achieved, the drug is useful against a variety of systemic infections (eg, nocardiosis, chancroid, trachoma). Administration is oral. The usual dosage for adults is 1 gm every 4 to 6 hours.
88.1.2.1.3
Sulfadiazine. Sulfadiazine is a short-acting sulfonamide with lower solubility than sulfisoxazole. Accordingly, if renal damage is to be avoided, high urine flow must be maintained. Sulfadiazine crosses the blood-brain barrier with ease, and hence is the best sulfonamide for prophylaxis of meningitis (although other drugs—ciprofloxacin, ceftriaxone, rifampin—are preferred). When combined with pyrimethamine, sulfadiazine is useful against toxoplasmosis. The drug is supplied in tablets for oral administration. The usual adult dosage
CHAPTER 87 Sulfonamides and Trimethoprim
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Pharmacology Care, 7th Edition preferred). for WhenNursing combined with pyrimethamine, sulfadiazine is useful against toxoplasmosis. The drug is supplied in tablets for oral administration. The usual adult dosage is 1 gm every 4 to 6 hours. 88.1.2.2
Topical Sulfonamides Topical sulfonamides have been associated with a high incidence of hypersensitivity and are not used routinely. The preparations discussed below have proven utility and a relatively low incidence of hypersensitivity.
88.1.2.2.1
Sulfacetamide. Sulfacetamide is widely used for superficial infections of the eye (eg, conjunctivitis, corneal ulcer). The drug may cause blurred vision, sensitivity to bright light, headache, brow ache, and local irritation. Hypersensitivity is rare, but severe reactions have occurred. Accordingly, sulfacetamide should not be used by patients with a history of hypersensitivity to sulfonamides, sulfonylureas, or thiazide or loop diuretics. Sulfacetamide is available in solution and ointment formulations for local application to the eye. Trade names include Isopto Cetamide and Sodium Sulamyd.
88.1.2.2.2
Silver Sulfadiazine and Mafenide. Both of these sulfonamides are employed to suppress bacterial colonization in patients with second- and third-degree burns. Mafenide acts by the same mechanism as other sulfonamides. In contrast, antibacterial effects of silver sulfadiazine are due primarily to release of free silver—and not to the sulfonamide portion of the molecule. Local application of mafenide is frequently painful. In contrast, application of silver sulfadiazine is usually pain free. Following topical application, both agents can be absorbed in amounts sufficient to produce systemic effects. Mafenide, but not silver sulfadiazine, is metabolized to a compound that can suppress renal excretion of acid, thereby causing acidosis. Accordingly, patients receiving mafenide should be monitored for acid-base status. If acidosis becomes severe, mafenide should be discontinued for 1 to 2 days. Mafenide is marketed under the trade name Sulfamylon. Trade names for silver sulfadiazine are Silvadene, Thermazene, and SSD Cream.
88.2
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TRIMETHOPRIM Like the sulfonamides, trimethoprim [Proloprim, Trimpex] suppresses synthesis of tetrahydrofolic acid. Trimethoprim is active against a broad spectrum of microbes.
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Pharmacology foris active Nursing Care, Edition acid. Trimethoprim against a broad7th spectrum of microbes. 88.2.1
Mechanism of Action As indicated in Figure 87-2, trimethoprim inhibits dihydrofolate reductase, the enzyme that converts dihydrofolic acid to its active form: tetrahydrofolic acid. Hence, like the sulfonamides, trimethoprim suppresses bacterial synthesis of DNA, RNA, and proteins. Depending on conditions at the site of infection, trimethoprim may be bactericidal or bacteriostatic. Although mammalian cells also contain dihydrofolate reductase, trimethoprim is selectively toxic to bacteria. Why? Because bacterial dihydrofolate reductase differs in structure from mammalian dihydrofolate reductase. As a result, trimethoprim inhibits the bacterial enzyme at concentrations about 40,000 times lower than those required to inhibit the mammalian enzyme. This allows suppression of bacterial growth with doses that have essentially no effect on the host.
88.2.2
Microbial Resistance Bacteria acquire resistance to trimethoprim in three ways: (1) synthesizing increased amounts of dihydrofolate reductase, (2) producing an altered dihydrofolate reductase that has a low affinity for trimethoprim, and (3) reduced cellular permeability to trimethoprim. Resistance has resulted from spontaneous mutation and from transfer of R factors. In the United States, bacterial resistance is uncommon.
88.2.3
Antimicrobial Spectrum Trimethoprim is active against most enteric gram-negative bacilli of clinical importance, including E. coli, Klebsiella pneumoniae, Proteus mirabilis, Serratia marcescens, Salmonella, and Shigella. The drug is also active against some gram-positive bacilli (eg, Corynebacterium diphtheriae, Listeria monocytogenes), as well as some pathogenic protozoa (eg, Toxoplasma gondii), and one fungus (P. jiroveci).
88.2.4
Therapeutic Uses Trimethoprim is approved only for initial therapy of acute, uncomplicated urinary tract infections due to susceptible organisms (eg, E. coli, Proteus mirabilis, K. pneumoniae, Enterobacter species, and coagulase-negative Staphylococcus species, including S. saprophyticus). When combined with sulfamethoxazole, trimethoprim has considerably more applications, as discussed later in the chapter.
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Pharmacology for Nursing Care, 7th Edition later in the chapter. 88.2.5
Pharmacokinetics Trimethoprim is absorbed rapidly and completely from the GI tract. The drug is lipid soluble, and therefore undergoes wide distribution to body fluids and tissues. Trimethoprim readily crosses the placenta. Most of an administered dose is excreted unchanged in the urine. Hence, in the presence of renal impairment, the half-life of trimethoprim is prolonged. The concentration of trimethoprim achieved in urine is considerably higher than the concentration in blood.
88.2.6
Adverse Effects Trimethoprim is generally well tolerated. The most frequent adverse effects are itching and rash. Gastrointestinal reactions (eg, epigastric distress, nausea, vomiting, glossitis, stomatitis) occur occasionally.
88.2.6.1
Hematologic Effects. Because mammalian dihydrofolate reductase is relatively insensitive to trimethoprim, toxicities related to impaired tetrahydrofolate production are rare. These rare effects—megaloblastic anemia, thrombocytopenia, and neutropenia—occur only in individuals with preexisting folic acid deficiency. Accordingly, caution is needed when administering trimethoprim to patients in whom folate deficiency might be likely (eg, alcoholics, pregnant women, debilitated patients). If early signs of bone marrow suppression occur (eg, sore throat, fever, pallor), complete blood counts should be performed. If a significant reduction in blood cell counts is observed, trimethoprim should be discontinued. Administering folinic acid (leucovorin) will restore normal hematopoiesis.
88.2.6.2
Use in Pregnancy and Lactation. Large doses of trimethoprim have caused fetal malformations in animals. To date, no developmental abnormalities have been observed in humans. Nonetheless, since trimethoprim readily crosses the placenta, prudence dictates avoiding routine use during pregnancy. The risk of exacerbating pregnancy-related folate deficiency is an additional reason to avoid the drug at this time. Trimethoprim is excreted in breast milk and may interfere with folic acid utilization by the nursing infant. The drug should be administered with caution to women who are breastfeeding.
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Pharmacology for Nursing Care, 7th Edition feeding. 88.2.7
Preparations, Dosage, and Administration Trimethoprim [Proloprim, Trimpex] is supplied in tablets (100 mg) and an oral solution (10 mg/ mL). For urinary tract infections, the usual dosage is 100 mg PO every 12 hours or 200 mg PO every 24 hours. Duration of treatment is 10 days. Dosage should be reduced in patients with renal impairment.
88.3
TRIMETHOPRIM/SULFAMETHOXAZOLE Trimethoprim (TMP) and sulfamethoxazole (SMZ) are marketed together in a fixed-dose combination product. This combination (TMP/SMZ) is a powerful antimicrobial preparation whose components act in concert to inhibit sequential steps in tetrahydrofolic acid synthesis. Trade names for TMP/SMZ are Bactrim, Cotrim, and Septra. In many countries, the combination is known generically as co-trimoxazole.
88.3.1
Mechanism of Action The antimicrobial effects of TMP/SMZ result from inhibiting consecutive steps in the synthesis of tetrahydrofolic acid: SMZ acts first to inhibit incorporation of PABA into folic acid; TMP then inhibits dihydrofolate reductase, the enzyme that converts dihydrofolic acid into tetrahydrofolate (see Fig. 87-2). As a result, the ability of the target organism to make nucleic acids and proteins is greatly suppressed. By inhibiting two reactions required for synthesis of tetrahydrofolate, TMP and SMZ potentiate each other's effects. That is, the antimicrobial effect of the combination is more powerful than the sum of the effects of TMP alone plus SMZ alone. TMP/SMZ is selectively toxic to microbes because (1) mammalian cells use preformed folic acid, and therefore are not affected by SMZ; and (2) dihydrofolate reductases of mammalian cells are relatively insensitive to inhibition by TMP.
88.3.2
Microbial Resistance Resistance to TMP/SMZ is less than to either drug alone. This is logical in that the chances of an organism acquiring resistance to both drugs are less than its chances of developing resistance to just one or the other. Specific mechanisms of resistance to sulfonamides and TMP are presented earlier in the chapter.
88.3.3
1029
Antimicrobial Spectrum TMP/SMZ is active against a wide range of gram-positive and gram-negative bacteria. This should be no surprise in that TMP and SMZ by themselves are broad-spectrum antimicrobial drugs. About 80% of urinary tract pathogens are susceptible. Specific bacteria against which TMP/SMZ is consistently effective include E. coli, Proteus mirabilis, Listeria monocytogenes, S.
CHAPTER 87 Sulfonamides and Trimethoprim
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Pharmacology forofNursing 7thareEdition drugs. About 80% urinary tractCare, pathogens susceptible. Specific bacteria against which TMP/SMZ is consistently effective include E. coli, Proteus mirabilis, Listeria monocytogenes, S. aureus (including methicillin-resistant isolates), Chlamydia trachomatis, Salmonella typhi, Shigella species, Vibrio cholerae, Haemophilus influenzae, and Yersinia pestis. TMP/SMZ is also active against Nocardia, certain protozoa (eg, T. gondii), and two fungi (P. jiroveci and Paracoccidioides brasiliensis). 88.3.4
Therapeutic Uses TMP/SMZ is a preferred or alternative medication for a variety of infectious diseases. The combination is especially valuable for urinary tract infections, otitis media, bronchitis, shigellosis, and pneumonia caused by P. jiroveci.
88.3.4.1
Urinary Tract Infection. TMP/SMZ is indicated for chemotherapy of uncomplicated urinary tract infection caused by susceptible strains of E. coli, Klebsiella, Enterobacter, Proteus mirabilis, Proteus vulgaris, and Morganella morganii. The combination is particularly useful for chronic and recurrent infections.
88.3.4.2
Pneumocystis Pneumonia (PCP). TMP/SMZ is the treatment of choice for PCP, an infection caused by Pneumocystis jiroveci, formerly thought to be Pneumocystis carinii. Pneumocystis jiroveci is an opportunistic fungus that thrives in immunocompromised hosts (eg, cancer patients, organ transplant recipients, individuals with AIDS). When given to AIDS patients, TMP/SMZ produces a high incidence of adverse effects.
88.3.4.3
Gastrointestinal Infections. TMP/SMZ is a drug of choice for infections caused by several gram-negative bacilli, including Yersinia enterocolitica and Aeromonas. In addition, the combination is a preferred treatment for shigellosis caused by susceptible strains of Shigella flexneri and S. sonnei.
88.3.4.4
Other Infections. TMP/SMZ can be used for otitis media and acute exacerbations of chronic bronchitis when these infections are due to susceptible strains of H. influenzae or Streptococcus pneumoniae. The preparation is also useful against urethritis and pharyngeal infection caused by penicillinase-producing Neisseria gonorrhoeae. Other infections that can be treated with TMP/ SMZ include whooping cough, nocardiosis, brucellosis, melioidosis, listeria, and chancroid.
CHAPTER 87 Sulfonamides and Trimethoprim
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Pharmacology Nursing 7th brucellosis, Edition melioidosis, listeria, and chancroid. SMZ includefor whooping cough,Care, nocardiosis, 88.3.5
Pharmacokinetics
88.3.5.1
Absorption and Distribution. TMP/SMZ may be administered orally or by IV infusion. Both components of TMP/SMZ are well distributed throughout the body. Therapeutic concentrations are achieved in tissues and body fluids (eg, vaginal secretions, cerebrospinal fluid, pleural effusions, bile, aqueous humor). Both TMP and SMZ readily cross the placenta, and both enter breast milk.
88.3.5.2
Plasma Drug Levels. Optimal antibacterial effects are produced when the ratio of TMP to SMZ is 1:20. To achieve this ratio in plasma, TMP and SMZ must be administered in a ratio of 1:5. Hence, standard tablets contain 80 mg of TMP and 400 mg of SMZ. Because the plasma half-lives of TMP and SMZ are similar (10 hours for TMP and 11 hours for SMZ), levels of both drugs decline in parallel, and the 1:20 ratio is maintained as the drugs are eliminated.
88.3.5.3
Elimination. Both TMP and SMZ are excreted primarily by the kidneys. About 70% of urinary SMZ is present as inactive metabolites. In contrast, TMP undergoes little metabolism prior to excretion. Both agents are concentrated in the urine. Hence, levels of active drug are higher in the urine than in plasma, despite some conversion to inactive products.
88.3.6
Adverse Effects TMP/SMZ is generally well tolerated; toxicity from routine use is rare. The most common adverse effects are nausea, vomiting, and rash. However, although infrequent, all of the serious toxicities associated with sulfonamides can occur with TMP/SMZ. That is, the combination can cause hypersensitivity reactions (including Stevens-Johnson syndrome), blood dyscrasias (hemolytic anemia, agranulocytosis, leukopenia, thrombocytopenia, aplastic anemia), kernicterus, and renal damage. Primarily because of its TMP component, TMP/SMZ can induce megaloblastic anemia, but only in patients who are folate deficient. TMP/SMZ may also cause adverse CNS effects (headache, depression, hallucinations). Hyperkalemia is a potential complication of TMP/SMZ therapy, especially when the dosage is high. Patients suffering from AIDS are unusually susceptible to TMP/SMZ toxicity. In this group, the incidence of adverse effects (rash, recurrent fever, leukopenia) is about 55%. Several measures can reduce the incidence and severity of adverse effects. Crystalluria can be avoided by maintaining adequate hydration. Periodic blood tests permit early detection of hematologic disorders. To avoid kernicterus, TMP/SMZ should be withheld from pregnant
CHAPTER 87 Sulfonamides and Trimethoprim
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Pharmacology for Nursing 7thPeriodic Edition avoided by maintaining adequateCare, hydration. blood tests permit early detection of hematologic disorders. To avoid kernicterus, TMP/SMZ should be withheld from pregnant women near term, nursing mothers, and infants under the age of 2 months. The risk of megaloblastic anemia can be reduced by withholding sulfonamides from individuals likely to be folate deficient (eg, debilitated patients, pregnant women, alcoholics). Hypersensitivity reactions can be minimized by avoiding TMP/SMZ in patients with a history of hypersensitivity to sulfonamides or to chemically related drugs, including thiazide diuretics, loop diuretics, and sulfonylurea-type oral hypoglycemics. 88.3.7
Drug Interactions Interactions of TMP/SMZ with other drugs are due primarily to the presence of SMZ. Hence, like sulfonamides used alone, SMZ in the combination can intensify the effects of warfarin, phenytoin, and sulfonylurea-type oral hypoglycemics (eg, tolbutamide). Accordingly, when these drugs are combined with TMP/SMZ, a reduction in their dosage may be needed. TMP/SMZ may also intensify bone marrow suppression in patients receiving methotrexate.
88.3.8
Preparations, Dosage, and Administration
88.3.8.1
Preparations. Trimethoprim/sulfamethoxazole [Bactrim, Cotrim, Septra] is supplied in tablets and a suspension for oral use, and in solution for IV infusion. The ratio of TMP to SMZ in all preparations is 1:5. Two tablet strengths are available: standard tablets contain 80 mg TMP and 400 mg SMZ; double-strength tablets contain 160 mg TMP and 800 mg SMZ. Each milliliter of the oral suspension contains 8 mg TMP and 40 mg SMZ. Each milliliter of the stock solution for IV infusion contains 16 mg TMP and 80 mg SMZ; this stock solution must be greatly diluted before use.
88.3.8.2
Oral Dosing. For management of most infections, the usual adult dosage is 160 mg TMP plus 800 mg SMZ administered every 12 hours for 10 to 14 days. To treat shigellosis or traveler's diarrhea, the same dose is administered every 12 hours for 5 days. In the presence of renal impairment (creatinine clearance 15 to 30 mL/min), the dosage should be reduced by 50%. If creatinine clearance is below 15 mL/min, TMP/SMZ should not be used. To treat urinary tract infections and acute otitis media in children, the usual dosage is 4 mg/kg TMP plus 20 mg/kg SMZ administered every 12 hours for 10 days. The same dose, administered every 12 hours for 5 days, is used to treat shigellosis. As in adults, the dosage should be reduced in patients with renal dysfunction.
CHAPTER 87 Sulfonamides and Trimethoprim
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Pharmacology for Nursing Care, Edition should be reduced in patients with renal7th dysfunction. For prophylaxis of PCP in patients with AIDS, the usual dosage is 160 mg TMP plus 800 mg SMZ once daily. 88.3.8.3
Intravenous Dosing. Intravenous TMP/SMZ is reserved for severe infections. The following dosages are for adults and children, and are based on the TMP component of TMP/SMZ. For urinary tract infection or shigellosis, the total daily dose is 8 to 10 mg/kg. This total dose is administered in two to four divided doses given at equally spaced intervals. Duration of treatment is 14 days for urinary tract infection and 5 days for shigellosis. For treatment of PCP, the total daily dose is 15 to 20 mg/kg, administered in three or four divided doses given at equally spaced intervals. Duration of treatment is 3 weeks or more. Dosage for all indications should be reduced in patients with renal impairment. Intravenous TMP/SMZ represents a large fluid load, and hence must be used with care in patients needing fluid restriction.
88.3.8.3.1
1029 1030
KEY POINTS ▪ The sulfonamides and trimethoprim act by inhibiting bacterial synthesis of folic acid. ▪ Sulfonamides are used primarily for urinary tract infections. ▪ The principal adverse effects of sulfonamides are (1) hypersensitivity reactions, ranging from rash and photosensitivity to Stevens-Johnson syndrome; (2) hemolytic anemia; (3) kernicterus; and (4) renal damage. ▪ The combination product TMP/SMZ inhibits sequential steps in bacterial folic acid synthesis, and therefore is much more powerful than TMP or SMZ alone. ▪ TMP/SMZ is a preferred drug for urinary tract infections and is the drug of choice for PCP in patients with AIDS and other immunodeficiency states. ▪ The principal adverse effects of TMP/SMZ are like those caused by sulfonamides (ie, hypersensitivity reactions, hemolytic anemia, kernicterus, and renal injury).
88.3.8.3.2 88.3.8.3.2.1
Summary of Major Nursing Implications* SULFONAMIDES (SYSTEMIC) Sulfadiazine
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PharmacologySulfadiazine for Nursing Care, 7th Edition Sulfamethoxazole† Sulfisoxazole The nursing implications summarized here apply only to systemic sulfonamides. Implications specific to topical sulfonamides are not summarized. 88.3.8.3.2.... 88.3.8.3.2....
Preadministration Assessment Therapeutic Goal Sulfonamides are used primarily for urinary tract infections caused by E. coli and other susceptible organisms.
88.3.8.3.2....
Identifying High-Risk Patients Sulfonamides are contraindicated for nursing mothers, pregnant women near term, infants under 2 months old, and patients with a history of severe hypersensitivity to sulfonamides and chemically related drugs, including thiazide diuretics, loop diuretics, and sulfonylurea-type oral hypoglycemics. Exercise caution in patients with renal impairment.
88.3.8.3.2.... 88.3.8.3.2....
Implementation: Administration Routes All systemic sulfonamides can be administered orally. Sulfisoxazole can also be administered parenterally (IV, IM, subQ).
88.3.8.3.2....
Administration Instruct patients to complete the prescribed course of treatment, even though symptoms may abate before the full course is over. Advise patients to take oral sulfonamides on an empty stomach and with a full glass of water. Administer IV sulfisoxazole by slow injection or IV drip.
CHAPTER 87 Sulfonamides and Trimethoprim
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Pharmacology for Nursing Care,by7th Administer IV sulfisoxazole slowEdition injection or IV drip. 88.3.8.3.2.... 88.3.8.3.2.... 88.3.8.3.2....
Ongoing Evaluation and Interventions Minimizing Adverse Effects Hypersensitivity Reactions. Sulfonamides can induce severe hypersensitivity reactions (eg, Stevens-Johnson syndrome). Do not give sulfonamides to patients with a history of severe hypersensitivity to sulfonamides or to chemically related drugs, including sulfonylureas, thiazide diuretics, and loop diuretics. Instruct patients to discontinue drug use at the first sign of hypersensitivity (eg, rash).
88.3.8.3.2....
Photosensitivity. Photosensitivity reactions may occur. Advise patients to avoid prolonged exposure to sunlight, wear protective clothing, and apply a sunscreen to exposed skin.
88.3.8.3.2....
Hematologic Effects. Sulfonamides can cause hemolytic anemia and other blood dyscrasias (agranulocytosis, leukopenia, thrombocytopenia, aplastic anemia). Observe patients for signs of hemolysis (fever, pallor, jaundice). When sulfonamide therapy is prolonged, periodic blood cell counts should be made.
88.3.8.3.2....
Kernicterus. Sulfonamides can cause kernicterus in newborns. Do not give these drugs to pregnant women near term, nursing mothers, or infants under 2 months old.
88.3.8.3.2....
Renal Damage. Deposition of sulfonamide crystals can injure the kidney. To minimize crystalluria, maintain hydration sufficient to produce a daily urine flow of 1200 mL in adults. Alkalinization of urine (eg, with sodium bicarbonate) can also help. Advise outpatients to consume 8 to 10 glasses of water per day.
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PharmacologyAdvise for Nursing 7th 8Edition outpatientsCare, to consume to 10 glasses of water per day. 88.3.8.3.2.... 88.3.8.3.2....
Minimizing Adverse Interactions Metabolism-Related Interactions. Sulfonamides can intensify the effects of warfarin, phenytoin, and sulfonylureatype oral hypoglycemics (eg, tolbutamide). When combined with sulfonamides, these drugs may require a reduction in dosage.
88.3.8.3.2....
1030 1031
Allergy-Inducing Drugs. People who are hypersensitive to sulfonamide antibiotics may also be hypersensitive to chemically related drugs—thiazide diuretics, loop diuretics, and sulfonylurea-type oral hypoglycemics—as well as to penicillins and other drugs that induce allergic reactions.
88.3.8.3.2.2 88.3.8.3.2.... 88.3.8.3.2....
TRIMETHOPRIM Preadministration Assessment Therapeutic Goal Initial treatment of uncomplicated urinary tract infections caused by E. coli and other susceptible organisms.
88.3.8.3.2....
Identifying High-Risk Patients Trimethoprim is contraindicated in patients with folate deficiency (manifested as megaloblastic anemia). When possible, the drug should be avoided during pregnancy and lactation.
88.3.8.3.2.... 88.3.8.3.2....
Implementation: Administration Route Oral.
88.3.8.3.2....
Dosage and Administration Instruct patients to complete the prescribed course of treatment, even though symptoms may abate before the full course is over. Reduce the dosage in patients with renal dysfunction.
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Pharmacology forthe Nursing Reduce dosage inCare, patients7th with Edition renal dysfunction. 88.3.8.3.2.... 88.3.8.3.2.... 88.3.8.3.2....
Ongoing Evaluation and Interventions Minimizing Adverse Effects Hematologic Effects. Trimethoprim can cause blood dyscrasias (megaloblastic anemia, thrombocytopenia, neutropenia) by exacerbating pre-existing folic acid deficiency. Avoid trimethoprim when folate deficiency is likely (eg, in alcoholics, pregnant women, debilitated patients). Inform patients about early signs of blood disorders (eg, sore throat, fever, pallor), and instruct them to notify the prescriber if these occur. Complete blood counts should be performed. If a significant reduction in counts is observed, discontinue trimethoprim. Normal hematopoiesis can be restored with folinic acid (leucovorin).
88.3.8.3.2....
Use in Pregnancy and Lactation. Trimethoprim should be avoided during pregnancy and lactation. The drug can exacerbate folate deficiency in pregnant women and cause folate deficiency in the nursing infant.
88.3.8.3.2.3 88.3.8.3.2.... 88.3.8.3.2....
TRIMETHOPRIM/SULFAMETHOXAZOLE Preadministration Assessment Therapeutic Goal Indications include urinary tract infections caused by E. coli and other susceptible organisms, shigellosis, and Pneumocystis pneumonia (PCP).
88.3.8.3.2....
Identifying High-Risk Patients TMP/SMZ is contraindicated for nursing mothers, pregnant women near term, infants under 2 months old, patients with folate deficiency (manifested as megaloblastic anemia), and patients with a history of hypersensitivity to sulfonamides and chemically related drugs, including thiazide diuretics, loop diuretics, and sulfonylurea-type oral hypoglycemics.
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Pharmacology for Nursing Care, 7th diuretics, and sulfonylurea-type oralEdition hypoglycemics. 88.3.8.3.2....
Implementation: Administration
88.3.8.3.2....
Routes Oral; IV (for severe infections).
88.3.8.3.2....
Dosage Adjustment In patients with renal impairment (creatinine clearance of 15 to 30 mL/min), decrease dosage by 50%. If creatinine clearance falls below 15 mL/min, discontinue drug use.
88.3.8.3.2....
Administration Instruct patients to complete the prescribed course of treatment, even though symptoms may abate before the full course is over.
88.3.8.3.2....
Ongoing Evaluation and Interventions
88.3.8.3.2....
Minimizing Adverse Effects Although serious adverse reactions are rare, TMP/SMZ can nonetheless cause all of the toxicities associated with sulfonamides and trimethoprim used alone. Hence, the nursing implications summarized above regarding adverse effects of the sulfonamides alone and trimethoprim alone also apply to the combination of TMP/ SMZ.
88.3.8.3.2....
Minimizing Adverse Interactions TMP/SMZ has the same drug interactions as sulfonamides used alone. That is, TMP/ SMZ can increase the effects of warfarin, phenytoin, and sulfonylurea-type oral hypoglycemics. When combined with TMP/SMZ, these drugs may require a reduction in dosage. *
Patient education information is highlighted as blue text.
†
Sulfamethoxazole is available only in combination with trimethoprim.
CHAPTER 87 Sulfonamides and Trimethoprim
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Pharmacology for Nursing Care, 7th Edition 1032
89
CHAPTER 88 Drug Therapy of Urinary Tract Infections Urinary tract infections (UTIs) are the most common infections encountered today. In the United States, UTIs account for over 7 million visits to healthcare providers each year. Among sexually active young women, 25% to 35% develop at least one UTI a year. Among elderly women in nursing homes, between 30% and 50% have bacteriuria at any given time. UTIs occur much less frequently in males, but are more likely to be associated with complications (eg, septicemia, pyelonephritis). Infections may be limited to bacterial colonization of the urine, or bacteria may invade tissues of the urinary tract. When bacteria invade tissues, characteristic inflammatory syndromes result: urethritis (inflammation of the urethra), cystitis (inflammation of the urinary bladder), pyelonephritis (inflammation of the kidney and its pelvis), and prostatitis (inflammation of the prostate). UTIs may be classified according to their location, in either the lower urinary tract (bladder and urethra) or upper urinary tract (kidney). Within this classification scheme, cystitis and urethritis are considered lower tract infections, whereas pyelonephritis is considered an upper tract infection. UTIs are referred to as being complicated or uncomplicated. Complicated UTIs occur in both males and females and, by definition, are associated with some predisposing factor, such as calculi (stones), prostatic hypertrophy, an indwelling catheter, or an impediment to the flow of urine (eg, physical obstruction). Uncomplicated UTIs occur primarily in women of child-bearing age and are not associated with any particular predisposing factor. Several classes of antibiotics are used to treat UTIs. Among these are sulfonamides, trimethoprim, penicillins, aminoglycosides, cephalosporins, fluoroquinolones, and the urinary tract antiseptics: nitrofurantoin, methenamine, nalidixic acid, and cinoxacin. With the exception of the urinary tract antiseptics, these drugs are discussed at length in other chapters. The basic pharmacology of the urinary tract antiseptics is introduced here.
89.1
ORGANISMS THAT CAUSE URINARY TRACT INFECTIONS The bacteria that cause UTIs differ between communityacquired infections and hospital-acquired (nosocomial) infections. The majority (more than 80%) of uncomplicated, community-acquired UTIs are caused by Escherichia coli. Rarely, other gram-negative bacilli—Klebsiella pneumoniae, Enterobacter, Proteus, Providencia, and Pseudomonas—are the cause. Gram-positive cocci, especially Staphylococcus saprophyticus, account for 10% to 15% of communityacquired infections. Hospital-acquired UTIs are frequently caused by Klebsiella, Proteus, Enterobacter, Pseudomonas, staphylococci, and enterococci; E. coli is responsible for less than 50% of these infections. Although most UTIs involve only one organism, infection with multiple organisms may
CHAPTER 88 Drug Therapy of Urinary Tract Infections
Page 1 of 15
Pharmacology for Nursing Care, 7thE.Edition Pseudomonas, staphylococci, and enterococci; coli is responsible for less than 50% of these infections. Although most UTIs involve only one organism, infection with multiple organisms may occur, especially in patients with an indwelling catheter, renal stones, or chronic renal abscesses. 89.2
SPECIFIC URINARY TRACT INFECTIONS AND THEIR TREATMENT In this section, we consider the characteristics and treatment of the major UTIs: acute cystitis, acute urethral syndrome, acute pyelonephritis, acute bacterial prostatitis, and recurrent UTIs. Most of these can be treated with oral therapy at home. The principal exception is severe pyelonephritis, which requires IV therapy in a hospital. Drugs and dosages for outpatient therapy in nonpregnant women are summarized in Table 88-1.
89.2.1
Acute Cystitis Acute cystitis is a lower urinary tract infection that occurs most often in women of child-bearing age. Clinical manifestations are dysuria, urinary urgency, urinary frequency, suprapubic discomfort, pyuria, and bacteriuria (more than 100,000 bacteria per milliliter of urine). It is important to note that many women (30% or more) with symptoms of acute cystitis also have asymptomatic upper urinary tract infection (subclinical pyelonephritis). In uncomplicated, community-acquired cystitis, the principal causative organisms are E. coli (80%), S. saprophyticus (11%), and Enterococcus faecalis.
CHAPTER 88 Drug Therapy of Urinary Tract Infections
1032 1033
Page 2 of 15
Pharmacology for Nursing Care, faecalis. 7th Edition saprophyticus (11%), and Enterococcus TABLE 88-1 Regimens for Oral Therapy of Urinary Tract Infections in Nonpregnant Women Drug
Dose
Duration
Trimethoprim/sulfamethoxazole
160/800 mg 2 times/day
3 days
Trimethoprim
100 mg 2 times/day
3 days
Ciprofloxacin
250 mg 2 times/day
3 days
Norfloxacin
400 mg 2 times/day
3 days
Levofloxacin
250 mg once daily
3 days
Nitrofurantoin (macrocrystals)
50–100 mg 4 times/day
7 days
Nitrofurantoin (monohydrate/macrocrystals)
100 mg 2 times/day
7 days
Fosfomycin
3 gm once
1 day
Trimethoprim/sulfamethoxazole
160/800 mg 2 times/day
14 days
Trimethoprim
100 mg 2 times/day
14 days
Ciprofloxacin
250–500 mg 2 times/day
14 days
Levofloxacin
500 mg once daily
10–14 days
Amoxicillin (with clavulanic acid)
500 mg 3 times/day
14 days
Cephalexin
500 mg 4 times/day
14 days
Cefotaxime
1 gm 3 times/day
14 days
Ceftriaxone
1–2 gm once daily
14 days
Trimethoprim/sulfamethoxazole
160/800 mg 2 times/day
7–14 days
Norfloxacin
400 mg 2 times/day
7–14 days
Ciprofloxacin
250–500 mg 2 times/day
7–14 days
Levofloxacin
500 mg once daily
7–14 days
Amoxicillin (with clavulanic acid)
500 mg 3 times/day
7–14 days
Cephalexin
500 mg 3 times/day
Page 3 of 15
Acute Cystitis First-Line Drugs
Second-Line Drugs
Acute Uncomplicated Pyelonephritis First-Line Drugs
Second-Line Drugs
Complicated Urinary Tract Infections
CHAPTER 88 Drug Therapy of Urinary Tract Infections
7–14 days
Pharmacology forclavulanic Nursing Amoxicillin (with acid)Care, 7th Edition 500 mg 3 times/day Cephalexin
7–14 days
500 mg 3 times/day
7–14 days
Trimethoprim/sulfamethoxazole
40/200 mg* at bedtime 3 times/wk
6 months
Trimethoprim
100 mg at bedtime
6 months
Nitrofurantoin
50–100 mg at bedtime
6 months
Norfloxacin
200 mg at bedtime
6 months
Prophylaxis of Recurrent Infection
*
One-half of a single-strength tablet.
For community-acquired infections, three types of oral therapy can be employed: (1) single-dose therapy, (2) short-course therapy (3 days), and (3) conventional therapy (7 days). Single-dose therapy and short-course therapy are recommended only for uncomplicated, community-acquired infections in women who are not pregnant and whose symptoms began less than 7 days before starting treatment. As a rule, short-course therapy is more effective than single-dose therapy and hence is generally preferred. Advantages of short-course therapy over conventional therapy are lower cost, greater adherence, fewer side effects, and less potential for promoting emergence of bacterial resistance. Conventional therapy is indicated for all patients who do not meet the criteria for short-course therapy. Among these are males, children, pregnant women, and women with suspected upper tract involvement. As indicated in Table 88-1, a variety of drugs can be used for treatment. Trimethoprim/ sulfamethoxazole and trimethoprim alone are traditional agents of choice. In communities where resistance to these drugs exceeds 20%, the fluoroquinolones (eg, ciprofloxacin, norfloxacin) are good alternatives. When adherence is a concern, fosfomycin, which requires just one dose, is an attractive choice. As a rule, beta-lactam antibiotics (eg, amoxicillin; cephalexin and other cephalosporins) should be avoided. Why? Because they are less effective than the alternatives, and less well tolerated. 89.2.2
Acute Uncomplicated Pyelonephritis Acute uncomplicated pyelonephritis is an infection of the kidneys. The disorder is common in young children, the elderly, and women of child-bearing age. Clinical manifestations include fever, chills, severe flank pain, dysuria, urinary frequency, urinary urgency, pyuria, and, usually, bacteriuria (more than 100,000 bacteria per milliliter of urine). Escherichia coli is the causative organism in 90% of initial community-acquired infections.
CHAPTER 88 Drug Therapy of Urinary Tract Infections
1033
Page 4 of 15
Pharmacology for Nursing Care, 7th Edition organism in 90% of initial community-acquired infections.
1033
Mild to moderate infection can be treated at home with oral antibiotics. Preferred options are trimethoprim/sulfamethoxazole, trimethoprim alone, ciprofloxacin, and levofloxacin. Treatment should last 14 days. Some regimens for oral therapy are shown in Table 88-1.
1034
Severe pyelonephritis requires hospitalization and IV antibiotics. Options include ciprofloxacin, ceftriaxone, ceftazidime, ampicillin plus gentamicin, and ampicillin/sulbactam. Once the infection has been controlled with IV antibiotics, a switch to oral antibiotics should be made (usually within 24 to 48 hours). 89.2.3
Complicated Urinary Tract Infections Complicated UTIs occur in males and females who have a structural or functional abnormality of the urinary tract that predisposes them to developing infection. Such predisposing factors include prostatic hypertrophy, renal calculi (stones), nephrocalcinosis, renal or bladder tumors, ureteric stricture, or an indwelling urethral catheter. Symptoms of complicated UTIs can range from mild to severe. Some patients even develop systemic illness, manifesting as fever, bacteremia, and septic shock. The microbiology of complicated UTIs is less predictable than that of uncomplicated UTIs. Although E. coli is a common pathogen, it is by no means the only one. Other possibilities include Klebsiella, Proteus, Pseudomonas, Staphylococcus aureus, Enterobacter species, Serratia species, and even Candida species. Accordingly, if treatment is to succeed, we must determine the identity and drug sensitivity of the causative organism. To do so, urine for microbiologic testing should be obtained before giving any antibiotics. If symptoms are relatively mild, treatment should wait until test results are available. However, if symptoms are severe, immediate treatment with a broad-spectrum antibiotic can be instituted. Some options are presented in Table 88-1. Once test results are known, a drug specific to the pathogen can be substituted. Duration of treatment ranges from 7 days (for cystitis) to 14 days (for pyelonephritis or when there is systemic involvement).
89.2.4
Recurrent Urinary Tract Infection Recurrent UTIs result from relapse or from reinfection. Relapse is caused by recolonization with the same organism responsible for the initial infection. In contrast, reinfection is caused by colonization with a new organism.
CHAPTER 88 Drug Therapy of Urinary Tract Infections
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Pharmacology fora new Nursing Care, 7th Edition colonization with organism. 89.2.4.1
Reinfection. More than 80% of recurrent UTIs in females are due to reinfection. These usually involve the lower urinary tract and may be related to sexual intercourse or use of a contraceptive diaphragm. If reinfections are infrequent (only one or two a year), each episode should be treated as a separate infection. Single-dose or short-course therapy can be used. When reinfections are frequent (three or more a year), long-term prophylaxis may be indicated. Prophylaxis can be achieved with low daily doses of several agents, including trimethoprim (100 mg), nitrofurantoin (50 or 100 mg), or trimethoprim/sulfamethoxazole (160 mg/800 mg). Prophylaxis should continue for at least 6 months. During this time, periodic urine cultures should be obtained. If a symptomatic episode occurs, standard therapy for acute cystitis should be given. If reinfection is associated with sexual intercourse, the risk can be decreased by voiding after intercourse and by single-dose prophylaxis (eg, trimethoprim/sulfamethoxazole [160 mg/800 mg] taken after intercourse).
89.2.4.2
Relapse. Recolonization with the original infecting organism accounts for 20% of recurrent UTIs. Symptoms that reappear shortly after completion of a course of therapy suggest either a structural abnormality of the urinary tract, involvement of the kidneys, or chronic bacterial prostatitis (the most common cause of recurrent UTI in males). If obstruction of the urinary tract is present, it should be corrected surgically. If renal calculi are the cause, they should be removed. Drug therapy is progressive. When relapse occurs in women after short-course therapy, a 2week course of therapy should be tried. If this fails, an additional 4 to 6 weeks of therapy should be tried. If this too is unsuccessful, long-term therapy (6 months) may be indicated. Drugs employed for long-term therapy of relapse include trimethoprim/sulfamethoxazole, norfloxacin, and cephalexin.
89.2.5
Acute Bacterial Prostatitis Acute bacterial prostatitis is defined as inflammation of the prostate caused by local bacterial infection. Clinical manifestations include high fever, chills, malaise, myalgia, localized pain, and various urinary tract symptoms (dysuria, nocturia, urinary urgency, urinary frequency, urinary retention). In most cases (80%), E. coli is the causative organism. Infection is frequently associated with an indwelling urethral catheter, urethral instrumentation, or transurethral
CHAPTER 88 Drug Therapy of Urinary Tract Infections
Page 6 of 15
Pharmacology forcases Nursing Care, Editionorganism. Infection is frequently retention). In most (80%), E. coli is7th the causative associated with an indwelling urethral catheter, urethral instrumentation, or transurethral prostatic resection. However, in many patients, the infection has no obvious cause. Bacterial prostatitis responds well to antimicrobial therapy. Because of local inflammation, antibiotics can readily penetrate to the site of infection. (In the absence of inflammation, penetration of the prostate is difficult.) Drug selection and route depend on the causative organism and infection severity. For severe infection with E. coli, treatment starts with an IV agent (either aztreonam or a fluoroquinolone [eg, ciprofloxacin]), followed by 4 weeks with an oral agent (either doxycycline or a fluoroquinolone). For severe infection with vancomycinsensitive Enterococcus faecalis, treatment starts with IV ampicillin/sulbactam, followed by 4 weeks with PO amoxicillin, levofloxacin, or doxycycline. 89.3
URINARY TRACT ANTISEPTICS Four urinary tract antiseptics are available: nitrofurantoin, methenamine, nalidixic acid, and cinoxacin. These drugs are used only for UTIs. All four become concentrated in the urine, and are active against the common urinary tract pathogens. These drugs do not achieve effective antibacterial concentrations in blood or tissues, and hence are not indicated for infections outside the urinary tract. As a rule, the urinary tract antiseptics are second-choice drugs for treatment or prophylaxis of UTIs.
89.3.1
Nitrofurantoin
89.3.1.1
Mechanism of Action Nitrofurantoin [Furadantin, Macrodantin, Macrobid] is a broad-spectrum antimicrobial drug. The agent is bacteriostatic in low concentrations and bactericidal in high concentrations. Therapeutic levels are achieved only in urine. Hence the drug is useful only against infections of the urinary tract. Nitrofurantoin can cause serious adverse effects. Nitrofurantoin injures bacteria by damaging DNA. However, in order to damage DNA, the drug must first be converted to a reactive form. Nitrofurantoin is selectively toxic to bacteria because, unlike mammalian cells, bacteria possess relatively high levels of the enzyme that activates the drug.
89.3.1.2
1034 1035
Antimicrobial Spectrum Nitrofurantoin is active against a large number of gram-positive and gram-negative bacteria. Susceptible organisms include staphylococci, streptococci, Neisseria, Bacteroides, and most strains of E. coli. These sensitive bacteria rarely acquire resistance. Organisms that are
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Pharmacology for Nursing 7th Edition Susceptible organisms include Care, staphylococci, streptococci, Neisseria, Bacteroides, and most strains of E. coli. These sensitive bacteria rarely acquire resistance. Organisms that are frequently insensitive include Proteus, Pseudomonas, Enterobacter, and Klebsiella. 89.3.1.3
Therapeutic Use Nitrofurantoin is indicated for acute infections of the lower urinary tract caused by susceptible organisms. In addition, the drug can be used for prophylaxis of recurrent lower UTI. Nitrofurantoin is not recommended for infections of the upper urinary tract.
89.3.1.4 89.3.1.4.1
Pharmacokinetics Absorption and Distribution. Nitrofurantoin is available in three crystalline forms: microcrystals, macrocrystals, and monohydrate/macrocrystals. The two macrocrystalline forms are absorbed relatively slowly and produce less GI distress than the microcrystalline form. All formulations produce equivalent therapeutic effects. Nitrofurantoin is distributed to tissues, but only in small amounts. Therapeutic concentrations are achieved only in urine.
89.3.1.4.2
Metabolism and Excretion. About two-thirds of each dose undergoes metabolic degradation, primarily in the liver; the remaining one-third is excreted intact in the urine. Nitrofurantoin achieves a urinary concentration of about 200 mcg/mL (compared with less than 2 mcg/mL in plasma). The drug imparts a harmless brown color to the urine; patients should be informed of this effect. For two reasons, nitrofurantoin should not be administered to individuals with renal impairment, defined here as creatinine clearance less than 40 mL/min. First, in the absence of good renal function, levels of nitrofurantoin in the urine are too low to be effective. Second, renal impairment reduces nitrofurantoin excretion, causing plasma levels of the drug to rise, thereby posing a risk of systemic toxicity.
89.3.1.5 89.3.1.5.1
Adverse Effects Gastrointestinal Effects. The most frequent adverse reactions are GI disturbances (eg, anorexia, nausea, vomiting, diarrhea). These can be minimized by administering nitrofurantoin with milk or with meals, by reducing the dosage, and by using the macrocrystalline formulation.
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Pharmacology Nursing Edition by reducingfor the dosage, and Care, by using7th the macrocrystalline formulation. 89.3.1.5.2
Pulmonary Reactions. Nitrofurantoin can induce two kinds of pulmonary reactions: acute and subacute. Acute reactions, which are most common, manifest with dyspnea, chest pain, chills, fever, cough, and alveolar infiltrates. These symptoms resolve 2 to 4 days after discontinuing the drug. Acute pulmonary responses are thought to be hypersensitivity reactions. Patients with a history of these responses should not receive nitrofurantoin again. Subacute reactions are rare and occur during prolonged treatment. Symptoms (eg, dyspnea, cough, malaise) usually regress over weeks to months following nitrofurantoin withdrawal. However, in some patients, permanent lung damage may occur.
89.3.1.5.3
Hematologic Effects. Nitrofurantoin can cause a variety of hematologic reactions, including agranulocytosis, leukopenia, thrombocytopenia, and megaloblastic anemia. In addition, hemolytic anemia may occur in infants and in patients whose red blood cells have an inherited deficiency in glucose-6-phosphate dehydrogenase. Because of the potential for hemolytic anemia in newborns, nitrofurantoin is contraindicated for pregnant women near term and for infants under the age of 1 month.
89.3.1.5.4
Peripheral Neuropathy. Damage to sensory and motor nerves is a serious concern. Demyelinization and nerve degeneration can occur and may be irreversible. Early symptoms include muscle weakness, tingling sensations, and numbness. Patients should be informed about these symptoms and instructed to report them immediately. Neuropathy is most likely in patients with renal impairment and in those taking nitrofurantoin chronically.
89.3.1.5.5
Other Adverse Effects. Nitrofurantoin can cause multiple neurologic effects (eg, headache, vertigo, drowsiness, nystagmus); all are readily reversible. Hepatotoxicity (cholestatic jaundice, chronic hepatitis, hepatocellular damage) occurs rarely.
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Pharmacology fordamage) Nursing Care, hepatocellular occurs rarely.7th Edition 89.3.1.6 89.3.1.6.1
Preparations, Dosage, and Administration Preparations. Nitrofurantoin is available in three crystalline forms: microcrystals, macrocrystals, and monohydrate/macrocrystals. Nitrofurantoin microcrystals [Furadantin] are supplied as an oral suspension (5 g/mL). Nitrofurantoin macrocrystals [Macrodantin] are supplied in capsules (25, 50, and 100 mg). Nitrofurantoin monohydrate/macrocrystals [Macrobid] are supplied in 100-mg capsules.
89.3.1.6.2
Administration. Dosing is oral. To reduce GI distress, nitrofurantoin can be administered with meals or with milk.
89.3.1.6.3
Dosage. For acute cystitis, dosage depends on which formulation is used. With the macrocrystals, the adult dosage is 50 to 100 mg 4 times a day for 7 days. With the monohydrate/macrocrystals, the adult dosage is 100 mg twice a day for 7 days. For prophylaxis of recurrent cystitis, low doses are employed (eg, 50 to 100 mg at bedtime for adults and 1 mg/kg/day in one or two doses for children).
89.3.2
Methenamine
89.3.2.1
Mechanism of Action Methenamine [Mandelamine, Hiprex, Urex] is a prodrug that, under acidic conditions, breaks down into ammonia and formaldehyde. The formaldehyde denatures bacterial proteins, causing cell death. For formaldehyde to be released, the urine must be acidic (pH 5.5 or less). Since formaldehyde is not formed at physiologic systemic pH, methenamine is devoid of systemic toxicity.
89.3.2.2
Antimicrobial Spectrum Virtually all bacteria are susceptible to formaldehyde; there is no resistance. Certain bacteria (eg, Proteus species) can elevate urinary pH (by splitting urea to form ammonia). Since formaldehyde is not released under alkaline conditions, infections with urea-splitting
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Pharmacology for Nursing Care, 7th (eg, Proteus species) can elevate urinary pH Edition (by splitting urea to form ammonia). Since formaldehyde is not released under alkaline conditions, infections with urea-splitting organisms are often unresponsive. 89.3.2.3
Therapeutic Uses Methenamine is used for chronic infection of the lower urinary tract. However, trimethoprim/ sulfamethoxazole is preferred. Methenamine is not active against infection of the upper tract. Why? Because, there is insufficient time for formaldehyde to form as the drug passes through. Methenamine does not prevent UTIs associated with catheters.
89.3.2.4 89.3.2.4.1
Pharmacokinetics Absorption and Distribution. Methenamine is rapidly absorbed after oral administration. However, approximately 30% of each dose may be converted to ammonia and formaldehyde in the acidic environment of the stomach. This can be minimized by using an enteric-coated formulation. The drug is distributed throughout total body water.
89.3.2.4.2
Excretion. Methenamine is eliminated by the kidneys. Within the urinary tract, about 20% of the drug decomposes to form formaldehyde. Levels of formaldehyde are highest in the bladder. Since formaldehyde generation takes place slowly, and since transit time through the kidney is brief, formaldehyde levels in the kidney remain subtherapeutic. Ingestion of large volumes of fluid reduces antibacterial effects by diluting methenamine and raising urinary pH. Poorly metabolized acids (eg, hippuric acid, mandelic acid, ascorbic acid) have been administered with methenamine in attempts to acidify the urine, and thereby increase formaldehyde formation. However, there is no evidence that these acids enhance therapeutic effects.
89.3.2.5
Adverse Effects and Precautions Methenamine is relatively safe and generally well tolerated. Gastric distress occurs occasionally, probably from formaldehyde in the stomach. Use of enteric-coated preparations may reduce this effect. Chronic high-dose therapy can cause bladder irritation, manifested as dysuria, frequent voiding, urinary urgency, proteinuria, and hematuria. Since decomposition of methenamine generates ammonia (in addition to formaldehyde), the drug is contraindicated for patients with liver dysfunction. Methenamine salts (methenamine mandelate, methenamine hippurate) should not be used by patients with renal impairment, since crystalluria may be
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Pharmacology 7th Edition patients with for liver Nursing dysfunction.Care, Methenamine salts (methenamine mandelate, methenamine hippurate) should not be used by patients with renal impairment, since crystalluria may be caused by precipitating the mandelate or hippurate moiety. 89.3.2.6 89.3.2.6.1
Drug Interactions Urinary Alkalinizers. Drugs that elevate urinary pH (eg, acetazolamide, sodium bicarbonate) inhibit formaldehyde production, and can thereby reduce the antibacterial effects. Patients taking methenamine should not receive alkalinizing agents.
89.3.2.6.2
Sulfonamides. Methenamine should not be combined with sulfonamides. Why? Because formaldehyde forms an insoluble complex with sulfonamides, thereby posing a risk of urinary tract injury from crystalluria.
89.3.2.7
Preparations, Dosage, and Administration Methenamine is available as two salts: methenamine mandelate and methenamine hippurate. Methenamine mandelate [Mandelamine] is supplied in enteric-coated tablets (0.5 and 1 gm) and an oral suspension (0.1 gm/mL). The usual adult dosage is 1 gm 4 times a day. The dosage for children ages 6 to 12 years is 0.5 gm 4 times a day. For children under 6 years, the dosage is 18 mg/kg 4 times a day. Methenamine hippurate [Hiprex, Urex] is supplied in 1-gm tablets. The dosage for adults and for children over 12 years is 1 gm twice a day. For children ages 6 to 12 years, the dosage is 500 mg to 1 gm twice a day.
89.3.3
1036
Nalidixic Acid
89.3.3.1
1035
Mechanism of Action Nalidixic acid [NegGram], a relative of the fluoroquinolones, inhibits replication of bacterial DNA, thereby causing DNA degradation and cell death. The precise target of nalidixic acid is DNA gyrase, the bacterial enzyme that converts closed circular DNA into a supercoiled configuration. If supercoiling does not occur, DNA replication cannot take place.
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Pharmacology Nursing does Care, 7th Edition configuration.for If supercoiling not occur, DNA replication cannot take place. 89.3.3.2
Microbial Resistance Resistant bacteria often emerge during treatment. Two mechanisms have been described: (1) production of an altered DNA gyrase that has reduced sensitivity to nalidixic acid and (2) reduced bacterial uptake of nalidixic acid. Crossresistance with cinoxacin is common. A frequent factor in resistance is suboptimal dosing. (Low levels of nalidixic acid favor overgrowth with drug-resistant organisms.) Fortunately, resistance to nalidixic acid is not carried on R factors, and therefore is not transferable.
89.3.3.3
Antimicrobial Spectrum Nalidixic acid is active against most gram-negative urinary tract pathogens, including E. coli, Klebsiella, Enterobacter, and Proteus species. Pseudomonas aeruginosa is resistant, as are most gram-positive aerobic cocci.
89.3.3.4
Therapeutic Uses Nalidixic acid is approved only for UTIs. The drug has been used to control acute infection and to prevent recurrent UTI. However, for both applications, other drugs are preferred. Nalidixic acid is not useful against infections outside the urinary tract.
89.3.3.5
Pharmacokinetics Nalidixic acid is well absorbed from the GI tract, and then undergoes rapid hepatic metabolism. Only one metabolite—hydroxynalidixic acid—has antibacterial actions. Nalidixic acid and its metabolites are excreted in the urine. The concentration of active drug in urine is about 10 times greater than in plasma. Therapeutic levels are achieved in urine even in patients with moderate to severe renal impairment. Drug concentrations outside the urinary tract are too low for antibacterial effects.
89.3.3.6
Adverse Effects Although nalidixic acid can cause multiple adverse effects, the incidence of severe effects is low. The most common effects are GI disturbances (nausea, vomiting, abdominal discomfort), visual disturbances (blurred vision, diplopia, poor accommodation, photophobia, altered color perception), and rash. Patients who experience a reduction in visual acuity should exercise appropriate caution (eg, when driving). Photosensitivity reactions can occur. Accordingly, patients should be advised to avoid excessive exposure to sunlight, wear protective clothing, and apply a sunscreen to exposed skin. Convulsions have occurred on occasion. Accordingly, nalidixic acid should be avoided by individuals with a history of convulsive disorders.
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Pharmacology for Nursing Care, Edition and apply a sunscreen to exposed skin. 7th Convulsions have occurred on occasion. Accordingly, nalidixic acid should be avoided by individuals with a history of convulsive disorders. Nalidixic acid may produce intracranial hypertension in pediatric patients, and hence should not be given to children under the age of 3 months. Blood dyscrasias (thrombocytopenia, leukopenia, hemolytic anemia) and jaundice are rare. Nonetheless, when nalidixic acid is used for more than 2 weeks, blood cell counts and liver function tests should be performed. Like the fluoroquinolone antibiotics, nalidixic acid may pose a risk of tendon rupture (eg, in the shoulder, hand, or lower leg). Accordingly, the drug should be discontinued if the patient experiences pain, inflammation, or tendon rupture. 89.3.3.7
Drug Interactions Nalidixic acid can intensify the effects of warfarin (by displacing the anticoagulant from binding sites on plasma proteins). Accordingly, when warfarin is combined with nalidixic acid, a reduction in warfarin dosage may be needed.
89.3.3.8
Preparations, Dosage, and Administration Nalidixic acid [NegGram] is supplied in 500-mg tablets. The adult dosage is 1 gm PO 4 times a day for 1 or 2 weeks. For children under the age of 12 years, the dosage is 55 mg/kg/day in four divided doses. Nalidixic acid should not be given to children under 3 months old.
89.3.4
Cinoxacin Cinoxacin [Cinobac] is a close relative of nalidixic acid. Both drugs have the same mechanism of action, antimicrobial spectrum, and indications. Furthermore, organisms that are resistant to nalidixic acid are often resistant to cinoxacin. As with other urinary tract antiseptics, therapeutic levels are achieved only in the urine. Adverse effects are like those of nalidixic acid, but their incidence is relatively low. Cinoxacin is excreted by the kidneys, primarily unchanged. The drug is supplied in 250- and 500-mg capsules for oral use. The usual adult dosage is 1 gm/day administered in two or four divided doses. Dosage should be reduced in patients with renal impairment; if not, cinoxacin might accumulate to toxic levels.
89.3.4.1
KEY POINTS ▪ Escherichia coli is the most common cause of uncomplicated, community-acquired UTIs. ▪ Except for pyelonephritis, most UTIs can be treated with oral therapy at home.
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Pharmacology Care, ▪ Exceptfor for Nursing pyelonephritis, most 7th UTIs Edition can be treated with oral therapy at home. ▪ Trimethoprim/sulfamethoxazole is frequently the treatment of choice for oral therapy of UTIs. ▪ Many drugs, including penicillins, cephalosporins, and fluoroquinolones, may be used for parenteral therapy of UTIs. ▪ Prophylaxis of recurrent UTI can be achieved with daily low doses of oral antibiotics (eg, trimethoprim/sulfamethoxazole). ▪ The urinary tract antiseptics—nitrofurantoin, methenamine, nalidixic acid, and cinoxacin—are second-choice drugs for UTIs.
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Pharmacology for Nursing Care, 7th Edition 90
CHAPTER 89 Antimycobacterial Agents: Drugs for Tuberculosis, Leprosy, and Mycobacterium avium Complex Infection
1037
Our topic for this chapter is infections caused by three species of mycobacteria: Mycobacterium tuberculosis, Mycobacterium leprae, and Mycobacterium avium. The mycobacteria are slow-growing microbes, and the infections they cause require prolonged treatment. Because therapy is prolonged, drug toxicity and poor patient adherence are significant obstacles to success. In addition, prolonged treatment promotes the emergence of drug-resistant mycobacteria. Because mycobacteria resist decolorizing by the dilute acid used in some staining protocols, these microorganisms are often referred to as acid-fast bacteria. 90.1
DRUGS FOR TUBERCULOSIS Tuberculosis (TB) is a global epidemic. Worldwide, approximately 2 billion people are infected— nearly one-third of the Earth's population. Each year, TB kills about 2 million people—more than any other infectious disease. Although new cases in the United States continue to decline (down from 20,673 in 1992 to 12,898 in 2008), in the rest of the world, new cases are on the rise. The current estimate is 9 million new cases a year. Of these, the vast majority (95%) occur in developing countries. There are two reasons for this resurgence: HIV/AIDS and the emergence of multidrug-resistant mycobacteria.
90.2
CLINICAL CONSIDERATIONS
90.2.1
Pathogenesis Tuberculosis is caused by Mycobacterium tuberculosis, an organism also known as the tubercle bacillus. Infections may be limited to the lungs or may become disseminated. In most cases, the bacteria are quiescent, and the infected individual has no symptoms. However, when the disease is active, morbidity can be significant. In the United States, approximately 10 million people harbor tubercle bacilli. However, only a small fraction have symptomatic disease.
90.2.1.1
Primary Infection Infection with M. tuberculosis is transmitted from person to person by inhaling infected sputum that has been aerosolized, usually by coughing or sneezing. As a result, initial infection is in the lung. Once in the lung, tubercle bacilli are taken up by phagocytic cells (macrophages and neutrophils). At first, the bacilli are resistant to the destructive activity of phagocytes and multiply freely within them. Infection can spread from the lungs to other organs via the
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Pharmacology for At Nursing Care, Edition and neutrophils). first, the bacilli are7th resistant to the destructive activity of phagocytes and multiply freely within them. Infection can spread from the lungs to other organs via the lymphatic and circulatory systems. In most cases, immunity to M. tuberculosis develops within a few weeks, and the infection is brought under complete control. The immune system facilitates control by increasing the ability of phagocytes to suppress multiplication of tubercle bacilli. Because of this rapid response by the immune system, most individuals (90%) with primary infection never develop clinical or radiologic evidence of disease. However, even though symptoms are absent and the progression of infection is halted, the infected individual is likely to harbor tubercle bacilli lifelong (unless drugs are given to eliminate quiescent bacilli). Hence, in the absence of treatment, there is always some risk that latent infection may become active. If the immune system fails to control the primary infection, clinical disease (tuberculosis) develops. The result is necrosis and cavitation of lung tissue. Lung tissue may also become caseous (cheese-like in appearance). In the absence of treatment, tissue destruction progresses, and death may result. 90.2.1.2
1037 1038
Reactivation The term reactivation refers to renewed multiplication of tubercle bacilli that had been dormant following control of a primary infection. Until recently, it was assumed that most new cases of symptomatic TB resulted from reactivation of an old (latent) infection. However, we now know that, among some groups, reactivation may be responsible for only 60% of new infections—the remaining 40% result from recent person-to-person transmission.
90.2.2
Diagnosis and Treatment of Active Tuberculosis The availability of modern chemotherapeutic agents has dramatically altered the treatment of TB. In the past, most patients required lengthy hospitalization. Today, hospitalization is generally unnecessary. Prolonged bed rest is neither required nor recommended. To reduce emergence of resistance, treatment is always done with two or more drugs. In addition, direct observation of drug administration is now considered standard care. The goal of treatment is to eliminate symptoms and prevent relapse. To accomplish this, treatment must kill tubercle bacilli that are actively dividing as well as those that are “resting.” Success is indicated by an absence of observable mycobacteria in sputum and by the failure of sputum cultures to yield colonies of M. tuberculosis.
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Pharmacology Nursing 7th Edition sputum culturesfor to yield coloniesCare, of M. tuberculosis. 90.2.2.1
Diagnosis Diagnostic testing is indicated for (1) individuals with clinical manifestations that suggest TB and (2) individuals with a positive skin test or blood test (see below under Diagnosis and Treatment of Latent Tuberculosis), who are at high risk of developing active disease. A definitive diagnosis is made with a chest radiograph and microbiologic evaluation of sputum. A chest radiograph should be ordered for all persons suspected of active infection. To determine if M. tuberculosis is present, sputum is evaluated in two ways: by (1) microscopic examination of sputum smears and (2) culturing of sputum samples followed by laboratory evaluation. Microscopic examination cannot provide a definitive diagnosis. Why? Because direct observation cannot distinguish between M. tuberculosis and other mycobacteria. Furthermore, microscopic examination is much less sensitive than evaluation of cultured samples. Accordingly, sputum cultures are required for definitive diagnosis. Depending on the technology employed, identification can take several days to several weeks. Evaluation of drug susceptibility can take 10 days to 1 month.
90.2.2.2
Drug Resistance Drug resistance is a major impediment to successful therapy. Some infecting bacilli are inherently resistant; others develop resistance over the course of treatment. Some bacilli are resistant to just one drug; others are resistant to multiple drugs. Infection with a resistant organism may be acquired in two ways: (1) through contact with someone who harbors resistant bacteria, and (2) through repeated ineffectual courses of therapy (see below). The emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDRTB) are recent and ominous developments. MDR-TB is defined as TB that is resistant to both isoniazid and rifampin, our two most effective antituberculosis (anti-TB) drugs. XDR-TB, a severe form of MDR-TB, is defined as TB that is resistant not only to isoniazid and rifampin, but also to all fluoroquinolones (eg, moxifloxacin), and at least one of the injectable secondline anti-TB drugs (amikacin, kanamycin, or capreomycin). Infection with multidrugresistant organisms greatly increases the risk of death, especially among patients with AIDS. In addition, multidrug resistance is expensive: The cost of treating one case of resistant TB is about $180,000, compared with $12,000 per case of nonresistant TB. Fortunately, multidrug resistance is rare in the United States: In 2006, there were 166 reported cases of MDR-TB and only 4 reported cases of XDR-TB.
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Pharmacology forcases Nursing Care, 7th Edition only 4 reported of XDR-TB. The principal cause underlying the emergence of resistance is inadequate drug therapy. Treatment may be too short; dosage may be too low; patient adherence may be erratic; and, perhaps most importantly, the regimen may contain too few drugs. 90.2.2.3
The Prime Directive: Always Treat Tuberculosis with Two or More Drugs Antituberculosis regimens must always contain two or more drugs to which the infecting organism is sensitive. To understand why this is so, we need to begin with five facts: • Resistance in M. tuberculosis occurs because of spontaneous mutations. • Each mutational event confers resistance to only one drug. • Mutations conferring resistance to a single drug occur in about 1 of every 100 million (108) bacteria.
• The bacterial burden in active TB is well above 108 organisms but far below 1016. • M. tuberculosis grows slowly, hence treatment is prolonged. Now, let's assume we initiate therapy with a single drug, and that all bacteria present are
sensitive when we start. What will happen? Over time, at least one of the more than 108 bacteria in our patient will mutate to a resistant form. Hence, as we proceed with treatment, we will kill all sensitive bacteria, but the descendants of the newly resistant bacterium will continue to flourish, thereby causing treatment failure. In contrast, if we initiate therapy with two drugs, treatment will succeed. Why? Because failure would require that at least one bacterium undergo two resistance-conferring mutations, one for each drug. Since two such mutations occur in only 1 of every 1016 bacteria (1016 is the product of the probabilities for
each mutation), and since the total bacterial load is much less than 1016, the chances of the two events occurring in one of the bacteria in our patient are nil. Not only do drug combinations decrease the risk of resistance, they can reduce the incidence of relapse. Because some drugs (eg, isoniazid, rifampin) are especially effective against actively dividing bacilli, whereas other drugs (eg, pyrazinamide) are most active against intracellular (quiescent) bacilli, by using certain combinations of anti-TB agents, we can increase the chances of killing all tubercle bacilli present, whether they are actively multiplying or dormant.
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Pharmacology for Nursing Care, 7th Edition (quiescent) bacilli, by using certain combinations of anti-TB agents, we can increase the chances of killing all tubercle bacilli present, whether they are actively multiplying or dormant. Hence, the risk of relapse is lowered.
1039
In Chapter 82 (Basic Principles of Antimicrobial Therapy), we noted that treatment with multiple antibiotics broadens the spectrum of antimicrobial coverage, thereby increasing the risk of suprainfection. This is not the case with multidrug therapy of TB. The major drugs used against M. tuberculosis are selective for this organism. As a result, these drugs, even when used in combination, do not kill off other microorganisms, and therefore do not create the conditions that lead to suprainfection. In summary, because treatment is prolonged, there is a high risk that drug-resistant bacilli will emerge if only one anti-TB agent is employed. Because the chances of a bacterium developing resistance to two drugs are very low, treatment with two or more drugs minimizes the risk of drug resistance. Therefore, when treating TB, we must always use two or more drugs to which the organism is sensitive. 90.2.2.4
Determining Drug Sensitivity Because resistance to one or more anti-TB drugs is common, and because many patterns of resistance are possible, it is essential that we determine drug sensitivity in isolates from each patient at treatment onset. Unfortunately, the process of culturing samples and testing them for susceptibility is slow, usually taking 6 to 16 weeks to complete. Until test results are available, drug selection must be empiric, based on (1) patterns of drug resistance in the community and (2) the immunocompetence of the patient. However, once test results are available, the regimen should be adjusted accordingly. In the event of treatment failure, sensitivity tests should be repeated.
90.2.2.5
Treatment Regimens Several regimens may be employed for active TB. Drug selection is based largely on the susceptibility of the infecting organism and the immunocompetence of the host. Therapy is usually initiated with a four-drug regimen; isoniazid and rifampin are almost always included. In the event of suspected or proved resistance, more drugs are added; the total may be as high as seven. Representative regimens are shown in Table 89-1 and discussed below. Treatment can be divided into two phases. The goal of the initial phase (induction phase) is to eliminate actively dividing extracellular tubercle bacilli, and thereby render the sputum noninfectious. The goal of the second phase (continuation phase) is to eliminate intracellular
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Pharmacology for Nursing Care, 7th Edition eliminate actively dividing extracellular tubercle bacilli, and thereby render the sputum noninfectious. The goal of the second phase (continuation phase) is to eliminate intracellular “persisters.” 90.2.2.5.1
Drug-Sensitive Tuberculosis. If the infecting organisms are not resistant to isoniazid or rifampin, treatment is relatively simple. As indicated in Table 89-1, the induction phase, which lasts 2 months, consists of four drugs: isoniazid, rifampin, pyrazinamide, and ethambutol. Dosing may be done daily, twice weekly, or thrice weekly. The continuation phase, which lasts 4 months, consists of two drugs—isoniazid and rifampin—administered daily, twice weekly, or thrice weekly. Note that the entire course of treatment is prolonged, making adherence a significant problem.
90.2.2.5.2
Isoniazid- or Rifampin-Resistant Tuberculosis. Infection that is resistant to a single drug—isoniazid or rifampin—usually responds well. Isoniazid-resistant TB can be treated for 6 months with three drugs: rifampin, ethambutol, and pyrazinamide. Rifampin-resistant TB can also be treated with three drugs—isoniazid, ethambutol, and pyrazinamide—but the duration is longer: 18 to 24 months, rather than 6 months.
90.2.2.5.3
Multidrug-Resistant TB and Extensively Drug-Resistant TB. MDR-TB and XDR-TB are much harder to manage than drug-sensitive TB. Treatment is prolonged (at least 24 months) and must use second- and third-line drugs, which are less effective than the first-line drugs (eg, isoniazid and rifampin) and are generally more toxic. Initial therapy may consist of five, six, or even seven drugs. Hence, an initial regimen might include (1) isoniazid; (2) rifampin; (3) pyrazinamide; (4) ethambutol; (5) kanamycin, amikacin, or capreomycin; (6) ciprofloxacin or ofloxacin; and (7) cycloserine, ethionamide, or para-aminosalicylic acid. As a last resort, infected tissue may be removed by surgery. Even with all of these measures, the prognosis is often poor: Among patients with XDR-TB, between 40% and 60% die. Factors that determine outcome include the extent of drug resistance, infection severity, and the immunocompetence of the host.
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Pharmacology Nursing Edition resistance, for infection severity,Care, and the7th immunocompetence of the host. TABLE 89-1 Representative Antituberculosis Regimens HIV-Negative Drug Resistance Patients* None
HIV-Positive
Patients*
Induction Induction Phase: IRPE for 2 Phase: IRPE for months 2 months Continuation Phase: IR for Continuation 4–7 months Phase: IR for 4 OR months Induction Phase: IPE + rifabutin for 2 months Continuation Phase: I + rifabutin for 4–7 months
Isoniazid resistance
RPE for 6 months
RPE for 6–9 months OR PE + rifabutin for 6–9 months
Rifampin resistance
IPE for 18–24 months
Interaction with Drugs for HIV Infection†
PIs: Rifampin can be used with ritonavir, but not with other PIs. NNRTIs: Rifampin can be used with high-dose nevirapine or efavirenz, but not with delavirdine. PIs: Rifabutin can be used with all PIs. NNRTIs: Rifabutin can be used with normal-dose nevirapine or efavirenz, but not with delavirdine. PIs and NNRTIs: Same as for rifampin above. PIs and NNRTIs: Same as for rifabutin above.
IPE for 18–24 months
All drugs for HIV infection can be used.
OR
All drugs for HIV infection can be used.
Induction Phase: IPSE for 2 months Continuation Phase: IPS for 7–10 months
90.2.2.5.4
*
Drugs used in these regimens: E = ethambutol, I = isoniazid, P = pyrazinamide, R = rifampin, S = streptomycin.
†
PI = HIV-protease inhibitor; NNRTI = non-nucleoside reverse transcriptase inhibitor.
Patients with TB and HIV Infection. Between 2% and 20% of patients with HIV infection develop active TB. Because of their reduced ability to fight infection, these patients require therapy that is more aggressive than in immunocompetent patients, and should last several months longer.
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Pharmacology for Nursing Care, 7th last Edition in immunocompetent patients, and should several months longer. Drug interactions are a big problem, especially for patients taking rifampin. Why? Because rifampin, a cornerstone of TB therapy, can accelerate the metabolism of antiretroviral drugs (ie, drugs used to fight HIV), and can thereby decrease their effects. Specifically, rifampin can decrease the effects of most protease inhibitors and most non-nucleoside reverse transcriptase inhibitors (NNRTIs). Accordingly, it is best to avoid combining rifampin with these agents. Unfortunately, this means that patients will be denied optimal treatment for one of their infections. That is, if they take rifampin to treat TB, they will be unable to take most protease inhibitors or NNRTIs for HIV. Conversely, if they take protease inhibitors and NNRTIs to treat HIV, they will be unable to take rifampin for TB. This dilemma does not have an easy solution. Like rifampin, rifabutin can accelerate metabolism of antiretroviral drugs. However, the degree of acceleration is much less. As a result, many of the antiretroviral drugs that must be avoided in patients taking rifampin can still be used in patients taking rifabutin. 90.2.2.6
Duration of Treatment The ideal duration of treatment has not been established. For patients with drug-sensitive TB, the minimum duration is 6 months. For patients with multidrug-resistant infection, and for patients with HIV/AIDS, treatment may last as long as 24 months after sputum cultures have become negative.
90.2.2.7
Promoting Adherence: Directly Observed Therapy Combined with Intermittent Dosing Patient nonadherence is the most common cause of treatment failure, relapse, and increased drug resistance. Recall that patients with TB must take multiple drugs for 6 months or more, making adherence a very real problem. Directly observed therapy (DOT), combined with intermittent dosing, helps ensure adherence and thereby increases the chances of success. In DOT, administration of each dose is done in the presence of an observer, usually a representative of the health department. DOT is now considered the standard of care for TB. In addition to promoting bacterial kill, DOT permits ongoing evaluation of the clinical response to treatment and adverse drug effects. Intermittent dosing is defined as dosing 2 or 3 times a week, rather than every day. Of course, each dose is larger than with daily dosing. Clinical studies have shown that intermittent dosing is just as effective as daily dosing, and no more toxic. The great advantage of intermittent
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Pharmacology for Nursing Care, 7thClinical Edition each dose is larger than with daily dosing. studies have shown that intermittent dosing is just as effective as daily dosing, and no more toxic. The great advantage of intermittent dosing is that it makes DOT more convenient, and hence enhances adherence. 90.2.2.8
Evaluating Treatment Three modes are employed to evaluate therapy: bacteriologic evaluation of sputum, clinical evaluation, and chest radiographs. In patients with positive pretreatment sputum tests, sputum should be evaluated every 2 to 4 weeks initially, and then monthly after sputum cultures become negative. With proper drug selection and good adherence, sputum cultures become negative in over 90% of patients after 3 months of treatment. Treatment failures should be evaluated for drug resistance and patient adherence. In the absence of demonstrated drug resistance, treatment with the same regimen should continue, using direct observation of drug administration to ensure that medication is being taken as prescribed. In patients with drug-resistant TB, two effective drugs should be added to the regimen. In patients with negative pretreatment sputum tests, treatment is monitored by chest radiographs and clinical evaluation. In most patients, clinical manifestations (eg, fever, malaise, anorexia, cough) should decrease markedly within 2 weeks. The radiograph should show improvement within 3 months. After completing therapy, patients should be examined every 3 to 6 months for signs and symptoms of relapse.
90.2.3
Diagnosis and Treatment of Latent Tuberculosis In the United States, an estimated 9 to 14 million people have latent TB. In the absence of treatment, 5% to 10% of these people will develop active TB. Because latent TB can become active, the condition poses a threat to the infected individual and to the community as well. Accordingly, testing and treatment are clearly desirable—but not for everyone: Because treatment of latent TB is prolonged and carries a risk of drug toxicity, testing and treatment should be limited to people who really need it. In 2000, the American Thoracic Society and the Centers for Disease Control and Prevention (CDC) issued revised clinical guidelines—Targeted Tuberculin Testing and Treatment of Latent Tuberculosis Infection—that specify who should be tested, who should be treated, and what drugs should be used. Recommendations specific to drug
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Pharmacology forand Nursing Care, 7thTuberculosis Edition Infection—that specify who should be Tuberculin Testing Treatment of Latent tested, who should be treated, and what drugs should be used. Recommendations specific to drug therapy were revised again in 2003. The discussion below reflects the updated recommendations. 90.2.3.1
Who Should Be Tested for Latent Tuberculosis? Testing should be limited to people who are at high risk of either (1) having acquired the infection recently or (2) progressing from latent TB to active TB. Included in this group are people with HIV infection, people receiving immunosuppressive drugs, recent contacts of TB patients, and people with high-risk medical conditions, such as diabetes, silicosis, or chronic renal failure. A complete list of candidates for testing is given in Table 89-2. Routine testing of low-risk individuals is not recommended.
90.2.3.2
How Do We Test for Latent Tuberculosis? There are two tests for latent TB: (1) the tuberculin skin test (TST), which has been in use for over 100 years; and (2) the QuantiFERON-TB Gold (QFT-G) blood test, which was approved for American use in 2005.
90.2.3.2.1
1040 1041
Tuberculin Skin Test. The TST is performed by giving an intradermal injection of a preparation known as purified protein derivative (PPD), an antigen derived from M. tuberculosis. If the individual has an intact immune system and has been exposed to M. tuberculosis in the past, the PPD will elicit a local immune response. The test is read 48 to 72 hours after the injection. A positive reaction is indicated by a region of induration (hardness) around the injection site.
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Pharmacology for Nursing Care, 7th Edition reaction is indicated by a region of induration (hardness) around the injection site. TABLE 89-2 Candidates for Targeted Tuberculosis Testing Individuals at High Risk of Recent Tuberculosis Infection Contacts of TB patients Residents and staff of high-risk congregate settings: • Prisons and jails • Nursing homes • Hospitals and other healthcare facilities • Homeless shelters • Residential facilities for patients with AIDS Persons who, in the last 5 years, immigrated from a country where TB is prevalent Staff of mycobacteriology laboratories Children and adolescents exposed to high-risk adults Children under the age of 4 years Individuals at High Risk of Progression from Latent to Active Tuberculosis HIV-infected persons Intravenous drug abusers Patients taking immunosuppressive drugs for 1 month or more Patients with a chest radiograph indicating fibrotic changes consistent with prior TB Patients with other high-risk medical conditions, including • Diabetes mellitus • Chronic renal failure • Silicosis • Leukemia or lymphoma • Clinical conditions associated with substantial weight loss, including postgastrectomy state, intestinal bypass surgery, chronic peptic ulcer disease, chronic malabsorption syndromes, and carcinomas of the oropharynx and upper GI tract that inhibit
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Pharmacology forstate, Nursing 7th Edition intestinalCare, bypass surgery, chronic peptic ulcer disease, chronic malabsorption syndromes, and carcinomas of the oropharynx and upper GI tract that inhibit adequate nutritional intake
The decision to treat latent TB is based on two factors: (1) the risk category of the individual and (2) the size of the region of induration produced by the TST (Table 89-3). For individuals at high risk, treatment is recommended if the region of induration is relatively small (5 mm). For individuals at moderate risk, treatment is indicated when the region of induration is larger (10 mm). And for individuals at low risk (who should not be routinely tested), the region must be larger still (15 mm) to justify treatment. 90.2.3.2.2
QuantiFERON-TB Gold Blood Test. The QFT-G test is a simple, one-step blood test that can be used in all situations in which the traditional TST has been used. Comparative studies indicate that the QFT-G test and the TST are equally sensitive, and that the QFT-G test is more specific. Results for the QFT-G test are available faster than with the TST (24 hours vs. 48 to 72 hours), and only one office visit is required, compared with two visits for the TST. Current CDC guidelines permit using the QFT-G test in all situations in which the TBT is used.
90.2.3.3
How Do We Treat Latent Tuberculosis? Isoniazid has been the treatment of choice for latent TB for over 30 years, and remains so today. The drug is effective, relatively safe, and inexpensive. However, isoniazid does have two drawbacks. First, to be effective, isoniazid must be taken for a long time—at least 6 months and preferably 9 months. Second, isoniazid poses a risk of liver damage. Because of these problems, alternative regimens have been developed (Table 89-4). Unfortunately, although the alternative regimens are of shorter duration, they still pose a risk of liver damage. Before starting treatment for latent TB, active TB must be ruled out. Why? Because latent TB is treated with just one (or two) drugs, and hence, if active TB were present, treatment would promote emergence of resistant bacilli. To exclude active disease, the patient should receive a physical examination and chest radiograph; if indicated, bacteriologic studies may also be ordered.
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Pharmacology for Nursing Care, 7th Edition ordered. TABLE 89-3 Tuberculin Skin Test Results That Are Considered Positive—and Hence Justify Treatment—in Patients at Low, Moderate, and High Risk of Latent Tuberculosis Risk Category Who Is In the Risk Category?
Test Result Considered Positive
High
5 mm of induration
HIV-positive people Recent contacts of patients with TB People with fibrotic changes on their chest radiograph consistent with prior TB People taking immunosuppressive drugs for more than 1 month
Moderate Recent immigrants from countries with a high prevalence of TB
10 mm of induration
Intravenous drug abusers Residents and staff of high-risk congregate settings (eg, prisons, nursing homes, hospitals, homeless shelters) Mycobacteriology laboratory personnel Persons with high-risk medical conditions (eg, diabetes mellitus, chronic renal failure, silicosis, leukemia, lymphoma) Children and adolescents exposed to high-risk adults Children under 4 years old Low
Persons with no risk factors for TB
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15 mm of induration
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Pharmacology for Nursing Care, 7th Edition TABLE 89-4 Options for Treating Latent Tuberculosis Infection Recommendation*
Duration (months)
Drugs
Dosing Schedule
Dosage
Daily
Adults: 5 mg/kg (max 300 mg)
HIV neg HIV pos
Preferred Regimen Isoniazid
9
A
A
B
B
B
C
B
C
B
B
Children: 10–20 mg/kg (max 300 mg) Alternative Regimens Isoniazid
Isoniazid
9
6
Twice
weekly† Daily
Adults: 15 mg/kg (max 900 mg) Children: 20–40 mg/kg (max 900 mg) Adults: 5 mg/kg (max 300 mg) Children: Not recommended
Isoniazid
Rifampin
6
4
Twice
weekly† Daily
Adults: 15 mg/kg (max 900 mg) Children: Not recommended Adults: 10 mg/kg (max 600 mg) Children: 10–20 mg/kg (max 600 mg)
Data from Centers for Disease Control and Prevention: Update: Adverse event data and revised American Thoracic Society/CDC recommendations against the use of rifampin and pyrazinamide for treatment of latent tuberculosis infection—United States, 2003. MMWR Morb Mortal Wkly Rep 52:735–739, 2003.
90.2.3.3.1
*
A = preferred treatment, B = acceptable alternative to A, C = offer when A and B cannot be given.
†
Twice-weekly dosing should be administered by directly observed therapy.
Isoniazid. Isoniazid is the preferred drug for treating latent TB in all patients, including those who are HIV positive. Ideally, treatment should continue for 9 months. Treatment for 6 months is an option, but is not as reliable. Two dosing schedules can be used: daily or twice weekly. When twice-weekly dosing is selected, each dose should be administered under direct
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Pharmacology 7thschedules Editioncan be used: daily or twice weekly. option, but for is notNursing as reliable. Care, Two dosing When twice-weekly dosing is selected, each dose should be administered under direct observation of a healthcare provider (to ensure adherence). Isoniazid is hepatotoxic. To reduce the risk of liver injury, liver function should be evaluated at the beginning of therapy and every 4 weeks thereafter. If hepatotoxicity develops, isoniazid should be withdrawn. 90.2.3.3.2
Short-Course Therapy: Rifampin Alone. Four months of daily therapy with rifampin alone is an alternative for patients who cannot take isoniazid. Dosing is done daily. Twice-weekly dosing is not an option.
90.2.3.3.3
Short-Course Therapy: Rifampin Plus Pyrazinamide. Owing to high rates of hospitalization and death from liver injury (rifampin and pyrazinamide are hepatotoxic), use of this combination for latent TB is no longer recommended. However, both drugs are still recommended for use in multidrug regimens to treat active TB. If rifampin and pyrazinamide must be used, close monitoring is needed. Serum aminotransferases and bilirubin should be measured at baseline and at 2, 4, 6, and 8 weeks of treatment. Treatment should stop immediately if (1) aminotransferase levels exceed 5 times the upper limit of normal (in an asymptomatic patient); (2) aminotransferase levels exceed the upper limit of normal (in a patient with symptoms of hepatitis); or (3) bilirubin levels exceed normal, regardless of hepatitis symptoms. Rifampin plus pyrazinamide should never be used in patients with active liver disease or a history of isoniazid-induced liver injury, and should be used with caution in patients who are taking hepatotoxic drugs or who drink alcohol in excess (even if drinking is discontinued during treatment).
90.2.4
Vaccination Against Tuberculosis Protection against TB can be conferred by inoculation with BCG vaccine, a freeze-dried preparation of attenuated Mycobacterium bovis (bacillus of Calmette and Guérin). In countries where TB is endemic, the World Health Organization recommends BCG vaccination in infancy, to protect children against severe, life-threatening infection (ie, miliary TB and tuberculous meningitis). In the United States, routine vaccination is not done. Why? Because there is a low risk of infection with M. tuberculosis and protection against pulmonary TB in adulthood is variable. Furthermore, vaccination with BCG can produce a false-positive result in the tuberculin skin test, which can't distinguish between antigens in M. bovis and antigens in M. tuberculosis. (Since the QFT-G is highly specific for antigens in M. tuberculosis, vaccination with BCG does not affect the results of this test.) As discussed in Chapter 102, BCG vaccine is also used to treat
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Pharmacology foris Nursing Care, 7th Edition (Since the QFT-G highly specific for antigens in M. tuberculosis, vaccination with BCG does not affect the results of this test.) As discussed in Chapter 102, BCG vaccine is also used to treat carcinoma of the bladder. 90.3
PHARMACOLOGY OF INDIVIDUAL ANTITUBERCULOSIS DRUGS Based on their clinical utility, the anti-TB drugs can be divided into two groups: first-line drugs and second-line drugs. The first-line drugs are isoniazid, rifampin, rifapentine, rifabutin, pyrazinamide, and ethambutol. Of these, isoniazid and rifampin are the most important. The second-line drugs— levofloxacin, moxifloxacin, kanamycin, amikacin, capreomycin, para-aminosalicylic acid, ethionamide, and cycloserine—are generally less effective, more toxic, and more expensive than the primary drugs. Second-line agents are used in combination with the primary drugs to treat disseminated TB and TB caused by organisms resistant to first-line drugs. Adverse effects and routes of administration of the anti-TB drugs are summarized in Table 89-5.
90.3.1
Isoniazid Isoniazid is the primary agent for treatment and prophylaxis of TB. This drug is superior to alternative drugs with regard to efficacy, toxicity, ease of use, patient acceptance, and affordability. With the exception of patients who cannot tolerate the drug, isoniazid should be taken by all individuals infected with isoniazid-sensitive strains of M. tuberculosis.
90.3.1.1
Antimicrobial Spectrum and Mechanism of Action Isoniazid is highly selective for M. tuberculosis. The drug can kill tubercle bacilli at concentrations 10,000 times lower than those needed to affect gram-positive and gramnegative bacteria. Isoniazid is bactericidal to mycobacteria that are actively dividing, but is only bacteriostatic to “resting” organisms.
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Pharmacology for Nursing 7th Edition only bacteriostatic to “resting”Care, organisms. TABLE 89-5 Antituberculosis Drugs: Routes and Major Adverse Effects Drug
Route Major Adverse Effects
First-Line Drugs Isoniazid
PO, IM Hepatotoxicity, peripheral neuritis
Rifampin
PO, IV Hepatotoxicity
Rifapentine
PO
Hepatotoxicity
Rifabutin
PO
Hepatotoxicity
Pyrazinamide
PO
Hepatotoxicity
Ethambutol
PO
Optic neuritis
Second-Line Drugs Fluoroquinolones Levofloxacin
PO, IV GI intolerance
Moxifloxacin
PO, IV GI intolerance
Injectable Drugs Capreomycin
IM
Eighth nerve damage, nephrotoxicity
Kanamycin
IM, IV Eighth nerve damage, nephrotoxicity
Amikacin
IM, IV Eighth nerve damage, nephrotoxicity
Others p-Aminosalicylic acid
PO
GI intolerance
Ethionamide
PO
GI intolerance, hepatotoxicity
Cycloserine
PO
Psychoses, seizure, rash
Although the mechanism by which isoniazid acts is not known with certainty, available data suggest the drug suppresses bacterial growth by inhibiting synthesis of mycolic acid, a component of the mycobacterial cell wall. Since mycolic acid is not produced by other bacteria or by cells of the host, this mechanism would explain why isoniazid is so selective for tubercle bacilli.
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Pharmacology for Nursing Care, 7th Edition bacilli. 90.3.1.2
Resistance Tubercle bacilli can develop resistance to isoniazid during treatment. Acquired resistance results from spontaneous mutation—not from transfer of R factors. The precise mechanism underlying resistance has not been established. Emergence of resistance can be decreased through multidrug therapy. Organisms resistant to isoniazid are cross-resistant to ethionamide, but not to other drugs used for TB.
90.3.1.3 90.3.1.3.1
Pharmacokinetics Absorption and Distribution. Isoniazid is administered orally and IM. Absorption is good with both routes. Once in the blood, isoniazid is widely distributed to tissues and body fluids. Concentrations in cerebrospinal fluid (CSF) are about 20% of those in plasma.
90.3.1.3.2
Metabolism. Isoniazid is inactivated in the liver, primarily by acetylation. The ability to acetylate isoniazid is genetically determined: about 50% of people in the United States are rapid acetylators and the other 50% are slow acetylators. The drug's half-life is about 1 hour in rapid acetylators and 3 hours in slow acetylators. It is important to note that differences in rates of acetylation generally have little impact on the efficacy of isoniazid, provided patients are taking the drug daily. However, nonhepatic toxicities may be more likely in slow acetylators, because drug accumulation is greater in these patients.
90.3.1.3.3
Excretion. Isoniazid is excreted in the urine, primarily as inactive metabolites. In patients who are slow acetylators and who also have renal insufficiency, the drug may accumulate to toxic levels.
90.3.1.4
Therapeutic Use Isoniazid is indicated only for treating active and latent TB. When used for latent TB, the drug is administered alone. When used for active TB, it must be taken in combination with at least one other agent (eg, rifampin).
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Pharmacology for(eg,Nursing one other agent rifampin).Care, 7th Edition 90.3.1.5 90.3.1.5.1
Adverse Effects Peripheral Neuropathy. Dose-related peripheral neuropathy is the most common adverse effect. Principal symptoms are symmetric paresthesias (tingling, numbness, burning, pain) of the hands and feet. Clumsiness, unsteadiness, and muscle ache may also develop. Peripheral neuropathy results from isoniazid-induced deficiency in pyridoxine (vitamin B6). If peripheral neuropathy develops, it can be reversed by administering pyridoxine (50 to 200 mg daily). In patients predisposed to neuropathy (eg, alcohol abusers and diabetics), small doses of pyridoxine (6 to 50 mg/day) can be administered with isoniazid as prophylaxis against peripheral neuritis. This practice reduces the risk of neuropathy from 20% down to less than 1%.
90.3.1.5.2
Hepatotoxicity. Isoniazid can cause hepatocellular injury and multilobular necrosis. Deaths have occurred. Liver injury is thought to result from production of a toxic isoniazid metabolite. The greatest risk factor for liver damage is advancing age: The incidence is extremely low in patients under 20 years; 1.2% in those ages 35 to 49, 2.3% in those ages 50 to 64, and 8% in those over 65. Patients should be informed about signs of hepatitis (anorexia, malaise, fatigue, nausea, yellowing of the skin or eyes) and instructed to notify the prescriber if these develop. Patients should also undergo monthly evaluation for these signs. Some clinicians perform monthly determinations of serum aspartate aminotransferase (AST) activity, because elevation of AST activity is indicative of liver injury. However, because AST levels may rise and then return to normal, despite continued isoniazid use, increases in AST may not be predictive of clinical hepatitis. It is recommended that isoniazid be withdrawn if signs of hepatitis develop or if AST activity exceeds 3 to 5 times the pretreatment baseline. Caution should be exercised when giving isoniazid to alcoholics and individuals with pre-existing disorders of the liver.
90.3.1.5.3
1043 1044
Other Adverse Effects. A variety of central nervous system (CNS) effects can occur, including optic neuritis, seizures, dizziness, ataxia, and psychologic disturbances (depression, agitation, impairment of memory, hallucinations, toxic psychosis). Anemia may result from isoniazid-induced deficiency in pyridoxine. GI distress, dry mouth, and urinary retention occur on occasion. Allergy to isoniazid can produce fever, rashes, and a syndrome resembling lupus
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Pharmacology for Nursing Edition deficiency in pyridoxine. GI Care, distress,7th dry mouth, and urinary retention occur on occasion. Allergy to isoniazid can produce fever, rashes, and a syndrome resembling lupus erythematosus. 90.3.1.6 90.3.1.6.1
Drug Interactions Phenytoin. Isoniazid can interfere with the metabolism of phenytoin, thereby causing phenytoin to accumulate to toxic levels. Signs of phenytoin excess include ataxia and incoordination. Plasma levels of phenytoin should be monitored, and phenytoin dosage should be reduced as appropriate. Dosage of isoniazid should not be changed.
90.3.1.6.2
Alcohol, Rifampin, and Pyrazinamide. Daily ingestion of alcohol or concurrent therapy with rifampin or pyrazinamide increases the risk of hepatotoxicity. Patients should be encouraged to reduce or eliminate alcohol intake.
90.3.1.7 90.3.1.7.1
Preparations, Dosage, and Administration Preparations. Isoniazid is supplied in tablets (100 and 300 mg) and a syrup (10 mg/mL) for oral use, and in solution (100 mg/mL in 10-mL vials), sold as Nydrazid, for IM injection. Isoniazid is also available in two fixed-dose combinations: (1) capsules, sold as Rifamate, contain 150 mg of isoniazid and 300 mg of rifampin, and (2) tablets, sold as Rifater, contain 50 mg of isoniazid, 120 mg of rifampin, and 300 mg of pyrazinamide.
90.3.1.7.2
Oral Dosage. For treatment of active TB, the adult dosage is 5 mg/kg/day or 15 mg/kg 2 or 3 times a week; the pediatric dosage is 10 to 20 mg/kg/day or 20 to 40 mg/kg 2 or 3 times a week. For treatment of latent TB, the preferred adult dosage is 5 mg/kg/day and the preferred pediatric dosage is 10 mg/kg/day.
90.3.1.7.3
Intramuscular Dosage. Parenteral therapy is administered in critical situations when oral treatment is not possible. The dosage is 300 mg/day.
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Pharmacology Nursing The dosagefor is 300 mg/day. Care, 7th Edition 90.3.2
Rifampin Rifampin [Rifadin, Rimactane] equals isoniazid regarding importance as an anti-TB drug. Prior to the appearance of resistant tubercle bacilli, the combination of rifampin plus isoniazid was the most frequently prescribed regimen for uncomplicated pulmonary TB. Rifampin is a powerful inducer of cytochrome P450 enzymes, and hence can decrease the levels of many other drugs.
90.3.2.1
Antimicrobial Spectrum Rifampin is a broad-spectrum antibiotic. The drug is active against most gram-positive bacteria as well as many gram-negative bacteria. The drug is bactericidal to M. tuberculosis and M. leprae. Other bacteria that are highly sensitive include Neisseria meningitidis, Haemophilus influenzae, Staphylococcus aureus, and Legionella species.
90.3.2.2
Mechanism of Action and Bacterial Resistance Rifampin inhibits bacterial DNA-dependent RNA polymerase, and thereby suppresses RNA synthesis and, consequently, protein synthesis. The results are bactericidal. Because mammalian RNA polymerases are not affected, rifampin is selectively toxic to microbes. Bacterial resistance to rifampin results from production of an altered form of RNA polymerase.
90.3.2.3 90.3.2.3.1
Pharmacokinetics Absorption and Distribution. Rifampin is well absorbed if taken on an empty stomach. However, if dosing is done with or shortly after a meal, both the rate and extent of absorption can be significantly lowered. Rifampin is distributed widely to tissues and body fluids, including the CSF. The drug is lipid soluble, and hence has ready access to intracellular bacteria.
90.3.2.3.2
Elimination. Rifampin is eliminated primarily by hepatic metabolism. Only about 20% of the drug leaves in the urine. Rifampin induces hepatic drug-metabolizing enzymes, including those responsible for its own inactivation. As a result, the rate at which rifampin is metabolized increases over the first weeks of therapy, causing the half-life of the drug to decrease—from an initial value of about 4 hours down to 2 hours at the end of 2 weeks.
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Pharmacology for ofNursing Care, an initial value about 4 hours down7th to 2 Edition hours at the end of 2 weeks. 90.3.2.4 90.3.2.4.1
Therapeutic Use Tuberculosis. Rifampin is one of our most effective anti-TB drugs. This agent is bactericidal to tubercle bacilli at extracellular and intracellular sites. Rifampin is a drug of choice for treating pulmonary TB and disseminated disease. Because resistance can develop rapidly when rifampin is employed alone, the drug is always employed in combination with at least one other anti-TB agent. Despite the capacity of rifampin to produce a variety of adverse effects, toxicity rarely requires discontinuing treatment.
90.3.2.4.2
Leprosy. Rifampin is bactericidal to M. leprae and has become an important agent for treating leprosy (see below under Drugs for Leprosy [Hansen's Disease]).
90.3.2.4.3
Meningococcus Carriers. Rifampin is highly active against Neisseria meningitidis and is indicated for short-term therapy to eliminate this bacterium from the nasopharynx of asymptomatic carriers. Because resistant organisms emerge rapidly, rifampin should not be used for active meningococcal disease.
90.3.2.5
Adverse Effects Rifampin is generally well tolerated. When employed at recommended dosages, the drug rarely causes significant toxicity. The most common adverse effect of concern is hepatitis.
90.3.2.5.1
Hepatotoxicity. Rifampin is toxic to the liver, posing a risk of jaundice and even hepatitis. Asymptomatic elevation of liver enzymes occurs in about 14% of patients. However, the incidence of overt hepatitis is less than 1%. Hepatotoxicity is most likely in alcohol abusers and patients with pre-existing liver disease. These individuals should be monitored closely for signs of liver dysfunction. Tests of liver function (serum aminotransferase levels) should be made prior to treatment and every 2 to 4 weeks thereafter. Patients should be informed about signs of hepatitis (jaundice, anorexia, malaise, fatigue, nausea) and instructed to notify the prescriber if they develop.
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Pharmacology for Nursing Care, 7th Edition if they develop. 90.3.2.5.2
Discoloration of Body Fluids. Rifampin frequently imparts a red-orange color to urine, sweat, saliva, and tears. Patients should be informed of this harmless effect. Permanent staining of soft contact lenses has occurred on occasion; the patient should consult an ophthalmologist regarding the advisability of contact lens use.
90.3.2.5.3
Other Adverse Effects. Gastrointestinal disturbances (anorexia, nausea, abdominal discomfort) and cutaneous reactions (flushing, itching, rash) occur occasionally. Rarely, intermittent high-dose therapy has produced a flu-like syndrome, characterized by fever, chills, muscle aches, headache, and dizziness. This reaction appears to have an immunologic basis. In some patients, high-dose therapy has been associated with shortness of breath, hemolytic anemia, shock, and acute renal failure.
90.3.2.6 90.3.2.6.1
1044 1045
Drug Interactions Accelerated Metabolism of Other Drugs. Because rifampin induces cytochrome P450 enzymes, it can hasten the metabolism of many drugs, thereby reducing their effects. This interaction is of special concern with oral contraceptives, warfarin (an anticoagulant), and certain protease inhibitors and NNRTIs used for HIV infection. Women taking oral contraceptives should consider a nonhormonal form of birth control. The dosage of warfarin may need to be increased.
90.3.2.6.2
Isoniazid and Pyrazinamide. Rifampin, isoniazid, and pyrazinamide are all hepatotoxic. Hence, when these drugs are used in combination, as they often are, the risk of liver injury is greater than when they are used alone.
90.3.2.7 90.3.2.7.1
Preparations, Dosage, and Administration Preparations. Rifampin [Rifadin, Rimactane], by itself, is available in 150- and 300-mg capsules. In addition, rifampin is available in two fixed-dose combinations: (1) capsules, sold as Rifamate, contain 300 mg of rifampin and 150 mg of isoniazid, and (2) tablets, sold as
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Pharmacology for Nursing Care, Edition addition, rifampin is available in two 7th fixed-dose combinations: (1) capsules, sold as Rifamate, contain 300 mg of rifampin and 150 mg of isoniazid, and (2) tablets, sold as Rifater, contain 120 mg of rifampin, 50 mg of isoniazid, and 300 mg of pyrazinamide. 90.3.2.7.2
Intravenous. Rifampin [Rifadin] is available in powdered form (600 mg) to be reconstituted for IV infusion.
90.3.2.7.3
Oral Dosage and Administration. For treatment of TB, the usual adult dosage is 600 mg, taken once a day, twice a week, or 3 times a week. The pediatric dosage is 10 to 20 mg/kg taken once a day, twice a week, or 3 times a week. Rifampin is administered 1 hour before meals or 2 hours after. Because rifampin is eliminated by hepatic metabolism, patients with liver impairment require a reduction in dosage. No change in dosage is needed in patients with kidney disease.
90.3.2.7.4
Intravenous Administration. Dissolve 600 mg of powdered rifampin in 10 mL of sterile water for injection to make a concentrated solution (60 mg/mL). Dilute an appropriate dose of the concentrate in 500 mL of 5% dextrose and infuse over 3 hours.
90.3.3
Rifapentine Rifapentine [Priftin] is a long-acting analog of rifampin. Both drugs have the same mechanism of action, adverse effects, and drug interactions. When rifapentine was approved in 1998, it was the first new drug for TB in over 25 years.
90.3.3.1
Actions and Uses. Rifapentine is indicated only for pulmonary TB. At therapeutic doses, the drug is lethal to M. tuberculosis. The mechanism underlying cell kill is inhibition of DNA-dependent RNA polymerase. To minimize emergence of resistance, rifapentine must always be combined with at least one other anti-TB drug.
90.3.3.2
Pharmacokinetics. Rifapentine is well absorbed from the GI tract, especially in the presence of food. Plasma levels peak 5 to 6 hours after dosing. In the liver, rifapentine undergoes conversion to 25desacetyl rifapentine, an active metabolite. Excretion is primarily (70%) fecal. Rifapentine and
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Pharmacology Nursing Care,In7th Edition levels peak 5 for to 6 hours after dosing. the liver, rifapentine undergoes conversion to 25desacetyl rifapentine, an active metabolite. Excretion is primarily (70%) fecal. Rifapentine and its metabolite have the same half-life—about 13 hours. 90.3.3.3
Adverse Effects. Rifapentine is well tolerated at recommended doses. Like rifampin, the drug imparts a redorange color to urine, sweat, saliva, and tears. Permanent staining of contact lenses can occur. Hepatotoxicity is the principal concern. In clinical trials, serum transaminase levels increased in 5% of patients. However, overt hepatitis occurred in only one patient. Because of the risk of hepatotoxicity, liver function tests (bilirubin, serum transaminases) should be performed at baseline and monthly thereafter. Patients should be informed about signs of hepatitis (jaundice, anorexia, malaise, fatigue, nausea) and instructed to notify the prescriber if these develop.
90.3.3.4
Drug Interactions. Like rifampin, rifapentine is a powerful inducer of cytochrome P450 drug-metabolizing enzymes. As a result, it can decrease the levels of other drugs. Important among these are protease inhibitors and NNRTIs (used for HIV infection), oral contraceptives, and warfarin.
90.3.3.5
Preparation, Dosage, and Administration. Rifapentine [Priftin] is available in 150-mg tablets. For the first 2 months, the dosage is 600 mg twice a week (with at least 3 days between doses). For the next 4 months, the dosage is 600 mg once a week. Like all other drugs for TB, rifapentine must always be combined with at least one other anti-TB agent.
90.3.4
Rifabutin
90.3.4.1
Actions and Uses. Rifabutin [Mycobutin] is a close chemical relative of rifampin. Like rifampin, rifabutin inhibits mycobacterial DNA-dependent RNA polymerase, and thereby suppresses protein synthesis. The drug is approved for prevention of disseminated M. avium complex (MAC) disease in patients with advanced HIV infection (CD4 lymphocyte counts below 200 cells/mm3). In addition to this approved application, rifabutin is used off-label to treat active MAC disease and TB in patients with HIV infection.
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Pharmacology for Nursing Care, 7th Edition and TB in patients with HIV infection. 90.3.4.2
Pharmacokinetics. Rifabutin is administered orally. Absorption is unaffected by food. Plasma levels peak in 2 to 3 hours. The drug is widely distributed and achieves high concentrations in the lungs. Rifabutin is metabolized in the liver and excreted in the urine, bile, and feces. Its half-life is 45 hours.
90.3.4.3
Adverse Effects. Rifabutin is generally well tolerated. The most common side effects are rash (4%), GI disturbances (3%), and neutropenia (2%). Like rifampin, rifabutin can impart a harmless redorange color to urine, sweat, saliva, and tears; soft contact lenses may be permanently stained. Rifabutin poses a risk of uveitis, and hence should be discontinued if ocular pain or blurred vision develops. Other adverse effects include myositis, hepatitis, arthralgia, chest pain with dyspnea, and a flu-like syndrome.
90.3.4.4
Drug Interactions. Like rifampin, rifabutin induces cytochrome P450 enzymes, although less strongly than rifampin does. By increasing enzyme activity, rifabutin can decrease blood levels of other drugs, especially oral contraceptives and delavirdine, an NNRTI. Women using oral contraceptives should be advised to use a nonhormonal method of birth control.
90.3.4.5
Preparations, Dosage, and Administration. Rifabutin [Mycobutin] is supplied in 150-mg capsules. For treatment of TB, the adult dosage is 300 mg taken once a day, twice a week, or 3 times a week. The pediatric dosage is 10 to 20 mg/kg taken once a day or twice a week.
90.3.5
Pyrazinamide
90.3.5.1
Antimicrobial Activity and Therapeutic Use Pyrazinamide is bactericidal to M. tuberculosis. How it kills bacteria is unknown. Currently, the combination of pyrazinamide with rifampin, isoniazid, and ethambutol is a preferred regimen for initial therapy of active disease caused by nonresistant M. tuberculosis. In addition, pyrazinamide, in combination with rifampin, may be used for short-course therapy of latent TB, although other regimens are preferred.
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Pharmacology for Nursing Care, Edition latent TB, although other regimens are 7th preferred. 90.3.5.2
Pharmacokinetics Pyrazinamide is well absorbed following oral administration and undergoes wide distribution to tissues and body fluids. In the liver, the drug is converted to pyrazinoic acid, an active metabolite, and then to 5-hydroxypyrazinoic acid, which is inactive. Excretion is renal, primarily as inactive metabolites.
90.3.5.3 90.3.5.3.1
Adverse Effects and Interactions Hepatotoxicity. Liver injury is the principal adverse effect. High-dose therapy has caused hepatitis, and, rarely, fatal hepatic necrosis. The earliest manifestations of liver damage are elevations in serum levels of transaminases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]). Levels of these enzymes should be measured prior to treatment and every 2 weeks thereafter. Patients should be informed about signs of hepatitis (eg, malaise, anorexia, nausea, vomiting, yellowish discoloration of the skin and eyes) and instructed to notify the prescriber if they develop. Pyrazinamide should be discontinued if significant injury to the liver occurs. The drug should not be used by patients with preexisting liver disease. The risk of liver injury is increased by concurrent therapy with isoniazid or rifampin, both of which are hepatotoxic. Pyrazinamide plus rifampin is contraindicated for patients with active liver disease or a history of isoniazid-induced liver injury, and should be used with caution in patients who are taking hepatotoxic drugs or who drink alcohol in excess.
90.3.5.3.2
1045 1046
Other Adverse Effects. Pyrazinamide and its metabolites can inhibit renal excretion of uric acid, thereby causing hyperuricemia. Although usually asymptomatic, pyrazinamide-induced hyperuricemia has (rarely) resulted in gouty arthritis. Additional adverse effects include arthralgia, GI disturbances (nausea, vomiting, diarrhea), rashes, and photosensitivity.
90.3.5.4
Preparations, Dosage, and Administration Pyrazinamide is supplied in 500-mg tablets. The dosage for adults is 15 to 30 mg/kg taken once a day or 50 to 70 mg/kg taken 2 or 3 times a week. The dosage for children is 15 to 20 mg/kg taken once a day or 50 to 70 mg/kg taken 2 or 3 times a week. For all patients, the maximum
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Pharmacology Nursing 7tha Edition a day or 50 tofor 70 mg/kg taken 2Care, or 3 times week. The dosage for children is 15 to 20 mg/kg taken once a day or 50 to 70 mg/kg taken 2 or 3 times a week. For all patients, the maximum daily dosage is 2 gm. Pyrazinamide is also available in a fixed-dose combination with isoniazid and rifampin, sold as Rifater. 90.3.6
Ethambutol
90.3.6.1
Antimicrobial Action Ethambutol [Myambutol] is active only against mycobacteria; nearly all strains of M. tuberculosis are sensitive. The drug is bacteriostatic, not bactericidal. In most cases, ethambutol is active against tubercle bacilli that are resistant to isoniazid and rifampin. Although we know that ethambutol can suppress incorporation of mycolic acid in the cell wall, the precise mechanism by which it suppresses bacterial growth has not been established.
90.3.6.2
Therapeutic Use Ethambutol is an important anti-TB drug. This agent is employed for initial treatment of TB and for treating patients who have received therapy previously. Like other drugs for TB, ethambutol is always employed as part of a multidrug regimen.
90.3.6.3
Pharmacokinetics Ethambutol is readily absorbed following oral administration. The drug is widely distributed to most tissues and body fluids; levels in CSF, however, remain low. Ethambutol undergoes little hepatic metabolism and is excreted primarily in the urine. The half-life is 3 to 4 hours in patients with healthy kidneys, and increases to 8 hours in those with significant renal impairment.
90.3.6.4
Adverse Effects Ethambutol is generally well tolerated. The only significant adverse effect is optic neuritis.
90.3.6.4.1
Optic Neuritis. Ethambutol can produce dose-related optic neuritis, resulting in blurred vision, constriction of the visual field, and disturbance of color discrimination. The mechanism underlying these effects is unknown. Symptoms usually resolve upon discontinuation of treatment. However, for some patients, visual disturbance may persist. Color discrimination and visual acuity should be assessed prior to treatment and monthly thereafter. Patients should be advised to report any alteration in vision. If ocular toxicity develops, ethambutol should be withdrawn
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Pharmacology for Nursing Care, 7th Edition should be assessed prior to treatment and monthly thereafter. Patients should be advised to report any alteration in vision. If ocular toxicity develops, ethambutol should be withdrawn immediately. Because visual changes can be difficult to monitor in pediatric patients, ethambutol is not recommended for children younger than 8 years. 90.3.6.4.2
Other Adverse Effects. Ethambutol can produce allergic reactions (dermatitis, pruritus), GI upset, and confusion. The drug inhibits renal excretion of uric acid, causing asymptomatic hyperuricemia in about 50% of patients; occasionally, elevation of uric acid levels results in acute gouty arthritis. Rare adverse effects include peripheral neuropathy, renal damage, and thrombocytopenia.
90.3.6.5
Preparations, Dosage, and Administration Ethambutol [Myambutol] is supplied in 100- and 400-mg tablets. For initial therapy of TB, the dosage for adults and children is 15 to 25 mg/kg once a day, 50 mg/kg twice a week, or 25 to 30 mg/kg 3 times a week. For re-treatment therapy, the usual dosage is 25 mg/kg/day for the first 60 days and 15 mg/kg/day thereafter. Ethambutol may be taken with food if GI upset occurs.
90.3.7
Second-Line Antituberculosis Drugs The group of second-line anti-TB drugs consists of two fluoroquinolones (levofloxacin and moxifloxacin), three injectable drugs (kanamycin, capreomycin, amikacin), and three other drugs (para-aminosalicylic acid [PAS], ethionamide, and cycloserine). In general, these drugs are less effective, more toxic, and more expensive than the first-line drugs. As a result, their principal indication is TB caused by organisms that have proved resistant to first-line agents. In addition, second-line drugs are used to treat severe pulmonary TB as well as disseminated (extrapulmonary) infection. The second-line drugs are always employed in conjunction with a major anti-TB drug. Principal toxicities are summarized in Table 89-5.
90.3.7.1
Fluoroquinolones Levofloxacin [Levaquin] and moxifloxacin [Avelox] are fluoroquinolone antibiotics indicated for a wide variety of bacterial infections (see Chapter 90). Both drugs have good activity against M. tuberculosis. As therapy for TB, these drugs are reserved for infection caused by multidrug-resistant organisms. Both drugs are generally well tolerated, although GI disturbances are relatively common. Tendon rupture occurs rarely. Oral dosages for adults are as follows: levofloxacin, 500 to 750 mg/day and moxifloxacin, 400 mg/day. These drugs are
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Pharmacology forrelatively Nursing Care,Tendon 7th Edition disturbances are common. rupture occurs rarely. Oral dosages for adults are as follows: levofloxacin, 500 to 750 mg/day and moxifloxacin, 400 mg/day. These drugs are not recommended for children. 90.3.7.2 90.3.7.2.1
Injectable Drugs Capreomycin Capreomycin [Capastat Sulfate] is an antibiotic derived from a species of Streptomyces. Antibacterial effects probably result from inhibiting protein synthesis. The drug is bacteriostatic to M. tuberculosis. Capreomycin is used only for TB resistant to primary agents. The principal toxicity is renal damage, and hence the drug should not be taken by patients with kidney disease. Capreomycin may also cause eighth cranial nerve damage, resulting in hearing loss, tinnitus, and disturbed balance. Administration is by deep IM injection (the drug is not absorbed from the GI tract, and therefore cannot be administered PO). The usual adult dosage is 1 gm/day for 60 to 120 days, followed by 1-gm doses 2 to 3 times a week. The pediatric dosage is 15 mg/kg/day (up to a maximum of 1 gm).
90.3.7.2.2
Kanamycin and Amikacin. Kanamycin [Kantrex] and amikacin [Amikin] are aminoglycoside antibiotics that have good activity against M. tuberculosis. Like other aminoglycosides, kanamycin and amikacin are nephrotoxic and may also damage the eighth cranial nerve. Neither drug is absorbed from the GI tract, and hence administration is parenteral (IM or IV). The adult dosage for both routes is 15 mg/kg/day; the pediatric dosage is 15 to 30 mg/kg/day. The pharmacology of kanamycin, amikacin, and the other aminoglycosides is discussed in Chapter 86.
90.3.7.3 90.3.7.3.1
Other Second-Line Drugs Para-Aminosalicylic Acid. Actions and Uses. PAS [Paser Granules] is similar in structure and actions to the sulfonamides. Like the sulfonamides, PAS exerts its antibacterial effects by inhibiting synthesis of folic acid. However, in contrast to the sulfonamides, which are broad-spectrum antibiotics, PAS is active only against mycobacteria. In the United States, PAS has been employed primarily as a substitute for ethambutol in pediatric patients. The drug is always used in combination with other anti-TB agents.
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Pharmacology for Nursing Care, 7th Edition used in combination with other anti-TB agents. 90.3.7.3.2
Pharmacokinetics. PAS is administered orally, and absorption is good. The drug is distributed widely to most tissues and body fluids, although levels in CSF remain low. PAS undergoes extensive hepatic metabolism. Metabolites and parent drug are excreted in the urine.
90.3.7.3.3
Adverse Effects. PAS is poorly tolerated by adults; children accept the drug somewhat better. The most frequent adverse effects are GI disturbances (nausea, vomiting, diarrhea). Because PAS is administered in large doses as a sodium salt, substantial sodium loading may occur. Additional adverse effects are allergic reactions, hepatotoxicity, and goiter.
90.3.7.3.4
Preparations, Dosage, and Administration. Para-aminosalicylate [Paser Granules] is supplied in 4-gm packets containing delayedrelease granules. Administration is oral. If stomach upset occurs, PAS may be administered with food. The daily dosage for adults is 4 gm 3 times a day. The daily dosage for children is 275 to 420 mg/kg in three to four divided doses. The drug loses its effectiveness if exposed to heat, and hence should be stored cool (below 59°F).
90.3.7.3.5
Ethionamide. Actions and Uses. Ethionamide [Trecator], a relative of isoniazid, is active against mycobacteria, but less so than isoniazid itself. Ethionamide is administered with other antiTB drugs to treat TB that is resistant to first-line agents. Gastrointestinal disturbances limit patient acceptance. Ethionamide is the least well tolerated of all anti-TB agents, and hence should be used only when there is no alternative.
90.3.7.3.6
Pharmacokinetics. Ethionamide is readily absorbed following oral administration. The drug is widely distributed to tissues and body fluids, including the CSF. Ethionamide undergoes extensive metabolism and is excreted in the urine, primarily as metabolites.
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Pharmacology Care, 7thprimarily Edition metabolismfor and Nursing is excreted in the urine, as metabolites. 90.3.7.3.7
Adverse Effects. Gastrointestinal effects (anorexia, nausea, vomiting, diarrhea, metallic taste) occur often; intolerance of these effects frequently leads to discontinuation. Ethionamide is toxic to the liver. Hepatotoxicity is assessed by measuring serum transaminases (AST, ALT) prior to treatment and periodically thereafter. Additional adverse effects include peripheral neuropathy, CNS effects (convulsions, mental disturbance), and allergic reactions.
90.3.7.3.8
Preparations, Dosage, and Administration. Ethionamide [Trecator] is supplied in 250-mg tablets. The usual adult dosage is 15 to 20 mg/ kg taken once daily or in two or three divided doses (to reduce GI upset). The recommended pediatric dosage is 15 to 20 mg/kg/day taken in two or three divided doses.
90.3.7.3.9
Cycloserine. Actions and Uses. Cycloserine [Seromycin Pulvules] is an antibiotic produced by a species of Streptomyces. The drug is bacteriostatic and acts by inhibiting cell wall synthesis. Cycloserine is used against TB resistant to first-line drugs.
90.3.7.3.10
Pharmacokinetics. Cycloserine is rapidly absorbed following oral administration. The drug is widely distributed to tissues and body fluids, including the CSF. Elimination is by hepatic metabolism and renal excretion; about 50% of the drug leaves the body unchanged in the urine. Cycloserine may accumulate to toxic levels in patients with renal impairment.
90.3.7.3.11
Adverse Effects. CNS effects occur frequently and can be severe. Possible reactions include anxiety, depression, confusion, hallucinations, paranoia, hyperreflexia, and seizures. Psychotic episodes occur in approximately 10% of patients; symptoms usually subside within 2 weeks following drug withdrawal. Pyridoxine may prevent neurotoxic effects. Other adverse effects include peripheral neuropathy, hepatotoxicity, and folate deficiency. To minimize the risk of adverse effects, serum concentrations of cycloserine should be measured periodically; peak concentrations, measured 2 hours after dosing, should be 25 to 35 mcg/mL.
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Pharmacology for measured Nursing2 hours Care, 7th Edition concentrations, after dosing, should be 25 to 35 mcg/mL. 90.3.7.3.12
Preparations, Dosage, and Administration. Cycloserine [Seromycin Pulvules] is supplied in 250-mg capsules. The initial dosage for adults is 250 mg twice daily for 2 weeks; the maintenance dosage is 500 mg to 1 gm daily in divided doses. The dosage for children is 10 to 20 mg/kg/day.
90.3.8
R207910, a Promising Investigational Drug R207910 is the working name for the first representative of a new class of antimicrobial drugs, the diarylquinolines. This drug works faster and better than all other anti-TB drugs, and may also prove safer. In addition, R207910 does not accelerate the metabolism of other drugs, and hence can be used safely in patients taking drugs for HIV. Because of these attributes, R207910 is considered the most promising agent for TB to emerge in decades. R207910 is highly effective. In a mouse model of TB, a three-drug regimen consisting of R207910 plus rifampin and pyrazinamide was compared with a conventional three-drug regimen consisting of isoniazid plus rifampin and pyrazinamide. The result? After one month with the R207910 regimen, bacterial load was as low as seen after two months with the conventional regimen, indicating accelerated bacterial kill. And after two months with the R207910 regimen, mycobacteria were cleared entirely from the lungs, an unprecedented outcome. In laboratory tests, R207910 was bactericidal to all isolates of M. tuberculosis resistant to conventional therapy, including strains that were multidrug resistant. R207910 has a unique mechanism of action: Bacterial kill results from inhibiting ATP synthase, an enzyme required by M. tuberculosis to make ATP. No other drug shares this mechanism, which explains why there's no cross-resistance between R207910 and conventional drugs. Since humans (and most other bacteria too) make ATP by a different pathway, R207910 should be highly specific for mycobacteria, and should also prove very safe. R207910 has desirable kinetics. The drug undergoes rapid absorption after oral administration, and distributes to all tissues. Of particular importance, it concentrates in cells of the lungs, reaching levels 10 times those in blood. Furthermore, R207910 remains in the body for days, permitting continued bactericidal effects with just once-a-week dosing. Although resistance to R207910 is uncommon, it does occur: About 1 in 200 million tubercle bacilli make a form of ATP synthase that is not inhibited by the drug. Accordingly, to prevent overgrowth with these resistant microbes, the regimen should always contain other anti-TB
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Pharmacology for of Nursing Care, bacilli make a form ATP synthase that7th is notEdition inhibited by the drug. Accordingly, to prevent overgrowth with these resistant microbes, the regimen should always contain other anti-TB drugs. Is R207910 safe and effective in humans? We don't know yet. When the drug was given to 50 healthy volunteers for 2 weeks, no significant side effects were observed. Whether prolonged use in many more patients will yield the same result remains to be seen. Tests of efficacy in patients with active TB are in progress. 90.4
DRUGS FOR LEPROSY (HANSEN'S DISEASE) Leprosy is a chronic infectious disease caused by M. leprae, an acid-fast bacillus. The infection is also known as Hansen's disease, in recognition of Gerhard Armauer Hansen, who demonstrated the involvement of M. leprae in 1873. Left untreated, leprosy can cause grotesque disfiguration. Fortunately, with the drugs available today, most patients can be cured. As a result, the worldwide incidence of leprosy has declined dramatically—from an estimated 12 million cases in the mid-1980s to 259,017 new cases in 2006. In the United States, only 66 new cases were reported in 2006, and these occurred primarily among immigrants from endemic areas (eg, India, Brazil, Indonesia). Infection with M. leprae affects the skin, peripheral nerves, and mucous membranes of the upper respiratory tract. Characteristic features are (1) skin lesions with local loss of sensation, (2) thickening of peripheral nerves, and (3) acid-fast bacilli in smears from skin lesions. Leprosy is divided into two main classes: (1) paucibacillary (PB) leprosy and (2) multibacillary (MB) leprosy. Classification is based on clinical manifestations and the presence of M. leprae in skin smears. If skin smears are negative, the diagnosis is PB leprosy. Conversely, if any smear is positive, the diagnosis is MB leprosy. In many places, microbiologic analysis of skin smears is either unavailable or unreliable. Hence, in these places, classification must be based on clinical findings alone. In this case, if the patient has one to five skin lesions, the diagnosis is PB leprosy; if the patient has six or more skin lesions, the diagnosis is MB leprosy. The distinction between PB leprosy and MB leprosy is important because treatment differs for the two forms.
90.4.1
Overview of Treatment As with TB, the cornerstone of treatment is multidrug therapy. If just one drug is used, resistance will occur. Most regimens include rifampin, the most effective drug for killing M. leprae. For patients with MB leprosy, the World Health Organization (WHO) recommends 12 months of treatment with three drugs: rifampin, dapsone, and clofazimine. For patients with PB leprosy, the WHO recommends 6 months of treatment with two drugs: rifampin and dapsone. For patients
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Pharmacology for Nursing Care, 7th Edition treatment with three drugs: rifampin, dapsone, and clofazimine. For patients with PB leprosy, the WHO recommends 6 months of treatment with two drugs: rifampin and dapsone. For patients with single-lesion PB leprosy (ie, PB leprosy with just one skin lesion), the WHO recommends a single dose of the “ROM” regimen: rifampin, ofloxacin, and minocycline. With all three regimens, the relapse rate is very low (about 0.1%). Accordingly, all three are considered curative. Specific dosages for these regimens are summarized in Table 89-6. 90.4.2
Pharmacology of Individual Antileprosy Drugs
90.4.2.1
Rifampin The basic pharmacology of rifampin [Rifadin, Rimactane] is discussed above under Pharmacology of Individual Antituberculosis Drugs. Discussion here is limited to its use in leprosy. Rifampin is by far our most effective agent for treating leprosy. In fact, the drug is more effective than any combination of other agents. A single dose kills more than 99.9% of viable M. leprae. After three monthly doses, less than 0.001% of the initial M. leprae population remains. Because of its powerful bactericidal actions, rifampin is a key component of standard antileprosy regimens. The dosage currently recommended by the WHO is 600 mg once a month. In the past, rifampin was administered daily. However, we now know that monthly administration is just as effective. Moreover, monthly administration is much less expensive and minimizes adverse effects, including hepatotoxicity. Resistance can occur if rifampin is used alone. Accordingly, the drug is always combined with other antileprosy agents (eg, dapsone plus clofazimine).
90.4.2.2 90.4.2.2.1
Dapsone Actions and Uses. Dapsone, taken orally, is weakly bactericidal to M. leprae. The drug is safe, inexpensive, and moderately effective. Dapsone is chemically related to the sulfonamides and shares their mechanism of action: inhibition of folic acid synthesis. Although once employed alone to treat leprosy, dapsone is now employed in combination with other antileprosy drugs, usually rifampin and clofazimine. In 2008, a topical formulation, sold as Aczone, was approved for treating acne (see chapter 104).
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Pharmacology for Care, 7th Edition treating acne (seeNursing chapter 104). 90.4.2.2.2
Pharmacokinetics. Dapsone is absorbed rapidly and nearly completely from the GI tract. Once in the blood, the drug is widely distributed to tissues and body fluids. Dapsone undergoes hepatic metabolism followed by excretion in the urine. The average half-life is 28 hours.
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Pharmacology Nursing 7th Edition followed byfor excretion in the Care, urine. The average half-life is 28 hours.
1047
TABLE 89-6 Adult Regimens for Leprosy, as Recommended by the World Health Organization
1048
Multibacillary Leprosy (Treat 12 Months with all 3 Drugs) Rifampin
600 mg once a month, supervised
Dapsone
100 mg daily, self-administered
Clofazimine
300 mg once a month, supervised or 50 mg daily, self-administered
Paucibacillary Leprosy (Treat 6 Months with Both Drugs) Rifampin
600 mg once a month, supervised
Dapsone
100 mg daily, self-administered
Single-Lesion Paucibacillary Leprosy (Take all 3 Drugs Once) Rifampin
600 mg
Ofloxacin
400 mg
Minocycline
100 mg
Rifampin-Resistant Leprosy (Treat 12 Months) First 6 Months (Take All 3 Drugs Daily) Clofazimine
50 mg
Ofloxacin
400 mg
Minocycline
100 mg
Next 6 Months (Take Either Pair of Drugs Daily) Clofazimine
50 mg
Ofloxacin
400 mg
or
90.4.2.2.3
Clofazimine
50 mg
Minocycline
100 mg
Adverse Effects. Dapsone is generally well tolerated. The drug has been taken for years without significant untoward effects. The most common adverse effects are GI disturbances, headache, rash, and a syndrome that resembles mononucleosis. Hemolytic anemia occurs occasionally; severe
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Pharmacology for Nursing Care, 7th Edition untoward effects. The most common adverse effects are GI disturbances, headache, rash, and a syndrome that resembles mononucleosis. Hemolytic anemia occurs occasionally; severe reactions are usually limited to patients with profound glucose-6-phosphate dehydrogenase deficiency. Rare reactions include agranulocytosis, exfoliative dermatitis, and hepatitis. 90.4.2.2.4
Preparations, Dosage, and Administration. Dapsone is formulated in 25- and 100-mg tablets. The usual dosage for adults is 100 mg/day. The dosage for children is 1 mg/kg/day. To prevent emergence of resistance, dapsone is always combined with another antileprosy drug (eg, rifampin, clofazimine).
90.4.2.3 90.4.2.3.1
Clofazimine Actions and Uses. Clofazimine [Lamprene] is slowly bactericidal to M. leprae. Its mechanism of action is unknown. To prevent emergence of resistance, clofazimine is always combined with another antileprosy drug (eg, rifampin, dapsone). In addition to its antibacterial action, clofazimine has anti-inflammatory actions.
90.4.2.3.2
Pharmacokinetics Clofazimine is administered orally and undergoes partial absorption. Absorbed drug is retained in fatty tissue and the skin. Because of tissue retention, the half-life of clofazimine is extremely long—about 70 days.
90.4.2.3.3
Adverse Effects. Clofazimine is very safe. Dangerous reactions are rare. GI symptoms (nausea, vomiting, cramping, diarrhea) are common but mild. The drug frequently imparts a harmless red color to feces, urine, sweat, tears, and saliva. Deposition of clofazimine in the small intestine produces the most serious effects: intestinal obstruction, pain, and bleeding. Clofazimine causes reversible reddish-black discoloration of the skin in most patients. Pigmentation begins 4 to 8 weeks after the onset of treatment, and generally clears within 12 months of drug cessation. Because it can darken the skin, patients with light-colored skin often find clofazimine unacceptable.
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Pharmacology for Nursing Care, 7th Edition often find clofazimine unacceptable. 90.4.2.3.4
Preparations, Dosage, and Administration. Clofazimine [Lamprene] is formulated in 50- and 100-mg capsules. The usual adult dosage is 50 mg daily. Clofazamine is not available in the United States.
90.4.2.4
The ROM Regimen The ROM regimen (rifampin, ofloxacin, minocycline) is indicated for patients with singlelesion PB leprosy. Treatment consists of one-time dosing with rifampin (600 mg), ofloxacin (400 mg), and minocycline (100 mg). Ofloxacin [Floxin], a fluoroquinolone antibiotic, is discussed in Chapter 90. Minocycline [Minocin], a member of the tetracycline family, is discussed in Chapter 85.
90.5
DRUGS FOR MYCOBACTERIUM AVIUM COMPLEX INFECTION Mycobacterium avium complex (MAC) consists of two nearly indistinguishable organisms: M. avium and M. intracellulare. Colonization with MAC begins in the lungs or GI tract, but then may spread to the blood, bone marrow, liver, spleen, lymph nodes, brain, kidneys, and skin. Disseminated infection is common in patients with HIV infection; the incidence at autopsy is 50%. Among immunocompetent patients, symptomatic MAC infection is usually limited to the lungs. Signs and symptoms of disseminated MAC infection include fever, night sweats, weight loss, lethargy, anemia, and abnormal liver function tests. Drug therapy may be done for prophylaxis or to treat active infection. The preferred agents for prophylaxis of disseminated infection are azithromycin and clarithromycin. Regimens for treating active infection in immunocompetent hosts should include (1) azithromycin or clarithromycin plus (2) ethambutol plus (3) rifampin or rifabutin. Additional drugs may be added as needed; options include streptomycin, ciprofloxacin, clofazimine, and amikacin. Treatment of active infection in immunocompetent patients should continue for 12 months after cultures become negative. Representative regimens for immunocompetent patients are presented in Table 89-7. Regimens for patients with HIV infection are presented in Chapter 93.
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Pharmacology Nursing Care,in7th Edition patients with HIVfor infection are presented Chapter 93.
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TABLE 89-7 Regimens for MAC Infection in Immunocompetent Adults
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Pulmonary MAC Daily Regimen Clarithromycin (500 mg twice daily) or azithromycin (250 mg) plus Ethambutol (25 mg/kg for 2 months, then 15 mg/kg thereafter) plus Rifampin (600 mg) or rifabutin (300 mg) may also add Streptomycin (15 mg/kg 3 times a week for 2–6 months) Duration Treat until cultures remain negative for 12 months Disseminated MAC Daily Regimen Clarithromycin (500 mg twice daily) or azithromycin (250–500 mg) plus Ethambutol (15 mg/kg) plus Rifampin (600 mg) or rifabutin (300 mg) may also add Streptomycin (15 mg/kg 3 times a week for 2–6 months) Duration Treat until cultures remain negative for 12 months MAC = Mycobacterium avium complex. 90.5.1
KEY POINTS ▪ Most people infected with M. tuberculosis remain asymptomatic, although they will harbor dormant bacteria for life (in the absence of drug therapy). ▪ Symptomatic TB can result from reactivation of an old infection or from recent personto-person transmission of a new infection.
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Pharmacology for NursingofCare, 7th Edition to-person transmission a new infection. ▪ Drug resistance, and especially multidrug resistance, is a serious impediment to successful therapy of TB. ▪ The principal cause of drug resistance in TB is inadequate drug therapy, which kills sensitive bacteria while allowing resistant mutants to flourish. ▪ To prevent emergence of resistance, initial therapy of TB should consist of at least two drugs to which the infection is sensitive, and preferably four. Accordingly, isolates from all patients must undergo testing of drug sensitivity, a process that may take 6 to 16 weeks. ▪ Therapy of TB is prolonged, lasting from a minimum of 6 months to 2 years and even longer. As a result, patient adherence is a serious issue. ▪ Adherence can be greatly increased by using directly observed therapy (DOT) combined with intermittent dosing (rather than daily dosing). ▪ Three methods are employed to evaluate TB therapy: bacteriologic evaluation of sputum, clinical evaluation, and chest radiographs. ▪ The principal first-line drugs for TB are isoniazid, rifampin, pyrazinamide, and ethambutol. ▪ For initial therapy of active TB, patients may be given four drugs: isoniazid, rifampin, pyrazinamide, and ethambutol. ▪ Initial therapy of MDR-TB and XDR-TB may require up to seven drugs. ▪ Tuberculosis in HIV-positive patients often can be treated with the same regimens used for HIV-negative patients, although the duration of treatment may be longer. ▪ Isoniazid can cause peripheral neuropathy by depleting pyridoxine (vitamin B6). Peripheral neuropathy can be reversed or prevented with pyridoxine supplements. ▪ Isoniazid can injure the liver. The greatest risk factor is advancing age. ▪ Rifampin induces drug-metabolizing enzymes, and can thereby increase the metabolism of other drugs; important among these are oral contraceptives, warfarin, and certain protease inhibitors and NNRTIs used for HIV infection.
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Pharmacology Nursing Care,used 7thforEdition proteasefor inhibitors and NNRTIs HIV infection. ▪ Like isoniazid, rifampin and pyrazinamide are hepatotoxic. Accordingly, when these three drugs are combined, as they often are, the risk of liver injury can be significant. ▪ Ethambutol can cause optic neuritis. ▪ The tuberculin skin test (TST)—used to identify people with latent TB—is performed by giving an intradermal injection of PPD (purified protein derivative) and then measuring the zone of induration (hardness) at the site 48 to 72 hours later. ▪ A new blood test for latent TB—QuantiFERON-TB Gold (QFT-G)—is as sensitive as the TST and more specific. Moreover, results with the QFT-G are available faster (within 24 hours) and don't require a return visit to the office. ▪ Isoniazid, taken daily for 9 months, is the preferred treatment for latent TB. 90.5.2
Summary of Major Nursing Implications* The nursing implications summarized below are limited to the drug therapy of TB.
90.5.... 90.5....
IMPLICATIONS THAT APPLY TO ALL ANTITUBERCULOSIS DRUGS Promoting Adherence Treatment of active TB is prolonged and demands concurrent use of two or more drugs; as a result, adherence can be a significant problem. To promote adherence, educate the patient about the rationale for multidrug therapy and the need for long-term treatment. Encourage patients to take their medication exactly as prescribed, and to continue treatment until the infection has resolved. Adherence can be greatly increased by using directly observed therapy (DOT) combined with intermittent dosing (rather than daily dosing).
90.5....
Evaluating Treatment Success is indicated by (1) reductions in fever, malaise, anorexia, cough, and other clinical manifestations of TB (usually within weeks); (2) radiographic evidence of improvement (usually in 3 months); and (3) an absence of M. tuberculosis in sputum cultures (usually after 3 to 6 months).
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Pharmacology Nursing Care, 7th Edition after 3 to 6for months). 90.5....
ISONIAZID In addition to the implications summarized below, see above for implications on Promoting Adherence and Evaluating Treatment that apply to all anti-TB drugs.
90.5.... 90.5....
Preadministration Assessment Therapeutic Goal Treatment of active or latent infection with M. tuberculosis.
90.5....
Baseline Data Obtain a chest radiograph, microbiologic tests of sputum, and baseline tests of liver function.
90.5....
Identifying High-Risk Patients Isoniazid is contraindicated for patients with acute liver disease or a history of isoniazidinduced hepatotoxicity.
90.5.... 90.5....
Use with caution in alcohol abusers, diabetic patients, patients with vitamin B6
1049
deficiency, patients over the age of 50, and patients who are taking phenytoin, rifampin, or pyrazinamide.
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Implementation: Administration Routes Oral, IM.
90.5....
Administration Advise patients to take isoniazid on an empty stomach, either 1 hour before meals or 2 hours after. Advise patients to take the drug with meals if GI upset occurs.
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Pharmacology forafter. Nursing Edition or 2 hours Advise Care, patients7th to take the drug with meals if GI upset occurs. 90.5....
Ongoing Evaluation and Interventions
90.5....
Minimizing Adverse Effects
90.5....
Peripheral Neuropathy. Inform patients about symptoms of peripheral neuropathy (tingling, numbness, burning, or pain in the hands or feet), and instruct them to notify the prescriber if these occur. Peripheral neuritis can be reversed with small daily doses of pyridoxine (vitamin B6). In patients at high risk of neuropathy (eg, alcohol abusers, diabetic patients), give pyridoxine prophylactically.
90.5....
Hepatotoxicity. Isoniazid can cause hepatocellular damage and multilobular hepatic necrosis. Inform patients about signs of hepatitis (jaundice, anorexia, malaise, fatigue, nausea), and instruct them to notify the prescriber if these develop. Evaluate patients monthly for signs of hepatitis. Monthly determinations of AST activity may be ordered. If clinical signs of hepatitis appear, or if AST activity exceeds 3 to 5 times the pretreatment baseline, isoniazid should be withdrawn. Daily ingestion of alcohol increases the risk of liver injury; urge the patient to minimize or eliminate alcohol consumption.
90.5.... 90.5....
Minimizing Adverse Interactions Phenytoin. Isoniazid can suppress the metabolism of phenytoin, thereby causing phenytoin levels to rise. Plasma phenytoin should be monitored. If necessary, phenytoin dosage should be reduced.
90.5....
RIFAMPIN In addition to the implications summarized below, see above for implications on Promoting Adherence and Evaluating Treatment that apply to all anti-TB drugs.
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Pharmacology forEvaluating NursingTreatment Care, that 7thapply Edition Adherence and to all anti-TB drugs. 90.5.... 90.5....
Preadministration Assessment Therapeutic Goal Treatment of active TB or leprosy.
90.5....
Baseline Data Obtain a chest radiograph, microbiologic tests of sputum, and baseline tests of liver function.
90.5....
Identifying High-Risk Patients Rifampin is contraindicated for patients taking delavirdine (an NNRTI) and most protease inhibitors. Use with caution in alcohol abusers, patients with liver disease, and patients taking warfarin.
90.5.... 90.5....
Implementation: Administration Routes Oral, IV.
90.5....
Dosage Reduce the dosage in patients with liver disease.
90.5....
Administration Instruct the patient to take oral rifampin once a day, either 1 hour before a meal or 2 hours after. Administer IV rifampin by slow infusion (over 3 hours).
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Pharmacology forIVNursing Care, 7th Edition Administer rifampin by slow infusion (over 3 hours). 90.5.... 90.5.... 90.5....
Ongoing Evaluation and Interventions Minimizing Adverse Effects Hepatotoxicity. Rifampin may cause jaundice or hepatitis. Inform patients about signs of liver dysfunction (anorexia, darkened urine, pale stools, yellow discoloration of eyes or skin), and instruct them to notify the prescriber if these develop. Monitor patients for signs of liver dysfunction. Tests of liver function should be made prior to treatment and every 2 to 4 weeks thereafter.
90.5....
Discoloration of Body Fluids. Inform patients that rifampin may impart a harmless red-orange color to urine, sweat, saliva, and tears. Warn patients that soft contact lenses may undergo permanent staining; advise them to consult an ophthalmologist about continued use of these lenses.
90.5.... 90.5....
Minimizing Adverse Interactions Accelerated Metabolism of Other Drugs. Rifampin can accelerate the metabolism of many drugs, thereby reducing their effects. This action is of particular concern with oral contraceptives, warfarin, most protease inhibitors, and delavirdine (an NNRTI). Advise women taking oral contraceptives to use a nonhormonal form of birth control. Monitor warfarin effects and increase dosage as needed. Do not combine protease inhibitors or NNRTIs with rifampin.
90.5....
Pyrazinamide and Isoniazid. These hepatotoxic anti-TB drugs can increase the risk of liver injury when used with rifampin.
90.5....
PYRAZINAMIDE In addition to the implications summarized below, see above for implications on Promoting Adherence and Evaluating Treatment that apply to all anti-TB drugs.
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Pharmacology forEvaluating NursingTreatment Care, that 7thapply Edition Adherence and to all anti-TB drugs. 90.5.... 90.5....
Preadministration Assessment Therapeutic Goal Treatment of active and latent TB.
90.5....
Baseline Data Obtain a chest radiograph, microbiologic tests of sputum, and baseline tests of liver function.
90.5....
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Identifying High-Risk Patients Pyrazinamide is contraindicated for patients with severe liver dysfunction or acute gout. Use with caution in alcohol abusers.
90.5.... 90.5....
Implementation: Administration Route Oral.
90.5....
Administration Usually administered once a day.
90.5.... 90.5.... 90.5....
Ongoing Evaluation and Interventions Minimizing Adverse Effects Hepatotoxicity. Inform patients about symptoms of hepatitis (malaise, anorexia, nausea, vomiting, yellowish discoloration of the skin and eyes), and instruct them to notify the prescriber if these develop. Levels of AST and ALT should be measured prior to treatment and every 2 weeks thereafter. If severe liver injury occurs, pyrazinamide should be withdrawn. The risk of liver injury is increased by concurrent therapy with isoniazid and rifampin, both of which are hepatotoxic.
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Pharmacology forand Nursing 7th Edition isoniazid rifampin, Care, both of which are hepatotoxic. 90.5....
ETHAMBUTOL In addition to the implications summarized below, see above for implications on Promoting Adherence and Evaluating Treatment that apply to all anti-TB drugs.
90.5.... 90.5....
Preadministration Assessment Therapeutic Goal Treatment of active TB.
90.5....
Baseline Data Obtain a chest radiograph, microbiologic tests of sputum, and baseline vision tests.
90.5....
Identifying High-Risk Patients Ethambutol is contraindicated for patients with optic neuritis.
90.5.... 90.5....
Implementation: Administration Route Oral.
90.5....
Administration Usually administered once a day. Advise patients to take ethambutol with food if GI upset occurs.
90.5.... 90.5.... 90.5....
Ongoing Evaluation and Interventions Minimizing Adverse Effects Optic Neuritis. Ethambutol can cause dose-related optic neuritis. Symptoms include blurred vision, altered color discrimination, and constriction of visual fields. Baseline vision tests are required. Instruct patients to report any alteration in vision (eg, blurring of vision, reduced color discrimination). If ocular toxicity develops, ethambutol should be
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Pharmacology forInstruct Nursing Care, 7th Edition required. patients to report any alteration in vision (eg, blurring of vision, reduced color discrimination). If ocular toxicity develops, ethambutol should be withdrawn at once. *
Patient education information is highlighted as blue text.
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CHAPTER 90 Miscellaneous Antibacterial Drugs Fluoroquinolones, Metronidazole, Daptomycin, Rifampin, Bacitracin, and Polymyxins
91.1
FLUOROQUINOLONES The fluoroquinolones are fluorinated analogs of nalidixic acid, a narrow-spectrum quinolone antibiotic used only for urinary tract infections (UTIs). However, unlike nalidixic acid, the fluoroquinolones are broad-spectrum agents and have multiple applications. Benefits derive from disrupting DNA replication and cell division. Fluoroquinolones do not disrupt synthesis of proteins or the cell wall. All of the fluoroquinolones can be administered orally. As a result, these drugs are attractive alternatives for people who might otherwise require intravenous antibacterial therapy. Although side effects are generally mild, all fluoroquinolones can cause tendon rupture, usually of the Achilles tendon. Fortunately, the risk is low. Bacterial resistance develops slowly, but has become common in Neisseria gonorrhoeae, and hence these drugs are no longer recommended for this infection. Seven fluoroquinolones are currently available for systemic therapy. Five others— gatifloxacin, enoxacin, sparfloxacin, trovafloxacin, and alatrofloxacin—were recently discontinued.
91.1.1
Ciprofloxacin Ciprofloxacin [Cipro] was among the first fluoroquinolones available and will serve as our prototype for the group. The drug, which can be administered PO and IV, is active against a broad spectrum of bacterial pathogens. Ciprofloxacin has been used as an alternative to parenteral antibiotics for treatment of several serious infections. Because it can be administered by mouth, patients receiving ciprofloxacin can be treated at home, rather than going to the hospital for IV antibacterial therapy.
91.1.1.1
Mechanism of Action Ciprofloxacin inhibits two bacterial enzymes: DNA gyrase and topoisomerase IV. Both are needed for DNA replication and cell division. DNA gyrase converts closed circular DNA into a supercoiled configuration. In the absence of supercoiling, DNA replication cannot take place. Topoisomerase IV helps separate daughter DNA strands during cell division. Since the mammalian equivalents of DNA gyrase and topoisomerase IV are relatively insensitive to fluoroquinolones, cells of the host are spared. Ciprofloxacin is rapidly bactericidal.
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Pharmacology for cells Nursing Care, 7th Edition fluoroquinolones, of the host are spared. Ciprofloxacin is rapidly bactericidal. 91.1.1.2
Antimicrobial Spectrum Ciprofloxacin is active against a broad spectrum of bacteria, including most aerobic gramnegative bacteria and some gram-positive bacteria. Most urinary tract pathogens, including Escherichia coli and Klebsiella, are sensitive. The drug is also highly active against most bacteria that cause enteritis (eg, Salmonella, Shigella, Campylobacter jejuni, E. coli). Other sensitive organisms include Bacillus anthracis, Pseudomonas aeruginosa, Haemophilus influenzae, meningococci, and many streptococci. Activity against anaerobes is fair to poor. Clostridium difficile is resistant.
91.1.1.3
Bacterial Resistance Resistance to fluoroquinolones has developed during treatment of infections caused by Staphylococcus aureus, Serratia marcescens, C. jejuni, P. aeruginosa, and N. gonorrhoeae. Two mechanisms appear responsible: (1) alterations in DNA gyrase and topoisomerase IV and (2) increased export of these drugs. Bacteria do not directly inactivate these drugs, and there have been no reports of resistance transfer via R factors.
91.1.1.4
Pharmacokinetics Ciprofloxacin may be administered orally or IV. Following oral administration, the drug is absorbed rapidly but incompletely. High concentrations are achieved in urine, stool, bile, saliva, bone, and prostate tissue. Drug levels in cerebrospinal fluid remain low. Ciprofloxacin has a plasma half-life of about 4 hours. Elimination is by hepatic metabolism and renal excretion.
91.1.1.5
Therapeutic Uses Ciprofloxacin is approved for a wide variety of infections. Among these are infections of the respiratory tract, urinary tract, GI tract, bones, joints, skin, and soft tissues. Also, ciprofloxacin is a preferred drug for preventing anthrax in people who have inhaled anthrax spores. Because it is active against a variety of pathogens and can be given orally, ciprofloxacin represents an alternative to parenteral treatment for many serious infections. Owing to high rates of resistance, ciprofloxacin is a poor choice for staphylococeal infections. The drug is not useful against infections caused by anaerobes.
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Pharmacology for caused Nursing Care, 7th Edition against infections by anaerobes.
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Because of concerns about tendon injury (see below), systemic ciprofloxacin is generally avoided in children under 18 years old. Nonetheless, the drug does have two approved pediatric uses: (1) treatment of complicated urinary tract and kidney infections caused by E. coli, and (2) postexposure treatment of inhalational anthrax. Ciprofloxacin is the only systemic fluoroquinolone approved for pediatric use. 91.1.1.6
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Adverse Effects Ciprofloxacin can induce a variety of mild adverse effects, including GI reactions (nausea, vomiting, diarrhea, abdominal pain) and central nervous system (CNS) effects (dizziness, headache, restlessness, confusion). Candida infections of the pharynx and vagina may develop as a result of treatment. Very rarely, seizures have occurred. In the elderly, ciprofloxacin poses a significant risk of confusion, somnolence, psychosis, and visual disturbances. Rarely, ciprofloxacin and other fluoroquinolones have caused tendon rupture, usually of the Achilles tendon. The incidence is 1 in 10,000 or less. The highest risk is in people age 60 and older, and in people taking glucocorticoids. Risk in children is also elevated. How do fluoroquinolones damage tendons? When given to immature animals, fluoroquinolones disrupt the extracellular matrix of cartilage. A similar mechanism may underlie tendon rupture in humans. Since tendon injury is reversible if diagnosed early, fluoroquinolones should be discontinued at the first sign of tendon pain, swelling, or inflammation. In addition, patients should refrain from exercise until tendinitis has been ruled out. Although there are no controlled studies on the use of ciprofloxacin during pregnancy or lactation, available data indicate that such use poses little or no risk of tendon damage to the fetus or nursing infant. Ciprofloxacin and other fluoroquinolones pose a risk of phototoxicity (severe sunburn), characterized by burning, erythema, exudation, vesicles, blistering, and edema. These can occur following exposure to direct sunlight, indirect sunlight, and sunlamps—even if a sunscreen has been applied. Patients should be warned about phototoxicity and advised to avoid sunlight and sunlamps. People who must go outdoors should wear protective clothing and apply a sunscreen. Ciprofloxacin should be withdrawn at the first sign of a phototoxic reaction (eg, burning sensation, redness, rash).
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Pharmacology for Nursing Edition reaction (eg, burning sensation,Care, redness,7th rash). 91.1.1.7 91.1.1.7.1
Drug and Food Interactions Cationic Compounds. Absorption of ciprofloxacin can be reduced by compounds that contain cations. Among these are (1) aluminum- or magnesium-containing antacids, (2) iron salts, (3) zinc salts, (4) sucralfate, and (5) milk and other dairy products, all of which contain calcium ions. These cationic agents should be administered at least 6 hours before ciprofloxacin or 2 hours after.
91.1.1.7.2
Elevation of Drug Levels. Ciprofloxacin can increase plasma levels of several drugs, including theophylline (used for asthma), warfarin (an anticoagulant), and tinidazole (an antifungal drug). Toxicity could result. For patients taking theophylline, drug levels should be monitored and the dosage adjusted accordingly. For patients taking warfarin, prothrombin time should be monitored and the dosage of warfarin reduced as appropriate.
91.1.1.8 91.1.1.8.1
Preparations, Dosage, and Administration Preparations. Ciprofloxacin is available for oral and IV administration. For oral therapy, ciprofloxacin is supplied in standard tablets (100, 250, 500, and 750 mg) sold as Cipro, extended-release tablets (500 and 1000 mg) sold as Cipro XR and Proquin XR, and a suspension (250 and 500 mg/5 mL) sold as Cipro. For IV therapy, ciprofloxacin is supplied in solution (2 and 10 mg/ mL) sold as Cipro I.V.
91.1.1.8.2
Dosage and Administration. Oral. The dosage for urinary tract infections is 250 or 500 mg 2 times a day, usually for 7 to 14 days. For other infections, dosages range from 500 to 750 mg 2 times a day. Dosage should be reduced for patients with renal impairment. Dosages for anthrax prevention are presented below.
91.1.1.8.3
Intravenous. Intravenous dosages range from 200 to 400 mg every 12 hours. Infusions should be done slowly (over 60 minutes). Dosages for anthrax prevention are presented below.
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Pharmacology for Care,for7th Edition slowly (over 60 Nursing minutes). Dosages anthrax prevention are presented below. 91.1.1.8.4
Inhalational Anthrax. Ciprofloxacin is used to reduce the incidence of anthrax or prevent anthrax progression in people who have inhaled B. anthracis spores. The dosage for adults is 500 mg PO (or 400 mg IV) every 12 hours for 60 days. The dosage for children is 15 mg/kg PO (or 10 mg/kg IV) every 12 hours for 60 days (with the proviso that individual oral doses not exceed 500 mg, and individual IV doses not exceed 400 mg).
91.1.2
Other Fluoroquinolones
91.1.2.1 91.1.2.1.1
Ofloxacin Basic Pharmacology. Ofloxacin [Floxin] is similar to ciprofloxacin in mechanism of action, antimicrobial spectrum, therapeutic applications, and adverse effects. Like ciprofloxacin, the drug may be administered PO or IV. In the absence of food, bioavailability is 90%; food greatly reduces availability. Ofloxacin is widely distributed to tissues and excreted in the urine. Like ciprofloxacin, ofloxacin can cause a variety of mild adverse effects, including nausea, vomiting, headache, and dizziness. In addition, ofloxacin may intensify sensitivity to sunlight, thereby increasing the risk of severe sunburn. Like other fluoroquinolones, ofloxacin poses a risk of tendon rupture. Ofloxacin elevates plasma levels of warfarin, but, in contrast to ciprofloxacin, has little effect on levels of theophylline. Absorption of oral ofloxacin is reduced by cationic substances: milk, milk products, sucralfate, iron and zinc salts, and magnesium- and aluminum-containing antacids.
91.1.2.1.2
Preparations, Dosage, and Administration. Ofloxacin is available in tablets (200, 300, and 400 mg) for oral administration and in solution (4 and 40 mg/mL) for slow IV infusion; concentrated solutions must be diluted prior to administration. The usual oral dosage is 200 to 400 mg every 12 hours; treatment may last from 1 day to 6 weeks. Dosage should be reduced in patients with renal impairment. Ofloxacin may be taken with or without food.
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Pharmacology for be Nursing 7thfood. Edition Ofloxacin may taken withCare, or without 91.1.2.2 91.1.2.2.1
Lomefloxacin Actions, Uses, and Pharmacokinetics. Lomefloxacin [Maxaquin] is similar to ciprofloxacin with regard to mechanism and antimicrobial spectrum. Approved indications are limited to UTIs, acute bronchitis caused by H. influenzae or Moraxella catarrhalis, and preoperative prophylaxis of infection. Administration is oral, and bioavailability is high (98%), even in the presence of food. The drug is widely distributed to tissues and eliminated by the kidneys. Lomefloxacin has a prolonged half-life that permits once-a-day dosing.
91.1.2.2.2
Adverse Effects. Phototoxicity reactions (eg, sunburn, blistering) can be moderate to severe. These can occur following exposure to direct sunlight, indirect sunlight, and sunlamps—even if a sunscreen has been applied. Patients should be warned about phototoxicity and advised to avoid sunlight and sunlamps. Lomefloxacin should be withdrawn at the first sign of a phototoxic reaction (eg, burning sensation, redness, rash). Like ciprofloxacin, lomefloxacin can cause various mild adverse effects, including nausea, vomiting, headache, and dizziness. Like other fluoroquinolones, lomefloxacin poses a risk of tendon rupture. Rarely, patients have developed peripheral neuropathy, manifesting as pain, burning, tingling, numbness, or weakness, as well as deficits in light touch, temperature and position sense, and strength.
91.1.2.2.3
Drug and Food Interactions. Absorption of lomefloxacin is reduced by magnesium- and aluminum-containing antacids, iron and zinc salts, sucralfate, and milk products. In contrast to ciprofloxacin, lomefloxacin does not elevate plasma levels of theophylline.
91.1.2.2.4
Preparations, Dosage, and Administration. Lomefloxacin is available in 400-mg tablets for oral dosing. The drug may be taken without regard to meals. The usual dosage is 400 mg once a day for 10 to 14 days. Dosage should be reduced in patients with renal impairment.
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Pharmacology Nursing 7th Edition reduced in for patients with renalCare, impairment. 91.1.2.3 91.1.2.3.1
Sparfloxacin Actions and Uses. Sparfloxacin [Zagam] is an oral fluoroquinolone approved for once-daily treatment of community-acquired pneumonia (CAP) and acute bacterial exacerbations of chronic bronchitis. The drug is active against virtually all common respiratory tract pathogens, including drug resistant strains of Streptococcus pneumoniae, a major cause of CAP. Despite its efficacy, sparfloxacin has been withdrawn from the market.
91.1.2.3.2
1053 1054
Adverse Effects. Sparfloxacin is generally well tolerated. However, it can prolong the QT interval, thereby posing a risk of dysrhythmias. Accordingly, the drug should be avoided by patients with preexisting QT prolongation and by patients taking drugs that can prolong the QT interval (eg, quinidine, sotalol). Like other fluoroquinolones, sparfloxacin may pose a risk of tendon injury and phototoxicity. Additional side effects include tendinitis, GI disturbances (nausea, diarrhea, abdominal discomfort), headache, dizziness, and insomnia.
91.1.2.3.3
Drug Interactions. As with other fluoroquinolones, absorption of sparfloxacin is reduced by cations (eg, magnesium- and aluminum-containing antacids, zinc and iron salts, milk products, sucralfate). In contrast to some other fluoroquinolones, sparfloxacin does not elevate levels of theophylline.
91.1.2.4
Trovafloxacin and Alatrofloxacin Trovafloxacin [Trovan] and its prodrug form, alatrofloxacin [Trovan IV], are active against more bacterial pathogens than any other fluoroquinolone. Unfortunately, within a year of their introduction in 1998, reports of druginduced liver dysfunction began to appear, including several cases of fatal liver failure. Symptomatic pancreatitis has also been reported. Because of these serious adverse effects, and because safe and effective alternatives are available, these drugs have been withdrawn.
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Pharmacology forwithdrawn. Nursing Care, 7th Edition drugs have been 91.1.2.5 91.1.2.5.1
Moxifloxacin Basic Pharmacology. Moxifloxacin [Avelox] is a broad-spectrum fluoroquinolone indicated for respiratory tract infections (CAP, acute sinusitis, acute exacerbations of chronic bronchitis), intra-abdominal infections, and infections of the skin and skin structures. Administration is oral or IV. The drug is well absorbed from the GI tract, undergoes wide distribution, and is eliminated by hepatic metabolism and renal excretion. Side effects are generally mild, the most common being nausea, vomiting, diarrhea, stomach pain, dizziness, and altered sense of taste. Like other fluoroquinolones, moxifloxacin can cause tendon rupture, and may pose a risk of phototoxicity. The drug does not increase levels of warfarin or digoxin, but does prolong the QT interval, and hence may pose a risk of dysrhythmias. Accordingly, moxifloxacin should not be given to patients taking prodysrhythmic drugs or to those with hypokalemia or preexisting QT prolongation.
91.1.2.5.2
Preparations, Dosage, and Administration. For systemic therapy, moxifloxacin [Avelox, Avelox I.V.] is available in 400-mg tablets and in solution for IV infusion. Oral and IV dosages are the same. The dosage for sinusitis and pneumonia is 400 mg once a day for 10 days; the dosage for bronchitis is 400 mg once a day for 5 days. Oral dosing may be done without regard to meals. However, because absorption can be reduced by cationic substances (eg, milk, sucralfate, iron and zinc salts, magnesiumor aluminum-containing antacids), moxifloxacin should be administered at least 4 hours before these agents or 8 hours after.
91.1.2.6
Norfloxacin Norfloxacin [Noroxin] is a fluoroquinolone antibiotic with an antimicrobial spectrum like that of ciprofloxacin. The drug is used for oral therapy of UTIs and prostatitis.
91.1.2.6.1
Pharmacokinetics. Norfloxacin undergoes rapid but incomplete absorption from the GI tract. The drug is widely distributed to body tissues and fluids. Excretion is primarily renal, resulting in high concentrations in the urine. About 30% of the drug is eliminated in the bile and feces. In patients with normal kidney function, the half-life is approximately 4 hours; this value
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Pharmacology forinNursing Care,30% 7th Edition concentrations the urine. About of the drug is eliminated in the bile and feces. In patients with normal kidney function, the half-life is approximately 4 hours; this value doubles in patients with renal impairment. 91.1.2.6.2
Therapeutic Uses. Norfloxacin is approved for prostatitis caused by E. coli and for UTIs caused by P. aeruginosa and other gram-negative bacteria that can display multiple drug resistance. The drug is also approved for uncomplicated urethral and cervical gonorrhea, but is no longer recommended for this use.
91.1.2.6.3
Adverse Effects. Norfloxacin is generally well tolerated. Gastrointestinal effects (nausea, vomiting, anorexia) have been most frequent. The drug has produced a variety of CNS reactions, including headache, dizziness, drowsiness, lightheadedness, depression, and disturbance of vision. Skin rash develops occasionally. Like other fluoroquinolones, norfloxacin poses a risk of tendon rupture and phototoxicity.
91.1.2.6.4
Drug and Food Interactions. Norfloxacin shares the same interactions as ciprofloxacin. Absorption is suppressed by cationic agents, including milk products, aluminum- and magnesium-containing antacids, iron and zinc salts, and sucralfate. The drug can elevate levels of theophylline and intensify effects of warfarin.
91.1.2.6.5
Preparations, Dosage, and Administration. Norfloxacin [Noroxin] is supplied in 400-mg tablets. The drug should be taken on an empty stomach with a full glass of water. For uncomplicated UTIs, the usual dosage is 400 mg twice daily for 3 days. Prolonged treatment (10 days to 3 weeks) is employed for patients with complicated infections of the urinary tract. Dosage should be reduced in patients with renal impairment.
91.1.2.7
Levofloxacin Levofloxacin [Levaquin] is active against Strep. pneumoniae (also known as pneumococcus), H. influenzae, Staph. aureus, Enterococcus faecalis, Streptococcus pyogenes, and Proteus mirabilis. Approved indications include urinary tract infections, chronic bacterial prostatitis, inhalational anthrax, complicated skin and skin structure infections, and certain respiratory
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Pharmacology for Nursing Care, Edition mirabilis. Approved indications include7th urinary tract infections, chronic bacterial prostatitis, inhalational anthrax, complicated skin and skin structure infections, and certain respiratory tract infections: acute maxillary sinusitis, acute bacterial exacerbations of chronic bronchitis, and CAP, including CAP caused by penicillin-resistant pneumococci. Possible adverse effects include peripheral neuropathy, rhabdomyolysis, tendon rupture, and phototoxicity. To treat systemic infections, levofloxacin may be administered PO or IV. Absorption from the GI tract is reduced by cationic substances (eg, magnesium- and aluminum-containing antacids, zinc and iron salts, sucralfate, milk and milk products) but not by most foods. Levofloxacin is available in tablets (250, 500, and 750 mg), an oral solution (25 mg/mL), and solution for injection (5 and 25 mg/mL). The usual dosage is 500 mg once a day for 7 to 14 days. In patients with renal impairment, the dosage is 500 mg every 48 hours. 91.1.2.8 91.1.2.8.1
Gemifloxacin Therapeutic Use. Gemifloxacin [Factive] is an oral fluoroquinolone approved for two respiratory tract infections in adults: (1) mild to moderate CAP and (2) acute bacterial exacerbations of chronic bronchitis (ABECB). The drug is active against H. influenzae, Moraxella catarrhalis, Chlamydia pneumoniae, Mycoplasma pneumoniae, Legionella pneumophila, and Strep. pneumoniae, including strains that are multidrug resistant. Gemifloxacin causes a high incidence of rash and, compared with older fluoroquinolones used for respiratory infections, has no significant advantages and costs more. Accordingly, the older agents—levofloxacin and moxifloxacin—are preferred.
91.1.2.8.2
Adverse Effects. Gemifloxacin is generally well tolerated. The most common reactions are diarrhea, rash, nausea, headache, abdominal pain, vomiting, dizziness, and altered sense of taste. In addition, the drug may cause tendon injury, phototoxicity, hypersensitivity reactions, and liver damage. Like some other fluoroquinolones, gemifloxacin can prolong the QT interval, thereby posing a risk of dysrhythmias. Accordingly, the drug should not be used by patients taking prodysrhythmic drugs or those with hypokalemia or pre-existing QT prolongation. The incidence of rash with gemifloxacin is much higher than with other fluoroquinolones. Women under 40 years of age are at greatest risk. Symptoms are severe in about 10% of patients who develop a rash; in the rest, symptoms are mild to moderate. As a rule, gemifloxacin-induced rash resolves spontaneously in 1 to 2 weeks, although some patients require treatment with systemic glucocorticoids. If rash develops, gemifloxacin should be
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Pharmacology for Nursing Care, spontaneously 7th Edition gemifloxacin-induced rash resolves in 1 to 2 weeks, although some patients require treatment with systemic glucocorticoids. If rash develops, gemifloxacin should be discontinued. 91.1.2.8.3
Drug Interactions. As with ciprofloxacin, absorption of gemifloxacin can be reduced by compounds that contain cations. Among these are iron salts, zinc salts, sucralfate, aluminum- or magnesiumcontaining antacids, and milk and other dairy products, which contain calcium ions. To ensure adequate absorption, these cationic agents should be administered at least 6 hours before gemifloxacin or 2 hours after.
91.1.2.8.4
Preparations, Dosage, and Administration. Gemifloxacin [Factive] is available in 320-mg tablets for oral dosing, with or without food. The dosage for CAP is 320 mg once a day for 7 days, and the dosage for ABECB is 320 mg once a day for 5 days. For patients with severe renal impairment, the dosage should be reduced to 160 mg once a day. To prevent high concentrations in the urine, all patients should consume liberal amounts of fluid.
91.2
ADDITIONAL ANTIBACTERIAL DRUGS
91.2.1
Metronidazole Metronidazole [Flagyl, Protostat] is used for protozoal infections and infections caused by obligate anaerobic bacteria. The basic pharmacology of metronidazole is discussed in Chapter 98, as is the drug's use against protozoal infections. Consideration here is limited to antibacterial applications.
91.2.1.1
Mechanism of Antibacterial Action. Metronidazole is lethal to anaerobic organisms only. To exert bactericidal effects, metronidazole must first be taken up by cells and then converted into its active form; only anaerobes can perform the conversion. The active form interacts with DNA to cause strand breakage and loss of helical structure, effects that result in inhibition of nucleic acid synthesis and, ultimately, cell death. Since aerobic bacteria are unable to activate metronidazole, they are insensitive to the drug.
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Pharmacology Nursing Care, 7th Edition insensitive tofor the drug. 91.2.1.2
Antibacterial Spectrum. Metronidazole is active against obligate anaerobes only. Sensitive bacterial pathogens include Bacteroides fragilis (and other Bacteroides species), C. difficile (and other Clostridium species), Fusobacterium species, Gardnerella vaginalis, Peptococcus species, and Peptostreptococcus species.
91.2.1.3
Therapeutic Uses. Metronidazole is active against a variety of anaerobic bacterial infections, including infections of the CNS, abdominal organs, bones and joints, skin and soft tissues, and genitourinary tract. Frequently, such infections also involve aerobic bacteria, and hence therapy must include a drug active against them. Metronidazole is a drug of choice for antibiotic-associated colitis caused by C. difficile. In addition, the drug is employed for prophylaxis in surgical procedures associated with a high risk of infection by anaerobes (eg, colorectal surgery, abdominal surgery, vaginal surgery). Metronidazole is also used in combination with a tetracycline and bismuth subsalicylate to eradicate Helicobacter pylori in people with peptic ulcer disease. Development of resistance to metronidazole is rare.
91.2.1.4
Preparations, Dosage, and Administration. For initial treatment of serious bacterial infections, metronidazole is administered by IV infusion. Under appropriate conditions, the patient may switch to oral therapy.
91.2.1.5
Intravenous Formulations. Metronidazole is available in two formulations—powder and solution—for IV use. The powdered form [Flagyl IV] is supplied in 500-mg vials and must be reconstituted prior to use (see below). The solution (generic only) contains 5 mg of metronidazole per milliliter and is ready for IV use.
91.2.1.6
Preparation of Powdered Metronidazole for IV Infusion. The powder is readied for infusion in three steps: (1) reconstitution, (2) dilution in IV solution, and (3) neutralization. These steps must be performed in the order given. The powder is reconstituted using 4.4 mL of any of the following liquids: sterile water for injection, bacteriostatic water for injection, 0.9% sodium chloride injection, or bacteriostatic 0.9% sodium chloride injection. The resulting concentrated solution contains approximately 100 mg
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Pharmacology Care, Edition bacteriostaticfor waterNursing for injection, 0.9% 7th sodium chloride injection, or bacteriostatic 0.9% sodium chloride injection. The resulting concentrated solution contains approximately 100 mg of metronidazole per milliliter. This solution is then diluted to a concentration of 8 mg/mL (or less) using any of the following IV solutions: 0.9% sodium chloride injection, 5% dextrose injection, or lactated Ringer's injection. Neutralization of the diluted solution is accomplished by adding 5 mEq of sodium bicarbonate injection for each 500 mg of metronidazole present; this procedure should elevate pH to a value between 6 and 7. Neutralized solutions should not be refrigerated, because cooling may cause metronidazole to precipitate. 91.2.1.7
Intravenous Dosage and Administration. Infusions must be done slowly (over a 1-hour span). Therapy of anaerobic infections in adults is initiated with a loading dose of 15 mg/kg. After this, maintenance doses of 7.5 mg/kg are given every 6 to 8 hours. Treatment duration is usually 1 to 2 weeks. Patients with renal impairment and those receiving prolonged treatment may need a reduced dosage to avoid toxicity from drug accumulation.
91.2.1.8
Oral Preparations and Dosage. Metronidazole [Flagyl, Flagyl ER, Flagyl 375, Protostat] is supplied in capsules (375 mg), standard tablets (250 and 500 mg), and extended-release tablets (750 mg). The adult dosage for anaerobic infections is 7.5 mg/kg every 6 hours. For bacterial vaginosis in adults, a dosage of 750 mg (extended-release formulation) once daily for 7 days is effective. Pseudomembranous colitis caused by C. difficile is treated with 500 mg 3 times a day for 7 to 15 days.
91.2.2
Daptomycin Daptomycin [Cubicin] is the first representative of a new class of antibiotics, the cyclic lipopeptides. The drug has a unique mechanism of action and can rapidly kill virtually all clinically relevant gram-positive bacteria, including methicillin-resistant Staph. aureus. Daptomycin is devoid of significant drug interactions, and the only notable side effect is possible muscle injury. The drug is given once a day by IV infusion, and there is no need to monitor its plasma level.
91.2.2.1
Mechanism of Action. Daptomycin has a novel mechanism of action. The drug inserts itself into the bacterial cell membrane, and thereby forms channels that permit efflux of intracellular potassium (and possibly other cytoplasmic ions). Loss of intracellular ions has two effects: it (1) depolarizes the cell membrane, and (2) inhibits synthesis of DNA, RNA, and proteins, and thereby causes
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Pharmacology Nursing Care, 7th Editionions has two effects: it (1) depolarizes possibly otherfor cytoplasmic ions). Loss of intracellular the cell membrane, and (2) inhibits synthesis of DNA, RNA, and proteins, and thereby causes cell death. 91.2.2.2
Antibacterial Spectrum. Daptomycin is active only against gram-positive bacteria. The drug cannot penetrate the outer membrane of gram-negative bacteria, and hence cannot harm them. Daptomycin is rapidly bactericidal to staphylococci (including methicillin- and vancomycin-resistant Staph. aureus and methicillin-resistant Staph. epidermidis), enterococci (including vancomycin-resistant E. faecium and E. faecalis), streptococci (including penicillin-resistant Strep. pneumoniae), and most other aerobic and anaerobic gram-positive bacteria. As a rule, daptomycin is more rapidly bactericidal than either vancomycin, linezolid, or quinupristin/dalfopristin.
91.2.2.3
Therapeutic Use. Daptomycin has two approved indications: (1) bloodstream infection with Staph. aureus, and (2) complicated skin and skin structure infections caused by susceptible strains of the following gram-positive bacteria: Staph. aureus (including methicillin-resistant strains), Strep. pyogenes, Strep. agalactiae, Strep. dysgalactiae subspecies equisimilis, and E. faecalis (vancomycinsusceptible strains only). The drug is being tested for other possible uses, including endocarditis and infections caused by vancomycin-resistant enterococci. Daptomycin should not be used for CAP. Why? Because clinical trials have shown that, in patients receiving daptomycin, the rate of death and serious cardiorespiratory events is higher than in patients receiving equally effective alternatives.
91.2.2.4
Resistance. Out of more than 1000 patients receiving daptomycin in clinical trials, only 2 had infections resistant to the drug. The mechanism of resistance has not been identified. There is no known mechanism by which resistance can be transferred from one bacterium to another. Also, there is no cross-resistance between daptomycin and drugs in any other class of antibiotics.
91.2.2.5
Pharmacokinetics. Daptomycin is administered by IV infusion, and a significant fraction (92%) becomes bound to plasma proteins. The drug undergoes minimal metabolism, and most of each dose is excreted unchanged in the urine. In patients with normal renal function, the half-life is 9 hours. However, in those with severe renal impairment (creatinine clearance less than 30 mL/min), and in those on hemodialysis or continuous ambulatory peritoneal dialysis (CAPD), the half-
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Pharmacology for Nursing 7th Edition However, in those with severe Care, renal impairment (creatinine clearance less than 30 mL/min), and in those on hemodialysis or continuous ambulatory peritoneal dialysis (CAPD), the halflife increases threefold. As a result, if the dosage is not reduced, plasma drug levels can rise dangerously high. 91.2.2.6
Adverse Effects. Daptomycin is generally well tolerated. The most common adverse effects are constipation (6.2%), nausea (5.8%), diarrhea (5.2%), injection-site reactions (5.8%), headache (5.4%), insomnia (4.5%), and rash (4.3%). Daptomycin may pose a small risk of myopathy (muscle injury). In clinical trials with doses that were larger and more frequent than those used now, patients often experienced muscle pain and weakness in association with increased levels of creatine phosphokinase (CPK), a marker for muscle injury. However, with currently approved doses, elevation of CPK is rare. Nonetheless, patients should be warned about possible muscle injury, and told to report any muscle pain or weakness. In addition, CPK levels should be measured weekly. If the level rises markedly (to more than 10 times the upper limit of normal), daptomycin should be discontinued. Daptomycin should also be discontinued in patients who report muscle pain or weakness in conjunction with a more moderate rise in CPK.
91.2.2.7
Drug Interactions. Daptomycin appears devoid of significant drug interactions. It does not induce or inhibit cytochrome P450, and hence should not affect drugs that are metabolized by this enzyme system. In clinical studies, daptomycin did not affect the kinetics of warfarin, simvastatin, or aztreonam. Concurrent use of daptomycin plus tobramycin caused a moderate increase in daptomycin levels and a moderate decrease in tobramycin levels. Accordingly, caution is needed when these drugs are combined. Like daptomycin, the HMG-CoA reductase inhibitors (eg, simvastatin [Zocor]) can cause myopathy. However, in clinical trials, no patient receiving simvastatin plus daptomycin developed signs of muscle injury. Nonetheless, given our limited experience with daptomycin, it may be prudent to suspend HMG-CoA reductase inhibitors when daptomycin is being used.
91.2.2.8
Preparations, Dosage, and Administration. Daptomycin [Cubicin] is available as a powder in 500-mg single-use vials. Following reconstitution in 0.9% sodium chloride, the drug is given by a slow (30-minute) IV infusion. For patients with normal renal function, the dosage is 4 mg/kg once every 24 hours. For
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Pharmacology Nursing Edition reconstitutionfor in 0.9% sodium Care, chloride,7th the drug is given by a slow (30-minute) IV infusion. For patients with normal renal function, the dosage is 4 mg/kg once every 24 hours. For patients with severe renal impairment, and for those on hemodialysis or CAPD, the dosage is 4 mg/kg once every 48 hours. Daptomycin powder should be stored refrigerated at 2°C to 8°C (36°F to 46°F). After reconstitution, the solution may be stored at room temperature for 12 hours or refrigerated for 48 hours. Daptomycin is compatible with 0.9% sodium chloride solution and lactated Ringer's solution, but not with solutions that contain dextrose. 91.2.3
1056
Rifampin Rifampin [Rifadin, Rimactane] is a broad-spectrum antibacterial agent employed primarily for tuberculosis (see Chapter 89). However, the drug is also used against several nontuberculous infections. Rifampin is useful for treating asymptomatic carriers of Neisseria meningitidis, but is not given to treat active meningococcal infection. Unlabeled uses include treatment of leprosy, gram-negative bacteremia in infancy, and infections caused by Staph. epidermidis and Staph. aureus (eg, endocarditis, osteomyelitis, prostatitis). Rifampin has also been employed for prophylaxis of meningitis due to H. influenzae. Because resistance can develop rapidly, established bacterial infections should not be treated with rifampin alone. The basic pharmacology of rifampin and its use in tuberculosis are presented in Chapter 89.
91.2.4
Rifaximin Rifaximin [Xifaxan] is a nonabsorbable analog of rifampin approved for traveler's diarrhea caused by E. coli in patients at least 12 years old. The drug is not effective against severe diarrhea associated with fever or bloody stools, and hence should not be used if these are present. Like rifampin, rifaximin inhibits bacterial DNA-dependent RNA polymerase, and thereby inhibits RNA synthesis, resulting in inhibition of protein synthesis and subsequent bacterial death. Rifaximin is administered by mouth, and very little (less than 0.4%) is absorbed. As a result, the drug achieves high concentrations in the intestinal tract, and then is excreted unchanged in the stool. Rifaximin is well tolerated. Gastrointestinal effects—nausea, flatulence, defecation urgency— occur in some patients. Because so little drug is absorbed, systemic effects are minimal. However, studies in rats and rabbits indicate that rifaximin is teratogenic, and hence should not be used by pregnant women. There have been postmarketing reports of hypersensitivity reactions (rash, allergic dermatitis, urticaria, pruritus, angioneurotic edema), but rifaximin has not been
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Pharmacology for Nursing Care, 7th postmarketing Edition reports of hypersensitivity reactions be used by pregnant women. There have been (rash, allergic dermatitis, urticaria, pruritus, angioneurotic edema), but rifaximin has not been clearly identified as the cause. Rifaximin is available in 200-mg tablets for oral use. The recommended dosage is 200 mg 3 times a day for 3 days. Rifaximin may be taken with or without food. 91.2.5
Bacitracin Bacitracin is a polypeptide antibiotic produced by a strain of Bacillus subtilis. The drug is almost always employed topically. Because systemic administration can cause serious toxicity, and because superior systemic agents are available, bacitracin is no longer used for systemic infections.
91.2.5.1
Mechanism of Action and Antimicrobial Spectrum. Bacitracin inhibits synthesis of the bacterial cell wall, thereby promoting cell lysis and death. The drug is active against most gram-positive bacteria, including staphylococci, streptococci, and C. difficile. Neisseria species and H. influenzae are also susceptible, but most other gramnegative bacteria are resistant. Acquisition of resistance by sensitive organisms is uncommon.
91.2.5.2
Adverse Effects. Rarely, topical bacitracin causes local hypersensitivity reactions. Parenteral (IM) administration can produce severe nephrotoxicity.
91.2.5.3
Therapeutic Uses. Bacitracin is used for topical treatment of bacterial infections. The drug is very active against staphylococci and group A streptococci, the pathogens that cause most acute infections of the skin. Because of this activity, bacitracin has been marketed in a variety of topical preparations for treatment of skin infections. Many of these preparations contain additional antibiotics, usually polymyxin B, neomycin, or both.
91.2.6
Polymyxin B Polymyxin B is a bactericidal drug employed primarily for local effects. Because of serious systemic toxicity, parenteral administration is rare.
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Pharmacology forparenteral Nursing Care, 7th Edition systemic toxicity, administration is rare. 91.2.6.1
Antibacterial Spectrum and Mechanism of Action. Polymyxin B is bactericidal to a broad spectrum of aerobic, gram-negative bacilli. Grampositive bacteria and most anaerobes are resistant. Bactericidal effects result from binding of polymyxin B to the bacterial cell membrane, an action that disrupts membrane structure and thereby increases membrane permeability. The increase in permeability leads to inhibition of cellular respiration and cell death. The resistance displayed by gram-positive bacteria has been attributed to the thick gram-positive cell wall, a structure that may block access of polymyxin B to the cell membrane.
91.2.6.2
Therapeutic Uses. Polymyxin B is used primarily for topical treatment of the eyes, ears, and skin. Preparations designed for application to the skin frequently contain other antibiotics, such as bacitracin and neomycin. In addition to its topical uses, polymyxin B (together with neomycin) has been employed as a bladder irrigant to prevent infection in patients with indwelling catheters. Parenteral use is extremely limited; polymyxin B is not a drug of choice for any systemic infection. The primary indication for parenteral polymyxin B is serious infection caused by P. aeruginosa. Polymyxin B may be given when preferred drugs have been ineffective or intolerable.
91.2.6.3
Adverse Effects. The major adverse effects associated with parenteral therapy are neurotoxicity and nephrotoxicity. Both occur frequently and limit systemic use of the drug. Polymyxin B is not absorbed when applied topically, and hence topical use does not cause systemic effects. Rarely, topical polymyxin B produces hypersensitivity.
91.2.6.3.1
KEY POINTS ▪ Fluoroquinolones are broad-spectrum antibiotics with a wide variety of clinical applications. ▪ Patients who might otherwise require hospitalization for parenteral antibacterial therapy can often be treated as outpatients with an oral fluoroquinolone.
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Pharmacology forcan Nursing Care,as7th Edition therapy often be treated outpatients with an oral fluoroquinolone. ▪ Fluoroquinolones act by inhibiting bacterial DNA gyrase and topoisomerase IV. ▪ Because fluoroquinolones can cause tendon rupture, they should be discontinued at the first sign of tendon pain or inflammation. Also, the patient should not exercise until tendinitis has been ruled out. ▪ Fluoroquinolones pose a risk of phototoxicity. Accordingly, patients should avoid sunlight and sunlamps, and should use protective clothing and a sunscreen if they must go outdoors. ▪ Absorption of fluoroquinolones can be reduced by cationic substances, including milk products (calcium), aluminum- and magnesium-containing antacids, iron and zinc salts, and sucralfate. ▪ In addition to its use against protozoa, metronidazole is used against infections caused by obligate anaerobic bacteria (eg, Bacteroides fragilis, C. difficile).
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Pharmacology for Nursing Care, 7th Edition 1057
92
CHAPTER 91 Antifungal Agents The antifungal agents fall into two major groups: drugs for systemic mycoses (ie, systemic fungal infections) and drugs for superficial mycoses. A few drugs are used for both. Systemic infections occur much less frequently than superficial infections, but are much more dangerous. Accordingly, therapy of systemic mycoses is our main focus.
92.1
DRUGS FOR SYSTEMIC MYCOSES Systemic mycoses can be subdivided into two categories: opportunistic infections and nonopportunistic infections. The opportunistic mycoses—candidiasis, aspergillosis, cryptococcosis, and mucormycosis—are seen primarily in debilitated or immunocompromised hosts. In contrast, nonopportunistic infections can occur in any host. These latter mycoses, which are relatively uncommon, include sporotrichosis, blastomycosis, histoplasmosis, and coccidioidomycosis. Treating systemic mycoses can be difficult: These infections often resist treatment and hence may require prolonged therapy with drugs that frequently prove toxic. Drugs of choice for systemic mycoses are summarized in Table 91-1. The systemic antifungal drugs fall into four classes: polyene antibiotics, azoles, echinocandins, and pyrimidine analogs. Class members and mechanisms of action are summarized in Table 91-2.
92.1.1
Amphotericin B, a Polyene Antibiotic Amphotericin B [Abelcet, Amphotec, AmBisome] belongs to a group of drugs known as polyene antibiotics, so named because their structures contain a series of conjugated double bonds. Nystatin, another antifungal drug, is in the same family. Amphotericin B—an important but dangerous drug—is active against a broad spectrum of pathogenic fungi and a drug of choice for most systemic mycoses (see Table 91-1). Unfortunately, amphotericin B is highly toxic: To varying degrees, infusion reactions and renal damage occur in all patients. Because of its potential for harm, amphotericin B should be employed only against infections that are progressive and potentially fatal. Amphotericin B is available in four formulations: a conventional formulation (amphotericin B deoxycholate) and three lipid-based formulations. The lipid-based formulations are as effective as the conventional formulation and cause less toxicity—but are much more expensive. For treatment of systemic mycoses, all formulations are administered by IV infusion. Infusions are given daily or every other day for several months.
CHAPTER 91 Antifungal Agents
1057 1058
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Pharmacology for Nursing Edition given daily or every other day forCare, several7th months. TABLE 91-1 Drugs of Choice for Systemic Mycoses Infection
Causative Organism
Drugs of Choice
Alternative Drugs
Aspergillosis
Aspergillus species
Voriconazole
Amphotericin B, itraconazole, posaconazole, caspofungin, micafungin
Blastomycosis
Blastomyces dermatitidis
Amphotericin B or itraconazole
No alternative recommended
Candidiasis
Candida species
Amphotericin B or fluconazole, either one ± flucytosine
Itraconazole, voriconazole, caspofungin
Coccidioidomycosis
Coccidioides immitis
Amphotericin B or fluconazole
Itraconazole, ketoconazole
Cryptococcosis
Cryptococcus neoformans
Amphotericin B ± flucytosine
Itraconazole
Fluconazole
Amphotericin B
Amphotericin B or itraconazole
Fluconazole, ketoconazole
Itraconazole
Amphotericin B
Amphotericin B
No alternative recommended
Paracoccidioidomycosis Paracoccidioides brasiliensis
Amphotericin B or itraconazole
Ketoconazole
Sporotrichosis
Amphotericin B or itraconazole
Fluconazole
Chronic suppression Histoplasmosis
Histoplasma capsulatum
Chronic suppression Mucormycosis
Mucor
Sporothrix schenckii
CHAPTER 91 Antifungal Agents
Page 2 of 44
Pharmacology for Nursing Care, 7th Edition TABLE 91-2 Classes of Systemic Antifungal Drugs Drug Class
Mechanism of Action
Class Members
Polyene Antibiotics
Bind to ergosterol, and thereby disrupt the fungal cell membrane
Amphotericin B
Azoles
Inhibit synthesis of ergosterol, and thereby disrupt the fungal cell membrane
Fluconazole Itraconazole Ketoconazole Posaconazole Voriconazole
Echinocandins Inhibit synthesis of beta-1,3-D-glucan, and thereby disrupt the fungal cell wall
Anidulafungin Caspofungin Micafungin
Pyrimidine Analogs 92.1.1.1
Disrupt synthesis of RNA and DNA
Flucytosine
Mechanism of Action Amphotericin B binds to components of the fungal cell membrane, thereby increasing permeability. The resultant leakage of intracellular cations (especially potassium) reduces viability. Depending on the concentration of amphotericin B and the susceptibility of the fungus, the drug may be fungistatic or fungicidal. The component of the fungal membrane to which amphotericin B binds is ergosterol, a member of the sterol family of compounds. Hence, for a cell to be susceptible, its cytoplasmic membrane must contain sterols. Since bacterial membranes lack sterols, bacteria are not affected. Much of the toxicity of amphotericin is attributable to the presence of sterols (principally cholesterol) in mammalian cell membranes. When amphotericin binds with cholesterol in mammalian membranes, the effect is similar to that seen in fungi. However, there is some degree of selectivity: Amphotericin binds more strongly to ergosterol than it does to cholesterol, and hence fungi are hurt more than we are.
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Pharmacology forhence Nursing Care, 7ththan Edition cholesterol, and fungi are hurt more we are. 92.1.1.2
Microbial Susceptibility and Resistance Amphotericin B is active against a broad spectrum of fungi. Some protozoa (eg, Leishmania braziliensis) are also susceptible. As noted, bacteria are resistant. Emergence of resistant fungi is extremely rare, and occurs only with long-term amphotericin use. In all cases of resistance, the fungal membranes had reduced amounts of ergosterol or none at all.
92.1.1.3
Therapeutic Uses Amphotericin B is a drug of choice for most systemic mycoses (see Table 91-1). Before this drug became available, systemic fungal infections usually proved fatal. Treatment is prolonged; 6 to 8 weeks is common. In some cases, treatment may last for 3 or 4 months. In addition to its antifungal applications, amphotericin B is a drug of choice for leishmaniasis (see Chapter 98).
92.1.1.4 92.1.1.4.1
Pharmacokinetics Absorption and Distribution. Amphotericin is poorly absorbed from the GI tract, and hence oral therapy cannot be used for systemic infection. Rather, amphotericin must be administered IV. When the drug leaves the vascular system, it undergoes extensive binding to sterol-containing membranes of tissues. Levels about half those in plasma are achieved in aqueous humor and in peritoneal, pleural, and joint fluids. Amphotericin B does not readily penetrate to the cerebrospinal fluid (CSF).
92.1.1.4.2
Metabolism and Excretion. Little is known about the elimination of amphotericin B. We do not know whether the drug is metabolized or how most of it is removed from the body. Renal excretion of unchanged amphotericin is minimal. Accordingly, there is no need to reduce the dosage in patients with pre-existing renal impairment. Complete elimination of amphotericin takes a long time; the drug has been detected in tissues more than a year after cessation of treatment.
92.1.1.5
Adverse Effects Amphotericin can cause a variety of serious adverse effects. Patients should be under close supervision, preferably in a hospital.
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Pharmacology for Nursing Care, 7th Edition supervision, preferably in a hospital. 92.1.1.5.1
Infusion Reactions. Intravenous amphotericin frequently produces fever, chills, rigors, nausea, and headache. These reactions are caused by release of proinflammatory cytokines (tumor necrosis factor, interleukin-1, interleukin-6) from monocytes and macrophages. Symptoms begin 1 to 3 hours after starting the infusion and persist about 1 hour. Mild reactions can be reduced by pretreatment with diphenhydramine plus acetaminophen. Aspirin can also help, but it may increase kidney damage (see below). Intravenous meperidine or dantrolene can be given if rigors occur. If other measures fail, hydrocortisone (a glucocorticoid) can be used to decrease fever and chills. However, since glucocorticoids can reduce the patient's ability to fight infection, routine use of hydrocortisone should be avoided. Infusion reactions are less intense with lipid-based amphotericin formulations than with the conventional formulation. Amphotericin infusion produces a high incidence of phlebitis. This can be minimized by changing peripheral venous sites often, administering amphotericin through a large central vein, and pretreatment with heparin.
92.1.1.5.2
Nephrotoxicity. Amphotericin is toxic to cells of the kidney. Renal impairment occurs in practically all patients. The extent of kidney damage is related to the total dose administered over the full course of treatment. In most cases, renal function normalizes after amphotericin use stops. However, if the total dose exceeds 4 gm, residual impairment is likely. Kidney damage can be minimized by infusing 1 L of saline on the days of amphotericin administration. Other nephrotoxic drugs (eg, aminoglycosides, cyclosporine, nonsteroidal anti-inflammatory drugs [NSAIDs]) should be avoided. To evaluate renal injury, tests of kidney function should be performed every 3 to 4 days, and intake and output should be monitored. If plasma creatinine content rises above 3.5 mg/dL, amphotericin dosage should be reduced. Renal damage is less with lipid-based amphotericin than with the conventional formulation.
92.1.1.5.3
Hypokalemia. Damage to the kidneys often causes hypokalemia. Potassium supplements may be needed to correct the problem. Potassium levels and serum creatinine should be monitored often.
92.1.1.5.4
1058 1059
Hematologic Effects. Amphotericin can cause bone marrow suppression, resulting in normocytic, normochromic anemia. Hematocrit determinations should be conducted to monitor red blood cell status.
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Pharmacology for Nursing Care,should 7th Edition anemia. Hematocrit determinations be conducted to monitor red blood cell status. 92.1.1.5.5
Effects Associated with Intrathecal Injection. Intrathecal administration may cause nausea, vomiting, headache, and pain in the back, legs, and abdomen. Rare reactions include visual disturbances, impairment of hearing, and paresthesias (tingling, numbness, or pain in the hands and feet).
92.1.1.5.6
Other Adverse Effects. Infusion of amphotericin may be associated with delirium, hypotension, hypertension, wheezing, and hypoxia. Rarely, amphotericin has caused rash, convulsions, anaphylaxis, dysrhythmias, acute liver failure, and nephrogenic diabetes insipidus.
92.1.1.6 92.1.1.6.1
Drug Interactions Nephrotoxic Drugs. Use of amphotericin with other nephrotoxic drugs (eg, aminoglycosides, cyclosporine, NSAIDs) increases the risk of injury to the kidneys. Accordingly, these combinations should be avoided if possible.
92.1.1.6.2
Flucytosine. Amphotericin potentiates the antifungal actions of flucytosine, apparently by enhancing flucytosine entry into fungi. Because of this potentiative interaction, the combination of flucytosine with a relatively low dose of amphotericin can produce antifungal effects equivalent to those of a high dose of amphotericin alone. By allowing a reduction in amphotericin dosage, the combination decreases the risk of amphotericin-induced toxicity.
92.1.1.7 92.1.1.7.1
Preparations, Dosage, and Administration Preparations. Amphotericin B is available in a conventional formulation—amphotericin B deoxycholate (generic only)—and three lipid-based formulations: liposomal amphotericin B [AmBisome], amphotericin B cholesteryl sulfate complex [Amphotec], and amphotericin B lipid complex [Abelcet]. The lipid-based formulations cause less nephrotoxicity and fewer infusion reactions than the conventional formulation. However, these newer formulations are considerably more expensive.
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Pharmacology for Nursing Care, 7th Edition considerably more expensive. 92.1.1.7.2
Routes. For treatment of systemic mycoses, amphotericin B is almost always administered IV. Infusions should be performed slowly (over 2 to 4 hours) to minimize phlebitis and cardiovascular reactions. Alternate-day dosing can reduce adverse effects. For most patients, several months of therapy are required. Because amphotericin B does not readily enter the CSF, intrathecal injection is used for fungal meningitis.
92.1.1.7.3
Intravenous Dosage and Administration. Fungal Infections. Dosage is individualized and based on the severity of the disease and the patient's ability to tolerate treatment. Optimal dosage has not been established. A small test dose (1 mg) is often infused to assess patient reaction. After this, therapy is initiated with a dosage of 0.25 mg/kg/day. Maintenance dosages range from 1.5 to 6 mg/kg/day, depending on the severity of the infection and the form of amphotericin used. Dosage should be reduced in patients with renal impairment. The infusion solution should be checked periodically for a precipitate and, if one is seen, administration should be discontinued immediately. Because the treatment period is prolonged, the administration site should be rotated—so as to reduce the risk of phlebitis and help ensure continued availability of a suitable vein.
92.1.1.7.4
Leishmaniasis. Leishmaniasis can be treated with amphotericin B deoxycholate or liposomal amphotericin B [AmBisome]. For conventional amphotericin, the dosage is 0.5 to 1 mg/kg daily every other day for up to 8 weeks. For AmBisome, the dosage is 3 mg/kg on days 1, 2, 3, 4, 5, 14, and 21.
92.1.2
Azoles Like amphotericin B, the azoles are broad-spectrum antifungal drugs. As a result, azoles represent an alternative to amphotericin B for most systemic fungal infections (see Table 91-1). In contrast to amphotericin, which is highly toxic and must be given IV, the azoles have lower toxicity and can be administered by mouth. However, azoles do have one disadvantage: they inhibit hepatic P450 drug-metabolizing enzymes, and can thereby increase the levels of many other drugs. Of the fourteen azoles in current use, only five—itraconazole, ketoconazole, fluconazole, voriconazole, and posaconazole—are indicated for systemic mycoses. Azoles used for superficial mycoses are discussed separately below.
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Pharmacology for Nursing Care, 7th Edition for superficial mycoses are discussed separately below. 92.1.2.1
Itraconazole Itraconazole [Sporanox] is an alternative to amphotericin B for several systemic mycoses (see Table 91-1), and will serve as our prototype for the azole family. The drug is safer than amphotericin B and has the added advantage of oral dosing. Principal adverse effects are cardiosuppression and liver injury. Like other azoles, itraconazole can inhibit drugmetabolizing enzymes, and can thereby raise levels of other drugs.
92.1.2.1.1
Mechanism of Action. Itraconazole inhibits the synthesis of ergosterol, an essential component of the fungal cytoplasmic membrane. The result is increased membrane permeability and leakage of cellular components. Accumulation of ergosterol precursors may also contribute to antifungal actions. Itraconazole suppresses ergosterol synthesis by inhibiting fungal cytochrome P450-dependent enzymes.
92.1.2.1.2
Therapeutic Use. Itraconazole is active against a broad spectrum of fungal pathogens. At this time, it is a drug of choice for blastomycosis, histoplasmosis, paracoccidioidomycosis, and sporotrichosis, and an alternative to amphotericin B for aspergillosis, candidiasis, and coccidioidomycosis. Itraconazole may also be used for superficial mycoses.
92.1.2.1.3
Pharmacokinetics. Itraconazole is administered PO (in capsules or suspension); a formulation for IV use is no longer available. Food increases absorption of itraconazole capsules, but decreases absorption of itraconazole oral suspension. Interestingly, administration with a cola beverage enhances absorption. Once absorbed, the drug is widely distributed to lipophilic tissues. Concentrations in aqueous fluids (eg, saliva, CSF) are negligible. The drug undergoes extensive hepatic metabolism. About 40% of each dose is excreted in the urine as inactive metabolites.
92.1.2.1.4
Adverse Effects. Itraconazole is well tolerated in usual doses. Gastrointestinal reactions (nausea, vomiting, diarrhea) are most common, occurring in about 10% of patients. Other common reactions include rash (8.6%), headache (3.8%), abdominal pain (3.3%), and edema (3.5%). In addition to these relatively benign effects, itraconazole may cause two potentially serious effects: cardiac suppression and liver injury.
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Pharmacology for suppression Nursing and Care, Edition effects: cardiac liver7th injury. 92.1.2.1.4.1
Cardiac Suppression. Itraconazole has negative inotropic actions that can cause a transient decrease in ventricular ejection fraction. Cardiac function returns to normal by 12 hours after dosing. Because of its negative inotropic actions, itraconazole should not be used for superficial fungal infections (dermatomycoses, onychomycosis) in patients with heart failure, a history of heart failure, or other indications of ventricular dysfunction. The drug may still be used to treat serious fungal infections in patients with heart failure, but only with careful monitoring, and only if the benefits clearly outweigh the risks. If signs and symptoms of heart failure worsen, itraconazole should be discontinued.
92.1.2.1.4.2
Liver Injury. As of March 2001, the Food and Drug Administration (FDA) had received 24 reports of liver failure, including 11 deaths, in patients taking itraconazole. Although a causal link has not been established, caution is nonetheless advised. Patients should be informed about signs of liver dys function (persistent nausea, anorexia, fatigue, vomiting, right upper abdominal pain, jaundice, dark urine, pale stools) and, if they appear, should seek medical attention immediately.
1059 1060
TABLE 91-3 Some Drugs Whose Levels Can Be Increased by Azole Antifungal Drugs Target Drug
Class
Consequence of Excessive Level
Pimozide [Orap]
Antipsychotic
Fatal dysrhythmias
Dofetilide [Tikosyn]
Antidysrhythmic
Fatal dysrhythmias
Quinidine
Antidysrhythmic
Fatal dysrhythmias
Cisapride [Propulsid]*
Prokinetic agent
Fatal dysrhythmias
Warfarin [Coumadin]
Anticoagulant
Bleeding
Sulfonylureas
Oral hypoglycemic
Hypoglycemia
Phenytoin [Dilantin]
Antiseizure drug
Central nervous system toxicity
Cyclosporine [Sandimmune]
Immunosuppressant Increased nephrotoxicity
Tacrolimus [Prograf]
Immunosuppressant Increased nephrotoxicity
Lovastatin [Mevacor]
Antihyperlipidemic
Rhabdomyolysis
Simvastatin [Zocor]
Antihyperlipidemic
Rhabdomyolysis
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Pharmacology for Nursing Care, 7th Edition * 92.1.2.1.5
In 2000, cisapride was voluntarily withdrawn from the U.S. market and is now available only through an investigational limited-access program.
Drug Interactions. Inhibition of Hepatic Drug-Metabolizing Enzymes. Itraconazole inhibits CYP3A4 (the 3A4 isozyme of cytochrome P450) and can thereby increase levels of many other drugs (Table 91-3). The most important are cisapride, pimozide, dofetilide, and quinidine. Why? Because, when present at high levels, these drugs can cause potentially fatal ventricular dysrhythmias. Accordingly, concurrent use with itraconazole is contraindicated. Other drugs of concern include cyclosporine, digoxin, warfarin, and sulfonylurea-type oral hypoglycemics. In patients taking cyclosporine or digoxin, levels of these drugs should be monitored; in patients taking warfarin, prothrombin time should be monitored; and in patients taking sulfonylureas, levels of blood glucose should be monitored.
92.1.2.1.6
Drugs That Raise Gastric pH. Drugs that decrease gastric acidity—antacids, histamine (H2) antagonists, and proton pump inhibitors—can greatly reduce absorption of oral itraconazole. Accordingly, these agents should be administered at least 1 hour before itraconazole or 2 hours after. (Since proton pump inhibitors have a prolonged duration of action, patients using these drugs may have insufficient stomach acid for itraconazole absorption, regardless of when the proton pump inhibitor is given.)
92.1.2.1.7
Preparations, Dosage, and Administration. Itraconazole [Sporanox] is available in suspension (10 mg/mL) and capsules (100 mg) for oral use. The capsules should be taken with food and/or a cola beverage to increase absorption. The recommended dosage is 200 mg once a day. If needed, the dosage may be increased to 200 mg twice a day.
92.1.2.2 92.1.2.2.1
Fluconazole Actions and Uses. Fluconazole [Diflucan], a member of the azole family, is an important antifungal drug. It has the same mechanism as itraconazole: inhibition of cytochrome P450-dependent synthesis of ergosterol, with resultant damage to the cytoplasmic membrane and accumulation of ergosterol precursors. The drug is primarily fungistatic. Fluconazole is used for blastomycosis; histoplasmosis; meningitis caused by Cryptococcus neoformans and Coccidioides immitis; and vaginal, oropharyngeal, esophageal, and disseminated Candida
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Pharmacology for histoplasmosis; Nursing Care, 7th Edition blastomycosis; meningitis caused by Cryptococcus neoformans and Coccidioides immitis; and vaginal, oropharyngeal, esophageal, and disseminated Candida infections. In addition, fluconazole is used investigationally for leishmaniasis (see Chapter 98). 92.1.2.2.2
Pharmacokinetics. Fluconazole is well absorbed (90%) following oral administration, and undergoes wide distribution to tissues and body fluids, including the CSF. Most of each dose is eliminated unchanged in the urine. Fluconazole has a half-life of 30 hours, making once-a-day dosing sufficient.
92.1.2.2.3
Adverse Effects. Fluconazole is generally well tolerated. The most common reactions are nausea (3.7%), headache (1.9%), rash (1.8%), vomiting (1.7%), abdominal pain (1.7%), and diarrhea (1.5%). Rarely, treatment has been associated with hepatic necrosis, Stevens-Johnson syndrome, and anaphylaxis. Fluconazole is teratogenic in animals and may be in humans; appropriate caution is needed.
92.1.2.2.4
Drug Interactions. Like other azole antifungal drugs, fluconazole can inhibit CYP3A4, and can thereby increase levels of other drugs, including warfarin, phenytoin, cyclosporine, zidovudine, rifabutin, and sulfonylurea oral hypoglycemics.
92.1.2.2.5
Preparations, Dosage, and Administration. Fluconazole [Diflucan] is available in solution (2 mg/mL) for IV infusion, and in tablets (50, 100, 150, and 200 mg) and suspension (10 and 40 mg/mL) for oral use. Because oral absorption is rapid and nearly complete, oral and IV dosages are the same. For treatment of oropharyngeal and esophageal candidiasis, the usual dosage is 200 mg on the first day, followed by 100 mg once daily thereafter. For treatment of systemic candidiasis and cryptococcal meningitis, the usual dosage is 400 mg on the first day, followed by 200 mg once daily thereafter. Duration of treatment ranges from 3 weeks to more than 3 months, depending on the infection being treated.
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Pharmacology fortheNursing Care, 7th Edition depending on infection being treated. 92.1.2.3 92.1.2.3.1
Voriconazole Actions and Uses. Voriconazole [Vfend], a member of the azole family, is an important drug for treating lifethreatening fungal infections. Like other azoles, voriconazole inhibits cytochrome P450– dependent enzymes, and thereby suppresses synthesis of ergosterol, a critical component of the fungal cytoplasmic membrane. As a result, voriconazole is active against a broad spectrum of fungal pathogens, including Aspergillus species, Candida species, Scedosporium species, Fusarium species, Histoplasma capsulatum, Blastomyces dermatitidis, and Cryptococcus neoformans. At this time, voriconazole has four approved indications: (1) candidemia, (2) invasive aspergillosis, (3) esophageal candidiasis, and (4) serious infections caused by Scedosporium apiospermum or Fusarium species in patients unresponsive to or intolerant of other drugs. According to Infectious Disease Society of America guidelines, voriconazole has replaced amphotericin B as the drug of choice for invasive aspergillosis. Voriconazole is just as effective as amphotericin B and poses a much lower risk of kidney damage. However, voriconazole does have its own set of adverse effects, including hepatotoxicity, visual disturbances, hypersensitivity reactions, hallucinations, and fetal injury. In addition, like other azoles, voriconazole can interact with many drugs.
92.1.2.3.2
Pharmacokinetics. Voriconazole may be administered IV or PO. With oral administration, bioavailability is high (96%), but can be reduced by food. Plasma levels peak 2 hours after ingestion. The drug's half-life is dose dependent, and can range from 6 hours up to 24 hours. Voriconazole undergoes extensive metabolism by hepatic P450 enzymes.
92.1.2.3.3
Adverse Effects. The most common adverse effects are visual disturbances, fever, rash, nausea, vomiting, diarrhea, headache, sepsis, peripheral edema, abdominal pain, and respiratory disorders. During clinical trials, the effects that most often led to discontinuing treatment were liver damage, visual disturbances, and rash.
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Pharmacology for disturbances, Nursing Care, 7th Edition damage, visual and rash. 92.1.2.3.3.1
Hepatotoxicity. Voriconazole can cause hepatitis, cholestasis, and fulminant hepatic failure. Fortunately, these events are both uncommon and generally reversible. To monitor for injury, liver function tests should be obtained before treatment and periodically thereafter.
92.1.2.3.3.2
Visual Disturbances. Reversible, dose-related visual disturbances develop in 30% of patients. Symptoms include reduced visual acuity, increased brightness, altered color perception, and photophobia. As a rule, these begin within 30 minutes of dosing and then greatly diminish over the next 30 minutes. Owing to the risk of photophobia and blurred vision, patients should be warned against driving at night.
92.1.2.3.3.3
Hypersensitivity Reactions. Voriconazole may cause dermatologic reactions, ranging from rash to life-threatening Stevens-Johnson syndrome. During infusion, anaphylactoid reactions have occurred, manifesting with tachycardia, chest tightness, dyspnea, faintness, flushing, fever, and sweating. If these symptoms develop, the infusion should be stopped.
92.1.2.3.3.4
Teratogenicity. Voriconazole is teratogenic in rats and can cause fetal harm in humans. The drug is classified in FDA Pregnancy Risk Category D, and hence should not be used during pregnancy unless the potential benefits are deemed to outweigh the risk to the fetus. Women taking the drug should use effective contraception.
92.1.2.3.4
Drug Interactions. Voriconazole can interact with many other drugs. Several mechanisms are involved. Voriconazole is both a substrate for and inhibitor of hepatic P450 enzymes. As a result, drugs that inhibit P450 can raise voriconazole levels, and drugs that induce P450 can lower voriconazole levels. On the other hand, because voriconazole itself can inhibit P450, voriconazole can raise levels of other drugs. Therefore • To ensure that voriconazole levels are adequate, voriconazole should not be combined with powerful P450 inducers, including rifampin, rifabutin, carbamazepine, and phenobarbital.
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Pharmacology for Nursing Care, 7th Edition phenobarbital. • To avoid excessive voriconazole levels, voriconazole should not be combined with powerful P450 inhibitors. • To avoid toxicity from accumulation of other drugs, voriconazole should not be combined with some agents that are P450 substrates, including cisapride, pimozide, and sirolimus. 92.1.2.3.5
Preparations, Dosage, and Administration. Voriconazole [Vfend] is available in 200-mg, single-use vials for IV infusion, and in two oral formulations: tablets (50 and 200 mg) and a powder for oral suspension (40 mg/mL after reconstitution). Treatment is initiated with IV voriconazole and later can be switched to oral voriconazole as appropriate. Intravenous therapy consists of two loading doses (6 mg/kg each given 12 hours apart) followed by maintenance doses of 4 mg/kg every 12 hours. All IV doses should be infused slowly, over 1 to 2 hours (maximum rate is 3 mg/kg/hr). If the response is inadequate, maintenance doses can be increased by 50%. Patients with mild to moderate hepatic cirrhosis should receive the standard two loading doses, but maintenance doses should be halved. (There are no data on dosing in patients with severe cirrhosis.) Patients with significant renal impairment (creatinine clearance less than 50 mL/min), should use oral voriconazole, not IV voriconazole. Why? Because, in the absence of adequate kidney function, the solubilizing agent (not voriconazole itself) in the IV formulation can accumulate to dangerous levels. After receiving their IV loading doses, patients who can tolerate oral therapy may be switched to voriconazole tablets. The usual dosage is 200 mg every 12 hours for patients over 40 kg and 100 mg every 12 hours for patients under 40 kg. If the response is inadequate, doses can be increased by 50%. Oral dosing should be done 1 hour before meals or 1 hour after.
92.1.2.4 92.1.2.4.1
Ketoconazole Actions and Antifungal Spectrum. Ketoconazole (formerly available as Nizoral) belongs to the azole family of antifungal agents. Benefits derive from inhibiting synthesis of ergosterol, an essential component of the fungal cytoplasmic membrane. Ketoconazole is active against most fungi that cause systemic mycoses, as well as fungi that cause superficial infections (dermatophytes and Candida species).
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Pharmacology species). for Nursing Care, 7th Edition 92.1.2.4.2
Therapeutic Use. Ketoconazole is an alternative to amphotericin B for systemic mycoses. The drug is much less toxic than amphotericin and only somewhat less effective. Specific indications are listed in Table 91-1. Responses to ketoconazole are slow. Accordingly, the drug is less useful for severe, acute infections than for long-term suppression of chronic infections. Ketoconazole is also a valuable drug for treating superficial mycoses.
92.1.2.4.3
Pharmacokinetics. Absorption. Ketoconazole is a weak base and hence requires an acidic environment for dissolution and absorption. Oral ketoconazole is well absorbed from the GI tract, provided that gastric acid levels are normal. In patients with achlorhydria (absence of gastric acid), absorption is low. Drugs that reduce gastric acidity (eg, antacids, H2 blocking agents, proton pump inhibitors) decrease absorption.
92.1.2.4.3.1
Distribution. Most ketoconazole in the blood is bound to plasma proteins. The drug crosses the bloodbrain barrier poorly, and concentrations in the CSF remain low. In contrast, high levels of ketoconazole are achieved in the skin, making oral ketoconazole useful against superficial mycoses.
92.1.2.4.3.2
Elimination. Ketoconazole is eliminated by hepatic metabolism. Its half-life is approximately 3 hours. In patients with liver dysfunction, the half-life can be substantially prolonged. Because elimination is hepatic, renal impairment does not influence the intensity or duration of effects. Hence, no dosage adjustment is needed in patients with kidney disease.
92.1.2.4.4
Adverse Effects. Ketoconazole is generally well tolerated. The most common adverse reactions—nausea and vomiting—can be reduced by giving the drug with food. The most serious effects involve the liver.
92.1.2.4.4.1
Hepatotoxicity. Effects of ketoconazole on the liver are rare but potentially severe. Fatal hepatic necrosis has occurred. Liver function should be evaluated prior to treatment and at least monthly thereafter. Ketoconazole should be discontinued at the first sign of liver injury. The drug
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Pharmacology for Liver Nursing Care, Editionprior to treatment and at least monthly has occurred. function should7th be evaluated thereafter. Ketoconazole should be discontinued at the first sign of liver injury. The drug should be employed with caution in patients with a history of hepatic disease. Patients should be advised to notify the physician if they experience symptoms suggesting liver injury (eg, unusual fatigue, anorexia, nausea, vomiting, jaundice, dark urine, pale stools). 92.1.2.4.4.2
Effects on Sex Hormones. Just as ketoconazole inhibits steroid synthesis in fungi, the drug can inhibit steroid synthesis in humans. In males, inhibition of testosterone synthesis has caused gynecomastia, decreased libido, and reduced potency; reversible sterility has occurred with high doses. In females, reduction of estradiol synthesis has caused menstrual irregularities.
92.1.2.4.4.3
Other Adverse Effects. Ketoconazole can produce a variety of relatively mild adverse effects, including rash, itching, dizziness, fever, chills, constipation, diarrhea, photophobia, and headache. Rarely, ketoconazole has caused anaphylaxis, severe epigastric pain, and altered function of the adrenals.
92.1.2.4.5
Drug Interactions. Drugs that decrease gastric acidity—antacids, H2 antagonists, proton pump inhibitors—can greatly reduce ketoconazole absorption. Accordingly, these agents should be administered no sooner than 2 hours after ingestion of ketoconazole. Like other azoles, ketoconazole inhibits CYP3A4, and can thereby increase levels of other drugs. Rifampin reduces plasma levels of ketoconazole, apparently by enhancing hepatic metabolism. If these drugs are used concurrently, ketoconazole dosage should be increased— and even then it may be impossible to achieve therapeutic levels.
92.1.2.4.6
Preparations, Dosage, and Administration. Ketoconazole is supplied in 200-mg tablets for oral administration. The recommended adult dosage is 200 mg once a day. To treat severe infection, daily doses of 400 to 800 mg may be required. The dosage for children over 2 years old is 3.3 to 6.6 mg/kg/day in a single dose. Duration of treatment is 6 months or longer. Since an acidic environment is needed for ketoconazole absorption, patients with achlorhydria should dissolve the tablets in 4 mL of 0.2 N hydrochloric acid; the solution should be sipped through a plastic or glass straw to avoid damaging the teeth.
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Pharmacology for Nursing avoid damaging the teeth. Care, 7th Edition 92.1.2.5 92.1.2.5.1
Posaconazole Actions and Uses. Posaconazole [Noxafil] was approved in 2006, making it the newest member of the azole family. Like other azoles, the drug binds with ergosterol in the fungal cell membrane, and thereby compromises membrane integrity. In vitro, posaconazole has strong activity against Aspergillus and Candida, and good activity against several other fungi. Currently, the drug has only two indications: (1) treatment of oropharyngeal candidiasis, including infections resistant to itraconazole and/or fluconazole; and (2) prophylaxis of invasive Aspergillus and Candida infection in immunocompromised patients.
92.1.2.5.2
Pharmacokinetics. Posaconazole is administered by mouth, and food greatly enhances absorption. For example, when dosing is done with a low-fat meal or liquid nutritional supplement, peak plasma levels are 3 times higher than when dosing is done on an empty stomach. In the blood, posaconazole is highly (over 98%) protein bound. In the liver, posaconazole undergoes a process known as UDP glucuronidation, rather than metabolism by P450 enzymes (although it can inhibit CYP3A4). Elimination is mainly fecal (71%) and partly urinary (13%). The mean elimination half-life is 35 hours.
92.1.2.5.3
Adverse Effects. Posaconazole can cause a variety of adverse effects, but these are usually mild. In clinical trials, adverse effects were similar to those seen with itraconazole and fluconazole. The most common reactions were nausea (38%), vomiting (29%), and headache (28%). Like other azoles, posaconazole can cause liver dysfunction. In addition, there have been reports of QT prolongation and dysrhythmias.
92.1.2.5.4
1061 1062
Drug Interactions. Like other azoles, posaconazole inhibits CYP3A4, and can thereby increase levels of many other drugs. Two immunosuppressants—cyclosporine [Neoral] and tacrolimus [Prograf]— are of particular concern. If posaconazole is combined with cyclosporine or tacrolimus, their dosages should be reduced by 25% and 66%, respectively. Combined use of posaconazole with pimozide, halofantrine, or quinidine is contraindicated (because raising levels of these drugs can lead to QT prolongation and dysrhythmias), as is combined use with ergot alkaloids (because raising their levels can lead to ergotism).
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Pharmacology for Nursing Care, Edition alkaloids (because raising their levels7th can lead to ergotism). Two drugs—rifabutin and phenytoin—can induce UDP glucuronidase (the hepatic enzyme that metabolizes posaconazole) and can thereby reduce posaconazole levels by nearly 50%. Accordingly, an increase in posaconazole dosage may be needed. 92.1.2.5.5
Preparations, Dosage, and Administration. Posaconazole [Noxafil] is supplied as a 40-mg/mL oral suspension. To promote absorption, each dose should be taken with a full meal or a liquid nutritional supplement. Dosages are as follows: • Prophylaxis of invasive fungal infections—200 mg 3 times a day for as long as neutropenia or immunosuppression persists • Oropharyngeal candidiasis—200 mg twice daily on day 1, followed by 100 mg once daily for 13 days • Oropharyngeal candidiasis refractory to itraconazole and/or fluconazole—400 mg twice daily for as long as indicated
92.1.3
Echinocandins The echinocandins are the newest class of antifungal drugs. In contrast to amphotericin B and the azoles, which disrupt the fungal cell membrane, the echinocandins disrupt the fungal cell wall. Echinocandins cannot be dosed orally, and their antifungal spectrum is narrow, being limited mainly to Aspergillus and Candida species. Three echinocandins are currently available: caspofungin, micafungin, and anidulafungin. When dosage is appropriate, all three drugs appear therapeutically equivalent.
92.1.3.1 92.1.3.1.1
Caspofungin Actions and Uses. Caspofungin [Cancidas], introduced in 2001, was the first echinocandin available. Antifungal effects result from inhibiting the biosynthesis of beta-1,3-D-glucan, an essential component of the cell wall of some fungi, including Candida and Aspergillus. Caspofungin is approved for IV therapy of (1) invasive aspergillosis in patients unresponsive to or intolerant of traditional agents (eg, amphotericin B, itraconazole), and (2) systemic Candida infections, including candidemia and Candida-related peritonitis, pleural space infections, and intraabdominal abscesses. The drug is better tolerated than amphotericin B, and appears just as effective.
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Pharmacology effective. for Nursing Care, 7th Edition 92.1.3.1.2
Pharmacokinetics. Caspofungin is not absorbed from the GI tract, and hence must be given parenterally (by IV infusion). In the blood, most (97%) of the drug is protein bound. Caspofungin is cleared from the blood with a half-life of 9 to 11 hours. The principal mechanism of plasma clearance is redistribution to tissues, not metabolism or excretion. Over time, the drug undergoes gradual metabolism followed by excretion in the urine and feces.
92.1.3.1.3
Adverse Effects. Caspofungin is generally well tolerated. The most common adverse effects are fever (3.6% to 26%) and phlebitis at the injection site (11.3% to 15.7%). Less common reactions include headache (6% to 11.3%), rash (4.6%), nausea (2.5% to 6%), and vomiting (1.2% to 3.1%). In addition, caspofungin can cause effects that appear to be mediated by histamine release. Among these are rash, facial flushing, pruritus, and a sense of warmth. One case of anaphylaxis has been reported.
92.1.3.1.4
Use in Pregnancy. Caspofungin is embryotoxic in rats and rabbits. To date, there are no adequate data on effects in pregnant women. Currently, the drug is classified in FDA Pregnancy Risk Category C, and hence should be avoided during pregnancy unless the potential benefits outweigh the potential risks to the fetus.
92.1.3.1.5
Drug Interactions. Drugs that induce cytochrome P450 may decrease levels of caspofungin. Powerful inducers include efavirenz [Sustiva], nelfinavir [Viracept], rifampin [Rifadin], carbamazepine [Tegretol], and phenytoin [Dilantin]. Patients taking these drugs with caspofungin may need to increase caspofungin dosage. Caspofungin can decrease levels of tacrolimus [Prograf], an immunosuppressant. If these drugs are taken concurrently, levels of tacrolimus should be monitored and dosage increased as needed. Combining caspofungin with cyclosporine [Sandimmune] increases the risk of liver injury, as evidenced by a transient elevation in plasma levels of liver enzyme. Accordingly, the combination should generally be avoided.
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Pharmacology for Nursing 7th Edition combination should generallyCare, be avoided. 92.1.3.1.6
Preparations, Dosage, and Administration. Caspofungin [Cancidas] is supplied as a powder (50 and 70 mg) to be reconstituted in sterile saline for IV infusion. Treatment for adults consists of a 70-mg loading dose followed by daily maintenance doses of 50 mg each. All doses should be infused slowly (over 1 hour). Duration of treatment depends on the severity of the infection and the clinical response. For patients with moderate liver impairment, maintenance doses should be reduced to 35 mg. There are no data on dosage for patients with severe liver impairment.
92.1.3.2 92.1.3.2.1
Micafungin Actions and Uses. Micafungin [Mycamine], approved in 2005, was the second echinocandin antifungal agent available for general use. Like caspofungin, micafungin inhibits synthesis of beta-1,3-Dglucan, an essential component of the cell wall of Candida. Micafungin, administered IV, is indicated for (1) prevention of Candida infection in patients undergoing a bone marrow transplant; (2) treatment of esophageal candidiasis; (3) treatment of candidemia, the fourth most common bloodstream infection among hospitalized patients in the United States; and (4) treatment of disseminated infection, peritonitis, or abscesses caused by Candida. For all four indications, fluconazole and itraconazole are preferred.
92.1.3.2.2
Pharmacokinetics. Like caspofungin, micafungin is not absorbed from the GI tract, and hence is given IV. Protein binding in blood is high (greater than 99%). Micafungin undergoes hepatic metabolism—mainly by pathways that do not involve cytochrome P450—followed by excretion in the feces. The elimination half-life is 11 to 17 hours.
92.1.3.2.3
Adverse Effects. Micafungin is generally well tolerated. The most common adverse effects are headache, nausea, vomiting, diarrhea, fever, and phlebitis at the infusion site. Elevation of liver enzymes has also occurred, suggesting injury to the liver. Patients may also experience histamine-mediated reactions, including rash, itching, facial swelling, and vasodilation. There have been isolated reports of severe allergic reactions, including life-threatening anaphylaxis.
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Pharmacology for Nursing Care, 7th Edition anaphylaxis. 92.1.3.2.4
Drug Interactions. Micafungin appears largely devoid of significant drug interactions. Of note, micafungin does not alter the kinetics of the following immunosuppressants: mycophenolate [CellCept], cyclosporine [Sandimmune, others], tacrolimus [Prograf], and prednisolone—nor do those drugs alter the kinetics of micafungin. Micafungin can intensify the effects of sirolimus [Rapamune] (an immunosuppressant) and nifedipine [Procardia, others] (a calcium channel blocker). Accordingly, patients treated with sirolimus or nifedipine should be monitored closely for signs of toxicity. Because micafungin does not interact very much with the cytochrome P450 system, it is unlikely to alter the effects of drugs that do.
92.1.3.2.5
Preparations, Dosage, and Administration. Micafungin [Mycamine] is supplied as a lyophilized powder (50 and 100 mg) in single-use, light-protected vials, and must be reconstituted prior to infusion. The recommended dosage is 50 mg once a day to prevent Candida infection, 100 mg once a day to treat candidemia, and 150 mg once a day to treat esophageal candidiasis. All doses are given by a 1-hour IV infusion. Faster infusion rates increase the risk of a histamine reaction.
92.1.3.3 92.1.3.3.1
Anidulafungin Actions and Uses. Anidulafungin [Eraxis], approved in 2006, has good activity against Candida species, and poor activity against most other fungi. Indications are limited to IV therapy of esophageal candidiasis, candidemia, and other serious Candida infections. Like caspofungin and micafungin, anidulafungin inhibits synthesis of beta-1,3-D-glucan, and thereby disrupts the Candida cell wall.
92.1.3.3.2
Pharmacokinetics. Like other echinocandins, anidulafungin is not absorbed from the GI tract, and hence must be given by IV infusion. In the blood, 84% of the drug is protein bound. Clearance is the result of slow, spontaneous chemical degradation, followed by excretion in the feces. The plasma half-life is 40 to 50 hours.
92.1.3.3.3
Adverse Effects. Anidulafungin is generally well tolerated. The most common adverse effects are diarrhea (3.1%), hypokalemia (3.1%), and headache (1.3%). Possible histamine-mediated reactions (rash, urticaria, pruritus, flushing, dyspnea, hypotension) have been reported, especially at
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Pharmacology for Nursing 7th Edition (3.1%), hypokalemia (3.1%),Care, and headache (1.3%). Possible histamine-mediated reactions (rash, urticaria, pruritus, flushing, dyspnea, hypotension) have been reported, especially at higher infusion rates. Accordingly, the infusion rate should not exceed 1.1 mg/min. A few patients have developed signs of liver damage (hepatitis, elevation of circulating liver enzymes, worsening of hepatic failure). 92.1.3.3.4
Drug Interactions. No clinically relevant drug interactions have been reported. Anidulafungin is neither a substrate for, inducer of, nor inhibitor of hepatic P450 drug-metabolizing enzymes, and hence will not interact with other drugs affected by this system.
92.1.3.3.5
Preparations, Dosage, and Administration. Anidulafungin [Eraxis] is available as a powder (50 and 100 mg) to be reconstituted in the supplied diluent, and then further diluted prior to infusion. To minimize histaminerelated reactions, the infusion rate should not exceed 1.1 mg/min. Dosages are as follows:
1062 1063
• Esophageal candidiasis—Infuse a single 100-mg loading dose on day 1, followed by 50 mg once a day thereafter, continuing for at least 14 days and at least 7 days after the last positive culture. • Candidemia and other serious Candida infections—Infuse a single 200-mg loading dose on day 1, followed by 100 mg once a day thereafter, continuing for at least 14 days after the last positive culture. 92.1.4
Flucytosine, a Pyrimidine Analog Flucytosine [Ancobon], a pyrimidine analog, is employed for serious infections caused by susceptible strains of Candida and Cryptococcus neoformans. Because development of resistance is common, flucytosine is almost always used in combination with amphotericin B. Extreme caution is needed in patients with renal impairment and hematologic disorders.
92.1.4.1
Mechanism of Action. Flucytosine is taken up by fungal cells, which then convert it to 5-fluorouracil (5-FU), a powerful antimetabolite. The ultimate effect of 5-FU is disruption of fungal DNA and RNA synthesis. Flucytosine is relatively harmless to us because mammalian cells lack cytosine deaminase, the enzyme that converts flucytosine to 5-FU.
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Pharmacology for Nursing Care,flucytosine 7th Edition deaminase, the enzyme that converts to 5-FU. 92.1.4.2
Fungal Resistance. Development of resistance during therapy is common and constitutes a serious clinical problem. Several mechanisms have been described, including (1) a reduction in cytosine permease (needed for fungal uptake of flucytosine) and (2) loss of cytosine deaminase (needed to convert flucytosine to its active form).
92.1.4.3
Antifungal Spectrum and Therapeutic Uses. Flucytosine has a narrow antifungal spectrum. Fungicidal activity is highest against Candida species and Cryptococcus neoformans. Most other fungi are resistant. Because of this narrow spectrum, flucytosine is indicated only for candidiasis and cryptococcosis. For treatment of serious infections (eg, cryptococcal meningitis, systemic candidiasis), flucytosine should be combined with amphotericin B. This combination offers two advantages over flucytosine alone: (1) antifungal activity is enhanced and (2) emergence of resistant fungi is reduced.
92.1.4.4
Pharmacokinetics. Flucytosine is readily absorbed from the GI tract and is well distributed throughout the body. The drug has good access to the central nervous system; levels in the CSF are about 80% of those in plasma. Flucytosine is eliminated by the kidneys, principally as unchanged drug. The half-life is about 4 hours in patients with normal renal function. However, in patients with renal insufficiency, the half-life is greatly prolonged, and hence dosage must be reduced.
92.1.4.5
Adverse Effects. Hematologic Effects. Bone marrow suppression is the most serious complication of treatment. Marrow suppression usually manifests as reversible neutropenia or thrombocytopenia. Rarely, fatal agranulocytosis develops. Platelet and leukocyte counts should be determined weekly. Adverse hematologic effects are most likely when plasma levels of flucytosine exceed 100 mcg/mL. Accordingly, the dosage should be adjusted to keep drug levels below this value. Flucytosine should be used with caution in patients with pre-existing bone marrow suppression.
92.1.4.5.1
Hepatotoxicity. Mild and reversible liver dysfunction occurs frequently, but severe hepatic injury is rare. Liver function should be monitored (by making weekly determinations of serum transaminase and alkaline phosphatase levels).
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Pharmacology for Care, 7th Edition transaminase andNursing alkaline phosphatase levels). 92.1.4.6
Drug Interactions. Flucytosine is often combined with amphotericin B. As noted, this combination offers several advantages. However, the combination can also be detrimental. Since amphotericin B is nephrotoxic, and since flucytosine is eliminated by the kidneys, amphotericin B–induced kidney damage may suppress flucytosine excretion, and may thereby promote flucytosine toxicity. Therefore, it is important to monitor renal function and flucytosine levels when amphotericin B and flucytosine are combined. Like itraconazole, flucytosine inhibits hepatic drug-metabolizing enzymes, and can thereby raise levels of several other drugs. With at least four drugs—cisapride, pimozide, dofetilide, and quinidine—elevated levels can lead to potentially fatal cardiac dysrhythmias. Accordingly, flucytosine must not be combined with these drugs.
92.1.4.7
Preparations, Dosage, and Administration. Flucytosine [Ancobon] is available in 250- and 500-mg capsules for oral administration. The usual dosage for patients with normal kidney function is 50 to 150 mg/kg/day administered in divided doses at 6-hour intervals. At this dosage, some patients must ingest 10 or more capsules 4 times a day. Dosages must be reduced for patients with renal insufficiency. Nausea and vomiting associated with drug administration can be decreased by taking flucytosine capsules over a 15-minute interval.
92.2
DRUGS FOR SUPERFICIAL MYCOSES The superficial mycoses are caused by two groups of organisms: (1) Candida species and (2) dermatophytes (species of Epidermophyton, Trichophyton, and Microsporum). Candida infections usually occur in mucous membranes and moist skin; chronic infections may involve the scalp, skin, and nails. Dermatophytoses are generally confined to the skin, hair, and nails. Superficial infections with dermatophytes are more common than superficial infections with Candida.
92.2.1
Overview of Drug Therapy Superficial mycoses can be treated with a variety of topical and oral drugs. For mild to moderate infections, topical agents are generally preferred. Specific indications for the drugs used against superficial mycoses are summarized in Tables 91-4 and 91-5. Some of these drugs are also used for systemic mycoses.
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Pharmacology for Nursing Care, 7th Edition for systemic mycoses. 92.2.1.1
Dermatophytic Infections (Ringworm) Dermatophytic infections are commonly referred to as ringworm (because of the characteristic ring-shaped lesions). There are four principal dermatophytic infections, defined by their location: tinea pedis (ringworm of the foot, or “athlete's foot”), tinea corporis (ringworm of the body), tinea cruris (ringworm of the groin, or “jock itch”), and tinea capitis (ringworm of the scalp).
92.2.1.1.1
Tinea Pedis. Tinea pedis, the most common fungal infection, generally responds well to topical therapy. Available agents are listed in Table 91-4. Patients should be advised to wear absorbent cotton socks, change their shoes often, and dry their feet after bathing.
92.2.1.1.2
Tinea Corporis. Tinea corporis usually responds to a topical azole or allylamine (see Table 91-4). Treatment should continue for at least 1 week after symptoms have cleared. Severe infection may require a systemic antifungal agent (eg, griseofulvin).
92.2.1.1.3
Tinea Cruris. Tinea cruris responds well to topical therapy. Treatment should continue for at least 1 week after symptoms have cleared. If the infection is severely inflamed, a systemic antifungal drug (eg, clotrimazole) may be needed; topical or systemic glucocorticoids may be needed as well.
92.2.1.1.4
Tinea Capitis. Tinea capitis is difficult to treat. Topical drugs are not likely to work. Oral griseofulvin, taken for 6 to 8 weeks, is considered standard therapy. However, oral terbinafine, taken for only 2 to 4 weeks, may be more effective.
CHAPTER 91 Antifungal Agents
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Page 25 of 44
Pharmacology Nursing Care, 7th Edition only 2 to 4 for weeks, may be more effective.
1063 1064
TABLE 91-4 Drugs for Superficial Fungal Infections* Candida Infection
Route
Ringworm†
Skin
Mouth Onychomycosis‡
Clotrimazole
Topical
✓
✓
✓
Econazole
Topical
✓
✓
Fluconazole
Oral
✓
Itraconazole
Oral
✓
Ketoconazole
Oral
✓
Topical
✓
✓
Miconazole
Topical
✓
✓
Oxiconazole
Topical
✓
Sertaconazole
Topical
✓
Sulconazole
Topical
✓
Butenafine
Topical
✓
Naftifine
Topical
✓
Terbinafine
Oral
✓
Topical
✓
Drug Azoles
✓
✓ ✓
✓
✓
Allylamines
✓
Others Amphotericin B
Topical
✓
Ciclopirox
Topical
✓
Griseofulvin
Oral
✓
Haloprogin
Topical
✓
Nystatin
Topical
Tolnaftate
Topical
✓
Undecylenate
Topical
✓
✓
✓ ✓
✓
✓
*
Vulvovaginal candidiasis is addressed in Table 91-5.
†
Ringworm is a popular term for dermatophytic infections, including tinea pedis (ringworm of the foot, “athlete's foot”), tinea cruris (ringworm of the groin, “jock itch”), tinea corporis (ringworm of the body), and tinea capitis (ringworm of the
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Pharmacology(ringworm for Nursing Care, 7thfoot”), Edition of the foot, “athlete's tinea cruris (ringworm of the groin, “jock itch”), tinea corporis (ringworm of the body), and tinea capitis (ringworm of the scalp). ‡ 92.2.1.2 92.2.1.2.1
Onychomycosis is a clinical term for fungal infection of the toenails and fingernails.
Candidiasis Vulvovaginal Candidiasis. Vulvovaginal candidiasis is very common, occurring in 75% of women at least once in their lives. Most cases are caused by Candida albicans, and many of the rest are caused by Candida glabrata, especially in patients with HIV/AIDS. Factors that predispose to Candida infection include pregnancy, obesity, diabetes, debilitation, HIV infection, and use of certain drugs, including oral contraceptives, systemic glucocorticoids, anticancer agents, immunosuppressants, and systemic antibiotics. In the past, most regimens required daily application of a topical drug for 1 to 2 weeks. However, with current drugs, just 1 to 3 days of topical therapy can be curative. In addition, oral therapy may be used: A single 150-mg dose of fluconazole can be curative—but it causes more side effects (headache, rash, GI disturbance) than the topical agents. For women with recurrent vulvovaginal candidiasis, weekly prophylaxis with oral fluconazole is highly effective—but relapse is common when treatment is stopped. The drugs used for vulvovaginal candidiasis are summarized in Table 91-5. All appear equally effective. Hence, drug selection is largely a matter of patient preference. The longer regimens have no demonstrated advantage over the shorter ones.
92.2.1.2.2
Oral Candidiasis. Oral candidiasis, also known as thrush, is seen often. Topical agents—nystatin, clotrimazole, and amphotericin B—are generally effective. In the immunocompromised host, oral therapy with fluconazole or ketoconazole is usually required.
92.2.1.3
Onychomycosis (Fungal Infection of the Nails) Fungal infection of the nails, known as onychomycosis, is difficult to eradicate and requires prolonged therapy. Infections may be caused by dermatophytes or Candida species. Because onychomycosis is largely a cosmetic concern, treatment is usually optional. Onychomycosis may be treated with oral antifungal drugs or with topical ciclopirox. Success rates with oral therapy are quite low, and rates with topical therapy are even lower.
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Pharmacology Nursing 7th Edition rates with oralfor therapy are quiteCare, low, and rates with topical therapy are even lower. 92.2.1.3.1
Oral Therapy. The drugs used most often are terbinafine [Lamisil] and itraconazole [Sporanox]. Both are active against Candida species and dermatophytes. Once in the body, these drugs become incorporated into keratin as the nails grow. Drug may also diffuse into the nails from the tissue below. Side effects include GI disturbances (eg, nausea, vomiting, abdominal pain), headache, and skin reactions (eg, itching, rash). Treatment generally lasts 3 to 6 months. Unfortunately, even with this prolonged therapy, the cure rate is relatively low (about 50%).
CHAPTER 91 Antifungal Agents
1064 1065
Page 28 of 44
Pharmacology foreven Nursing 7ththerapy, Edition Unfortunately, with thisCare, prolonged the cure rate is relatively low (about 50%). TABLE 91-5 Some Preferred Products for Vulvovaginal Candidiasis Generic Name
Trade Name
Formulation
Dosage
Diflucan
150-mg oral tablet
1 tablet once
Gynazole-1
2% vaginal cream, SR
5 gm once
Femstat 3
2% vaginal cream
5 gm at bedtime × 3 days
Mycelex-3
2% vaginal cream
5 gm at bedtime × 3 days
Gyne-Lotrimin 3
200-mg vaginal suppository
1 suppository at bedtime × 3 days
Mycelex-7
1% vaginal cream
5 gm at bedtime × 7– 14 days
Femizol-M
2% vaginal cream
5 gm at bedtime × 7 days
Monistat 7
2% vaginal cream
5 gm at bedtime × 7 days
(a component of Monistat Dual Pack)
1200-mg vaginal suppository
1 suppository once, day or night
Oral Preparation Fluconazole Topical Preparations Butoconazole
Clotrimazole
Miconazole
Terconazole
Tioconazole
(a component of 200-mg vaginal Monistat 3 suppository Combination Pack)
1 suppository at bedtime × 3 days
(a component of 100-mg vaginal Monistat 7 suppository Combination Pack)
1 suppository at bedtime × 7 days
Terazol 3
80-mg vaginal suppository
1 suppository at bedtime × 3 days
Terazol 3
0.8% vaginal cream
5 gm at bedtime × 3 days
Terazol 7
0.4% vaginal cream
5 gm at bedtime × 7 days
Monistat 1
6.5% vaginal ointment
4.6 gm at bedtime once
Vagistat-1
6.5% vaginal ointment
4.6 gm at bedtime once
SR = sustained-release formulation.
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Pharmacology for Nursing Care, 7th Edition 92.2.1.3.2
Topical Therapy with Ciclopirox. Ciclopirox [Penlac Nail Lacquer] is the only topical agent for onychomycosis. In contrast to oral terbinafine or itraconazole, which are active against Candida species and several dermatophytes, topical ciclopirox is active against only one dermatophyte—Trichophyton rubrum—and has no activity against Candida. Ciclopirox is applied once a day to the nails and immediately adjacent skin. New coats are applied over old ones. Once a week, all coats are removed with alcohol. Side effects are minimal and localized. Unfortunately, despite prolonged use (up to 48 weeks), ciclopirox confers only modest benefits: Complete cure occurs in less than 12% of patients and, even when complete cure does occur, the recurrence rate is high—about 40%. Compared with oral therapy, topical ciclopirox is safer and cheaper, but much less effective. Use of ciclopirox for superficial fungal infections of the skin is discussed below.
92.2.2
Azoles Twelve members of the azole family are used for superficial mycoses (see Tables 91-4 and 91-5). The usual route is topical. Three of the twelve—itraconazole, fluconazole, and ketoconazole— are also used for systemic mycoses (see above). The azoles are active against a broad spectrum of pathogenic fungi, including dermatophytes and Candida species. Antifungal effects result from inhibiting the biosynthesis of ergosterol, an essential component of the fungal cytoplasmic membrane.
92.2.2.1 92.2.2.1.1
Clotrimazole Therapeutic Uses. Topical clotrimazole is a drug of choice for dermatophytic infections and candidiasis of the skin, mouth, and vagina.
92.2.2.1.2
Adverse Effects. When applied to the skin, clotrimazole can cause stinging, erythema, edema, urticaria, pruritus, and peeling. However, the incidence is low. Intravaginal administration occasionally causes a burning sensation and lower abdominal cramps. Oral clotrimazole can cause GI distress.
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Pharmacology for Nursing Care, 7th Edition cause GI distress. 92.2.2.1.3
Preparations, Dosage, and Administration. Clotrimazole is available as an oral troche, as a cream or suppository for intravaginal use, and in three formulations for application to the skin: cream, lotion, and solution. For fungal infections of the skin, the drug is applied twice daily for 2 to 4 weeks. For vulvovaginal candidiasis, several dosing schedules have been employed, including (1) intravaginal insertion of one 200-mg suppository nightly for 7 days, (2) intravaginal insertion of one 500mg suppository once at bedtime, and (3) intravaginal application of 5 gm of 1% cream once a day for 7 days. Trade names for dermatologic products are Desenex, Cruex, and Lotrimin, and trade names for vaginal products are Gyne-Lotrimin and Mycelex.
92.2.2.2
Ketoconazole Ketoconazole [Kuric, Extina, Nizoral, Xolegel] is approved for oral and topical therapy of superficial mycoses. Oral ketoconazole provides effective treatment of dermatophytic infections as well as candidiasis of the skin, mouth, and vagina. However, because of the toxicity associated with oral use, this route should be reserved for infections that have failed to respond to topical agents. Ketoconazole for topical use is available in five formulations: 2% foam [Extina] and 2% gel [Xolegel] for seborrheic dermatitis, 1% shampoo [Nizoral-AD] for dandruff, 2% shampoo [Nizoral] for tinea versicolor, and 2% cream [Kuric] for dermatophytic infections and candidiasis of the skin. The basic pharmacology of ketoconazole is discussed above under Drugs for Systemic Mycoses.
92.2.2.3 92.2.2.3.1
Miconazole Therapeutic Uses. Miconazole [Micatin, Monistat 3, Monistat 7, others] is an azole antifungal drug available for topical and systemic administration. Topical miconazole is a drug of choice for dermatophytic infections and for cutaneous and vulvovaginal candidiasis.
92.2.2.3.2
1065 1066
Adverse Effects. Adverse effects of topical miconazole are generally mild. Intravaginal administration causes burning, itching, and irritation in about 7% of users. When applied to the skin, miconazole occasionally causes irritation, burning, and maceration. Topical application is not associated with systemic toxicity.
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Pharmacology fortoxicity. Nursing Care, 7th Edition with systemic 92.2.2.3.3
Drug Interactions. Intravaginal miconazole can intensify the anticoagulant effects of warfarin. One woman using the combination reported bruising, bleeding gums, and a nosebleed. We have long known that systemic miconazole can inhibit metabolism of warfarin, thereby causing warfarin levels to rise. Apparently, intravaginal miconazole can be absorbed in amounts sufficient to do the same. Because of this interaction, women taking warfarin should not use intravaginal miconazole. If the drugs must be used concurrently, anticoagulation should be monitored closely and warfarin dosage reduced as indicated.
92.2.2.3.4
Preparations, Dosage, and Administration. Miconazole is available in cream, liquid, and powder formulations for application to the skin, and in cream and suppository formulations for intravaginal application. Cutaneous mycoses are treated with twice-daily applications for 2 to 4 weeks. For vulvovaginal candidiasis, 2% miconazole cream or a 100-mg suppository is administered nightly for 1 week. Alternatively, a 200-mg suppository can be inserted on three consecutive nights.
92.2.2.4
Fluconazole Fluconazole [Diflucan] can be used for oral therapy of vulvovaginal candidiasis, oropharyngeal candidiasis, and onychomycosis. For vulvovaginal candidiasis, the dosage for treating ongoing infection is 150 mg once, and the dosage for preventing recurrent infection is 150 mg once a week for 6 months. The dosage for oropharyngeal candidiasis is 200 mg on day 1 followed by 100 mg daily for 2 weeks. The dosage for onychomycosis is 100 mg daily for 3 to 12 weeks. The basic pharmacology of fluconazole is discussed above under Drugs for Systemic Mycoses.
92.2.2.5 92.2.2.5.1
Newer Azole Drugs Econazole. Econazole [Spectazole] is available for topical application only. The drug is indicated for ringworm infections and superficial candidiasis. Local adverse effects (burning, erythema, stinging, itching) occur in about 3% of patients. Less than 1% of topical econazole is absorbed, and systemic toxicity has not been reported. Econazole, supplied in a 1% cream, is applied twice daily for 2 to 4 weeks.
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Pharmacology fordaily Nursing applied twice for 2 to 4Care, weeks. 7th Edition 92.2.2.5.2
Oxiconazole and Sulconazole. Oxiconazole [Oxistat] and sulconazole [Exelderm] are broad-spectrum antifungal drugs. Both are approved for topical treatment of tinea infections. Local adverse effects (itching, burning, irritation, erythema) occur in less than 3% of patients. Neither drug is absorbed to a significant degree. Systemic toxicity has not been reported. Oxiconazole is supplied as a cream and lotion, and sulconazole is supplied as a cream and solution. Both drugs are applied once daily for 2 to 4 weeks.
92.2.2.5.3
Butoconazole, Terconazole, and Tioconazole. These azole drugs are approved only for topical treatment of vulvovaginal candidiasis. All three are fungicidal. Local adverse effects (burning, itching) occur in 2% to 6% of users. Absorption following intravaginal administration is low, and systemic reactions are rare (except for headache from terconazole). Because of a small risk of fetal injury, these drugs are not recommended for use during the first trimester of pregnancy. Trade names, formulations, and dosages are presented in Table 91-5.
92.2.2.5.4
Sertaconazole. Sertaconazole [Ertaczo], available by prescription, is the ninth azole approved for topical therapy of tinea pedis. The 2% cream is applied twice daily for 4 weeks. Mild local reactions (itching, burning, irritation, erythema) occur in 2% of patients. Blood levels are undetectable following repeated applications, and systemic effects have not been reported. Cure rates are like those seen with generic clotrimazole and miconazole—older azoles that are much cheaper and can be purchased without a prescription.
92.2.3
Griseofulvin Griseofulvin [Grifulvin, Gris-PEG] is administered orally to treat superficial mycoses. The drug is inactive against organisms that cause systemic mycoses.
92.2.3.1
Mechanism of Action. Following absorption, griseofulvin is deposited in the keratin precursor cells of skin, hair, and nails. Because griseofulvin is present, newly formed keratin is resistant to fungal invasion. Hence, as infected keratin is shed, it is replaced by fungus-free tissue.
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Pharmacology for Nursing Care, 7th Edition Hence, as infected keratin is shed, it is replaced by fungus-free tissue. Griseofulvin kills fungi by inhibiting fungal mitosis. How? By binding to components of microtubules, the structures that form the mitotic spindle. Because griseofulvin acts by disrupting mitosis, the drug only affects fungi that are actively growing. 92.2.3.2
Pharmacokinetics. Griseofulvin is administered by mouth. Absorption can be enhanced by taking the drug with a fatty meal. As noted, griseofulvin is deposited in the keratin precursor cells of skin, hair, and nails. Elimination is by hepatic metabolism and renal excretion.
92.2.3.3
Therapeutic Uses. Griseofulvin is employed orally to treat dermatophytic infections of the skin, hair, and nails. The drug is not active against Candida species, nor is it useful against systemic mycoses. Dermatophytic infections of the skin respond relatively quickly (in 3 to 8 weeks). However, infections of the palms may require 2 to 3 months of treatment, and a year or more may be needed to eliminate infections of the toenails.
92.2.3.4
Adverse Effects. Most untoward effects are not serious. Transient headache is common, occurring in about 15% of patients. Other mild reactions include rash, insomnia, tiredness, and GI effects (nausea, vomiting, diarrhea). Griseofulvin may cause hepatotoxicity and photosensitivity in patients with porphyria. The drug is contraindicated for individuals with a history of porphyria or hepatocellular disease.
92.2.3.5
Drug Interactions. Griseofulvin induces hepatic drug-metabolizing enzymes and can thereby decrease the effects of warfarin. When this combination is used, the dosage of warfarin may need to be increased.
92.2.3.6
Preparations, Dosage, and Administration. Griseofulvin is formulated in two particle sizes: microsized and ultra-microsized. The microcrystalline form [Grifulvin V] is supplied in tablets (250 and 500 mg), capsules (250 mg), and a suspension (25 mg/mL). The ultra-microcrystalline form [Gris-PEG] is supplied in tablets (125, 165, 250, and 330 mg). Dosage depends to some degree upon the formulation (microsized or ultra-microsized). With microsized formulations, the usual adult dosage is 500 mg to 1 gm/day, and the usual pediatric dosage is 11 mg/kg/day. The ultra-microsized particles are better absorbed than the microsized particles. As a result, doses of ultra-microcrystalline griseofulvin are about 30% lower than
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Pharmacology for Nursing Care, 7th Edition dosage is 11 mg/kg/day. The ultra-microsized particles are better absorbed than the microsized particles. As a result, doses of ultra-microcrystalline griseofulvin are about 30% lower than doses of microcrystalline griseofulvin. 92.2.4
Polyene Antibiotics
92.2.4.1 92.2.4.1.1
Nystatin Actions, Uses, and Adverse Effects. Nystatin [Mycostatin, Nilstat, others] is a polyene antibiotic used only for candidiasis. Nystatin is the drug of choice for intestinal candidiasis, and is also employed to treat candidal infections of the skin, mouth, esophagus, and vagina. Nystatin can be administered orally and topically. There is no significant absorption from either route. Oral nystatin occasionally causes GI disturbance (nausea, vomiting, diarrhea). Topical application may produce local irritation.
92.2.4.1.2
Preparations, Dosage, and Administration. For oral administration, nystatin is supplied as a suspension and in tablets and lozenges; dosages range from 100,000 to 1 million units 3 to 4 times a day. Vaginal tablets are employed for vaginal candidiasis; the usual dosage is 100,000 units once a day for 2 weeks. Nystatin is supplied as a cream, ointment, and powder to treat candidiasis of the skin. The cream and ointment formulations are applied twice daily; the powder is applied 3 times daily. Trade names for nystatin include Mycostatin and Nilstat.
92.2.5
Allylamines
92.2.5.1
Naftifine Naftifine [Naftin] was the first allylamine available. Although approved only for topical treatment of dermatophytic infections, naftifine is active against a broad spectrum of pathogenic fungi. The drug works by inhibiting squalene epoxidase, and thereby inhibits synthesis of ergosterol, a key component of the fungal cell membrane. The most common adverse effects are burning and stinging. Absorption following topical administration is low (about 6%). Systemic effects have not been reported. Naftifine is supplied in two formulations: 1% cream and 1% gel. The cream is applied once daily, the gel twice daily. The usual duration of treatment is 4 weeks.
CHAPTER 91 Antifungal Agents
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Pharmacology for Nursing Care, 7th Edition of treatment is 4 weeks.
1066
92.2.5.2
1067
92.2.5.2.1
Terbinafine Actions and Uses. Terbinafine [Lamisil] belongs to the same chemical family as naftifine and has the same mechanism of action: inhibition of squalene epoxidase with resultant inhibition of ergosterol synthesis. The drug is highly active against dermatophytes, and less active against Candida species. Terbinafine is available in topical and oral formulations. Topical therapy is used for ringworm infections (eg, tinea corporis, tinea cruris, tinea pedis). Oral therapy is used for ringworm and onychomycosis (fungal infection of the nails).
92.2.5.2.2
Adverse Effects. Adverse effects with topical terbinafine are minimal. The discussion that follows applies to oral therapy. The most common side effects are headache, diarrhea, dyspepsia, and abdominal pain. Oral terbinafine may also cause skin reactions and disturbance of taste. Of much greater concern, terbinafine may pose a risk of liver failure. As of April 2001, the FDA had received 16 reports of liver failure—including 11 deaths and 2 liver transplantations—in patients taking oral terbinafine. Although a causal link has not been established, caution is nonetheless advised. Baseline tests for serum alanine and aspartate aminotransferases (ALT and AST) are recommended. In addition, patients should be informed about signs of liver dysfunction (persistent nausea, anorexia, fatigue, vomiting, jaundice, right upper abdominal pain, dark urine, pale stools) and, if they appear, should discontinue terbinafine immediately and undergo evaluation of liver function. Terbinafine is not recommended for patients with pre-existing liver disease.
92.2.5.2.3
Preparations, Dosage, and Administration. Terbinafine for oral therapy is available in 250-mg tablets sold as Lamisil. The dosage for nail infections is 250 mg/day for 6 to 12 weeks, and the dosage for ringworm is 250 mg/day for 2 to 6 weeks. Terbinafine for topical therapy is available in two formulations: 1% cream [Lamisil] and 1% gel [Lamisil DermGel]. Topical therapy typically lasts 1 to 2 weeks.
92.2.5.3
Butenafine Butenafine [Lotrimin Ultra, Mentax] is chemically similar to naftifine and terbinafine, although the drug is not a true allylamine. However, it does have the same mechanism of action: inhibition of squalene epoxidase with resultant inhibition of ergosterol synthesis. Butenafine is indicated for topical therapy of tinea pedis (athlete's foot), tinea corporis (ringworm), tinea cruris (jock itch), and tinea versicolor. Absorption is minimal, and systemic side effects have
CHAPTER 91 Antifungal Agents
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Pharmacology Nursing 7th(athlete's Edition indicated for for topical therapy ofCare, tinea pedis foot), tinea corporis (ringworm), tinea cruris (jock itch), and tinea versicolor. Absorption is minimal, and systemic side effects have not been reported. Local reactions include burning, stinging, erythema, irritation, and itching. Butenafine 1% cream is applied once daily for 2 to 4 weeks. 92.2.6
Other Drugs for Superficial Mycoses
92.2.6.1
Tolnaftate Tolnaftate is employed topically to treat a variety of superficial mycoses. The drug is active against dermatophytes, but not against Candida species. The mechanism of antifungal action is unknown. Adverse effects (sensitization, irritation) are extremely rare. Tolnaftate is available in several formulations. Creams, gels, and solutions are most effective; powders are used adjunctively. The drug is applied twice daily for 2 to 4 weeks. Trade names include Aftate, Tinactin, and Ting.
92.2.6.2
Undecylenic Acid Undecylenic acid [Desenex, Cruex, others] is a topical agent used to treat superficial mycoses. The drug is active against dermatophytes but not Candida species. Its major indication is tinea pedis (athlete's foot). However, other drugs (tolnaftate, the azoles) are more effective.
92.2.6.3
Ciclopirox Ciclopirox [Loprox, Penlac Nail Lacquer] is a broad-spectrum, topical antifungal drug. Benefits derive from chelating iron and aluminum present in metal-dependent enzymes that protect fungi from peroxides. Ciclopirox is used for infections of the skin (discussed here) and for infections of the fingernails and toenails (discussed above under Onychomycosis). The formulations used for skin infections are marketed as Loprox. The formulation used for nail infections is marketed as Penlac Nail Lacquer. When applied to the skin, ciclopirox is active against dermatophytes and Candida species. The drug is effective against superficial candidiasis and tinea pedis, tinea cruris, and tinea corporis. Ciclopirox penetrates the epidermis to the dermis, but systemic absorption is minimal, and hence no significant systemic accumulation occurs. There is no toxicity from local application. For treatment of skin infections, ciclopirox is available as a 1% shampoo and as a 0.77% cream, gel, or suspension. The shampoo is used twice weekly for 4 weeks. The cream, gel, and suspension are applied twice daily for 2 to 4 weeks.
CHAPTER 91 Antifungal Agents
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Pharmacology for Nursing Care, suspension are applied twice daily for 27th to 4 Edition weeks. 92.2.6.3.1
KEY POINTS ▪ Amphotericin B is a drug of choice for most systemic mycoses—despite its potential for serious harm. ▪ Amphotericin B binds to ergosterol in the fungal cell membrane, thereby making the membrane more permeable. The resultant leakage of intracellular cations reduces viability. ▪ Much of the toxicity of amphotericin B results from binding to cholesterol in host cell membranes. ▪ Because absorption of oral amphotericin B is poor, treatment of systemic mycoses requires intravenous administration. ▪ Amphotericin B infusion frequently causes fever, chills, rigors, nausea, and headache. Pretreatment with diphenhydramine plus an analgesic (eg, acetaminophen) can reduce mild symptoms. A glucocorticoid can be used for severe reactions. Meperidine or dantrolene can reduce rigors. ▪ Amphotericin B causes renal injury in most patients. Kidney damage can be minimized by infusing 1 L of saline on the day amphotericin is infused. ▪ If possible, amphotericin B should not be combined with other nephrotoxic drugs (eg, aminoglycosides, cyclosporine, NSAIDs). ▪ Itraconazole, our prototype for the azole antifungal agents, is active against a broad spectrum of fungi. ▪ Itraconazole inhibits cytochrome P450, and thereby inhibits synthesis of ergosterol, an essential component of the fungal cell membrane. As a result, cell membrane permeability increases, causing cellular components to leak out. ▪ Itraconazole is an alternative to IV amphotericin for many fungal infections. Advantages are lower toxicity and oral usability. ▪ Itraconazole has two major adverse effects: cardiosuppression and liver damage. ▪ Itraconazole inhibits CYP3A4, and can thereby raise levels of many drugs. High levels of cisapride, pimozide, dofetilide, and quinidine can cause fatal dysrhythmias, and hence use of these drugs with itraconazole is contraindicated.
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Pharmacology Care, 7thitraconazole Edition is contraindicated. and for henceNursing use of these drugs with ▪ Drugs that reduce gastric acidity (eg, H2 antagonists, proton pump inhibitors) can greatly reduce absorption of itraconazole. ▪ Topical clotrimazole, a member of the azole family of antifungals, is a drug of choice for many superficial mycoses caused by dermatophytes and Candida species. ▪ Onychomycosis (fungal infection of the fingernails and toenails) is difficult to treat and requires prolonged therapy. Preferred treatments are terbinafine and itraconazole. ▪ Vulvovaginal candidiasis can be treated with a single oral dose of fluconazole or with short-term topical therapy (eg, one 500-mg vaginal suppository of clotrimazole). 92.2.6.3.2
Summary of Major Nursing
1067 1068
Implications*
The implications summarized below pertain only to use of antifungal drugs against systemic mycoses. 92.2.6.3.2.1 92.2.6.3.2.... 92.2.6.3.2....
AMPHOTERICIN B Preadministration Assessment Therapeutic Goal Treatment of progressive and potentially fatal systemic fungal infections. Flucytosine may be given to enhance therapeutic effects.
92.2.6.3.2....
Identifying High-Risk Patients When used as it should be (ie, for life-threatening infections), amphotericin has no contraindications.
92.2.6.3.2.... 92.2.6.3.2....
Implementation: Administration Routes Intravenous, intrathecal.
CHAPTER 91 Antifungal Agents
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Pharmacology for Nursing Care, 7th Edition Intravenous, intrathecal. 92.2.6.3.2....
Intravenous Administration Use aseptic technique when preparing infusion solutions. Infuse slowly (over 2 to 4 hours). Check the solution periodically for a precipitate and, if one forms, discontinue the infusion immediately. Therapy lasts several months; rotate the infusion site to reduce phlebitis and ensure availability of a usable vein. Dosage must be individualized. Alternate-day dosing may be ordered to reduce adverse effects.
92.2.6.3.2....
Ongoing Evaluation and Interventions
92.2.6.3.2....
Minimizing Adverse Effects
92.2.6.3.2....
General Considerations. Amphotericin B can produce serious adverse effects. The patient should be under close supervision, preferably in a hospital.
92.2.6.3.2....
Infusion Reactions. Amphotericin can cause fever, chills, rigors, nausea, and headache. Pretreatment with diphenhydramine plus acetaminophen can minimize these reactions. Give meperidine or dantrolene if rigors develop. If other measures fail, give hydrocortisone to suppress symptoms. Rotate the infusion site and pretreat with heparin to minimize phlebitis. Infusion reactions can be reduced by using a lipidbased formulation rather than conventional amphotericin.
92.2.6.3.2....
Nephrotoxicity. Almost all patients experience renal impairment. Monitor and record intake and output. Kidney function should be tested every 3 to 4 days; if plasma creatinine content rises above 3.5 mg/dL, amphotericin dosage should be reduced. The risk of renal damage can be decreased by infusing 1 L of saline on the day of amphotericin administration, avoiding other nephrotoxic drugs (eg, aminoglycosides, cyclosporine, NSAIDs), and using a lipid-based formulation instead of conventional amphotericin.
CHAPTER 91 Antifungal Agents
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Pharmacologyinstead for Nursing Care, 7th Edition of conventional amphotericin. 92.2.6.3.2....
Hypokalemia. Renal injury may cause hypokalemia. Serum potassium should be measured frequently. Correct hypokalemia with potassium supplements.
92.2.6.3.2....
Hematologic Effects. Normocytic, normochromic anemia has occurred secondary to amphotericininduced suppression of bone marrow. Hematocrit determinations should be performed to monitor for this anemia.
92.2.6.3.2.... 92.2.6.3.2....
Minimizing Adverse Interactions Nephrotoxic Drugs. Unless clearly required, amphotericin should not be combined with other nephrotoxic drugs, such as the aminoglycosides, cyclosporine, and NSAIDs.
92.2.6.3.2.2 92.2.6.3.2.... 92.2.6.3.2....
ITRACONAZOLE Preadministration Assessment Therapeutic Goal Treatment of systemic and superficial mycoses.
92.2.6.3.2....
Baseline Data Assess for heart disease or a history thereof. The physician may order baseline tests of liver function.
92.2.6.3.2....
Identifying High-Risk Patients Itraconazole is contraindicated for patients taking pimozide, quinidine, dofetilide, or cisapride. Use with great caution, if at all, in patients with cardiac disease, significant pulmonary disease, active liver disease, or a history of liver injury with other drugs.
CHAPTER 91 Antifungal Agents
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Pharmacology for Nursing Care, 7th Edition pulmonary disease, active liver disease, or a history of liver injury with other drugs. 92.2.6.3.2.... 92.2.6.3.2....
Implementation: Administration Route Oral.
92.2.6.3.2....
Administration Advise patients to take itraconazole capsules with food and/or a cola beverage to enhance absorption. Advise patients using antacids and other drugs that reduce gastric acidity to take them at least 1 hour before itraconazole or 2 hours after.
92.2.6.3.2.... 92.2.6.3.2.... 92.2.6.3.2....
Ongoing Evaluation and Interventions Minimizing Adverse Effects Liver Injury. Rarely, itraconazole has been associated with fatal liver failure. If signs of liver injury appear, discontinue itraconazole and obtain tests of liver function. Inform patients about signs of liver dysfunction (persistent nausea, anorexia, fatigue, vomiting, right upper abdominal pain, jaundice, dark urine, pale stools), and instruct them to notify the prescriber if these occur.
92.2.6.3.2....
Cardiac Suppression. Itraconazole can suppress ventricular function, posing a risk of heart failure. Monitor for signs and symptoms of heart failure, and discontinue itraconazole if they develop. Inform patients about signs of heart failure (fatigue, cough, dyspnea, edema, jugular distention), and instruct them to seek immediate medical attention if they occur.
92.2.6.3.2.... 92.2.6.3.2....
Minimizing Adverse Interactions Pimozide, Quinidine, Dofetilide, and Cisapride. By inhibiting CYP3A4, itraconazole can raise levels of these drugs, posing a risk of fatal dysrhythmias. Accordingly, concurrent use of these drugs with itraconazole is contraindicated.
CHAPTER 91 Antifungal Agents
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Pharmacologyitraconazole for Nursing Care, 7th Edition is contraindicated. 92.2.6.3.2....
Cyclosporine, Digoxin, Warfarin, and Sulfonylureas.
1068
By inhibiting CYP3A4, itraconazole can raise levels of these drugs. Monitor cyclosporine and digoxin blood levels. Monitor prothrombin time in patients taking warfarin. Monitor blood glucose in patients taking a sulfonylurea. 92.2.6.3.2....
1069
Drugs That Raise Gastric pH. Antacids, H2 antagonists, proton pump inhibitors, and other drugs that decrease gastric acidity can reduce itraconazole absorption. Advise patients using these agents to take them at least 1 hour before itraconazole or 2 hours after.
92.2.6.3.2.3 92.2.6.3.2.... 92.2.6.3.2....
FLUCYTOSINE Preadministration Assessment Therapeutic Goal Treatment of serious infections caused by Candida species and Cryptococcus neoformans. Flucytosine is usually combined with amphotericin B.
92.2.6.3.2....
Baseline Data Obtain baseline tests of renal function, hematologic status, and serum electrolytes.
92.2.6.3.2....
Identifying High-Risk Patients Use with extreme caution in patients with kidney disease or bone marrow suppression.
92.2.6.3.2.... 92.2.6.3.2....
Implementation: Administration Route Oral.
92.2.6.3.2....
Dosage and Administration Treatment may require ingestion of 10 or more capsules 4 times a day. Advise patients to take capsules a few at a time over a 15-minute interval to minimize nausea and vomiting. Dosage must be reduced in patients with renal impairment.
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Pharmacology forand Nursing nausea vomiting.Care, Dosage 7th must Edition be reduced in patients with renal impairment. 92.2.6.3.2....
Ongoing Evaluation and Interventions
92.2.6.3.2....
Monitoring Summary Obtain weekly tests of liver function (serum transaminase and alkaline phosphatase levels) and hematologic status (leukocyte counts). In patients receiving amphotericin B concurrently, and in those with pre-existing renal impairment, monitor kidney function and flucytosine levels.
92.2.6.3.2....
Minimizing Adverse Effects
92.2.6.3.2....
Hematologic Effects. Flucytosine-induced bone marrow suppression can cause neutropenia, thrombocytopenia, and fatal agranulocytosis. Risk can be minimized by adjusting the dosage to keep plasma flucytosine levels below 100 mcg/mL. Obtain weekly leukocyte counts to monitor hematologic effects.
92.2.6.3.2....
Hepatotoxicity. Mild and reversible liver dysfunction occurs frequently; severe hepatic damage is rare. Obtain weekly determinations of serum transaminase and alkaline phosphatase levels to evaluate liver function.
92.2.6.3.2....
Minimizing Adverse Interactions
92.2.6.3.2....
Amphotericin B. Kidney damage from amphotericin B may decrease flucytosine excretion, thereby increasing toxicity secondary to flucytosine accumulation. When these drugs are combined, renal function and flucytosine levels must be monitored. *
Patient education information is highlighted as blue text.
CHAPTER 91 Antifungal Agents
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Pharmacology for Nursing Care, 7th Edition 1070
93
CHAPTER 92 Antiviral Agents I: Drugs for Non-HIV Viral Infections JACK LE FROCK RICH LEHNE Antiviral drugs are discussed in this chapter and the one that follows. In this chapter, we consider drugs used to treat infections caused by viruses other than HIV. In Chapter 93, we consider drugs used against HIV infection. Drugs for non-HIV infections are summarized in Table 92-1. Although antiviral therapy has made significant advances in the last decade, our ability to treat viral infections remains limited. Compared with the dramatic advances made in antibacterial therapy over the past half-century, efforts to develop safe and effective antiviral drugs have been less successful. A major reason for this lack of success resides in the process of viral replication: Viruses are obligate intracellular parasites that use the biochemical machinery of host cells to reproduce. Because the viral growth cycle employs host-cell enzymes and substrates, it is difficult to suppress viral replication without doing significant harm to the host. The antiviral drugs used clinically act by suppressing biochemical processes unique to viral reproduction. As our knowledge of viral molecular biology expands, additional virus-specific processes will be discovered, giving us new targets against which to direct drugs.
CHAPTER 92 Antiviral Agents I: Drugs for Non-HIV Viral Infections
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Pharmacology for Nursing Care, 7th Edition to direct drugs. TABLE 92-1 Major Drugs for Non-HIV Viral Infections Drug
Antiviral Spectrum
Drugs for Herpes Simplex Virus and Varicella-Zoster Virus Infections Acyclovir
HSV, VZV
Famciclovir
HSV, VZV
Valacyclovir
HSV, VZV
Vidarabine
HSV, VZV
Penciclovir
HSV
Trifluridine
HSV keratitis
Idoxuridine
HSV keratitis
Drugs for Hepatitis Adefovir
HBV
Entecavir
HBV
Peginterferon alfa-2a
HBV
Interferon alfa-2b
HBV, HCV
Lamivudine
HBV*
Telbivudine
HBV
Drugs for Cytomegalovirus Infection Ganciclovir
CMV
Valganciclovir
CMV
Cidofovir
CMV
Fomivirsen†
CMV
Foscarnet
CMV, HSV resistant to acyclovir, VZV
Drugs for Influenza Oseltamivir
Influenza A and B
Zanamivir
Influenza A and B
Drugs for Respiratory Syncytial Virus Infection Ribavirin
RSV, influenza A and B
Palivizumab
RSV
CMV = cytomegalovirus, HBV = hepatitis B virus, HCV = hepatitis C virus, HSV = herpes simplex virus, RSV = respiratory syncytial virus, VZV = varicella-zoster virus.
CHAPTER 92 Antiviral Agents I: Drugs for Non-HIV Viral Infections
Page 2 of 56
Pharmacology for Nursing Care, 7th Edition *
Also active against HIV-1 and HIV-2.
†
Withdrawn from the United States market.
CHAPTER 92 Antiviral Agents I: Drugs for Non-HIV Viral Infections
1070
Page 3 of 56
Pharmacology for Nursing Care, 7th Edition
1070
TABLE 92-2 Treatment of Herpes Simplex Virus and Varicella-Zoster Virus Infections Infection
Drug
Route
Dosage
Duration
PO
400 mg 3 times/day
7–10 days
Valacyclovir PO
1 gm 2 times/day
7–10 days
Famciclovir PO
250 mg 3 times/day
7–10 days
Acyclovir
PO
400 mg 3 times/day
3–5 days
Valacyclovir PO
500 mg 2 times/day
3 days
Famciclovir PO
1000 mg 2 times/day
1 day
Recurrent genital, chronic Acyclovir PO suppression Valacyclovir PO
400 mg 2 times/day
Up to 1 yr
500–1000 mg/day
Up to 1 yr
Famciclovir PO
250 mg 2 times/day
Up to 1 yr
Encephalitis
Acyclovir
IV
10–15 mg/kg every 8 hr
14–21 days
Mucocutaneous in ICH
Acyclovir
IV
5 mg/kg every 8 hr
7–10 days
PO
400 mg 5 times/day
7–14 days
Valacyclovir PO
50 mg 2 times/day
7–10 days
Famciclovir PO
500 mg 2 times/day
7–10 days
1071
Herpes Simplex Virus Infections Primary genital
Recurrent genital, single episode suppression
Acyclovir
Foscarnet*
IV
400 mg 2–3 times/day
7–21 days
Neonatal
Acyclovir
IV
10–15 mg/kg every 8 hr
14 days
Orolabial
Acyclovir
Topical
5% cream 5 times/day
4 days
Penciclovir
Topical
1% cream every 2 hr
4 days
Docosanol
Topical
10% cream 5 times/day
4 days
Varicella-Zoster Virus Infections Varicella
Acyclovir
PO
20 mg/kg (800 mg max) 4 times/day
5 days
Varicella in ICH*
Acyclovir
IV
10 mg/kg every 8 hr
7 days
Herpes zoster
Acyclovir
PO
800 mg 5 times/day
7–10 days
Valacyclovir PO
1 gm 3 times/day
7 days
Famciclovir PO
500 mg 3 times/day
7 days
Herpes zoster in ICH*
Acyclovir
IV
10 mg/kg every 8 hr
7 days
Acyclovir-resistant zoster
Foscarnet
IV
40 mg/kg every 28 hr
10 days
Keratoconjunctivitis
Trifluridine
Topical
1 drop every 2 hr while awake (max 9
Up to 21
CHAPTER 92 Antiviral Agents I: Drugs for Non-HIV Viral Infections
Page 4 of 56
Pharmacology 7th40Edition Acyclovir-resistant for zosterNursing Foscarnet Care, IV mg/kg every 28 hr Keratoconjunctivitis
Trifluridine
Topical
10 days
1 drop every 2 hr while awake (max 9 Up to 21 drops/day) until healed, then 1 drop every days 4 hr while awake for 7 days
ICH = immunocompromised host.
* 93.1
Reserve foscarnet for acyclovir-resistant infection.
DRUGS FOR INFECTION WITH HERPES SIMPLEX VIRUSES AND VARICELLAZOSTER VIRUS Herpes simplex virus (HSV) and varicella-zoster virus (VZV) are members of the herpesvirus group. HSV causes infection of the genitalia, mouth and face, and other sites. VZV is the cause of varicella (chickenpox) and herpes zoster (shingles), a painful condition resulting from reactivation of VZV that had been dormant within sensory nerve roots. Both conditions are discussed further in Chapter 67 (Childhood Immunization), along with the vaccine used to prevent VZV infection. Drugs for infection with HSV and VZV are summarized in Table 92-2. Genital herpes is discussed in Chapter 94.
93.1.1
Acyclovir Acyclovir [Zovirax] is the agent of first choice for most infections caused by herpes simplex viruses and varicella-zoster virus. The drug can be administered topically, orally, and intravenously. Serious side effects are uncommon.
93.1.1.1
Antiviral Spectrum Acyclovir is active only against members of the herpesvirus family, a group that includes herpes simplex viruses (HSVs), varicella-zoster virus (VZV), and cytomegalovirus (CMV). Of these, HSVs are most sensitive, VZV is moderately sensitive, and most strains of CMV are resistant.
93.1.1.2
Mechanism of Action Acyclovir inhibits viral replication by suppressing synthesis of viral DNA. To exert antiviral effects, acyclovir must first undergo activation. The critical step in activation is conversion of acyclovir to acyclo-GMP by thymidine kinase. Once formed, acyclo-GMP is converted to acyclo-GTP, the compound directly responsible for inhibiting DNA synthesis. Acyclo-GTP suppresses DNA synthesis by (1) inhibiting viral DNA polymerase and (2) becoming incorporated into the growing strand of viral DNA, which blocks further strand growth.
CHAPTER 92 Antiviral Agents I: Drugs for Non-HIV Viral Infections
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Pharmacology Nursing Care,of7th incorporated for into the growing strand viral Edition DNA, which blocks further strand growth. The selectivity of acyclovir is based in large part on the ability of certain viruses to activate the drug. HSVs are especially sensitive to acyclovir because the drug is a much better substrate for thymidine kinase produced by HSVs than it is for mammalian thymidine kinase. Hence, formation of acyclo-GMP, the limiting step in the activation of acyclovir, occurs almost exclusively in cells infected with HSV. Cytomegalovirus is inherently resistant to the drug because acyclovir is a poor substrate for the form of thymidine kinase produced by this virus. 93.1.1.3
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Resistance Herpesviruses develop resistance to acyclovir by three mechanisms: (1) decreased production of thymidine kinase, (2) alteration of thymidine kinase such that it no longer converts acyclovir to acyclo-GMP, and (3) alteration of viral DNA polymerase such that it is less sensitive to inhibition. Of these mechanisms, thymidine kinase deficiency is the most common. Resistance is rare in immunocompetent patients, but many cases have been reported in transplant patients and patients with AIDS. Lesions caused by resistant HSVs can be extensive and severe, progressing despite continued acyclovir therapy. Acyclovir-resistant HSVs and VZV usually respond to IV foscarnet or cidofovir, which are primarily used for treatment of cytomegalovirus infection (see below).
93.1.1.4 93.1.1.4.1
Therapeutic Uses Herpes Simplex Genitalis. Most genital herpes infections are caused by type 2 HSV (HSV-2). For patients with initial infection, topical acyclovir reduces the duration of viral shedding, but does not accelerate healing. Topical acyclovir is not effective for recurrent genital infections. Oral acyclovir is superior to topical therapy for initial genital infections and for recurrent infections. For patients with initial infection, oral therapy decreases formation of additional lesions and decreases the duration and severity of the initial episode. For patients with recurrent herpes genitalis, continuous oral therapy reduces the frequency at which lesions appear. When initial genital infection is especially severe, intravenous acyclovir may be indicated. Patients with primary or recurrent herpes genitalis should be informed that, although acyclovir can decrease symptoms, the drug does not eliminate the virus and does not produce cure. Patients should be advised to avoid all sexual contact when lesions are present, and should use a condom even when lesions are absent. In pregnant women with recurrent genital herpes, infection can be transmitted to the newborn during delivery. Treatment with acyclovir near term can suppress recurrence, and may thereby eliminate the need for a cesarean section, which would otherwise be required to
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Pharmacology for Nursing Care, 7th near Edition during delivery. Treatment with acyclovir term can suppress recurrence, and may thereby eliminate the need for a cesarean section, which would otherwise be required to prevent neonatal HSV exposure. 93.1.1.4.2
Mucocutaneous Herpes Simplex Infections. Herpes infections of the face and oropharynx are usually caused by HSV-2. For immunocompetent patients, oral acyclovir can be used to treat primary infections of the gums and mouth. Oral acyclovir can also be taken prophylactically to prevent episodes of recurrent herpes labialis (cold sores). However, there is no truly effective treatment for active herpes labialis. Mucocutaneous herpes infections can be especially severe in immunocompromised patients. For these people, intravenous acyclovir is the treatment of choice.
93.1.1.4.3
Varicella-Zoster Infections. High doses of oral acyclovir are effective for herpes zoster (shingles) in older adults. Oral therapy is also effective for varicella (chickenpox) in children, adolescents, and adults, provided that dosing is begun early (within 24 hours of rash onset). Intravenous acyclovir is the treatment of choice for varicella-zoster infection in the immunocompromised host.
93.1.1.5
Pharmacokinetics Acyclovir may be administered topically, orally, or intravenously. Oral bioavailability is low, ranging from 15% to 30%. No significant absorption occurs with topical use. Once in the blood, acyclovir is distributed widely to body fluids and tissues. Levels achieved in cerebrospinal fluid are 50% of those in plasma. Elimination is renal, primarily as the unchanged drug. In patients with normal kidney function, acyclovir has a half-life of 2.5 hours. The half-life is prolonged by renal impairment, reaching 20 hours in anuric patients. Accordingly, dosages should be reduced in patients with kidney disease.
93.1.1.6 93.1.1.6.1
Adverse Effects Intravenous Therapy. Intravenous acyclovir is generally well tolerated. The most common reactions are phlebitis and inflammation at the site of infusion. Reversible nephrotoxicity, manifested as elevations in serum creatinine and blood urea nitrogen, occurs in some patients. The cause of nephrotoxicity is deposition of acyclovir in renal tubules. The risk of renal injury is increased by dehydration and by use of other nephrotoxic drugs. Kidney damage can be minimized by infusing acyclovir slowly (over 1 hour) and by ensuring adequate hydration during the
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Pharmacology for and Nursing 7th Edition by dehydration by use ofCare, other nephrotoxic drugs. Kidney damage can be minimized by infusing acyclovir slowly (over 1 hour) and by ensuring adequate hydration during the infusion and for 2 hours after. Neurologic toxicity—agitation, tremors, delirium, hallucinations, and myoclonus—occurs rarely, primarily in patients with renal impairment. In patients on dialysis, very low doses can cause severe neurotoxicity, characterized by delirium and coma. 93.1.1.6.2
Oral and Topical Therapy. Oral acyclovir is devoid of serious adverse effects. Renal impairment has not been reported. The most common reactions to oral therapy are nausea, vomiting, diarrhea, headache, and vertigo. Topical acyclovir frequently causes transient burning or stinging; systemic reactions do not occur. Oral acyclovir is safe during pregnancy, and hence can be used to suppress recurrent genital herpes near term.
93.1.1.7 93.1.1.7.1
Preparations, Dosage, and Administration Topical: Ointment. Acyclovir [Zovirax] is supplied as a 5% ointment for topical therapy of herpes genitalis and mild mucocutaneous HSV infection in the immunocompromised host. Application is done 6 times a day at 3-hour intervals for 7 days. Patients should use a finger cot or rubber glove to avoid viral transfer to other parts of the body or to other people.
93.1.1.7.2
Topical: Cream. Acyclovir [Zovirax] is supplied as a 5% cream for topical therapy of recurrent herpes labialis (cold sores) in patients at least 12 years old. Application is done 5 times a day for 4 days.
93.1.1.7.3
Oral. Oral acyclovir [Zovirax] is available in capsules (200 mg), tablets (400 and 800 mg), and a suspension (200 mg/5 mL). Dosages for patients with normal kidney function are given below. Dosages must be reduced for patients with renal impairment. • For initial episodes of herpes genitalis, the usual dosage is 400 mg 3 times a day for 7 to 10 days.
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Pharmacology to 10for days.Nursing Care, 7th Edition • For episodic recurrences of herpes genitalis, the usual dosage is 400 mg 3 times a day for 5 days. • For long-term suppressive therapy of recurrent genital infections, the usual dosage is 400 mg twice daily for up to 12 months. • For acute therapy of herpes zoster, the dosage is 800 mg 5 times a day (at 4-hour intervals) for 7 to 10 days. • For varicella (chickenpox), the dosage is 20 mg/kg (but no more than 800 mg) 4 times a day for 5 days. Treatment should begin at the earliest sign of rash. 93.1.1.7.4
1072 1073
Intravenous. Acyclovir [Zovirax] for IV use is available (1) in solution (25 and 50 mg/mL) and (2) as a powder (500 mg/10-mL vial, 1000 mg/20-mL vial) to be reconstituted in sterile water to a final concentration of 50 mg/mL. Administration is by slow IV infusion (over 1 hour or more). Acyclovir must not be given by IV bolus or by IM or subQ injection. To minimize the risk of renal damage, hydrate the patient during the infusion and for 2 hours after. Dosages for patients with normal kidney function are given below. Dosages should be reduced for patients with renal impairment. • For mucocutaneous herpes simplex infection in the immunocompromised host, the adult dosage is 5 mg/kg infused every 8 hours for 7 days. The dosage for children under 12 years is 250 mg/m2 infused every 8 hours for 7 days.
• For varicella-zoster infection in the immunocompromised host, the adult dosage is 10 mg/kg infused every 8 hours for 7 days. The dosage for children under 12 years is 500 mg/m2 infused every 8 hours for 7 days.
• For severe episodes of herpes genitalis in the immunocompetent host, the adult dosage is 5 to 10 mg/kg infused every 8 hours for 5 to 7 days (or until symptoms resolve). The dosage for children under 12 years is 250 mg/m2 infused every 8 hours for 5 days.
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Pharmacology forforNursing Care, 7thisEdition dosage children under 12 years 250 mg/m2 infused every 8 hours for 5 days. 93.1.2
Valacyclovir
93.1.2.1
Actions and Uses. Valacyclovir [Valtrex], a prodrug form of acyclovir, has three approved indications: (1) herpes zoster (shingles), (2) herpes simplex genitalis, and (3) herpes labialis (cold sores). In all three infections, benefits depend on conversion of valacyclovir to acyclovir, its active form. In a clinical trial in patients with herpes zoster, valacyclovir (1000 mg 3 times a day for 7 or 14 days) was somewhat more effective than acyclovir (800 mg 5 times a day for 7 days) in reducing the duration of pain and the duration of postherpetic neuralgia. In clinical trials in patients with initial or recurrent herpes genitalis, valacyclovir (1000 mg twice a day) and acyclovir (200 mg 5 times a day) produced similar results. In a recent study, valacyclovir was shown to reduce—but not eliminate—the risk of transmitting genital herpes between monogamous heterosexual partners. In patients receiving immunosuppressive drugs following a kidney transplant, prophylaxis with valacyclovir (2 gm 4 times a day for 90 days) can reduce the risk of CMV disease, a major complication of transplant surgery.
93.1.2.2
Pharmacokinetics. After oral dosing, valacyclovir undergoes rapid absorption followed by rapid and essentially complete conversion to acyclovir. When acyclovir itself is given PO, bioavailability is only 15% to 30%. In contrast, when valacyclovir is given PO, the effective bioavailability of acyclovir is greatly increased—to about 55%. Hence, valacyclovir represents a more efficient way of getting acyclovir into the body. Following conversion of valacyclovir to acyclovir, the kinetics are the same as if acyclovir itself had been given.
93.1.2.3
Adverse Effects. In some immunocompromised patients, valacyclovir has produced a syndrome known as thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS). This syndrome, which is potentially fatal, has not occurred in immunocompetent patients. Valacyclovir is not approved for use in immunocompromised hosts. Aside from causing TTP/ HUS, valacyclovir is generally well tolerated, producing the same side effects seen with oral acyclovir (eg, nausea, vomiting, diarrhea, headache, vertigo).
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Pharmacology Nursing Care, 7th Edition acyclovir (eg,for nausea, vomiting, diarrhea, headache, vertigo). 93.1.2.4
Preparations, Dosage, and Administration. Valacyclovir [Valtrex] is available in 500- and 1000-mg oral capsules. Dosing may be done without regard to meals. In patients with renal impairment, dosages should be reduced. For patients with herpes zoster, the recommended dosage is 1000 mg 3 times a day for 7 days. Therapy should begin as soon as possible after symptom onset. For patients with herpes simplex genitalis, the dosage is 1 gm twice daily for 10 days (for the initial episode), 500 mg twice daily for 3 days (for episodic recurrences), and 500 to 1000 mg once daily (for long-term suppression). For patients with herpes labialis, the dosage is 2 gm twice, taken 12 hours apart. Dosing should begin as soon as possible after onset of symptoms.
93.1.3
Famciclovir Famciclovir [Famvir] is a prodrug used to treat acute herpes zoster and genital herpes infection. Benefits are equivalent to those of acyclovir. Adverse effects are minimal.
93.1.3.1
Pharmacokinetics. Famciclovir undergoes rapid absorption from the GI tract followed by enzymatic conversion to penciclovir, its active form. Food decreases the rate of famciclovir absorption but not the extent. As a result, the amount of penciclovir produced is the same whether famciclovir is taken with or without food. Penciclovir is excreted in the urine, largely unchanged. The plasma half-life of penciclovir is about 2.5 hours. However, the half-life of penciclovir within cells is much longer. In patients with renal impairment, the plasma half-life of penciclovir is prolonged.
93.1.3.2
Mechanism of Action and Antiviral Spectrum. Penciclovir undergoes intracellular conversion to penciclovir triphosphate, a compound that inhibits viral DNA polymerase, and thereby prevents replication of viral DNA. Under clinical conditions, formation of penciclovir triphosphate requires viral thymidine kinase. As a result, inhibition of DNA synthesis is limited to cells that are infected, leaving the vast majority of host cells unharmed. In vitro, penciclovir is active against HSV type 1 (HSV-1), HSV-2, and VZV.
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Pharmacology for Nursing Care, 7th Edition VZV. 93.1.3.3
Therapeutic Use. Famciclovir is approved for treatment of acute herpes zoster (shingles) and herpes simplex genitalis. In patients with herpes zoster, the drug can decrease the time to full crusting from 7 days down to 5 days. Famciclovir does not decrease the incidence of postherpetic neuralgia, but can decrease the duration (from 112 days down to 61 days). In a trial comparing famciclovir with acyclovir, both drugs had equivalent effects against herpes zoster. In patients with genital herpes simplex infection, famciclovir is active against the first episode and recurrent episodes. In addition, it can be used for long-term suppression.
93.1.3.4
Adverse Effects. Famciclovir is very well tolerated. In clinical trials, the incidence of side effects was the same as with placebo. Safety for use during pregnancy or breast-feeding and in children under the age of 18 has not been established.
93.1.3.5
Preparations, Dosage, and Administration. Preparations. Famciclovir [Famvir] is supplied in tablets (125, 250, and 500 mg) for oral use. Dosing can be done without regard to meals.
93.1.3.5.1
Acute Herpes Zoster. The recommended dosage is 500 mg every 8 hours for 7 days. Treatment should start no later than 72 hours after symptom onset. In patients with renal impairment, the interval between doses should be increased to 12 hours or 24 hours, depending on the degree of impairment.
93.1.3.5.2
Herpes Simplex Genitalis. For initial episodes, the dosage is 250 mg 3 times a day for 5 to 10 days. For episodic recurrence, the dosage is 125 mg twice a day for 5 days (or two 1000-mg doses 12 hours apart). For long-term suppression, the dosage is 250 mg twice daily.
93.1.4
Topical Drugs for Herpes Labialis We have three topical drugs for recurrent herpes labialis (cold sores). Two of these drugs— penciclovir and docosanol—are discussed below. The third drug—acyclovir—is discussed above.
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Pharmacology for Nursing Care, 7th Edition above. 93.1.4.1
Penciclovir Cream Penciclovir [Denavir] is a topical drug indicated for recurrent herpes labialis (cold sores), an infection caused by HSV-1 and HSV-2. The drug suppresses viral replication by inhibiting DNA polymerase, the enzyme that makes DNA. Penciclovir is supplied as a 1% cream to be applied every 2 hours (except when sleeping) for 4 days. In clinical trials, benefits were modest: The average time to healing and duration of pain were decreased by just half a day, from 5 days down to 4.5 days. The only common adverse effect is mild local erythema.
93.1.4.2
Docosanol Cream Docosanol [Abreva] is a topical preparation indicated for recurrent herpes labialis. The drug is available over the counter as a 10% cream. Application is done 5 times a day, beginning at the first sign of recurrence. Benefits are modest. In one clinical trial, treatment reduced the time to healing from 4.8 days down to 4.1 days—about the same response seen with penciclovir. Docosanol cream appears devoid of adverse effects. Docosanol has a broad antiviral spectrum and a unique mechanism of action. Unlike penciclovir, which inhibits viral DNA synthesis (and thereby suppresses replication), docosanol blocks viral entry into host cells. The drug does not kill viruses and does not prevent them from binding to cells. As a result, viable virions can remain attached to the cell surface for a long time. Because docosanol does not affect processes of replication, it is unlikely to promote resistance.
93.1.5
Topical Drugs for Ocular Herpes Infections
93.1.5.1
Trifluridine Ophthalmic Solution Trifluridine [Viroptic] is indicated only for topical treatment of ocular infections caused by HSV-1 and HSV-2. The drug is given to treat acute keratoconjunctivitis and recurrent epithelial keratitis. Antiviral actions result from inhibiting DNA synthesis. The most common side effects are localized burning and stinging. Edema of the eyelid occurs in about 3% of patients. Systemic absorption is minimal following topical administration, and hence the drug is devoid of systemic toxicity. Trifluridine is supplied as a 1% ophthalmic solution. Treatment consists of placing 1 drop on the cornea every 2 hours while the patient is awake, for a maximum of 9 drops/day. Once re-epithelialization of the cornea has occurred, the dosage is reduced to 1 drop every 4 hours. Treatment continues for 7 days.
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Pharmacology for every Nursing Care, 7th continues Editionfor 7 days. reduced to 1 drop 4 hours. Treatment 93.1.5.2
Vidarabine Ointment Like trifluridine, topical vidarabine [Vira-A] is indicated for acute keratoconjunctivitis and recurrent epithelial keratitis caused by HSV-1 and HSV-2. Antiviral effects result from inhibition of viral DNA polymerase and from premature termination of the growing viral DNA chain. The most frequent side effects are burning sensations, photophobia, and lacrimation. Absorption of topical vidarabine is insignificant, and systemic toxicity has not been reported. Vidarabine is available in a 3% ointment for application to the eye. About ½ inch of ointment is administered into the lower conjunctival sac 5 times a day at 3-hour intervals. As a rule, treatment lasts for no more than 3 weeks.
93.2
DRUGS FOR CYTOMEGALOVIRUS INFECTION Cytomegalovirus (CMV) is a member of the herpesvirus group, which includes herpes simplex virus types 1 and 2, varicella-zoster virus (the cause of chickenpox), and Epstein-Barr virus (the cause of infectious mononucleosis). Transmission of CMV occurs person to person—through direct contact with saliva, urine, blood, tears, breast milk, semen, and other body fluids. Infection can also be acquired by way of blood transfusion or organ transplantation. Infection with CMV is very common: Between 50% and 85% of Americans age 40 and older harbor the virus. After the initial infection, which has minimal symptoms in healthy people, the virus remains dormant within cells for life, without causing detectable injury or clinical illness. Hence, for most healthy people, CMV infection is of little concern. By contrast, people who are immunocompromised—owing to HIV infection, cancer chemotherapy, or use of immunosuppressive drugs—are at high risk of serious morbidity and even death, both from initial CMV infection and from reactivation of dormant CMV. Common sites for infection are the lungs, eyes, and GI tract. Among people with AIDS, CMV retinitis is the principal reason for loss of vision (see Chapter 93). The five drugs used against CMV are discussed below.
93.2.1
Ganciclovir Ganciclovir [Cytovene, Vitrasert] is a synthetic antiviral agent with activity against herpesviruses, including CMV. Because the drug can cause serious adverse effects, especially granulocytopenia and thrombocytopenia, use should be restricted to prevention and treatment of CMV infection in the immunocompromised host.
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Pharmacology Care, 7thhost. Edition CMV infectionfor in theNursing immunocompromised 93.2.1.1
Mechanism of Action. Ganciclovir is converted to its active form, ganciclovir triphosphate, inside infected cells. As ganciclovir triphosphate, it suppresses replication of viral DNA by (1) inhibiting viral DNA polymerase and (2) undergoing incorporation into the growing DNA chain, which causes premature chain termination.
93.2.1.2
Pharmacokinetics. Bioavailability of oral ganciclovir is low: only 5% under fasting conditions and 9% when taken with food. Once in the blood, the drug is widely distributed to body fluids and tissues. Ganciclovir is excreted unchanged in the urine. In patients with normal renal function, the halflife is about 3 hours. In patients with renal impairment, the half-life is prolonged. Accordingly, dosages should be reduced in patients with kidney disease.
93.2.1.3
Therapeutic Use. Ganciclovir is used only for prevention and treatment of CMV infection in immunocompromised patients, including those with HIV infection and those receiving immunosuppressive drugs. Specific uses include: • Treatment of sight-threatening CMV retinitis • Treatment of CMV pneumonitis • Treatment of acute CMV colitis • Prevention of CMV infection in transplant recipients • Preemptive treatment of patients with CMV antigenemia or viremia In patients with AIDS, CMV retinitis has an incidence of 15% to 40%. Although most AIDS patients respond initially, the relapse rate is high. Accordingly, for most patients, maintenance therapy should continue indefinitely. The risk of relapse is higher with oral ganciclovir than with IV ganciclovir. Since viral resistance can develop during treatment, this possibility should be considered if the patient responds poorly.
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Pharmacology Nursing Care,poorly. 7th Edition be consideredfor if the patient responds 93.2.1.4
Adverse Effects. Granulocytopenia and Thrombocytopenia. The adverse effect of greatest concern is bone marrow suppression, which can result in granulocytopenia (40%) and thrombocytopenia (20%). These effects, which are usually reversible, are more likely with IV therapy than with oral therapy. These hematologic responses can be exacerbated by concurrent therapy with zidovudine. Conversely, granulocytopenia can be reduced with granulocyte colony-stimulating factors (see Chapter 55). Because of the risk of adverse hematologic effects, blood cell counts must be monitored. Treatment should be interrupted if the absolute neutrophil count falls below 500/mm3 or if the platelet count falls below 25,000/mm3. Cell counts usually begin to recover within 3 to 5 days. Ganciclovir should be used with caution in patients with preexisting cytopenias, in those with a history of cytopenic reactions to other drugs, and in those taking other bone marrow suppressants (eg, zidovudine, trimetrexate).
93.2.1.4.1
Reproductive Toxicity Ganciclovir is teratogenic and embryotoxic in laboratory animals and probably in humans. Women should be advised to avoid pregnancy during therapy and for 90 days after ending treatment. At doses equivalent to those used therapeutically, ganciclovir inhibits spermatogenesis in mice; sterility is reversible with low doses and irreversible with high doses. Female infertility may also occur. Patients should be forewarned of these effects.
93.2.1.4.2
Other Adverse Effects. Incidental effects include nausea, fever, rash, anemia, liver dysfunction, and confusion and other central nervous system (CNS) symptoms. In mice, very high doses (1000 mg/kg) have caused cancer.
93.2.1.5
Preparations, Dosage, and Administration. Intravenous. Ganciclovir [Cytovene] is available as a powder to be reconstituted for IV infusion. Solutions are alkaline and must be infused into a freely flowing vein to avoid local injury. For treatment of CMV retinitis, the initial dosage for adults with normal renal function is 5 mg/kg (infused over 1 hour) every 12 hours for 14 to 21 days. Two maintenance dosages can be used: (1) 5 mg/kg infused over 1 hour once every day or (2) 6 mg/kg infused over 1 hour once a day, 5 days each week. Dosages must be reduced for patients with renal impairment. Since many patients with AIDS must continue maintenance therapy for life, they need a permanent IV line and equipment for home infusion. Adequate hydration must be
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Pharmacology for Nursing Care, 7th Edition impairment. Since many patients with AIDS must continue maintenance therapy for life, they need a permanent IV line and equipment for home infusion. Adequate hydration must be maintained in all patients to ensure renal excretion of ganciclovir. 93.2.1.5.1
1074 1075
Oral. Oral ganciclovir [Cytovene] is indicated for maintenance therapy in patients with CMV retinitis. The dosage is 1000 mg 3 times daily with food.
93.2.1.5.2
Intraocular. The ganciclovir intraocular implant [Vitrasert] is indicated for CMV retinitis in patients with AIDS. Surgical implantation, which takes about 1 hour, is performed under local anesthesia on an outpatient basis. Vision is usually blurred for 2 to 4 weeks after the procedure. The implant must be replaced every 5 to 8 months. Clinical trials indicate that CMV retinitis progresses more slowly in patients who receive intraocular ganciclovir compared with those on IV ganciclovir.
93.2.2
Valganciclovir
93.2.2.1
Basic and Clinical Pharmacology. Valganciclovir [Valcyte] is a prodrug version of ganciclovir [Cytovene] with greater oral bioavailability (60% vs. 9%). Like ganciclovir, valganciclovir is indicated for CMV retinitis. Following absorption from the GI tract, valganciclovir is rapidly metabolized to ganciclovir, its active form—and eventually undergoes excretion as unchanged ganciclovir in the urine. When compared with intravenous ganciclovir in patients with active CMV retinitis, oral valganciclovir was just as effective—and much more convenient. Recently, valganciclovir was shown to reduce transmission of genital herpes (see Chapter 94). Adverse effects are the same as with ganciclovir. The principal concern is blood dyscrasias— granulocytopenia (27%), anemia (26%), and thrombocytopenia (6%)—secondary to bone marrow suppression. In addition, valganciclovir frequently causes diarrhea (41%), nausea (30%), vomiting (21%), fever (31%), and headache (22%). Valganciclovir is presumed to pose the same risks of mutagenesis, aspermatogenesis, and carcinogenesis as ganciclovir.
93.2.2.2
Preparations, Dosage, and Administration. Valganciclovir [Valcyte] is available in 450-mg tablets for oral use. The dosage for induction (treatment of active CMV retinitis) is 900 mg (2 tablets) twice daily for 21 days. The dosage for maintenance is 900 mg once daily. All doses should be taken with food to enhance
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Pharmacology Care, 7thmgEdition (treatment of for activeNursing CMV retinitis) is 900 (2 tablets) twice daily for 21 days. The dosage for maintenance is 900 mg once daily. All doses should be taken with food to enhance bioavailability. Dosage must be reduced for patients with renal impairment. Because valganciclovir has the potential for mutagenesis and carcinogenesis, it should be handled carefully. Tablets should be ingested intact, without crushing or chewing. Direct contact with broken tablets should be avoided. If contact does occur, the area should be washed with soap and water. When handling or disposing of the drug, healthcare workers should follow the same guidelines established for cytotoxic anticancer drugs. 93.2.3
Cidofovir Cidofovir [Vistide] is an IV drug with just one indication: CMV retinitis in patients with AIDS who have failed on ganciclovir or foscarnet. Alternative drugs for this infection are foscarnet, which is given IV, and ganciclovir, which may be administered IV, PO, or by ocular insert. Compared with IV foscarnet or IV ganciclovir, cidofovir has the distinct advantage of needing fewer infusions: Whereas foscarnet and ganciclovir must be infused daily, cidofovir is infused just once a week or every other week. The major adverse effect of the drug is kidney damage.
93.2.3.1
Mechanism of Action. Once inside cells, cidofovir is converted to cidofovir diphosphate, its active form. As the diphosphate, cidofovir causes selective inhibition of viral DNA polymerase, and thereby inhibits viral DNA synthesis. Intracellular concentrations of cidofovir diphosphate are too low to inhibit human DNA polymerases. Hence, host cells are spared.
93.2.3.2
Antiviral Spectrum and Therapeutic Use. Cidofovir is active against herpesviruses, including CMV, HSV-1, HSV-2, and VZV. At this time, the drug is approved only for CMV retinitis in patients with AIDS. Whether cidofovir is active against CMV infections in other patients or at other sites (eg, GI tract, lungs) is unknown. In clinical trials in patients with AIDS and established CMV retinitis, cidofovir significantly delayed progression of retinitis.
93.2.3.3
Pharmacokinetics. Cidofovir is administered by IV infusion and is excreted by the kidneys. Probenecid competes with cidofovir for renal tubular secretion, and thereby delays elimination. Cidofovir has a prolonged intracellular half-life (17 to 65 hours), and hence a long interval (2 weeks) can separate doses. In contrast, IV foscarnet and ganciclovir must be infused daily.
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Pharmacology for Nursing separate doses. In contrast, IV Care, foscarnet7th and Edition ganciclovir must be infused daily. 93.2.3.4
Adverse Effects. Nephrotoxicity. The principal adverse effect is dose-dependent nephrotoxicity, manifesting as decreased renal function and symptoms of a Fanconi-like syndrome (proteinuria, glucosuria, bicarbonate wasting). To reduce the risk of renal injury, all patients must receive probenecid and IV hydration therapy with each infusion. Also, serum creatinine and urine protein should be checked within 48 hours prior to each dose and, if these values indicate kidney damage, cidofovir should be withheld or the dosage reduced. Cidofovir is contraindicated for patients taking other drugs that can injure the kidney, and for patients with proteinuria (2+ or greater) or baseline serum creatinine greater than 1.5 mg/dL.
93.2.3.5
Other Adverse Effects. Neutropenia develops in about 20% of patients, and hence neutrophil counts should be monitored. Ocular disorders—iritis, uveitis, or ocular hypotony (low intraocular pressure)— can also occur. Adverse effects are more common in patients taking antiretroviral drugs. In animal studies, cidofovir was carcinogenic and teratogenic, and caused hypospermia. Adverse effects are more likely in patients taking antiretroviral drugs (ie, drugs for HIV).
93.2.3.6
Preparations, Dosage, and Administration. Cidofovir [Vistide] is supplied in solution (75 mg/mL) in 5-mL ampules. To reduce the risk of renal injury, cidofovir infusions must be accompanied by IV hydration therapy and PO probenecid. Each cidofovir dose—for induction or maintenance—consists of 5 mg/kg infused IV over 1 hour. For induction, two doses are given 1 week apart. For maintenance, one dose is given every 2 weeks. The size of each dose must be reduced for patients with renal impairment. If impairment is severe, cidofovir should be withheld. Oral probenecid must accompany each infusion. The dosage is 2 gm given 3 hours before the infusion, 1 gm given 1 hour after the infusion, and 1 gm more given 8 hours after that. Ingesting food before each dose can decrease probenecid-induced nausea and vomiting. An antiemetic may also be used. Hydration is accomplished by infusing 1 L of 0.9% saline solution over 1 to 2 hours immediately before infusing cidofovir. For patients who can tolerate it, 1 L more can be infused over 1 to 3 hours, beginning when the cidofovir infusion begins or as soon as it is over.
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Pharmacology Care,when 7ththeEdition infused over 1for to 3Nursing hours, beginning cidofovir infusion begins or as soon as it is over. 93.2.4
Foscarnet Foscarnet [Foscavir] is an IV drug active against all known herpesviruses, including CMV, HSV-1, HSV-2, and VZV. Compared with ganciclovir, foscarnet is more difficult to administer, less well tolerated, and much more expensive (the cost to the pharmacy is about $20,000 a year). The major adverse effect is renal injury.
93.2.4.1
Mechanism of Action. Foscarnet, an analog of pyrophosphate, inhibits viral DNA polymerases and reverse transcriptases, and thereby inhibits synthesis of viral nucleic acids. At the concentrations achieved clinically, the drug does not inhibit host DNA replication. Unlike many other antiviral drugs, which must undergo conversion to an active form, foscarnet is active as administered.
93.2.4.2
Therapeutic Use. Foscarnet has two approved indications: (1) CMV retinitis in patients with AIDS and (2) acyclovir-resistant mucocutaneous HSV and VZV infection in the immunocompromised host. CMV retinitis resistant to ganciclovir may respond to foscarnet.
93.2.4.3
Pharmacokinetics. Foscarnet has low oral bioavailability and must be administered IV. The drug is poorly soluble in water and does not penetrate cells easily. As a result, it must be given in large doses with large volumes of fluid. Between 10% and 28% of each dose is deposited in bone; the remainder is excreted unchanged in the urine. Because foscarnet is eliminated by the kidneys, dosages must be reduced in patients with renal impairment. The plasma half-life is 3 to 5 hours.
93.2.4.4
Adverse Effects and Interactions. Foscarnet is generally less well tolerated than ganciclovir. However, unlike ganciclovir, foscarnet does not cause granulocytopenia or thrombocytopenia.
93.2.4.4.1
Nephrotoxicity. Renal injury, as evidenced by a rise in serum creatinine concentration, is the most common dose-limiting toxicity. Most patients develop some degree of renal impairment. Renal injury occurs most often during the second week of therapy. The risk of nephrotoxicity is increased by concurrent use of other nephrotoxic drugs, including amphotericin B, aminoglycosides (eg, gentamicin), and pentamidine. Prehydration with IV saline may reduce the risk of renal
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Pharmacology foruseNursing Care, 7th Edition by concurrent of other nephrotoxic drugs, including amphotericin B, aminoglycosides (eg, gentamicin), and pentamidine. Prehydration with IV saline may reduce the risk of renal injury. Renal function (creatinine clearance) should be monitored closely and the dosage should be reduced if renal impairment develops. 93.2.4.4.2
Electrolyte and Mineral Imbalances. Foscarnet frequently causes hypocalcemia, hypokalemia, hypomagnesemia, and hypo- or hyperphosphatemia. Ionized serum calcium may be reduced despite normal levels of total serum calcium. Patients should be informed about symptoms of low ionized calcium (eg, paresthesias, numbness in the extremities, perioral tingling) and instructed to report these. Severe hypocalcemia can result in dysrhythmias, tetany, and seizures. Serum levels of calcium, magnesium, potassium, and phosphorus should be measured frequently. Special caution is required in patients with pre-existing electrolyte, cardiac, or neurologic abnormalities. The risk of hypocalcemia is increased by concurrent use of pentamidine.
93.2.4.4.3
Other Adverse Effects. Common reactions include fever (65%), nausea (47%), anemia (33%), diarrhea (30%), vomiting (26%), and headache (26%). In addition, foscarnet can cause fatigue, tremor, irritability, genital ulceration, abnormal liver function tests, neutropenia, and seizures.
93.2.4.5
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Preparations, Dosage, and Administration. Foscarnet [Foscavir] is dispensed in solution (24 mg/mL) for IV infusion. An infusion pump is essential to reduce the risk of accidental overdose. Infusions may be administered through a central venous line or a peripheral vein. When a central line is used, a concentrated (24 mg/ mL) solution may be given. When a peripheral vein is used, the solution should be diluted to 12 mg/mL. For patients with normal kidney function, the initial dosage is 60 mg/kg (for CMV infection) or 40 mg/kg (for HSV infection) infused over 1 hour (or longer) every 8 hours for 2 to 3 weeks. The maintenance dosage (for CMV or HSV infection) is 90 to 120 mg/kg infused over 2 hours once daily. All dosages must be reduced for patients with renal impairment.
93.2.5
Fomivirsen
93.2.5.1
Clinical Pharmacology. Fomivirsen [Vitravene] is a unique drug approved for treating CMV retinitis in HIV-infected patients who are intolerant of or unresponsive to other drugs. Administration is by direct injection into the vitreous humor. The dosage is 0.05 mL (0.33 mg) on days 1 and 14, and every 4 weeks thereafter. Enzymes within the eye degrade fomivirsen to inactive
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Pharmacology Nursing Care, 7th Edition injection intofor the vitreous humor. The dosage is 0.05 mL (0.33 mg) on days 1 and 14, and every 4 weeks thereafter. Enzymes within the eye degrade fomivirsen to inactive mononucleotide fragments over a span of 7 to 10 days. The most common adverse effect is ocular inflammation, which develops in 25% of patients. Inflammation can be suppressed with topical glucocorticoids. Other common reactions include vision changes and elevated intraocular pressure. In 2009, fomivirsen was withdrawn from the United States market. 93.2.5.2
Mechanism of Action. Fomivirsen is the first representative of a new class of drugs, known as “antisense” agents. Antisense drugs consist of a single strand of DNA designed to bind to specific molecules of messenger RNA and thereby block synthesis of disease-causing proteins. Benefits of fomivirsen derive from blocking production of viral proteins required by CMV for replication.
93.3
DRUGS FOR HEPATITIS Viral hepatitis is the most common liver disorder. Millions of Americans are infected. Viral hepatitis can be caused by six different hepatitis viruses, labeled A, B, C, D, E, and G. All six can cause acute hepatitis, but only B, C, and D also cause chronic hepatitis. Acute hepatitis lasts for 6 months or less and is characterized by liver inflammation, jaundice, and elevation of serum alanine aminotransferase (ALT) activity. In most cases, acute hepatitis resolves spontaneously, and hence intervention is generally unnecessary. In contrast, chronic hepatitis can lead to cirrhosis, hepatocellular carcinoma, and life-threatening liver failure, and hence treatment should be considered. Most cases (90%) of chronic hepatitis are caused by either hepatitis B virus (HBV) or hepatitis C virus (HCV). Accordingly, our discussion focuses on hepatitis B and hepatitis C. About 1.5% of Americans are infected with HBV or HCV, which is 5 times more than the number infected with HIV. Comparisons between hepatitis A, B, and C are summarized in Table 92-3. Vaccines for hepatitis A and B are discussed in Chapter 67. Drugs for hepatitis B and C are discussed below.
93.3.1
Hepatitis C About 2.7 million Americans have chronic hepatitis C. Transmission occurs primarily through exchange of blood. Whether sexual transmission occurs is controversial. Furthermore, if sexual transmission does occur, the risk of transmission between monogamous heterosexual partners is extremely low. Among people who acquire HCV, 75% to 85% develop active infection. However, most people with chronic hepatitis C have no symptoms, although they can transmit HCV to others. Chronic HCV infection undergoes slow progression, and, in some people, eventually causes liver failure, cancer, and death. Chronic hepatitis C is the leading reason for liver transplants, and kills about 12,000 Americans each year. Currently, treatment is
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Pharmacology forliver Nursing Care,and7th Edition eventually causes failure, cancer, death. Chronic hepatitis C is the leading reason for liver transplants, and kills about 12,000 Americans each year. Currently, treatment is recommended only for patients with HCV viremia, persistent elevation of ALT, and evidence of hepatic fibrosis and inflammation upon liver biopsy. The most effective treatment for hepatitis C is pegylated interferon alfa (peginterferon alfa) combined with ribavirin. There is no vaccine for hepatitis C. It is important to note that not all hepatitis C viruses are the same. There are 6 genotypes of HCV, and more than 50 subtypes. In the United States, 75% of HCV infections are caused by HCV genotype 1, which, unfortunately, is less responsive to treatment than other HCV genotypes. Before drug therapy is initiated, HCV genotype should be determined. 93.3.1.1
Interferon Alfa Preparations Human interferons are naturally occurring compounds with complex antiviral, immunomodulatory, and antineoplastic actions. The interferon family has three major classes, designated alpha, beta, and gamma. All of the interferons used for hepatitis belong to the alpha class (Table 92-4). In the discussion below, these compounds are referred to collectively as interferon alfa. None of these agents can be used orally, and hence administration is parenteral —almost always subQ. Commercial production is by recombinant DNA technology.
1076 1077
TABLE 92-3 Characteristics of Hepatitis A, Hepatitis B, and Hepatitis C Point of Comparison
Hepatitis A
Hepatitis B
Hepatitis C
Causative agent
Hepatitis A virus
Hepatitis B virus
Hepatitis C virus
Infections that become chronic
None
3–5%
Over 70%
Acute infections each year in the United States
179,000
185,000
38,000
U.S. residents with chronic infection
None
1.25 million
2.7 million
Annual deaths in the United States from chronic infection
None
6000
8000–10,000
People worldwide with chronic infection
None
350 million
170 million
Method of prevention
Hepatitis A vaccine
Hepatitis B vaccine
None available
Preferred treatment
None
Interferon alfa or lamivudine
Peginterferon alfa plus ribavirin
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Pharmacology for Nursing Care, 7th Edition 93.3.1.1.1
Mechanism of Action. Interferon alfa has multiple effects on the viral replication cycle. After binding to receptors on host cell membranes, the drug blocks viral entry into cells, synthesis of viral messenger RNA and viral proteins, and viral assembly and release.
93.3.1.1.2
Conventional Versus Long-Acting Interferons. The alfa interferons can be divided into two groups—conventional and long acting—based on their time course of action (see Table 92-4). The conventional preparations have short half-lives, and hence must be administered frequently—at least 3 times a week. In contrast, the long-acting preparations are administered less frequently—just once a week—making them more convenient. In addition, with the long-acting preparations, blood levels remain high between doses, and hence clinical responses are better. How are long-acting interferons made? By conjugating a conventional interferon (eg, interferon alfa-2a) with polyethylene glycol (PEG), in a process known as pegylation. Therapeutic effects of the pegylated product are due solely to its interferon component. The PEG component serves only to delay elimination. At this time, two long-acting interferons are available: pegylated interferon (peginterferon) alfa-2a [Pegasys] and peginterferon alfa-2b [PEG-Intron]. Because of their convenience and superior efficacy, these products are preferred to conventional interferons. However, please note that several side effects— injection-site reactions, dose-related neutropenia, and thrombocytopenia—are more common with pegylated interferon than with the conventional formulation.
93.3.1.1.3
Effects in Chronic Hepatitis C. In patients with chronic hepatitis C, responses are equally modest with all forms of interferon alfa. After 12 months of treatment, serum ALT normalizes in 40% to 50% of patients, and serum levels of HCV RNA (a marker for HCV in blood) become undetectable in 30% to 40%. Unfortunately, about half of these people relapse when treatment is stopped; sustained responses are maintained in only 5% to 15% of patients. As discussed below, combining interferon alfa with ribavirin can improve response rates.
93.3.1.1.4
Adverse Effects. All formulations of interferon alfa produce the same spectrum of adverse effects. However, the incidence is higher with the long-acting preparations.
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Pharmacology foris higher Nursing Care, 7th Edition the incidence with the long-acting preparations. The most common side effect is a flu-like syndrome characterized by fever, fatigue, myalgia, headache, and chills. The incidence is about 50%. Fortunately, symptoms tend to diminish with continued therapy. Some symptoms (fever, headache, myalgia) can be reduced with acetaminophen. Interferon alfa frequently causes neuropsychiatric effects—especially depression. Suicidal ideation and suicide have occurred. The risk of depression is increased by large doses and prolonged treatment. The mechanism underlying depression is unknown. In many patients, depression responds to antidepressant drugs (eg, paroxetine). If depression persists, a reduction in dosage or cessation of treatment is indicated. Prolonged or high-dose therapy can cause fatigue, thyroid dysfunction, heart damage, and bone marrow suppression, manifesting as neutropenia and thrombocytopenia. Other adverse effects include alopecia and GI effects: nausea, diarrhea, anorexia, and vomiting. Injection-site reactions (inflammation, bruising, itching, irritation) are common, especially with long-acting formulations. Also, interferon may induce or exacerbate autoimmune diseases, such as thyroiditis and autoimmune chronic hepatitis. 93.3.1.2 93.3.1.2.1
Ribavirin (Oral) Actions and Therapeutic Use. Oral ribavirin [Rebetol, Copegus], combined with subQ peginterferon alfa, is the treatment of choice for chronic hepatitis C. When used alone against HCV, ribavirin is not effective: Treatment produces a transient normalization of serum ALT, but does not reduce serum HCV RNA. Combining ribavirin with interferon alfa greatly improves response rates. Ribavirin was originally approved for combined use with conventional interferon alfa. However, combined use with peginterferon alfa is more effective, and hence is now preferred. Ribavirin has a broad spectrum of antiviral activity, but its mechanism of action remains unclear. In addition to its use against HCV, ribavirin is available as an aerosol for treating children infected with respiratory syncytial virus. This use is discussed below under Ribavirin (Inhaled).
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Pharmacology (Inhaled). for Nursing Care, 7th Edition TABLE 92-4 Interferon Alfa Preparations: Dosages for Chronic Hepatitis Dosage
Generic Name
Trade Name
Chronic Hepatitis B
Chronic Hepatitis C
Conventional Alfa Interferons Interferon alfa-2a
Roferon-A (not used)
3 million IU subQ 3 times/wk
Interferon alfa-2b
Intron A
5 million IU/day subQ or 10 million IU subQ 3 times/wk
3 million IU subQ 3 times/wk
Interferon alfacon-1
Infergen
(not used)
9 mcg subQ 3 times/wk
180 mcg subQ once/wk
180 mcg subQ once/wk
Long-Acting Alfa Interferons Peginterferon alfa-2a
Pegasys
Peginterferon alfa-2b
PEG-Intron (not used)
Monotherapy: 1 mcg/kg subQ once/ wk With ribavirin: 1.5 mcg/kg subQ once/wk
IU = international units. 93.3.1.2.2
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Clinical Trials. The objective of hepatitis C therapy is to elicit a sustained virologic response (SVR), defined as loss of detectable serum HCV RNA that persists for at least 6 months after treatment. By this criterion, treatment with ribavirin plus conventional interferon alfa for 24 to 48 weeks produces a SVR in 30% to 40% of previously untreated patients. In trials using peginterferon alfa, response rates were even higher. For example, in one trial, the response rate was 68% with peginterferon alfa plus ribavirin versus only 51% with conventional interferon alfa plus ribavirin.
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Pharmacology ribavirin. for Nursing Care, 7th Edition 93.3.1.2.3
Adverse Effects. Although ribavirin and interferon alfa are generally well tolerated, both drugs can cause significant adverse effects. As noted, interferon alfa frequently causes flu-like symptoms, and occasionally severe depression. The principal concerns with ribavirin are hemolytic anemia and birth defects. Because anemia can develop rapidly, blood counts should be made before treatment, 2 weeks and 4 weeks into treatment, and periodically thereafter. In laboratory animals, ribavirin is teratogenic and embryolethal when taken by females, and causes sperm abnormalities when taken by males. Accordingly, ribavirin is classified in Food and Drug Administration (FDA) Pregnancy Risk Category X, and therefore is contraindicated for use during pregnancy. Before initiating treatment, pregnancy must be ruled out. During treatment, pregnancy must be avoided—both by females taking ribavirin, and by female partners of men taking ribavirin. To avoid pregnancy, couples should use two reliable forms of birth control during treatment and for 6 months after.
93.3.1.2.4
Preparations, Dosage, and Administration. For treatment of chronic hepatitis C, ribavirin must be combined with interferon alfa; the drug is not effective when used alone. Ribavirin is approved specifically for combined use with interferon alfa-2b; however, combined use with a pegylated interferon is now preferred. Duration of therapy is prolonged, typically 24 to 48 weeks.
93.3.1.2.4.1
Preparations. Ribavirin is available (1) in 200-mg capsules and a 40-mg/mL oral solution, both marketed as Rebetol; (2) in tablets (200, 400, 500, and 600 mg), marketed as Copegus; and (3) in a kit, marketed as Rebetron, that contains ribavirin capsules plus interferon alfa-2b [Intron A].
93.3.1.2.4.2
Dosage for Ribavirin Capsules and Oral Solution (Rebetol). Rebetol is administered PO, and dosage depends on the patient's weight. For patients weighing 75 kg or less, the dosage is 1000 mg/day (400 mg in the morning and 600 mg in the evening). For patients weighing more than 75 kg, the dosage is 1200 mg/day (600 mg in the morning and 600 mg in the evening).
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Pharmacology for Nursing 7th Edition in the morning and 600 mgCare, in the evening). 93.3.1.2.4.3
Dosage for Ribavirin Tablets (Copegus). Copegus is administered PO with food. Dosage depends on (1) patient weight and (2) the strain (genotype) of the hepatitis C virus. • For Genotype 1 or 4. For patients weighing 75 kg or less, the dosage is 1000 mg/day (400 mg in the morning and 600 mg in the evening). For patients weighing more than 75 kg, the dosage is 1200 mg/day (600 mg in the morning and 600 mg in the evening). • For Genotype 2 or 3. For all patients, regardless of weight, the dosage is 800 mg/day (400 mg in the morning and 400 mg in the evening).
93.3.1.2.4.4
Dosage for Interferon Alfa Used with Ribavirin. Dosage of interferon alfa depends on the specific preparation employed. For example, the dosage for peginterferon alfa-2a [Pegasys] is 180 mcg subQ once a week, and the dosage for peginterferon alfa-2b [PEG-Intron] is 1.5 mcg/kg subQ once a week.
93.3.2
Hepatitis B In the United States, about 1.25 million people have chronic hepatitis B. Transmission is primarily through exchange of blood or semen. Between 45% and 60% of exposed adults develop acute hepatitis. Of these, about 11,000 require hospitalization for deep fatigue, muscle pain, and jaundice. In adults, acute infection usually leads to viral clearance by the immune system. As a result, only 3% to 5% of infected adults develop chronic infection. However, when chronic infection does develop, it can lead to cirrhosis, hepatic failure, hepatocellular carcinoma, and death. The best strategy against HBV is prevention: All children should receive HBV vaccine before entering school (see Chapter 67). Six drugs are used for chronic HBV. Two are alfa interferons—interferon alfa-2b [Intron A] and peginterferon alfa-2a [PEG-Intron]—and four are nucleoside analogs—lamivudine [Epivir HBV], adefovir [Hepsera], entecavir [Baraclude], and telbivudine [Tyzeka]. The alfa interferons are administered subQ; the nucleoside analogs are administered by mouth. The interferons are more effective than the nucleoside analogs, but are also more expensive and less well tolerated. Development of resistance is common with lamivudine and telbivudine, and relatively rare with the other four drugs. Two agents—lamivudine and adefovir—are active against HIV, and hence may promote emergence of resistant HIV in people co-infected with that virus.
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Pharmacology for Nursing Care, Edition may promote emergence of resistant HIV7th in people co-infected with that virus. With all six drugs—and especially the nucleoside analogs—the rate of relapse following cessation of treatment is high. As a result, treatment is usually prolonged, thereby amplifying concerns about adverse effects and drug costs. To decrease unnecessary drug exposure and expense, current guidelines recommend treatment only for patients at highest risk, indicated by elevated aminotransferase levels, or histologic evidence of moderate or severe hepatic inflammation or advanced fibrosis. We do not yet know if treatment should continue lifelong, or if clinical benefit can be maintained if treatment is stopped after several years. Given that relapse is common, patients should be followed closely if these drugs are withdrawn. Comparisons between the six drugs are summarized in Table 92-5. 93.3.2.1
Interferon Alfa Only two forms of interferon alfa—interferon alfa-2b [Intron A] and peginterferon alfa-2b [PEG-Intron]—are approved for chronic hepatitis B. Both preparations are given by subQ injection (see Table 92-4). In clinical trials, treatment for 4 months reduced serum ALT and improved liver histology in about 40% of recipients. Remissions have been prolonged in some patients, and resistance has not been reported. Unfortunately, although alfa interferons are effective, they are also expensive, and adverse effects—flu-like syndrome, depression, fatigue, and leukopenia—are common. The basic pharmacology of interferon alfa and its use in hepatitis C are discussed above.
93.3.2.2
Lamivudine Lamivudine [Epivir HBV] is a nucleoside analog approved for infections caused by HIV or HBV. The drug was originally developed to treat HIV infection, and was later proved effective against HBV. Formulations and dosages for treating HIV and HBV infections differ, and hence must not be thought of as interchangeable. The basic pharmacology of lamivudine is discussed in Chapter 93. Discussion here is limited to treatment of HBV. Lamivudine suppresses HBV replication by inhibiting viral DNA synthesis. The process begins with intracellular conversion of lamivudine to lamivudine triphosphate, the drug's active form. As the triphosphate, lamivudine undergoes incorporation into the growing DNA chain, and thereby causes premature chain termination.
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Pharmacology for Nursing 7th Edition thereby causes premature chainCare, termination. TABLE 92-5 Drugs for Chronic Hepatitis B Relapse
Route Rate*
Drug
Adverse Effects
Active Resistance Against Rate HIV
Alfa Interferons Interferon alfa-2b [Intron A]
SubQ
Moderate Flu-like symptoms, fatigue, neutropenia, depression
Zero
No
Peginterferon alfa-2a [PEGIntron]
SubQ
Moderate Same as interferon alfa-2b
Zero
No
PO
High
Well tolerated; lactic acidosis and hepatomegaly are possible
15–30% in Yes yr 1; 70% by yr 5
Adefovir [Hepsera] PO
High
Nephrotoxic at high doses; lactic acidosis and hepatomegaly are possible
Zero in yr Yes 1; 29% by yr 5
Entecavir [Baraclude]
PO
High
Well tolerated; lactic acidosis and hepatomegaly are possible
Zero in yr No 1; ≤1% by yr 3
Telbivudine [Tyzeka]
PO
Moderate Myopathy, lactic acidosis, hepatomegaly are possible
Nucleoside Analogs Lamivudine [Epivir HBV]
*
6–12% in yr No 1; 9– 22% by yr 2
Following discontinuation of treatment.
Lamivudine offers at least some benefit to most patients. In one trial, 52 weeks of daily lamivudine normalized serum ALT in 72% of patients, and reduced liver inflammation and fibrosis in 56%. Unfortunately, the rate of relapse is high when treatment stops. Also, emergence of resistance is a concern: Resistant isolates appear in 24% of patients after 1 year of continuous treatment, 42% after 2 years, 53% after 3 years, and 70% after 4 years. At the dosage employed to treat hepatitis B, side effects are minimal. In clinical trials, the incidence of most side effects was no greater than with placebo. Lactic acidosis, pancreatitis, and severe hepatomegaly are rare but dangerous complications. If one of these conditions develops, lamivudine should be discontinued.
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Pharmacology for Nursing 7th Edition develops, lamivudine should beCare, discontinued. For treatment of HBV, lamivudine [Epivir HBV] is formulated in 100-mg tablets and a 5-mg/ mL oral solution. The dosage is 100 mg once a day (compared with 150 mg twice a day for HIV). Since lamivudine is eliminated primarily by renal excretion, dosage must be reduced in patients with renal impairment. 93.3.2.3 93.3.2.3.1
Adefovir Therapeutic Use. Adefovir [Hepsera] is indicated for oral therapy of chronic hepatitis B. The drug was originally developed to fight HIV infection, but was not approved owing to a high incidence of nephrotoxicity at the doses required. The doses used for hepatitis B are much lower, and hence the risk of renal injury is lower too. Approval for chronic hepatitis B was based on two randomized, placebo-controlled trials, both lasting 48 weeks. In one trial, significant improvement was seen in 53% of those taking adefovir, compared with only 25% of those taking placebo. Results of the second trial were similar: Improvement was seen in 64% of those taking adefovir, compared with 35% of those taking placebo.
93.3.2.3.2
Mechanism of Action. Adefovir is a nucleoside analog with a mechanism similar to that of acyclovir. Both drugs inhibit viral DNA synthesis, and both must be converted to their active form within the body. Activation of adefovir is mediated by cellular kinases—enzymes that convert the drug into adefovir diphosphate, a compound with two actions: (1) it directly inhibits viral DNA polymerase (by competing with deoxyadenosine triphosphate, a natural substrate for the enzyme); and (2) it undergoes incorporation into the growing strand of viral DNA, and thereby causes premature strand termination. Host cells are spared because adefovir diphosphate is a poor inhibitor of human DNA polymerase.
93.3.2.3.3
Pharmacokinetics. Bioavailability is about 60% following oral administration, both in the presence and absence of food. Plasma levels peak about 2 hours after dosing. Elimination is renal, by a combination of glomerular filtration and active tubular secretion. In patients with normal kidney function, the half-life is 7.5 hours. In patients with renal impairment, the half-life is significantly increased.
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Pharmacology for Nursing Care, 7th Edition significantly increased. 93.3.2.3.4
Adverse Effects. Nephrotoxicity is the principal concern. Increased serum creatinine, a sign of kidney damage, was seen in 4% of patients who received 48 weeks of therapy, and in 9% of patients who received 96 weeks of therapy. To reduce risk, kidney function should be assessed at baseline and periodically thereafter, paying special attention to patients at high risk (ie, patients with pre-existing renal impairment and those taking nephrotoxic drugs [eg, cyclosporine, tacrolimus, aminoglycosides, vancomycin, aspirin and other nonsteroidal anti-inflammatory drugs]). When adefovir is discontinued, patients may experience acute exacerbation of hepatitis B. In clinical trials, serum ALT levels rose dramatically in 25% of patients when treatment was stopped. Hepatic function should be assessed periodically following adefovir withdrawal.
93.3.2.3.5
Drug Interactions. Drugs that are eliminated by active tubular secretion can compete with adefovir for renal excretion. As a result, if one of these agents were to be combined with adefovir, excretion of adefovir, the other drug, or both could be decreased, causing their plasma levels to rise.
93.3.2.3.6
Precautions. Because adefovir is related to the nucleoside analogs used against HIV, there is a concern that, if the patient were infected with HIV, giving adefovir in the low doses employed against HBV could allow emergence of HIV viruses resistant to nucleoside analogs. Accordingly, HIV infection should be ruled out before adefovir is used. The nucleoside analogs used to treat HIV infection can cause lactic acidosis and severe hepatomegaly. Hence, there is concern that adefovir can cause these effects too. If the patient develops clinical or laboratory findings that suggest lactic acidosis or pronounced hepatotoxicity, adefovir should be withdrawn.
93.3.2.3.7
Preparations, Dosage, and Administration. Adefovir [Hepsera] is supplied in 10-mg tablets. For patients with good kidney function, the dosage is 10 mg once a day, taken with or without food. For patients with impaired kidney function, as indicated by reduced creatinine clearance (CrCl), the dosing interval should be increased. Adjusted dosages are as follows:
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Pharmacology for Nursing 7th Edition increased. Adjusted dosages Care, are as follows: • CrCl 20 to 49 mL/min—10 mg every 48 hours • CrCl below 20 mL/min (not requiring dialysis)—10 mg every 72 hours • Patients on hemodialysis—10 mg once a week, taken after dialysis 93.3.2.4 93.3.2.4.1
1079 1080
Entecavir Therapeutic Use. Entecavir [Baraclude], approved in 2005, is indicated for oral therapy of chronic hepatitis B. Candidates for treatment should have evidence of active viral replication along with persistently elevated serum aminotransferases or histologic evidence of active disease. In clinical trials, entecavir was more effective than lamivudine. In patients with lamivudineresistant HBV, responses to entecavir were somewhat reduced, but were still better than responses to lamivudine. There is no published information comparing entecavir with adefovir.
93.3.2.4.2
Mechanism of Action. Entecavir is a nucleoside analog that undergoes conversion to entecavir triphosphate (its active form) within the body. As entecavir triphosphate, the drug inhibits HBV DNA polymerase, and thereby prevents viral replication. Entecavir triphosphate is a weak inhibitor of human DNA polymerases, both nuclear and mitochondrial, and hence host cells are spared. In contrast to lamivudine and adefovir, entecavir does not impede HIV replication, and hence should not promote emergence of resistant HIV.
93.3.2.4.3
Pharmacokinetics. Entecavir is available in tablets and solution for oral administration. Bioavailability with both formulations is the same. Plasma levels peak 0.5 to 1.5 hours after dosing. Entecavir undergoes extensive distribution to body tissues, with little binding to plasma proteins. Metabolism is minimal. Entecavir is neither a substrate for, inhibitor of, nor inducer of cytochrome P450 enzymes. Excretion is via the urine, primarily as unchanged drug. The half-life is about 5.5 days.
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Pharmacology for Nursing half-life is about 5.5 days. Care, 7th Edition 93.3.2.4.4
Adverse Effects and Precautions. Entecavir is very well tolerated. The most common adverse effects are dizziness, headache, fatigue, and nausea—and even these occur in less than 5% of patients. Patients treated with other nucleoside analogs have developed lactic acidosis and severe hepatomegaly, and hence there is concern that entecavir may cause these effects too. If the patient develops clinical or laboratory findings that suggest lactic acidosis or pronounced hepatotoxicity, entecavir should be withdrawn. Acute severe exacerbations of hepatitis B have developed following discontinuation of entecavir and other drugs for hepatitis B. Accordingly, if entecavir is discontinued, liver function should be monitored closely for several months.
93.3.2.4.5
Preparations, Dosage, and Administration. Entecavir [Baraclude] is available in tablets (0.5 and 1 mg) and an oral solution (0.05 mg/ mL). Dosing is done once a day, either 2 hours before eating or 2 hours after. Dosage depends on renal function (as indicated by CrCl) and on the infection's sensitivity to lamivudine. If the infection is lamivudine sensitive, daily dosages are as follows: • CrCl 50 mL/min or higher—0.5 mg • CrCl 30 to 49 mL/min—0.25 mg • CrCl below 30 mL/min (not requiring dialysis)—0.15 mg • Patients on hemodialysis—0.05 mg taken after dialysis If the infection is lamivudine resistant, daily dosages are as follows: • CrCl 50 mL/min or higher—1 mg • CrCl 30 to 49 mL/min—0.5 mg • CrCl below 30 mL/min (not requiring dialysis)—0.3 mg • Patients on hemodialysis—0.05 mg taken after dialysis
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Pharmacology foronNursing Care, 7th Edition • Patients hemodialysis—0.05 mg taken after dialysis 93.3.2.5 93.3.2.5.1
Telbivudine Therapeutic Use. Telbivudine [Tyzeka], approved in 2006, is a nucleoside analog indicated for chronic HBV infection in adults and adolescents 16 years of age or older. Patients must have evidence of active HBV replication, plus either persistent elevations in serum aminotransferases (ALT or AST) or histologic evidence of active liver disease. In nucleoside-naïve patients, telbivudine is at least as effective as lamivudine (as indicated by suppression of HBV DNA and either normalization of ALT or loss of serum HBeAg, a hepatitis B antigen). At this time, we don't know if telbivudine will improve long-term outcomes (eg, less hepatocellular carcinoma or decompensated cirrhosis). As with lamivudine, resistance can be significant: After 2 years of treatment with telbivudine, resistance develops in 9% to 22% of patients. Patients resistant to telbivudine show cross-resistance to lamivudine. In contrast to lamivudine and adefovir, telbivudine is not active against HIV.
93.3.2.5.2
Mechanism of Action. Telbivudine is a thymidine nucleoside analog that undergoes intracellular conversion to its active form: telbivudine triphosphate. As the triphosphate, it inhibits HBV replication in two ways. First, it directly inhibits HBV DNA polymerase (by competing with the natural substrate, thymidine triphosphate). Second, it undergoes incorporation in the growing viral DNA chain, and thereby causes chain termination.
93.3.2.5.3
Adverse Effects. The most common adverse effects are fever, fatigue/malaise, arthralgia, myalgia, cough, headache, and GI symptoms (eg, abdominal pain, nausea, vomiting, diarrhea, dyspepsia). Some patients have developed symptomatic myopathy, characterized by persistent muscle pain, tenderness, or weakness. Lactic acidosis and severe hepatomegaly have occurred with other nucleoside analogs, but have not been reported with telbivudine. As with other drugs for hepatitis B, severe exacerbations can occur when treatment is discontinued.
93.3.2.5.4
Drug Interactions. No significant interactions have been reported. However, since telbivudine is eliminated primarily by renal excretion, drugs that impair renal function may raise its level. Also, other drugs that cause muscle injury may increase risk in patients taking telbivudine. Telbivudine is neither a substrate for nor inhibitor of CYP isozymes, and hence will not be affected by
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Pharmacology for Nursing Care, 7th Edition drugs that cause muscle injury may increase risk in patients taking telbivudine. Telbivudine is neither a substrate for nor inhibitor of CYP isozymes, and hence will not be affected by drugs that inhibit or induce CYP isozymes, nor will it affect drugs that are metabolized by these isozymes. 93.3.2.5.5
Preparations, Dosage, and Administration. Telbivudine [Tyzeka] is supplied in 600-mg tablets. The usual dosage is 600 mg once a day, taken with or without food. For patients with renal impairment, as indicated by reduced CrCl, the dosing interval should be increased. For patients with hepatic impairment, no dosage adjustment is required. Dosages are as follows: • CrCl 50 mL/min or higher—600 mg once daily • CrCl 30 to 49 mL/min—600 mg once every 48 hours • CrCl below 30 mL/min (not requiring dialysis)—600 mg once every 72 hours • Patients on hemodialysis—600 mg once every 96 hours, taken after hemodialysis
93.4
DRUGS FOR INFLUENZA Influenza is a serious respiratory tract infection that constitutes a major cause of morbidity and mortality worldwide. During the 1918–1919 global pandemic, more than 500,000 people died in the United States and up to 50 million people died worldwide. In the United States today, complications of influenza (eg, bronchitis, pneumonia) cause up to 300,000 hospitalizations and 36,000 deaths each year. The cost of influenza is huge: Direct and indirect expenses total between $3 billion and $5 billion annually. Influenza is caused by influenza viruses, of which there are two major types: influenza A and influenza B. Type A influenza viruses cause far more infections than type B influenza viruses (about 96% vs. 4%). The influenza viruses are highly variable and undergo constant evolution. Because of this ongoing evolution, the World Health Organization (WHO) has established a global network of laboratories to monitor the emergence and spread of new variants. Influenza is a highly contagious infection spread via aerosolized droplets produced by coughing or sneezing. The virus enters the body through mucous membranes of the nose, mouth, or eyes. Viral replication takes place in the respiratory tract. Symptoms begin 2 to 4 days after exposure, and last 5 to 6 days. Influenza is characterized by fever, cough, chills, sore throat, headache, and myalgia (muscle pain). For typical patients, infection results in 5 to 6 days of restricted activity, 3 to 4 days of bed disability, and 3 days of absence from work or school. In the United States, the influenza
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Pharmacology Nursing Edition (muscle pain). Forfor typical patients,Care, infection7th results in 5 to 6 days of restricted activity, 3 to 4 days of bed disability, and 3 days of absence from work or school. In the United States, the influenza “season” begins in November and extends through March or April. Influenza is managed by vaccination and with drugs. Vaccination is the primary management strategy; drug therapy is secondary. The drugs for influenza fall into two groups: adamantanes, which have been used for decades, and neuraminidase inhibitors, which are relatively new. The adamantanes are active against influenza A only, whereas the neuraminidase inhibitors are active against influenza A and influenza B.
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TABLE 92-6 Influenza Vaccines Vaccine
Route
1080
Formulation
Approved Age Mercury/Dose* Group
Inactivated Influenza Vaccines Afluria
IM
0.5-mL syringe
None
Fluarix
IM
0.5-mL syringe
Under 1.25 mcg 18 yr and older
FluLaval
IM
5-mL multidose vial
25 mcg/dose
18 yr and older
Fluvirin
IM
0.5-mL syringe
Under 1 mcg
4 yr and older
5-mL multidose vial
24.5 mcg/0.5mL dose
4 yr and older
0.25-mL syringe
None
6–35 months
0.5-mL syringe
None
3 yr and older
5-mL multidose vial
24 mcg/0.5-mL dose
6 months and older
Single-dose sprayer†
None
2–49 yr
Fluzone
IM
18 yr and older
Live, Attenuated Influenza Vaccine FluMist
93.4.1
Nasal
*
Mercury, in the form of thimerosal, is used as a preservative in some vaccines.
†
Each syringe-like sprayer contains one 0.5-mL dose, given as 0.25 mL in each nostril.
Influenza Vaccines Annual vaccination is the best protection against influenza. Because influenza viruses are constantly evolving, influenza vaccines must continuously change too. Each year, manufacturers produce a new vaccine directed against the three strains of influenza virus deemed most likely to cause disease during the upcoming flu season. Identification of the three strains is done jointly by the Centers for Disease Control and Prevention (CDC), the FDA, and the WHO.
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Pharmacology Nursing Care, 7th Edition the Centers for for Disease Control and Prevention (CDC), the FDA, and the WHO. 93.4.1.1
Types of Influenza Vaccines. Two basic kinds of flu vaccine are available: (1) inactivated influenza vaccine and (2) live, attenuated influenza vaccine, also known as LAIV. The inactivated vaccine, which has been available for many years, is administered by IM injection. The live, attenuated vaccine, approved in 2003, is administered by intranasal spray. Both kinds of vaccine are directed at the same three influenza strains, and both are reformulated annually. At this time, there are six influenza vaccines on the market (Table 92-6). Five of these vaccines —Afluria, Fluarix, FluLaval, Fluvirin, and Fluzone—are given IM, and one—FluMist—is given intranasally. As indicated in Table 92-6, some of the IM products contain trace amounts of mercury. The table also shows that the six vaccines differ regarding the age groups for which they are approved. Of importance, the intranasal vaccine is approved only for people 2 to 49 years old, and hence cannot be used by two large groups considered at high risk, namely, the very young and the elderly.
93.4.1.2
Efficacy. Protection begins 1 to 2 weeks after vaccination and generally lasts 6 months or longer. However, among elderly vaccinees, protection may be lost in 4 months or even less. Efficacy of vaccination depends on the age and health status of the vaccinee, and on how well the vaccine matches the strains of influenza virus in circulation that year. Efficacy of the inactivated vaccine and the LAIV is about equal.
93.4.1.3
Adverse Effects. Adverse effects differ for the inactivated vaccine versus the LAIV. However, with both vaccines, significant adverse effects are rare.
93.4.1.3.1
Inactivated Influenza Vaccine Adverse effects are uncommon, except for possible soreness at the injection site. People who have not been vaccinated previously may experience fever, myalgia, and malaise lasting 1 or 2 days. Influenza vaccination may carry a very small risk of Guillain-Barré syndrome (GBS), a severe, paralytic illness. In 1976, swine flu vaccine was associated with GBS. However, there has been no clear link between GBS and influenza vaccines used since then. If there is a risk, it is very small, estimated at 1 to 2 cases per million vaccinees—much smaller than
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Pharmacology fornoNursing Care, GBS 7th and Edition there has been clear link between influenza vaccines used since then. If there is a risk, it is very small, estimated at 1 to 2 cases per million vaccinees—much smaller than the risk posed by severe influenza. 93.4.1.3.2
Live, Attenuated Influenza Vaccine LAIV has been given to millions of people, and reports of serious adverse events have been very rare. As of August 16, 2005, the Vaccine Adverse Event Reporting System had received 460 reports regarding LAIV. Among these were seven cases of possible anaphylaxis, two cases of GBS, and one case of Bell's palsy. More commonly, vaccinees experience mild, transient effects. Among children 5 to 17 years old, the most common reactions have been runny nose, nasal congestion, cough, headache, vomiting, muscle aches, and fever. Among adults 18 to 49 years old, the most common reactions have been runny nose, headache, sore throat, and cough.
93.4.1.4
Precautions and Contraindications. People with acute febrile illness should defer vaccination until symptoms abate. Minor illnesses (eg, common cold), with or without fever, do not preclude vaccination. Influenza vaccines are contraindicated for persons with hypersensitivity to eggs. Why? Because the vaccines are produced from viruses grown in eggs, and hence may contain trace amounts of egg proteins. Individuals suspected of egg hypersensitivity should undergo a skin test before receiving the vaccine. If the test is positive, the vaccine should be withheld.
93.4.1.5
Who Should Be Vaccinated? As of the 2008–2009 flu season, the Advisory Committee on Immunization Practices (ACIP) recommends annual vaccination for: 1. All children 6 months and older and all older adults • All children ages 6 months to 18 years of age • All people age 50 and older 2. All people at high risk of complications from the flu • Women who will be pregnant during the flu season • All residents of nursing homes and other facilities where persons with chronic medical conditions live
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Pharmacology medical for Nursing conditionsCare, live 7th Edition • Children 6 months to 18 years old receiving long-term therapy with aspirin (because they are at risk of developing Reye's syndrome if they get influenza) • Anyone with a weakened immune system due to HIV infection, immunosuppressant therapy, or other causes
1081
• Anyone with certain muscle or nerve disorders, such as seizure disorders or cerebral palsy, that can lead to breathing or swallowing problems
1082
• People who have long-term health problems, including asthma; heart, kidney, or lung disease; anemia and other blood disorders; and diabetes and other metabolic diseases 3. People who can transmit flu to others at high risk for complications. This includes • Healthcare workers • Household members and other close contacts of infants or children up to 5 years of age • Household members and other close contacts of people age 50 and older, and people with medical conditions that put them at higher risk for severe complications from influenza. 4. Annual vaccination is also recommended for • People who provide essential community services • People living in dormitories or other crowded conditions (to prevent outbreaks of influenza) • People at high risk of influenza complication who travel to the Southern hemisphere between April and September, or to the tropics or in organized tourist groups at any time 93.4.1.6
Who Should NOT Be Vaccinated? Some people should not be vaccinated without a physician's approval. In this group are • People who have a severe allergy to chicken eggs • People who have had a severe reaction to influenza vaccination in the past
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Pharmacology Care,reaction 7th Edition • People for who Nursing have had a severe to influenza vaccination in the past • People who have experienced GBS • People who have a moderate or severe illness with a fever (these individuals should wait until symptoms abate) 93.4.1.7
When Should Influenza Vaccine Be Administered? The best time is October or November. However, the vaccine should be offered until the end of influenza season in April.
93.4.1.8
Dosage and Administration: Inactivated Influenza Vaccine. Inactivated influenza vaccines are available under five trade names: Afluria, Fluarix, FluLaval, Fluvirin, and Fluzone. Afluria, Fluarix, and FluLaval are approved for people ages 18 years and older, Fluvirin for people 4 years and older, and Fluzone for people 6 months and older. Because the influenza virus evolves rapidly, all five products are reformulated annually. Accordingly, to maintain protection, revaccination is required each year. Vaccination is done by IM injection into the anterolateral aspect of the thigh (for infants and young children) or into the deltoid muscle (for older children, adolescents, and adults). Dosage is a function of age and vaccination history. Most vaccinees require just 1 injection a year. However, children under 9 years old who have not been vaccinated before require 2 injections, administered at least 4 weeks apart. The dosage size is 0.25 mL for vaccinees ages 6 months through 35 months, and 0.5 mL for vaccinees over the age of 3 years.
93.4.1.9
Dosage and Administration: Live, Attenuated Influenza Vaccine. LAIV [FluMist] is supplied in a single-dose sprayer for intranasal administration. Vaccinees must be 2 to 49 years old. FluMist is unstable at room temperature, and hence must be stored frozen. As with the inactivated flu vaccine, dosing with LAIV is a function of age and vaccination history. Most vaccinees get just one dose a year. However, children 5 through 8 years old who have not been vaccinated before require two doses, administered 46 to 74 days apart. For all vaccinees, the size of each dose is the same: 0.5 mL (administered as a 0.25-mL spray in each nostril).
93.4.1.10
Avian Influenza. The FDA has approved an inactivated vaccine against avian H5N1 influenza. It is not available commercially in the United States, but is being included in the CDC's Strategic National Stockpile in case H5N1 avian influenza strains become able to spread efficiently between
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Pharmacology Nursing Care, 7th Edition commerciallyfor in the United States, but is being included in the CDC's Strategic National Stockpile in case H5N1 avian influenza strains become able to spread efficiently between humans. The vaccine is given as 2 IM injections, 1 month apart. 93.4.2
Neuraminidase Inhibitors The neuraminidase inhibitors, introduced in 1999, are active against influenza A and influenza B. In contrast, the adamantanes are active against influenza A only (see below). Neuraminidase inhibitors cost more than adamantanes, but are more effective and better tolerated, and pose a lower risk of resistance. As with the adamantanes, these drugs should not be viewed as an alternative to vaccination. At this time, two neuraminidase inhibitors are available: oseltamivir and zanamivir.
93.4.2.1 93.4.2.1.1
Oseltamivir Therapeutic Effects. Oseltamivir [Tamiflu] is an oral drug approved for prevention and treatment of influenza. When used for treatment, dosing must begin early—no later than 2 days after symptom onset, and preferably much sooner. Why? Because benefits decline greatly when treatment is delayed: When treatment is started within 12 hours of symptom onset, symptom duration is reduced by more than 3 days; when started within 24 hours, symptom duration is reduced by less than 2 days; and when started within 36 hours, symptom duration is reduced by only 29 hours. In addition to reducing symptom duration, oseltamivir can reduce symptom severity and the incidence of complications (sinusitis, bronchitis). Unfortunately, treatment is expensive (about $60 for a 5-day course). Furthermore, in the real world, patients may be unable to obtain and fill a prescription soon enough for the drug to be of significant benefit. Oseltamivir has been studied for its ability to prevent influenza in residents of nursing homes, in family members of someone with the flu, and in the community at large. When used in nursing homes, most of whose residents had been vaccinated, oseltamivir decreased the incidence of influenza from 4.4% down to 0.4%. When used to protect family members, the drug decreased the incidence of influenza from 12% down to 1%. And when given to unvaccinated individuals during a community outbreak of influenza, it reduced the incidence of infection from 4.8% down to 1.2%. Oseltamivir is active against most isolates of influenza A type H5N1, the cause of avian flu, as well as the variants of type H1N1 that cause “swine flu.”
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Pharmacology forvariants Nursing 7thcause Edition as well as the of typeCare, H1N1 that “swine flu.” 93.4.2.1.2
Mechanism of Action. Antiviral effects derive from inhibiting neuraminidase, a viral enzyme required for replication. As a result of neuraminidase inhibition, newly formed viral particles are unable to bud off from the cytoplasmic membrane of infected host cells. Hence, viral spread is stopped. Oseltamivir is active against all strains of influenza A and influenza B. Emergence of resistance over the course of treatment is rare.
93.4.2.1.3
Pharmacokinetics. Oseltamivir is well absorbed following oral administration. In the liver, the drug undergoes conversion to oseltamivir carboxylate, its active form. Bioavailability of the carboxylate is 80%. Plasma levels of active drug peak 2.5 to 6 hours after dosing. The plasma half-life is 6 to 10 hours. The drug is eliminated in the urine, primarily as the carboxylate form.
93.4.2.1.4
Adverse Effects and Interactions. Oseltamivir is generally well tolerated. The most common side effects are nausea (9.9%) and vomiting (9.4%). Nausea can be reduced by giving oseltamivir with food. No interactions with other drugs have been reported.
93.4.2.1.5
Preparations, Dosage, and Administration. Oseltamivir [Tamiflu] is available in tablets (30, 45, and 75 mg) and as a powder to be reconstituted to a 12-mg/mL oral suspension. The drug may be administered without regard to meals, although taking it with food can reduce nausea.
1082 1083
For treatment of influenza, the dosage for patients age 13 years and older is 75 mg twice daily for 5 days, beginning no later than 2 days after the onset of symptoms. Dosage should be reduced to 75 mg once daily in patients with significant renal impairment. The dosage for children 1 year old through 12 years old is based on body weight as follows: under 15 kg, 30 mg twice daily; 15 to 23 kg, 45 mg twice daily; 23 to 40 kg, 60 mg twice daily; and over 40 kg, 75 mg twice daily. For prevention of influenza in patients age 13 years and older, the dosage is 75 mg once a day—one-half the dosage used for treatment. (Oseltamivir is not approved for prophylaxis in patients younger than 13.) Candidates for prophylactic therapy include family members of someone with flu and residents of nursing homes. To protect family members, dosing should begin within 48 hours of exposure and should continue for 7 days. To protect residents of nursing homes or high-risk members of the community at large, dosing can be done
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Pharmacology for Care,and7th Edition begin within 48 Nursing hours of exposure should continue for 7 days. To protect residents of nursing homes or high-risk members of the community at large, dosing can be done continuously for up to 42 days. 93.4.2.2 93.4.2.2.1
Zanamivir Actions and Uses. Zanamivir [Relenza], administered by oral inhalation, is approved for treatment of acute uncomplicated influenza in patients at least 7 years old, and for prophylaxis of influenza in people at least 5 years old. As with oseltamivir, benefits derive from inhibiting viral neuraminidase, an enzyme required for viral replication. Like oseltamivir, zanamivir is well tolerated, although benefits appear to be limited. In animal studies, zanamivir has been effective against some avian strains of influenza. Although human data are lacking, the drug should be effective for prophylaxis and treatment of H5N1 disease.
93.4.2.2.2
Clinical Trials. Zanamivir is moderately effective at shortening the duration of influenza symptoms. In Phase III clinical trials, improvement in symptoms was defined as (1) the absence of fever and (2) mild or no headache, myalgia, cough, or sore throat. In patients taking zanamivir (10 mg twice daily for 5 days, beginning no later than 36 hours after the onset of symptoms), the average duration of symptoms was 5 days, compared with 6.5 days for patients taking placebo. In addition, zanamivir reduced the incidence of complications (sinusitis, bronchitis) requiring antibacterial drugs. In a 4-week trial conducted during the influenza season, once-daily treatment with 10 mg of inhaled zanamivir was 84% effective at preventing febrile illness.
93.4.2.2.3
Pharmacokinetics. Zanamivir is formulated as a dry powder for oral inhalation. The drug is poorly absorbed from the GI tract, and hence cannot be administered by mouth. Most (70% to 90%) of an inhaled dose is deposited in the oropharynx and throat. About 10% to 20% reaches the tracheobronchial tree and lungs. Between 4% and 17% of each dose undergoes absorption into the systemic circulation. Zanamivir has a plasma half-life of 2.5 to 5 hours and is eliminated unchanged in the urine. No metabolites have been detected.
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Pharmacology Nursing 7th Edition eliminated for unchanged in the Care, urine. No metabolites have been detected. 93.4.2.2.4
Adverse Effects and Interactions. In patients with healthy lung function, adverse effects are rare. Because zanamivir is administered as an inhaled powder, patients may experience cough or throat irritation. Zanamivir appears devoid of drug interactions. In patients with pre-existing lung disorders (eg, asthma, chronic obstructive pulmonary disease), zanamivir may cause severe bronchospasm and respiratory decline. Some patients have required immediate treatment or hospitalization. Deaths have occurred—however, given the impact of flu itself on lung function, it's not clear that zanamivir was the cause. Nonetheless, owing to the potential risk, zanamivir is not generally recommended for patients with underlying airway disease.
93.4.2.2.5
Preparations, Dosage, and Administration. Zanamivir [Relenza] is supplied in blister packs that contain 5 mg of powdered drug. Administration is by oral inhalation using the Diskhaler provided by the manufacturer. The dosage is 10 mg (two 5-mg inhalations) twice daily for 5 days. Each 10-mg dose should be separated by 12 hours. However, on the first day of treatment, less separation (as little as 2 hours) is permitted if the first dose cannot be taken early enough in the day to allow 12 hours between doses. Patients who are using an inhaled bronchodilator (eg, albuterol) should administer the bronchodilator before inhaling zanamivir.
93.4.3
Adamantanes The adamantanes—amantadine and rimantadine—were the first influenza drugs available. These agents have moderate activity against influenza A, and none against influenza B. With amantadine, adverse CNS effects are common, and with both drugs, resistance can develop rapidly. In the United States, resistance among influenza A isolates has risen sharply, from just 2% in 2003 to 91% by 2005, causing the CDC to recommend against using these drugs for the 2005–2006 flu season. To date, resistance to neuraminidase inhibitors remains low.
93.4.3.1
Amantadine Amantadine [Symmetrel] is employed for prophylaxis and treatment of infections caused by type A influenza virus. As discussed in Chapter 21, the drug is also used to treat Parkinson's disease.
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Pharmacology for Nursing Care, 7th Edition disease. 93.4.3.1.1
Mechanism of Antiviral Action. Just how amantadine suppresses viral growth is not completely understood. The drug can prevent penetration of influenza A virus into host cells and can inhibit viral uncoating. In addition, it inhibits an early step in replication of viral components.
93.4.3.1.2
Therapeutic Use. Antiviral applications of amantadine are limited to prophylaxis and treatment of respiratory tract infections caused by type A influenza virus strains. The drug is not active against type B influenza. Prophylaxis should be instituted only in the presence of a documented influenza A epidemic. Candidates for prophylaxis include (1) individuals at high risk of developing complications from influenza (eg, elderly patients and those with cardiopulmonary disease) and (2) healthcare workers and family members who have extensive contact with patients at risk. Prophylaxis is continued until the epidemic abates (usually in 5 to 6 weeks). It should be noted that immunization against influenza A is preferred to prophylaxis with amantadine. Because amantadine does not impede the immune response to influenza A vaccine, individuals at risk can be vaccinated while receiving amantadine for prophylaxis. Amantadine can be discontinued 2 weeks after vaccination. For treatment of active influenza A infection, amantadine is most effective when therapy is instituted early (within 48 hours of the onset of symptoms).
93.4.3.1.3
Pharmacokinetics. Amantadine is well absorbed following oral administration and is distributed widely to body fluids and tissues. The drug crosses the blood-brain barrier and placenta. It also appears in saliva, nasal secretions, and breast milk. Amantadine is not metabolized. Excretion is renal. In patients with renal impairment, amantadine will accumulate to high levels if the dosage is not reduced.
93.4.3.1.4
Adverse Effects. Amantadine is generally well tolerated at the doses employed for prophylaxis and treatment of influenza.
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Pharmacology for Nursing Care, 7th Edition of influenza. 93.4.3.1.4.1
CNS Effects. CNS effects occur in 10% to 30% of patients. Reactions include dizziness, nervousness, insomnia, and difficulty concentrating. Individuals involved in hazardous activities should exercise appropriate caution. More serious CNS effects (depression, hallucinations, seizures) have occurred. Accordingly, care should be exercised in patients with a history of epilepsy or psychosis.
93.4.3.1.4.2
Cardiovascular Effects. Rarely, amantadine has caused heart failure (HF). The drug should be used with caution in patients with HF or peripheral edema. Patients should be instructed to contact their physician if they experience shortness of breath or swelling of the extremities. Orthostatic hypotension has occurred. Patients should be advised to move slowly when assuming an upright position. Also, they should be advised to sit or lie down if dizziness or lightheadedness occurs.
93.4.3.1.4.3
Use in Pregnancy and Lactation. Amantadine is teratogenic and embryotoxic in rats. Adequate studies during human pregnancy have not been performed. The drug crosses the placenta and is classified in FDA Pregnancy Risk Category C. It should be avoided by pregnant women unless the benefits of treatment are deemed to outweigh the potential risks to the fetus. Amantadine is secreted in breast milk and should not be used by nursing mothers.
93.4.3.1.5
Drug Interactions. Amantadine can intensify the peripheral and CNS effects of anticholinergic drugs. When amantadine has been combined with anticholinergic drugs, psychotic reactions resembling those associated with atropine poisoning have occurred. These responses can be reduced by lowering the dosage of either amantadine or the anticholinergic agent.
93.4.3.1.6
Preparations, Dosage, and Administration. Amantadine [Symmetrel] is supplied in a syrup (10 mg/mL) and in 100-mg tablets and capsules. For treatment or prophylaxis of influenza A, the dosage for patients older than 9 years is 100 mg twice daily. For children ages 1 to 9 years, the dosage is 4.4 to 8.8 mg/kg/ day in two or three divided doses. The dosage must be reduced in patients with kidney dysfunction. Prophylactic administration should commence prior to anticipated viral
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Pharmacology Nursing Care, 7th Edition day in two for or three divided doses. The dosage must be reduced in patients with kidney dysfunction. Prophylactic administration should commence prior to anticipated viral exposure and should continue for as long as the influenza A epidemic lasts. For treatment of active influenza A infection, therapy should begin within 48 hours of symptom onset and should continue for 4 to 5 days. 93.4.3.2
Rimantadine Rimantadine [Flumadine] is very similar to amantadine in structure, actions, and uses. Like amantadine, rimantadine is indicated only for prophylaxis and treatment of influenza A virus infections. During the 2005–2006 flu season, the CDC recommended against use of rimantadine (and amantadine) owing to widespread resistance. Rimantadine is administered by mouth, and bioavailability appears to be high (greater than 90%). In contrast to amantadine, which is not metabolized, rimantadine undergoes extensive metabolism prior to excretion in the urine. Primary adverse effects are nervousness, lightheadedness, difficulty in concentration, sleep disturbances, and fatigue. However, these occur less frequently than with amantadine (3% vs. up to 30%). The adult dosage for treatment or prophylaxis is 100 mg twice a day. The duration of therapy is 5 days for treatment of active infection and up to 6 weeks for prophylaxis. The dosage for prophylaxis in children is 5 mg/kg/day. Rimantadine is not approved for treating active infection in children. Rimantadine is available in 100-mg capsules.
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DRUGS FOR RESPIRATORY SYNCYTIAL VIRUS INFECTION Respiratory syncytial virus (RSV) infection is a major cause of lower respiratory tract disease. Symptomatic infection with RSV is most likely in the very young, the elderly, and persons with disorders of the respiratory, cardiac, or immune systems. In the United States, RSV infection is the most common cause of lower respiratory tract disease in infants and young children, leading to between 51,000 and 82,000 hospitalizations each year. Among children 5 years old and younger, RSV is the leading cause of viral death. The death rate from RSV in the elderly is also high. Like influenza, infection with RSV is seasonal, with most cases occurring in the winter (December through March). Only two antiviral drugs—ribavirin and palivizumab—are approved for treating RSV. Unfortunately, neither drug is very effective.
93.5.1
Ribavirin (Inhaled) Ribavirin, a broad-spectrum antiviral drug, is available in two formulations: aerosol and oral. The aerosol formulation, marketed as Virazole, is used for infection with RSV. The oral formulation, marketed as Rebetol, is used for chronic hepatitis C. Discussion here focuses on RSV. Use against hepatitis C is discussed above.
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Pharmacology Care, 7th Edition against hepatitisfor C isNursing discussed above. 93.5.1.1
Antiviral Actions. Ribavirin [Virazole] is virustatic. The drug is active against RSV, HCV, influenza virus (types A and B), and HSV. Although several biochemical actions of the drug have been described, it is not known which (if any) is responsible for antiviral effects.
93.5.1.2
Use in RSV Infection. Ribavirin is labeled only for severe viral pneumonia caused by RSV in carefully selected, hospitalized infants and young children. Unfortunately, benefits of treatment are usually minimal—and the cost is high (over $1300/day). Ribavirin should not be used for mild RSV infections.
93.5.1.3
Pharmacokinetics. For treatment of RSV, ribavirin is administered by oral inhalation. The drug is absorbed from the lungs and achieves high concentrations in respiratory tract secretions and erythrocytes. Concentrations in plasma remain low. The drug is metabolized to active and inactive products. Excretion is via the urine (30% to 55%) and feces (15%). Ribavirin that is sequestered in erythrocytes remains in the body for weeks.
93.5.1.4
Adverse Effects. Inhalation of ribavirin produces little or no systemic toxicity. However, although generally safe, inhaled ribavirin does pose a hazard to infants undergoing mechanical assistance of ventilation: The drug can precipitate in the respiratory apparatus, thereby interfering with safe and effective respiratory support. Consequently, ribavirin should not be administered to infants who need respiratory assistance. In some infants, and in adults who have asthma or chronic obstructive lung disease, ribavirin has caused deterioration of pulmonary function. Accordingly, respiratory function should be carefully monitored. If deterioration occurs, ribavirin should be discontinued. When administered systemically (PO or IV), ribavirin frequently causes anemia. This has not been reported with inhalational therapy.
93.5.1.5
Use in Pregnancy. Ribavirin is contraindicated for use during pregnancy. Although studies in primates indicate no effect on the developing fetus, ribavirin has proved either teratogenic or embryolethal in nearly all other species tested. No studies in humans have been performed. Ribavirin is classified under FDA Pregnancy Risk Category X: The risk of use during pregnancy clearly outweighs any potential benefits. Because of the risk of significant drug exposure, pregnant
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Pharmacology forFDA Nursing Care, 7th Edition classified under Pregnancy Risk Category X: The risk of use during pregnancy clearly outweighs any potential benefits. Because of the risk of significant drug exposure, pregnant women should not directly care for patients undergoing ribavirin aerosol therapy. 93.5.1.6
Preparations, Dosage, and Administration. For treatment of RSV, ribavirin [Virazole] is supplied as a powder (6 gm/100-mL vial) to be reconstituted for aerosol administration. According to the manufacturer, only one device—the Viratek Small Particle Aerosol Generator (SPAG) model SPAG-2—should be employed for ribavirin administration. The SPAG-2 is used to deliver ribavirin to an infant oxygen hood. Treatment is given 12 to 18 hours a day for no less than 3 days and no more than 1 week. The drug should not be administered to patients who require ventilatory assistance. To reconstitute powdered ribavirin, dissolve 6 gm of the drug in sterile water for injection or inhalation, transfer this concentrated solution to the SPAG-2 reservoir, and dilute to a final volume of 300 mL using sterile water for injection or inhalation. The final concentration of ribavirin is 20 mg/ mL. This solution is aerosolized and inhaled by the patient.
93.5.2
Palivizumab
93.5.2.1
Actions and Uses. Palivizumab [Synagis] is a monoclonal antibody indicated for preventing RSV infection in premature infants and in young children with chronic lung diseases. The antibody binds to a surface protein on RSV and thereby prevents replication. In clinical trials, the rate of hospitalization was 1.8% for premature infants treated with palivizumab, compared with 8.1% for those receiving placebo. In young children with chronic lung disease, the hospitalization rate was 7.9% for those receiving the antibody, versus 12.8% for those receiving placebo.
93.5.2.2
Adverse Effects. Except for hypersensitivity reactions, which are rare, palivizumab appears devoid of significant adverse effects. Acute hypersensitivity reactions have occurred with initial drug use and with subsequent use. Very rarely (less than 1 in 100,000 cases), palivizumab has caused anaphylaxis, but only with re-exposure, not with the initial dose. If a mild hypersensitivity reaction occurs, cautious use of palivizumab can continue. However, if a severe reaction occurs, the drug should be stopped and never used again. Severe reactions are managed with parenteral epinephrine and supportive care.
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Pharmacology for Nursing Care, care. 7th Edition parenteral epinephrine and supportive 93.5.2.3
Preparations, Dosage, and Administration. Palivizumab [Synagis] is supplied in solution (50 and 100 mg/mL). The dosage is 15 mg/kg once a month, injected IM into the anterolateral aspect of the thigh. Dosing should commence before the RSV season (December through March in the United States) and continue until the season ends. The cost for a full season of treatment is about $7000. However, although this seems high, it could save more than $50,000 by avoiding hospitalization.
93.5.2.3.1
KEY POINTS ▪ Because viruses use host-cell enzymes and substrates to reproduce, it is difficult to suppress viral reproduction without also harming cells of the host. ▪ Acyclovir is the drug of choice for most infections caused by herpes simplex viruses and varicella-zoster virus. ▪ Following conversion to its active form, acyclovir suppresses viral reproduction by inhibiting viral DNA polymerase and by causing premature termination of viral DNA strand growth. Because the active form of acyclovir is not a good inhibitor of human DNA polymerase, cells of the host are spared. ▪ In patients with genital herpes infections, oral acyclovir can decrease the duration and severity of the initial episode and the frequency of lesion recurrence. ▪ Although acyclovir reduces symptoms of genital herpes, the drug does not produce cure (ie, it does not eliminate the virus) and does not prevent transmission to sexual partners. ▪ Acyclovir is eliminated unchanged by the kidneys. Accordingly, dosage must be reduced in patients with renal impairment. ▪ Intravenous acyclovir can injure the kidneys. Renal damage can be minimized by infusing acyclovir slowly and by ensuring adequate hydration during and after the infusion. ▪ Ganciclovir is the drug of choice for prophylaxis and treatment of CMV infection in immunocompromised patients, including those with AIDS.
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▪ Ganciclovir does not cure CMV retinitis in patients with AIDS, and hence, in most cases, treatment must continue for life.
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Pharmacology fortreatment Nursing Edition cases, mustCare, continue7th for life. ▪ Like acyclovir, ganciclovir becomes activated within infected cells, after which it inhibits viral DNA polymerase and causes premature termination of viral DNA strand growth. ▪ Like acyclovir, ganciclovir is excreted unchanged in the urine. Hence, dosage must be reduced in patients with renal impairment. ▪ The major adverse effects of ganciclovir are granulocytopenia and thrombocytopenia. ▪ Chronic hepatitis is caused primarily by HBV and HCV. ▪ Hepatitis B can be prevented by vaccination. There is no vaccine for hepatitis C. ▪ The treatment of choice for chronic hepatitis C is peginterferon alfa plus ribavirin. ▪ The principal adverse effects of interferon alfa are a flu-like syndrome and severe depression. ▪ Ribavirin is teratogenic and embryolethal, and can cause sperm abnormalities. Accordingly, the drug is contraindicated for use during pregnancy. Pregnancy must be avoided by women taking ribavirin, and by female partners of men taking the drug. ▪ Hepatitis B can be treated with interferon alfa or a nucleoside analog, such as lamivudine. ▪ Rarely, lamivudine causes lactic acidosis and severe hepatomegaly. ▪ Vaccination is the best way to prevent influenza. ▪ Because influenza viruses evolve rapidly, influenza vaccines must be reformulated each year, and persons wanting protection must receive the new vaccine each year. ▪ Two types of influenza vaccine are available: inactivated influenza vaccine (administered by IM injection) and live, attenuated influenza vaccine (administered by nasal spray). ▪ Amantadine, a member of the adamantane family, is used for prophylaxis and treatment of influenza A infections, but not influenza B infections. ▪ Resistance to amantadine can develop rapidly.
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Pharmacology for Nursing Care, Edition ▪ Resistance to amantadine can 7th develop rapidly. ▪ In contrast to amantadine, the neuraminidase inhibitors—oseltamivir and zanamivir —are active against influenza A and influenza B. ▪ Resistance to neuraminidase inhibitors is rare. 93.5.2.3.2 93.5.2.3.2.1 93.5.2.3.2.... 93.5.2.3.2....
Summary of Major Nursing Implications* ACYCLOVIR Preadministration Assessment Therapeutic Goal Treatment of infections caused by herpes simplex viruses and varicella-zoster virus.
93.5.2.3.2....
Identifying High-Risk Patients Use with caution in patients with dehydration or renal impairment and in those taking other nephrotoxic drugs.
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Implementation: Administration Routes Topical, oral, IV.
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Dosage Oral and IV dosages must be reduced in patients with renal impairment.
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Administration Topical. Advise patients to apply the drug with a finger cot or rubber glove to avoid viral transfer to other body sites or other people.
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Oral. Dosages vary widely for different indications (see Table 92-2).
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PharmacologyDosages for Nursing Care, 7th Edition vary widely for different indications (see Table 92-2). 93.5.2.3.2....
Intravenous. Give by slow IV infusion (over 1 hour or more). Never administer by IV bolus.
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Implementation: Measures to Enhance Therapeutic Effects Inform patients with herpes simplex genitalis that acyclovir only decreases symptoms; it does not eliminate the virus and does not produce cure. Advise patients to cleanse the affected area with soap and water 3 to 4 times a day, drying thoroughly after each wash. Advise patients to avoid all sexual contact while lesions are present, and to use a condom even when lesions are absent.
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Ongoing Evaluation and Interventions Evaluating Therapeutic Effects Observe for decreased clinical manifestations of herpes simplex and varicella-zoster infections. Virologic testing may also be performed.
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Minimizing Adverse Effects Nephrotoxicity. Intravenous acyclovir can precipitate in renal tubules, causing reversible kidney damage. To minimize risk, infuse acyclovir slowly and ensure adequate hydration during the infusion and for 2 hours after. Exercise caution in patients with preexisting renal impairment and in those who are dehydrated or taking other nephrotoxic drugs.
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GANCICLOVIR Preadministration Assessment Therapeutic Goal Treatment and prevention of CMV infection in immunocompromised patients, including those with AIDS and those taking immunosuppressive drugs following an organ transplant.
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Pharmacology for Nursing Care, 7th Edition organ transplant. 93.5.2.3.2....
Baseline Data Obtain a complete blood count and platelet count.
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Identifying High-Risk Patients Ganciclovir is contraindicated during pregnancy and for patients with neutrophil counts below 500/mm3 or platelet counts below 25,000/mm3.
Use with caution in patients taking zidovudine or nephrotoxic drugs (eg, amphotericin B, cyclosporine) and in patients with a history of cytopenic reactions to other drugs. 93.5.2.3.2.... 93.5.2.3.2....
Implementation: Administration Routes Oral, IV, intraocular.
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Dosage Oral and IV dosages must be reduced in patients with renal impairment. AIDS patients with CMV retinitis must take ganciclovir for life.
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Administration
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Intravenous. Give by slow IV infusion (over 1 hour or more). Ensure adequate hydration to promote renal excretion.
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Oral. Advise patients to take oral ganciclovir with food.
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Intraocular Implants. Surgical implants are replaced every 5 to 8 months.
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PharmacologySurgical for Nursing Care, 7thevery Edition implants are replaced 5 to 8 months. 93.5.2.3.2....
Ongoing Evaluation and Interventions
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Minimizing Adverse Effects
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Granulocytopenia and Thrombocytopenia. Ganciclovir suppresses bone marrow function when given IV or PO. Obtain complete blood counts and platelet counts frequently. Discontinue ganciclovir if
the neutrophil count falls below 500/mm3 or the platelet count falls below 25,000/ mm3. The risk of granulocytopenia can be reduced by giving granulocyte colonystimulating factors. The risk of granulocytopenia is increased by concurrent therapy with zidovudine (a drug for AIDS). 93.5.2.3.2....
Reproductive Toxicity. In animals, ganciclovir is teratogenic and embryotoxic and suppresses spermatogenesis. Warn patients against becoming pregnant. Inform male patients about possible sterility. *
Patient education information is highlighted as blue text.
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Pharmacology for Nursing Care, 7th Edition 94
CHAPTER 93 Antiviral Agents II: Drugs for HIV Infection and Related Opportunistic Infections
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JACK LE FROCK RICH LEHNE In this chapter we discuss drug therapy of infection with the human immunodeficiency virus (HIV), the microbe that causes acquired immunodeficiency syndrome (AIDS). HIV promotes immunodeficiency by killing CD4 T lymphocytes (CD4 T cells), which are key components of the immune system (see Chapter 66). As a result of HIV-induced immunodeficiency, patients are at risk of opportunistic infections and certain neoplasms. It is important to appreciate that HIV infection is not synonymous with AIDS, which develops years after HIV infection is acquired. The definition of AIDS, established by the Centers for Disease Control and Prevention (CDC) in 1993, is a syndrome in which the individual is HIV positive and has either (1) CD4 T-cell counts below 200 cells/mL or (2) an AIDS-defining illness. Included in the CDC's long list of AIDS-defining illnesses are Pneumocystis pneumonia, cytomegalovirus retinitis, disseminated histoplasmosis, tuberculosis, and Kaposi's sarcoma. Since being identified as a new disease in 1981, AIDS has become a global epidemic. In the United States, over 1 million people are now infected, and more than 560,000 have died. Worldwide, an estimated 33 million people are living with HIV and approximately 2.1 million have died, including 260,000 children in 2007. The economic costs of AIDS are staggering, and the personal and societal costs are incalculable. Therapy of HIV infection has made dramatic advances. Today, standard antiretroviral therapy (ART) consists of three or four drugs. These combinations, often referred to as HAART (for highly active antiretroviral therapy), can decrease plasma HIV to levels that are undetectable with current technology, and can thereby delay or reverse loss of immune function, decrease certain AIDS-related complications, preserve health, and prolong life. In the United States, ART has reduced AIDS-related deaths by 72%—from a peak of 50,000 in 1995 to 14,000 in 2006. However, these benefits have not come without a price: ART is expensive, is often complex, poses a risk of long-term side effects and serious drug interactions, and, in most cases, must continue lifelong. Accordingly, if treatment is to succeed, patients must be highly motivated and well informed about all aspects of the treatment program. A strong support network is extremely valuable too.
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Pharmacology for Nursing 7thvaluable Edition program. A strong support network isCare, extremely too. ART cannot cure HIV infection. Although treatment can greatly reduce HIV levels—often rendering the virus undetectable—discontinuation has consistently been followed by a rebound in HIV replication. Because ART does not eliminate HIV, patients continue to be infectious and must be warned to avoid behaviors that can transmit the virus to others. Understanding this chapter requires a basic understanding of the immune system. Accordingly, you may find it helpful to read Chapter 66 (Review of the Immune System) before proceeding. 94.1
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PATHOPHYSIOLOGY
94.1.1
Characteristics of HIV HIV is a retrovirus. Like all other viruses, retroviruses lack the machinery needed for selfreplication, and hence are obligate intracellular parasites. However, in contrast to other viruses, retroviruses have positive-sense, single-stranded RNA as their genetic material. Accordingly, in order to replicate, retroviruses must first transcribe their RNA into DNA. The enzyme employed for this process is viral RNA-dependent DNA polymerase, commonly known as reverse transcriptase. (The enzyme is called reverse transcriptase to distinguish it from DNA-dependent RNA polymerase, the host enzyme that transcribes DNA into RNA, which is the usual [“forward”] transcription process.) The name retrovirus is derived from the first two letters of reverse and transcriptase. There are two types of HIV, referred to as HIV-1 and HIV-2. HIV-1 is found worldwide, whereas HIV-2 is found mainly in West Africa. Although HIV-1 and HIV-2 differ with respect to genetic makeup and antigenicity, they both cause similar disease syndromes. Not all drugs that are effective against HIV-1 are also effective against HIV-2.
94.1.1.1
Target Cells The principal cells attacked by HIV are CD4 T cells (helper T lymphocytes). As discussed in Chapter 66, these cells are essential components of the immune system. They are required for production of antibodies by B lymphocytes and for activation of cytolytic T lymphocytes. Accordingly, as HIV kills CD4 T cells, the immune system undergoes progressive decline. As a result, infected individuals become increasingly vulnerable to opportunistic infections, the major cause of death among people with AIDS. HIV targets CD4 T cells because the CD4 proteins on the surface of these cells provide points of attachment for HIV (see below). Without such a receptor, HIV would be unable to connect with and penetrate these cells. Once HIV has infected a CD4 T cell, the cell dies in about 1.25 days. It is important to appreciate that only a few percent of CD4 T cells circulate in the blood; the vast majority reside in lymph
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Pharmacology for aNursing Edition HIV has infected CD4 T cell,Care, the cell7th dies in about 1.25 days. It is important to appreciate that only a few percent of CD4 T cells circulate in the blood; the vast majority reside in lymph nodes and other lymphoid tissues. In addition to infecting CD4 T cells, HIV infects macrophages and microglial cells (the central nervous system [CNS] counterparts of macrophages), both of which carry CD4 proteins. Since macrophages and microglial cells are resistant to destruction by HIV, they can survive despite being infected. As a result, they serve as a reservoir of HIV during chronic infection. 94.1.1.2
Structure of HIV The structure of HIV is very simple. As shown in Figure 93-1, the HIV virion (ie, the entire virus particle) consists of nucleic acid (RNA) surrounded by core proteins, which in turn are surrounded by a capsid (protein shell), which in turn is surrounded by a lipid bilayer envelope (derived from the membrane of the host cell). The central core contains two separate but identical single strands of RNA, each with its own molecule of reverse transcriptase attached. The RNA serves as the template for DNA synthesis. The outer envelope of HIV contains glycoproteins that are needed for attachment to host cells. Each glycoprotein consists of two subunits, known as gp41 and gp120. The smaller protein (gp41) is embedded in the lipid bilayer of the viral envelope; the larger protein (gp120) is connected firmly to gp41. (The numbers 41 and 120 simply indicate the mass of these glycoproteins in thousands of daltons.)
94.1.1.3
Replication Cycle of HIV The replication cycle of HIV is depicted in Figure 93-2. The numbers below correspond to the steps in the figure. • Step 1—The cycle begins with attachment of HIV to the host cell. The primary connection takes place between gp120 on the HIV envelope and a CD4 protein on the host cell membrane. Other host proteins, known as co-receptors, act in concert with CD4 to tighten the bond with HIV. Two of these co-receptors—known as CCR5 and CXCR4 —are of particular importance. A new drug—maraviroc—blocks viral entry by binding CCR5. • Step 2—The lipid bilayer envelope of HIV fuses with the lipid bilayer of the host cell membrane. Fusion is followed by release of HIV RNA into the host cell. In 2003, the first HIV fusion inhibitor became available for general use.
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Pharmacology forfusion Nursing Edition first HIV inhibitorCare, became7th available for general use. • Step 3—HIV RNA is transcribed into single-stranded DNA by HIV reverse transcriptase. Eleven of the antiretroviral drugs in current use inhibit this enzyme. • Step 4—Reverse transcriptase converts the single strand of HIV DNA into doublestranded HIV DNA. • Step 5—Double-stranded HIV DNA becomes integrated into the host's DNA, under the direction of a viral enzyme known (aptly) as integrase. A new drug—raltegravir— inhibits this enzyme. • Step 6—HIV DNA undergoes transcription into RNA. Some of the resulting RNA becomes the genome for daughter HIV virions (step 6a). The rest of the RNA is messenger RNA that codes for HIV proteins (step 6b). • Step 7—Messenger RNA is translated into HIV glycoproteins (step 7a) and HIV enzymes and structural proteins (step 7b). • Step 8—The components of HIV migrate to the cell surface and assemble into a new virus. Prior to virus assembly, HIV glycoproteins become incorporated into the host cell membrane (step 8a). In steps 8b and 8c, the other components of the virion migrate to the cell surface, where they undergo assembly into the new virus. • Step 9—The newly formed virus buds off from the host cell. As indicated, the outer envelope of the virion is derived from the cell membrane of the host. • Step 10—In this step, which occurs either during or immediately after budding off, HIV undergoes final maturation under the influence of protease, an enzyme that cleaves certain large polyproteins into their smaller, functional forms. If protease fails to cleave these proteins, HIV will remain immature and noninfectious. HIV protease is the target of several important drugs. 94.1.1.4
Replication Rate HIV replicates rapidly during all stages of the infection. During the initial phase of infection, replication is massive. Why? Because (1) the population of CD4 cells is still large, thereby
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Pharmacology Nursing Care, (1) 7th replication is for massive. Why? Because theEdition population of CD4 cells is still large, thereby Figure 93-1 Structure of the human immunodeficiency virus. Note that HIV has two single strands of RNA, and that each strand is associated with a molecule of reverse transcriptase. (gp41 = glycoprotein 41, gp120 = glycoprotein 120.)
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providing a large viral breeding ground; and (2) the host has not yet mounted an immune response against HIV, hence replication can proceed unopposed. As a result of massive replication, plasma levels of HIV can exceed 10 million virions/mL. During this stage of high viral load, patients often experience an acute retroviral syndrome (see below). Over the next few months, as the immune system begins to attack HIV, plasma levels of HIV undergo a sharp decline and then level off. A typical steady-state level is between 1000 and 100,000 virions/mL. Please note, however, that steady-state numbers can be deceptive. The plasma half-life of HIV is only 6 hours; that is, every 6 hours, half of the HIV virions in plasma are lost. Accordingly, in order to maintain the steady-state levels typically seen during chronic HIV infection, the actual rate of replication is between 1 and 10 billion virions/day. Despite
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Pharmacology for Nursing 7ththeEdition are lost. Accordingly, in order Care, to maintain steady-state levels typically seen during chronic HIV infection, the actual rate of replication is between 1 and 10 billion virions/day. Despite this high rate of ongoing replication, infected individuals typically remain asymptomatic for about 10 years, after which symptoms of advanced HIV disease appear. 94.1.1.5
Mutation and Drug Resistance HIV mutates rapidly. Why? Because HIV reverse transcriptase is an error-prone enzyme. Hence, whenever it transcribes HIV RNA into single-stranded DNA and then into doublestranded DNA, there is a high probability of introducing base-pair errors. In fact, according to one estimate, up to 10 incorrect bases may be incorporated into HIV DNA during each round of replication. Because of these errors, HIV can rapidly mutate from a drug-sensitive form into a drug-resistant form. The probability of developing resistance in the individual patient is directly related to the total viral load. Hence, the more virions the patient harbors, the greater the likelihood that at least one will become resistant. To minimize the emergence of resistance, patients must be treated with a combination of antiretroviral drugs. This is the same strategy we employ to prevent emergence of resistance when treating tuberculosis (see Chapter 89).
94.1.2
Transmission of HIV HIV is transmitted sexually and by other means. The virus is present in all body fluids of infected individuals. Transmission can be via intimate contact with semen, vaginal secretions, and blood. The disease can be transmitted by sexual contact, transfusion, sharing IV needles, and accidental needle sticks. In addition, it can be transmitted to the fetus by an infected mother, usually during the perinatal period. Initially, HIV infection was limited largely to homosexual males, injection drug users, and hemophiliacs. However, the disease can now be found routinely in the population at large. The risk of contracting HIV can be greatly reduced by using condoms and by screening blood supplies for HIV.
94.1.3
Clinical Course of HIV Infection HIV infection follows a triphasic clinical course. During the initial phase, HIV undergoes massive replication, causing blood levels of HIV to rise very high. As a result, between 50% and 90% of patients experience a flu-like acute retroviral
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Pharmacology Nursing Care, 7th Edition 90% of patientsfor experience a flu-like acute retroviral
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Figure 93-2 Replication cycle of the human immunodeficiency virus. See text for description of events. (CCR5 = CCR5 coreceptor, CD4 = CD4 receptor, CXCR4 = CXCR4 coreceptor, dsDNA = double-stranded DNA, gp120 = glycoprotein 120, mRNA = messenger RNA, ssDNA = single-stranded DNA, ssRNA = single-stranded RNA.)
syndrome. Signs and symptoms include fever, lymphadenopathy, pharyngitis, rash, myalgia, and
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Pharmacology for Nursing Care, 7th Edition syndrome. Signs and symptoms include fever, lymphadenopathy, pharyngitis, rash, myalgia, and headache (Table 93-1). Soon, however, the immune system mounts a counterattack, causing HIV levels to fall. As a result, symptoms of the acute syndrome fade. Very often, the acute retroviral syndrome is perceived as influenza, and hence goes unrecognized for what it really is. The middle phase of HIV infection is characterized by prolonged clinical latency. Blood levels of HIV remain relatively low, and most patients are asymptomatic. However, as noted above, HIV continues to replicate despite apparent dormancy. Because of persistent HIV replication, CD4 T cells undergo progressive decline. The average duration of clinical latency is 10 years.
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Pharmacology for Nursing Care, 7th Edition cells undergo progressive decline. The average duration of clinical latency is 10 years.
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TABLE 93-1 Acute Retroviral Syndrome: Associated Signs and Symptoms • Fever (96%) • Lymphadenopathy (74%) • Pharyngitis (70%) • Rash and mucocutaneous ulceration (70%) • Erythematous maculopapular rash with lesions on face and trunk and sometimes extremities, including palms and soles • Mucocutaneous ulceration involving mouth, esophagus, or genitals • Myalgia or arthralgia (54%) • Diarrhea (32%) • Headache (32%) • Nausea and vomiting (27%) • Hepatosplenomegaly (14%) • Weight loss (13%) • Thrush (12%) • Neurologic symptoms (12%) • Meningoencephalitis or aseptic meningitis • Peripheral neuropathy or radiculopathy • Facial palsy • Guillain-Barré neuritis • Brachial neuritis • Cognitive impairment or psychosis
During the late phase of HIV infection, CD4 T cells drop below a critical level (200 cells/mL), rendering the patient highly vulnerable to opportunistic infections and certain neoplasms (eg, Kaposi's sarcoma). The late phase is when AIDS occurs.
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Pharmacology forThe Nursing Care, Edition Kaposi's sarcoma). late phase is when7th AIDS occurs. Many patients with HIV infection experience neurologic complications. Both the peripheral and central nervous systems may be involved. Peripheral neuropathies affect 20% to 40% of patients and may develop at any time over the course of HIV infection. In contrast, CNS complications usually occur late in the disease. Symptoms of CNS injury include decreased cognition, reduced concentration, memory loss, mental slowness, and motor complaints (eg, ataxia, tremors). Neuronal injury may be the direct result of HIV infection, or may develop secondary to an opportunistic infection in the CNS. 94.2
CLASSIFICATION OF ANTIRETROVIRAL DRUGS At this time, we have five types of antiretroviral drugs. Three types—reverse transcriptase inhibitors, integrase inhibitors, and protease inhibitors (PIs)—inhibit enzymes required for HIV replication. The other two types—fusion inhibitors and CCR5 antagonists—block viral entry into cells. As discussed below, the reverse transcriptase inhibitors are subdivided into two groups: nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), which are structural analogs of nucleosides or nucleotides and (2) non-nucleoside reverse transcriptase inhibitors (NNRTIs). Drugs that belong to these groups are listed in Table 93-2. All NRTIs, NNRTIs, PIs, CCR5 antagonists, and integrase inhibitors are administered orally, and one NRTI—zidovudine—may also be given IV. The one fusion inhibitor available—enfuvirtide [Fuzeon]—is administered subQ.
94.3
NUCLEOSIDE/NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITORS The nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) were the first drugs used against HIV infection, and remain mainstays of therapy today. In fact, these drugs constitute the backbone of all treatment regimens. As their name suggests, the NRTIs are chemical relatives of naturally occurring nucleosides or nucleotides, the building blocks of DNA. Antiretroviral effects derive from suppressing synthesis of viral DNA by reverse transcriptase. To be effective, all of the NRTIs must first undergo intracellular conversion to their active (triphosphate) forms. The NRTIs have few drug interactions, and most can be taken without regard to meals. Rarely, these agents cause a potentially fatal syndrome characterized by lactic acidosis and hepatomegaly with steatosis; pregnant women taking two NRTIs may be at increased risk. At this time, eight NRTIs are approved for general use. Major properties are summarized in Table 93-3.
94.3.1
Zidovudine Zidovudine [Retrovir] was the first NRTI available and will serve as our prototype for the group. The drug is an analog of thymidine, a naturally occurring nucleoside. When employed in combination with other antiretroviral drugs, zidovudine can decrease viral load, increase CD4 Tcell counts, delay onset of disease symptoms, and reduce symptom severity. The drug's principal
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Pharmacology forother Nursing Care, 7thzidovudine Editioncan decrease viral load, increase CD4 Tcombination with antiretroviral drugs, cell counts, delay onset of disease symptoms, and reduce symptom severity. The drug's principal dose-limiting toxicities are severe anemia and neutropenia. Abbreviations for this agent are ZDV (for zidovudine) and AZT (for azidothymidine, its original name). 94.3.1.1
Mechanism of Antiviral Action Zidovudine inhibits HIV replication by suppressing synthesis of viral DNA. To do this, zidovudine must first undergo intracellular conversion to its active form, zidovudine triphosphate (ZTP). As ZTP, the drug acts as a substrate for reverse transcriptase. However, when ZTP becomes incorporated into the growing DNA strand, it prevents reverse transcriptase from adding more bases; hence, further growth of the strand is blocked. In addition to causing premature strand termination, ZTP competes with natural nucleoside triphosphates for binding to the active site of reverse transcriptase; the result is competitive inhibition of the enzyme.
94.3.1.2
Therapeutic Use Zidovudine is indicated for HIV infection. This agent penetrates to the CNS better than most other antiretroviral drugs, and hence can be especially valuable for relieving cognitive symptoms. Because monotherapy with any antiretroviral drug can rapidly lead to resistance, zidovudine should always be combined with other antiretroviral agents. The role of zidovudine and other agents in the management of HIV infection is discussed at length later in the chapter.
94.3.1.3
Pharmacokinetics Zidovudine is readily absorbed following oral administration and distributes to all body tissues, including the CNS. After entering the blood, some of the drug is taken up by cells and converted to ZTP, the active form. The remainder undergoes rapid hepatic conversion to an inactive metabolite. Both zidovudine and its inactive metabolite are eliminated by renal excretion. The plasma half-life of the drug is 1.1 hours, and the intracellular half-life is 7 hours.
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Pharmacology for Nursing Care, 7th Edition hours.
1091 1092
TABLE 93-2 Classification of Antiretroviral Drugs Generic Name
Trade Name Chemical Name/Abbreviation
DRUGS THAT INHIBIT HIV ENZYMES Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs) Single-Drug Products Abacavir
Ziagen
ABC
Didanosine
Videx
Dideoxyinosine, ddI
Emtricitabine
Emtriva
FTC
Lamivudine
Epivir
3TC
Stavudine
Zerit
d4T
Tenofovir
Viread
PMPA, TDF
Zalcitabine*
Hivid
Dideoxycytidine, ddC
Zidovudine
Retrovir
Azidothymidine, AZT, ZDV
Fixed-Dose Combinations Abacavir/lamivudine
Epzicom
Abacavir/lamivudine/zidovudine
Trizivir
Emtricitabine/tenofovir
Truvada
Zidovudine/lamivudine
Combivir
Emtricitabine/tenofovir/efavirenz†
Atripla
Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Delavirdine
Rescriptor
DLV
Efavirenz
Sustiva
EFV
Etravirine
Intelence
ETR
Nevirapine
Viramune
NVP
Amprenavir
Agenerase
APV
Atazanavir
Reyataz
ATV
Darunavir
Prezista
DRV
Fosamprenavir
Lexiva
f-APV
Indinavir
Crixivan
IDV, MK-639
Nelfinavir
Viracept
NFV
Ritonavir
Norvir
RTV, ABT-538
Protease Inhibitors
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Pharmacology Nelfinavir for Nursing Care, 7th Edition Viracept
NFV
Ritonavir
Norvir
RTV, ABT-538
Saquinavir
Invirase
SQV
Tipranavir
Aptivus
TPV
Lopinavir/ritonavir
Kaletra
LPV/r
Isentress
RAL
Fuzeon
T-20
Selzentry
MAR
Integrase Inhibitor Raltegravir DRUGS THAT BLOCK HIV ENTRY INTO CELLS Fusion Inhibitor Enfuvirtide CCR5 Antagonist Maraviroc
94.3.1.4 94.3.1.4.1
*
Voluntarily withdrawn in 2006.
†
Efavirenz is an NNRTI, not an NRTI.
Adverse Effects Anemia and Neutropenia from Bone Marrow Suppression. Severe anemia and neutropenia are the principal toxic effects. Multiple transfusions may be required. The risk of hematologic toxicity is increased by high-dose therapy, advanced HIV infection, deficiencies in vitamin B12 and folic acid, and concurrent use of drugs that are myelosuppressive, nephrotoxic, or directly toxic to circulating blood cells. Anemia and neutropenia generally resolve following zidovudine withdrawal. Hematologic status (hemoglobin concentration and neutrophil counts) should be determined before treatment and at least every 4 weeks thereafter. Hemoglobin levels may fall significantly within 2 to 4 weeks; neutrophil counts may not fall until after week 6. For patients who develop severe anemia (hemoglobin below 5 gm/dL or down 25% from baseline) or severe neutropenia (neutrophil count below 750 cells/mL or down 50% from baseline), zidovudine should be interrupted until there is evidence of bone marrow recovery. If neutropenia and anemia are less severe, a reduction in dosage may be sufficient. Transfusions may permit some patients to continue drug use. Granulocyte colony-stimulating factors may be given to reverse zidovudine-induced neutropenia. Also, if erythropoietin levels are not already elevated, epoetin alfa (recombinant erythropoietin) can be given to reduce transfusion requirements in patients with anemia.
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Pharmacology for Nursing Care,levels 7th are Edition neutropenia. Also, if erythropoietin not already elevated, epoetin alfa (recombinant erythropoietin) can be given to reduce transfusion requirements in patients with anemia. Granulocyte colony-stimulating factors and epoetin alfa are discussed in Chapter 55. 94.3.1.4.2
1092 1093
Lactic Acidosis with Hepatic Steatosis. Rarely, zidovudine causes a syndrome of lactic acidosis with severe hepatomegaly (liver enlargement) and hepatic steatosis (fatty degeneration of the liver). Symptoms include nausea, vomiting, abdominal pain, malaise, fatigue, anorexia, and hyperventilation (blowing off carbon dioxide can reduce acidosis). Left untreated, the syndrome can be fatal. Diagnosis is based on lactic acid measurement in arterial blood. If clinically significant lactic acidosis is present, zidovudine should be discontinued. Lactic acidosis is caused by toxicity to mitochondria. Combining NRTIs during pregnancy may increase the risk of lactic acidosis. Several fatalities have occurred in pregnant women who were taking the NRTIs didanosine and stavudine. Because lactic acidosis and hepatitic steatosis are potential side effects of all NRTIs, it may be prudent to avoid combining any of these drugs during pregnancy.
94.3.1.4.3
Other Adverse Effects. Gastrointestinal effects (anorexia, nausea, vomiting, diarrhea, abdominal pain, stomach upset) occur on occasion. Possible CNS reactions include headache, insomnia, confusion, anxiety, nervousness, and seizures. Myopathy (damage to muscle fibers) may also occur.
94.3.1.5
Drug Interactions Drugs that are myelosuppressive, nephrotoxic, or directly toxic to circulating blood cells can increase the risk of zidovudine-induced hematologic toxicity. Notable among these is ganciclovir, an antiviral agent used to treat cytomegalovirus retinitis, a common infection in patients with AIDS. Other drugs of concern include dapsone, pentamidine, pyrimethamine, trimethoprim/sulfamethoxazole, amphotericin B, flucytosine, vincristine, vinblastine, and doxorubicin.
94.3.1.6 94.3.1.6.1
Preparations, Dosage, and Administration Preparations. Zidovudine [Retrovir] is available in capsules (100 mg), tablets (300 mg), and a syrup (10 mg/mL) for oral therapy and in solution (10 mg/mL) for IV use. The drug is also available in combination with lamivudine under the trade name Combivir, and in combination with
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Pharmacology 7th(10Edition mg/mL) forfor oralNursing therapy andCare, in solution mg/mL) for IV use. The drug is also available in combination with lamivudine under the trade name Combivir, and in combination with lamivudine and abacavir under the trade name Trizivir. 94.3.1.6.2
Oral Therapy. The recommended dosage is 300 mg twice a day or 200 mg 3 times a day. The dosage for treating CNS effects (cognitive slowing, motor slowing, dementia) is 1200 mg/day (ie, twice the normal dosage). Hematologic monitoring should be done every 2 weeks. If severe anemia or severe neutropenia develops, treatment should be interrupted until there is evidence of bone marrow recovery. If anemia or neutropenia is mild, a reduction in dosage may be sufficient.
94.3.1.6.3
Intravenous Therapy. Intravenous zidovudine is indicated for adults with AIDS who have a history of cytologically confirmed Pneumocystis pneumonia or a CD4 T-cell count below 200 cells/mL. The IV dosage is 1 to 2 mg/kg (infused over 1 hour) every 4 hours around-the-clock. Rapid infusion and bolus injection must be avoided. Intravenous therapy should be stopped as soon as oral therapy is appropriate. Intravenous solutions are prepared by withdrawing the calculated dose from the stock vial and diluting it to 4 mg/mL (or less) in 5% dextrose for injection. The solution should not be mixed with biologic or colloidal fluids (eg, blood products, protein solutions) and should be administered within 8 hours (if held at room temperature) or within 24 hours (if held under refrigeration).
94.3.2
Other NRTIs
94.3.2.1 94.3.2.1.1
Didanosine Actions and Uses. Didanosine [Videx, Videx EC], also known as dideoxyinosine (ddI), is an analog of inosine, a naturally occurring nucleoside. The drug is taken up by host cells, where it undergoes conversion to its active form, dideoxyadenosine triphosphate (ddATP). Like the active form of zidovudine, ddATP suppresses viral replication primarily by causing premature termination of the growing DNA strand. In addition, ddATP competes with natural nucleoside triphosphates for binding to the active center of reverse transcriptase, and thereby further suppresses DNA synthesis. In clinical trials, didanosine increased CD4 T-cell counts,
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Pharmacology Nursing nucleoside for triphosphates for Care, binding 7th to theEdition active center of reverse transcriptase, and thereby further suppresses DNA synthesis. In clinical trials, didanosine increased CD4 T-cell counts, decreased viremia, and reduced symptoms in patients with AIDS. Didanosine is approved only for HIV infection. Because monotherapy with any antiretroviral drug can rapidly lead to resistance, the regimen should always include other antiretroviral agents. 94.3.2.1.2
Pharmacokinetics. Didanosine is administered orally, and bioavailability is low (about 35%). Absorption is greatly reduced by food and gastric acidity. To decrease gastric acidity, and thereby enhance absorption, older formulations of didanosine [Videx] contain buffering agents; newer formulations [Videx EC] are protected by an enteric coating. Didanosine crosses the bloodbrain barrier poorly; levels in cerebrospinal fluid are only 20% of those in plasma. Much of the drug (35% to 60%) is excreted unchanged in the urine. The plasma half-life in patients with normal renal function is 1.5 hours, but is 3 times longer in patients with renal failure. The intracellular half-life is more than 20 hours.
94.3.2.1.3 94.3.2.1.3.1
Adverse Effects. Pancreatitis. Pancreatitis, which can be fatal, is the major dose-limiting toxicity. The incidence is 3% to 17%. Patients should be monitored for indications of developing pancreatitis (increased serum amylase in association with increased serum triglycerides; decreased serum calcium; and nausea, vomiting, or abdominal pain). If evolving pancreatitis is diagnosed, didanosine should be withdrawn. The risk of pancreatitis is increased by a history of pancreatitis or alcoholism and by use of IV pentamidine. Caution should be exercised in such patients.
94.3.2.1.3.2
Lactic Acidosis with Hepatic Steatosis. Like all other NRTIs, didanosine can cause lactic acidosis with hepatic steatosis. Fatalities have occurred in several pregnant women taking didanosine plus stavudine. Accordingly, the manufacturer warns against combining these drugs during pregnancy, unless resistance to all other antiretrovirals leaves no option. Because lactic acidosis and hepatic steatosis are potential side effects of all NRTIs, it may be prudent to avoid combining didanosine with any of these drugs during pregnancy.
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Pharmacology Nursing Care, 7th Edition with any for of these drugs during pregnancy. 94.3.2.1.3.3
Other Adverse Effects. Additional adverse effects include diarrhea (28%), peripheral neuropathy (20%), chills or fever (12%), and rash or pruritus (9%). In contrast to zidovudine, didanosine causes minimal bone marrow suppression.
94.3.2.1.4
Drug Interactions. For treatment of HIV infection, didanosine can be used in various regimens (see Table 93-8 on p. 1114). Buffered didanosine formulations can interfere with the absorption of drugs that require gastric acidity, including delavirdine and indinavir. Ribavirin can increase levels of didanosine, and may thereby pose a risk of toxicity. Accordingly, the combination should be used with caution.
94.3.2.1.5
Preparations, Dosage, and Administration. Didanosine is available in three formulations: buffered chewable tablets [Videx], entericcoated capsules [Videx EC], and a buffered powder for oral solution [Videx].
94.3.2.1.5.1
All Formulations. Because absorption is greatly reduced by food, didanosine should be administered on an empty stomach, either 30 minutes before meals or 2 hours after. Because didanosine is eliminated by the kidneys, dosage must be reduced in patients with renal impairment.
94.3.2.1.5.2
Buffered Chewable Tablets. Didanosine tablets [Videx] are available in five strengths: 25, 50, 100, 150, and 200 mg. Instruct patients to either (1) chew the tablets thoroughly, or (2) manually crush them or disperse them in at least 1 ounce of water. Dosage is based on body weight. For adults over 60 kg, the dosage is 400 mg once daily or 200 mg twice daily. For adults under 60 kg, the dosage is 250 mg once daily or 125 mg twice daily. To ensure adequate buffering of gastric acid, patients must take two tablets (of appropriate size) for each dose.
94.3.2.1.5.3
Enteric-Coated Capsules. Didanosine enteric-coated capsules [Videx EC] are available in four strengths: 125, 200, 250, and 400 mg. Dosage is 400 mg once daily (for patients over 60 kg) and 250 mg once daily (for patients under 60 kg). In contrast to the buffered tablets, which must be crushed
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Pharmacology Nursing Care, 250, and for 400 mg. Dosage is 400 mg7th onceEdition daily (for patients over 60 kg) and 250 mg once daily (for patients under 60 kg). In contrast to the buffered tablets, which must be crushed or chewed, the enteric-coated capsules must be swallowed intact. 94.3.2.1.5.4
Buffered Powder for Oral Solution. Didanosine powder for oral solution is available in single-dose packets (100, 167, and 250 mg) and in bottles (2 and 4 gm) for pediatric use. Instruct patients using the single-dose packets to (1) pour the contents of one packet into 4 ounces of water (not fruit juice or any other acid-containing beverage); (2) stir the mixture until the drug dissolves (about 2 to 3 minutes); and (3) drink the solution immediately. Dosage is 250 mg twice daily (for patients over 60 kg) or 167 mg twice daily (for patients under 60 kg).
94.3.2.2 94.3.2.2.1
Stavudine Actions and Uses. Stavudine [Zerit, Zerit XR], also known as didehydrodeoxythymidine (d4T), is an analog of thymidine, a naturally occurring nucleoside. Following uptake by cells, stavudine is converted to its active form, stavudine triphosphate. The active drug then suppresses HIV replication by (1) causing premature termination of the growing DNA strand and (2) competing with natural nucleoside triphosphates for binding to reverse transcriptase.
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Pharmacology Nursing Care,triphosphates 7th Edition competing for with natural nucleoside for binding to reverse transcriptase.
1094
TABLE 93-3 Properties of Nucleoside/Nucleotide Reverse Transcriptase Inhibitors Zidovudine (AZT, ZDV)
Didanosine Stavudine (ddI) (d4T)
Lamivudine (3TC)
Tenofovir (PMPA, Emtricitabine Abacavir (ABC) TDF) (FTC)
Trade Name
Retrovir
Videx, Videx Zerit, Zerit XR‡ EC†
Epivir
Ziagen
Formulations
Capsules: 100 mg
Buffered Capsules: 15, tablets: 25, 20, 30, 40 mg 50, 100, 150, Capsules, XR: 200 mg 37.5, 50, 75, EC capsules: 100 mg 125, 200, 250, 400 mg PO soln: 1 mg/ mL Buffered powder for PO soln: 100, 167, 250 mg
Tablets: 150, Tablets: 300 mg Tablets: 300 mg 300 mg PO soln: 20 mg/ PO soln: 10 mL mg/mL
Capsules: 200 mg
Adults: 150 mg 2 times/ day or 300 mg 3 times/ day
300 mg 2 times/ 300 mg day or 600 mg once/day once/day
200 mg once/day
Take without regard to meals — but alcohol increases levels by 41%
Take without regard to meals
Take without regard to meals
83%
39% (with
93%
Tablets: 300 mg Syrup: 10 mg/mL IV soln: 10 mg/mL
Dosage
200 mg 3 Tablets times/day or >60 kg: 200 300 mg 2 mg 2 times/ times/day day or 400 mg once/ day
Capsules, PO soln >60 kg: 40 mg 2 times/day
Viread
1093
Emtriva
PO soln: 10 mg/mL
60 kg: 400 mg daily
24 months: 30 mg/kg PO daily
Dapsone
50 mg PO twice daily or 100 mg PO daily 2 mg/kg (max of 100 mg) PO daily or 4 mg/kg (max of 200 mg) PO once a week
Dapsone + pyrimethamine + leucovorin
DAP 50 mg PO daily + PYR 50 mg PO every 7 days + LEU 25 mg PO every 7 days
*
Not recommended
Single-strength tablet = 80 mg TMP + 400 mg SMZ; double-strength tablet = 160 mg TMP + 800 mg SMZ.
Maintenance therapy is expensive. In 2003, wholesale prices for a year's supply were $13,093 for IV ganciclovir, $17,794 for PO ganciclovir, $6500 to $10,000 for ganciclovir intraocular implants, $20,904 for IV cidofovir, $21,582 for PO valganciclovir, and between $27,770 and $37,027 for IV foscarnet! 94.10.2.1
Ganciclovir. Ganciclovir [Cytovene, Vitrasert] is the drug of choice for CMV retinitis. For induction, IV administration is traditional, although intraocular implants or direct intraocular injections may also be used. For maintenance, intraocular implants or daily IV infusions via a central venous catheter are preferred. The implants are more effective than the infusions and cause fewer side effects. To reduce the risk of systemic CMV infection, patients with ocular implants can also take oral ganciclovir. Dose-limiting toxicities of IV ganciclovir are neutropenia and thrombocytopenia secondary to bone marrow suppression. In addition, there is a risk of infection in the central venous catheter.
94.10.2.2
Valganciclovir. Valganciclovir [Valcyte] is a prodrug version of ganciclovir, but has greater oral bioavailability. Adverse effects are the same as those of ganciclovir. The principal concerns are blood dyscrasias—granulocytopenia, anemia, and thrombocytopenia—secondary to bone marrow suppression.
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Pharmacology for Nursing Care, 7th Edition marrow suppression. 94.10.2.3
Foscarnet. Foscarnet [Foscavir] is less well tolerated than ganciclovir and much more expensive. As a rule, the drug is administered by IV infusion—twice daily for induction and once daily for maintenance. To receive infusions daily, patients require an indwelling central venous catheter, and hence face a risk of catheter-related infection. Dose-limiting toxicities are nephrotoxicity, electrolyte imbalance (especially hypocalcemia), genital ulceration, and fluid overload.
94.10.2.4
Cidofovir. Cidofovir [Vistide] is an IV drug for CMV retinitis. This agent has a longer effective half-life than ganciclovir or foscarnet, and hence can be administered less often. Specifically, whereas ganciclovir and foscarnet must be infused daily for maintenance therapy, cidofovir is infused just once every 2 weeks. Because cidofovir infusions are infrequent, patients do not require an indwelling central catheter, and hence do not face a risk of catheter-related infection. The major dose-limiting toxicities are kidney damage and neutropenia. To reduce the risk of kidney injury, all patients must receive probenecid and IV hydration therapy with each infusion.
94.10.3
Mycobacterium tuberculosis and Mycobacterium avium Complex Mycobacterium tuberculosis and Mycobacterium avium complex (MAC) are slow-growing microbes that require prolonged drug exposure for eradication. Because therapy is prolonged, emergence of resistance is a significant concern. To reduce emergence of resistance, these infections are always treated with multiple drugs—just like HIV itself. Mycobacterial infections and their treatment are discussed at length in Chapter 89. A brief summary of treatment is presented here.
94.10.3.1
Mycobacterium tuberculosis.
1122
Tuberculosis is the leading cause of death among patients with AIDS. If the infection is caused by drug-sensitive mycobacteria, treatment is relatively simple. In one protocol, treatment is initiated with a four-drug regimen—isoniazid, rifabutin, pyrazinamide, and ethambutol—and then switched to a two-drug regimen—isoniazid plus rifabutin—2 months later. Treatment should last for at least 9 months, and for at least 3 months after sputum tests for M. tuberculosis become negative. Treatment of drug-resistant infections can be very difficult, sometimes requiring as many as seven drugs. Specific regimens for drug-sensitive and drugresistant tuberculosis are summarized in Chapter 89 (Table 89-1).
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Pharmacology for Nursing Care,in7th Edition resistant tuberculosis are summarized Chapter 89 (Table 89-1). HIV-infected patients with a positive skin test or blood test for tuberculosis should take prophylactic drugs to prevent active M. tuberculosis infection. The preferred regimen consists of isoniazid for 9 months. 94.10.3.2
Mycobacterium avium Complex. MAC consists of two nearly identical microbes: Mycobacterium avium and Mycobacterium intracellulare. Infection with MAC begins in the lungs or GI tract, but may later disseminate to the blood, bone marrow, liver, spleen, lymph nodes, brain, kidneys, and skin. Among people with AIDS, disseminated infection is common, being present in 50% at autopsy. Signs and symptoms of disseminated MAC infection include fever, night sweats, weight loss, lethargy, anemia, and abnormal liver function tests. Primary prophylaxis against MAC is indicated for patients with fewer than 50 CD4 T cells/mL. Either azithromycin or clarithromycin should be used. If ART produces a 3-month increase in CD4 counts to 100 cells/mL or more, prophylaxis may be discontinued. If disseminated infection develops, the preferred treatment is clarithromycin plus ethambutol, with or without rifabutin. If needed, azithromycin can be substituted for clarithromycin. In the absence of immune recovery, treatment should continue lifelong. However, if the patient (1) has been treated for at least 12 months and is free of MAC symptoms, and (2) has had a 6month sustained CD4 elevation (above 100 cells/mL) following ART, discontinuing treatment for MAC is reasonable.
94.10.4
Toxoplasma Encephalitis Toxoplasma gondii is a protozoan of the Sporozoa class. In the immunocompetent host, infection with T. gondii is generally benign. However, in the immunocompromised host, infection can be lethal. Among patients with AIDS, toxoplasmosis usually manifests as encephalitis (inflammation of the brain or brainstem). Symptoms include fever, headache, seizures, aphasia (loss of speech), lethargy, confusion, dementia, focal neurologic deficits, and progression to coma. Toxoplasma encephalitis is most likely late in HIV disease, usually after CD4 T-cell counts fall below 100 cells/mL. In the United States, the incidence of Toxoplasma encephalitis among AIDS patients is 3% to 10%, making this the most common opportunistic infection of the CNS in these people. Patients who are seropositive for T. gondii and have low CD4 T-cell counts (below 100 cells/mL) should take drugs to prevent active infection. The preferred regimen is 1 double-strength tablet of TMP/SMZ daily (the same regimen used to prevent PCP). Prophylaxis can be discontinued if
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Pharmacology forto Nursing Care, 7thThe Edition should take drugs prevent active infection. preferred regimen is 1 double-strength tablet of TMP/SMZ daily (the same regimen used to prevent PCP). Prophylaxis can be discontinued if ART produces a sustained (3 month or longer) increase in CD4 T cells (above 200 cells/mL). If active infection develops, the treatment of choice is pyrimethamine plus sulfadiazine plus leucovorin. The sulfadiazine component can cause rash and crystalluria. For patients who cannot tolerate sulfadiazine, pyrimethamine plus clindamycin plus leucovorin is an alternative. Once toxoplasmosis has been controlled, lifelong suppressive therapy is needed. The preferred regimen is pyrimethamine plus sulfadiazine plus leucovorin. Pyrimethamine plus clindamycin is an alternative. However, clinical experience indicates discontinuing prophylaxis is reasonable in patients who (1) have remained free of encephalitis symptoms and (2) have had a 6-month sustained increase in CD4 T-cell counts (above 200 cells/mL) following ART. 94.10.5
Cryptococcal Meningitis Cryptococcus neoformans is a fungus that infects 9% to 13% of patients with AIDS. In 80% of these patients, cryptococcosis manifests as meningitis (inflammation of the meninges). The most common symptoms are fever and headache. Other symptoms include nausea, vomiting, photophobia, and altered mental status. Cryptococcal meningitis typically occurs late in HIV disease, usually after CD4 T-cell counts fall below 100 cells/mL. In addition to infecting the meninges, C. neoformans can infect the blood, lungs, skin, and prostate. The treatment of choice for cryptococcal meningitis is amphotericin B plus flucytosine, infused daily for 2 weeks or longer. The major adverse effect of amphotericin is kidney damage, whereas the major concern with flucytosine is bone marrow suppression (neutropenia, thrombocytopenia). Compared with amphotericin B alone, the combination of amphotericin plus flucytosine decreases rates of treatment failure and relapse. However, mortality rates with both treatments are similar. Because bone-marrow suppression is a significant concern for patients with AIDS, those taking flucytosine should be monitored closely. After the initial infection has been controlled, patients should continue maintenance therapy indefinitely. The treatment of choice is oral fluconazole daily. In the absence of maintenance therapy, patients are at increased risk of relapse and death. However, limited experience suggests that discontinuing maintenance therapy may be reasonable in patients who (1) have no signs or symptoms of cryptococcosis and (2) have developed a 6-month sustained increase in CD4 T-cell counts (200 cells/mL or higher) following ART. The basic pharmacology of amphotericin B, flucytosine, and fluconazole is discussed in Chapter 91.
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Pharmacology for Nursing Care, 7th Edition 91. 94.10.6
Varicella-Zoster Virus Infection Varicella-zoster virus (VZV) can cause chickenpox and herpes zoster, also known as shingles or simply zoster. Among adults with AIDS, VZV infection usually manifests as shingles, which results from reactivation of latent VZV infection. Preferred treatments are oral therapy with acyclovir (800 mg 5 times a day for 7 to 10 days), valacyclovir (1 gm 3 times a day), or famciclovir (500 mg 3 times a day for 5 to 7 days). For patients with disseminated VZV infection, the preferred treatment is IV acyclovir (10 mg/kg every 8 hours for 1 to 2 weeks); IV foscarnet is an alternative. The basic pharmacology of acyclovir, famciclovir, and foscarnet is discussed in Chapter 92.
94.10.7
Herpes Simplex Virus Infection Infection with herpes simplex virus (HSV) is common among patients with HIV disease. Lesions may occur at multiple sites, including the lips, tongue, oral cavity, genitals, and perianal region. In patients with advanced HIV disease, HSV may infect the esophagus, colon, lungs, eyes, and CNS. For infection at all sites, acyclovir is the drug of choice. Administration may be oral or IV. Responses usually occur within 3 to 10 days. Duration of treatment ranges from 7 to 21 days. For patients with acyclovir-resistant HSV, IV foscarnet or IV cidofovir can be used. Patients who experience frequent or severe recurrences can take oral acyclovir or famciclovir for prophylaxis.
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Candidiasis HIV-infected patients frequently develop infection with Candida species, usually Candida albicans. The most common sites are the oropharynx and esophagus. Up to 75% of patients experience oral candidiasis (thrush), which often responds to topical therapy, such as “swishing and swallowing” a nystatin suspension or sucking miconazole troches. Systemic therapy with an oral azole—fluconazole, ketoconazole, or itraconazole—is an alternative. Oral azoles are more convenient than topical therapy and probably more effective. However, they are also more expensive. Prophylaxis of recurrent oral candidiasis is not always needed. However, if recurrence is frequent or severe, chronic intermittent therapy with an oral azole may be considered. For esophageal candidiasis, systemic therapy is required. Options include oral ketoconazole, oral fluconazole, and IV amphotericin B. All patients with a documented history of esophageal candidiasis should be considered for chronic suppressive therapy with oral fluconazole.
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Pharmacology forbeNursing 7thsuppressive Edition therapy with oral fluconazole. candidiasis should consideredCare, for chronic 94...
HIV VACCINES Development of an HIV vaccine is critical to controlling the AIDS epidemic worldwide. Although HIV infection can now be managed with ART, treatment is expensive, complex, and potentially dangerous, and must continue lifelong. Furthermore, ART is largely unavailable in developing countries, where most AIDS cases occur. Accordingly, vaccine development has been assigned high priority.
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Obstacles to Vaccine Development Making a safe and effective vaccine against HIV has proved exceedingly and unexpectedly difficult. Obstacles include the wide global variation in HIV strains, lack of information on natural immunity to HIV, multiple modes of HIV transmission, and lack of an ideal animal model for studying vaccine efficacy. Also, scientists are concerned that the vaccine may need to (1) prevent HIV infection, rather than minimize it, and may need to (2) stimulate cell-mediated immunity in addition to humoral immunity. These two concerns are discussed below. Vaccines do not prevent infection—they only attenuate it. By priming the immune system, vaccines reduce microbial replication and accelerate microbial kill. As a result, infection does not spread as far as it would in an unvaccinated person and does not injure as many cells. Unfortunately, HIV is different from all other microbes: HIV kills the very cells that are meant to attack it and that vaccination is meant to stimulate. Given the nature of HIV, we must ask, “Will a vaccine that permits HIV to infect even a small number of immune cells be able to contain the infection—or will HIV eventually break through?” The answer is unknown. Vaccines elicit two kinds of immune responses: humoral immunity (production of antibodies) and cell-mediated immunity (activation of cytotoxic T lymphocytes, also known as killer T cells). Most authorities agree that, to be effective, an HIV vaccine should elicit both types of responses. Why? The answer is simple: We already know that HIV-positive people produce billions of antibodies against HIV, and yet the infection progresses relentlessly; hence, a vaccine that only stimulates humoral immunity would seem likely to fail. Unfortunately, although it's relatively easy to make a safe vaccine that stimulates humoral immunity, it's much harder to make a safe vaccine that stimulates cellular immunity. Why? Because the best way to stimulate cellular immunity is with a live virus vaccine—in this case, a vaccine made from HIV that has been attenuated by removing some of its genes, but has not been killed. The problem is that live virus vaccines pose a risk of infection—a risk that is unacceptable with HIV. The potential danger of this approach was underscored when monkeys were given a simian version of such a vaccine and
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Pharmacology Care, 7thisEdition vaccines pose afor risk Nursing of infection—a risk that unacceptable with HIV. The potential danger of this approach was underscored when monkeys were given a simian version of such a vaccine and subsequently developed simian AIDS, presumably from the vaccine itself. 94.11.2
Current Status of Vaccine Development Although HIV vaccines have undergone intensive study, the number of promising candidates has dropped substantially. In 2005, 34 candidate HIV vaccines were in early phases of human clinical trials. Today, only a handful are being tested in humans. To date, only one vaccine—AIDSVAX—has undergone a Phase III trial. AIDSVAX is a bivalent vaccine composed of gp120 proteins, which are found in the outer envelope of HIV. The vaccine activates the antibody-producing arm of the immune system, but does not activate killer T cells. The Phase III trial enrolled 5095 HIV-negative men and 308 HIV-negative women, all considered at high risk of acquiring HIV. One-third of participants received placebo, and twothirds were injected with vaccine. The result? HIV infection developed in 5.8% of placebo recipients and 5.7% of those given the vaccine. Clearly, AIDSVAX didn't work. These results were especially disappointing in that, in an earlier trial, the vaccine elicited production of neutralizing antibodies in 99% of vaccinees. Apparently, although antibodies were made, they were unable to prevent infection. The current best hope for protection is to combine a vaccine similar to AIDSVAX (ie, a purified HIV envelope protein) with a “vectored” vaccine, consisting of a harmless virus, such as canarypox, that has been genetically engineered to produce HIV proteins. In Phase I and II clinical trials, this approach appeared safe, and elicited both antibody production and activation of killer T cells.
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KEEPING CURRENT Drug therapy of HIV infection is continuously evolving. New drugs are being developed, knowledge of existing drugs is expanding, and new drug combinations are being studied. The following web sites are good sources of very current information: • AIDSinfo (aidsinfo.nih.gov). This site, maintained by the U.S. Department of Health and Human Services, has information on treatment guidelines, drugs, vaccines, and clini cal trials. Links to other HIV/AIDS-related sites are there too. Content is presented in English and Spanish. You can sign up for e-mail notification of updates.
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Pharmacology for Nursing 7thnotification Edition of updates. and Spanish. You can sign upCare, for e-mail • HIV and AIDS Activities (www.fda.gov/oashi/aids/hiv.html). This page on the FDA web site offers the latest information on approved drugs, drug development, and drugs in clinical trials. • AIDS Education Global Information System (www.aegis.com). Perhaps the best single web site for information on HIV and AIDS information. The site contains the world's largest HIV/AIDS information base, is continuously updated, and offers chat facilities. 94.12.1
KEY POINTS ▪ HIV is a retrovirus that, like all other retroviruses, has RNA as its genetic material. ▪ To infect our cells, HIV must bind to a cell-surface receptor (CD4) as well as a coreceptor (most often CCR5), and then fuse with the cell membrane. ▪ HIV uses reverse transcriptase to convert its RNA into DNA, and integrase to insert its DNA into ours. ▪ HIV uses protease to break large HIV polyproteins into their smaller, functional forms. ▪ The principal targets of HIV are CD4 T cells (helper T lymphocytes). These cells are attacked by HIV because they carry CD4 proteins on their surface, thereby providing HIV with a required point of attachment. ▪ Because of errors made by reverse transcriptase, HIV can mutate rapidly from a drugsensitive form into a drug-resistant form. ▪ HIV infection has three phases. During the initial phase, many patients experience a flulike acute retroviral syndrome. During the prolonged middle phase, patients are asymptomatic, although CD4 T cells undergo progressive decline. During the late phase, CD4 T cells drop below a critical level (200 cells/mL), rendering the patient vulnerable to opportunistic infections and certain neoplasms. ▪ HIV replicates rapidly during all phases of HIV infection, including the prolonged phase of clinical latency. ▪ We have six classes of antiretroviral drugs. Four classes—nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), integrase inhibitors, and protease inhibitors (PIs)—inhibit HIV enzymes. The two other classes—HIV fusion inhibitors and CCR5 antagonists—work outside CD4
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Pharmacology forintegrase Nursing Care,and 7th Edition (NNRTIs), inhibitors, protease inhibitors (PIs)—inhibit HIV enzymes. The two other classes—HIV fusion inhibitors and CCR5 antagonists—work outside CD4 cells to block HIV entry. ▪ NRTIs suppress HIV replication in two ways: (1) they become incorporated into the growing strand of viral DNA (through the actions of reverse transcriptase), and thereby prevent further strand growth; and (2) they compete with natural nucleoside triphosphates for binding to the active center of reverse transcriptase, and thereby competitively inhibit the enzyme. ▪ In order to interact with reverse transcriptase, NRTIs must first undergo intracellular conversion to their active (triphosphate) forms. ▪ All NRTIs can cause lactic acidosis and severe hepatomegaly with steatosis, which can be fatal. ▪ Zidovudine (an NRTI) can cause severe anemia and neutropenia. ▪ Didanosine and stavudine (both NRTIs) can cause peripheral neuropathy. ▪ Didanosine (an NRTI) can cause pancreatitis. ▪ Abacavir (an NRTI) can cause potentially fatal hypersensitivity reactions, and hence must not be given to patients with the HLA-B*5701 mutation, which predisposes them to abacavir hypersensitivity. ▪ NNRTIs (eg, efavirenz) differ from NRTIs in that they are not analogs of natural nucleosides, are active as administered, and cause direct noncompetitive inhibition of reverse transcriptase by binding to its active center. ▪ NNRTIs frequently cause rash, which can be severe and even life threatening. ▪ Efavirenz is the only NNRTI recommended for first-line therapy of HIV infection. ▪ Efavirenz frequently causes adverse CNS effects. ▪ Efavirenz is teratogenic, and must not be used during pregnancy. ▪ PIs (eg, lopinavir) are among the most effective antiretroviral drugs. ▪ PIs bind to HIV protease and thereby prevent the enzyme from cleaving HIV polyproteins. As a result, enzymes and structural proteins of HIV remain nonfunctional, and hence the virus remains immature and noninfectious.
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Pharmacology fortheNursing Care, 7th and Edition and hence virus remains immature noninfectious. ▪ All PIs pose a risk of hyperglycemia, new-onset diabetes, exacerbation of existing diabetes, fat maldistribution, hyperlipidemia, bone loss, elevation of transaminase levels, and increased bleeding in patients with hemophilia. ▪ All PIs inhibit cytochrome P450, and can thereby decrease metabolism of other drugs, causing their levels to rise. Accordingly, patients should avoid drugs whose accumulation could lead to serious toxicity. Among these are cisapride, alprazolam, triazolam, midazolam, ergot alkaloids, lovastatin, and simvastatin—as well as astemizole and terfenadine, which are no longer available in the United States. ▪ Ritonavir—a PI that strongly inhibits P450—is often combined with other PIs to raise their plasma levels, and thereby boost antiviral effects. ▪ Raltegravir, the first HIV integrase inhibitor, prevents insertion of HIV-derived DNA into DNA of CD4 cells, and thereby blocks HIV replication. ▪ Enfuvirtide, an HIV fusion inhibitor, binds with gp41 on the viral envelope, and thereby blocks entry of HIV into CD4 T cells. ▪ Enfuvirtide is indicated for HIV infection that is resistant to other antiretroviral drugs. ▪ The major adverse effect of enfuvirtide is injection-site reactions, which develop in nearly all patients. ▪ Maraviroc—the first CCR5 antagonist—blocks HIV entry into CD4 cells. Effects are limited to HIV strains that are CCR5 tropic (ie, strains that use the CCR5 co-receptor for cellular entry). Before maraviroc is used, the infecting strains must be tested for CCR5 tropism. ▪ Treatment of HIV infection has five goals: maximal and durable suppression of viral load, restoration and/or preservation of immune function, improvement of quality of life, reduction of HIV-related morbidity and mortality, and prevention of vertical HIV transmission.
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▪ Resistance to antiretroviral drugs is a major problem. To reduce emergence of resistance, these drugs should never be used alone. Rather, they should always be combined with at least one other antiretroviral drug, and preferably two or even three. ▪ The principal laboratory tests employed to monitor HIV infection and guide therapy are plasma HIV RNA (viral load) and CD4 T-cell counts. Plasma HIV RNA levels indicate the magnitude of HIV replication and predict the rate of CD4 T-cell destruction, whereas
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Pharmacology for RNA Nursing Care, plasma HIV (viral load) and7th CD4 Edition T-cell counts. Plasma HIV RNA levels indicate the magnitude of HIV replication and predict the rate of CD4 T-cell destruction, whereas CD4 T-cell counts indicate how much damage the immune system has already suffered. ▪ Plasma HIV RNA is the best measurement for predicting clinical outcome: if HIV RNA is high, the prognosis is poor; if HIV RNA is low, the risk of disease progression and death is greatly reduced. Accordingly, the goal of antiretroviral therapy is to decrease plasma HIV RNA to levels that are undetectable—now defined as less than 50 copies/ mL (using the Amplicor assay). ▪ Reducing plasma HIV RNA to undetectable levels does not mean that HIV has been eradicated. It only means there is too little HIV to measure. Nonetheless, patients still harbor HIV and are still infectious. Accordingly, treatment should continue indefinitely, and patients should be warned to avoid behaviors that can transmit HIV to others. ▪ All patients with acute primary HIV disease or advanced (symptomatic) HIV disease should receive maximally effective antiretroviral therapy. Two regimens are preferred: (1) efavirenz (an NNRTI) plus two NRTIs, and (2) ritonavir-boosted lopinavir (a PI) combined with two NRTIs. ▪ For some patients with chronic asymptomatic HIV disease, it may be appropriate to temporarily postpone antiretroviral therapy. ▪ In general, the principles that guide antiretroviral therapy in nonpregnant adults also apply during pregnancy. Put another way, women should receive optimal antiretroviral therapy, regardless of their pregnancy status. ▪ Mother-to-child transmission of HIV occurs primarily during labor and delivery. The risk of transmission can be greatly reduced by ART that minimizes maternal viral load. Zidovudine should be given to the mother during pregnancy (PO) and labor (IV), and to the infant (PO) for 6 weeks postpartum. ▪ In general, the principles that guide antiretroviral therapy in adults also apply to children. ▪ An important reason for changing an antiretroviral regimen is treatment failure, indicated by failure of plasma HIV RNA to drop to an undetectable level; a rebound in plasma HIV RNA after falling to an undetectable level; CD4 T-cell counts failing to rise (or continuing to decline); and progression of clinical disease despite antiretroviral treatment.
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Pharmacology for Nursing Care, 7th Edition treatment. ▪ When treatment failure is the result of drug resistance, the preferred response is to change all drugs in the regimen. Furthermore, the new drugs should be agents that the patient has not taken before and that are not cross-resistant with drugs the patient has taken before. ▪ Prophylactic drugs can reduce the risk of infection following accidental exposure to HIV (eg, from a needle stick). Prophylaxis is most effective when initiated within 1 or 2 hours, and may be ineffective if initiated after 72 hours. ▪ Because of declining CD4 T-cell counts, individuals with advanced HIV disease are at risk for opportunistic infections (OIs), and hence may need prophylactic antibiotics. ▪ By elevating CD4 T-cell counts, ART can restore immune function, and can thereby reduce both the risk of OIs and the need for prophylactic antibiotics. ▪ Among people with AIDS, Pneumocystis pneumonia (PCP) is the most common opportunistic infection. ▪ The preferred regimen for prophylaxis and treatment of PCP is trimethoprim plus sulfamethoxazole. ▪ Ganciclovir is the drug of choice for cytomegalovirus retinitis, an OI. 94.12.2 94.1...
Summary of Major Nursing Implications* NUCLEOSIDE/NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITORS Abacavir Didanosine Emtricitabine Lamivudine Stavudine
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Pharmacology for Nursing Care, 7th Edition Stavudine Tenofovir Zidovudine 94.1... 94.1...
Preadministration Assessment Therapeutic Goals Treatment has five goals: maximal and durable suppression of viral load, restoration and/ or preservation of immune function, improvement of quality of life, reduction of HIVrelated morbidity and mortality, and prevention of HIV transmission.
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Baseline Data
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All NRTIs. Assess the patient's clinical status and obtain a plasma HIV RNA level and CD4 T-cell count.
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Zidovudine. Obtain a hemoglobin value and granulocyte count.
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Abacavir. Screen for HLA-B*5701, which indicates abacavir hypersensitivity.
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Identifying High-Risk Patients Didanosine. The risk of pancreatitis is increased by a history of alcoholism or pancreatitis and by use of IV pentamidine.
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Zidovudine. The risk of hematologic toxicity is increased by a low granulocyte count; low levels of hemoglobin, vitamin B12, or folic acid; and concurrent use of drugs that are myelosuppressive, nephrotoxic, or toxic to circulating blood cells.
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Pharmacology for Nursing Care, 7th Edition myelosuppressive, nephrotoxic, or toxic to circulating blood cells. 94.1... 94.1... 94.1...
Implementation: Administration Routes All NRTIs. Oral.
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Zidovudine. Oral and IV.
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Administration All NRTIs. Instruct patients to adhere closely to the prescribed dosing schedule.
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Didanosine. Instruct patients to take all didanosine formulations 30 minutes before meals or 2 hours after. Instruct patients taking buffered didanosine tablets to either (1) chew them thoroughly or (2) manually crush them or disperse them in at least 1 ounce of water. Instruct patients using enteric-coated capsules to swallow them intact. Instruct patients taking powdered didanosine to pour the contents of one packet into 4 ounces of water (not fruit juice or any other acid-containing beverage), stir the mixture until the drug dissolves (about 2 to 3 minutes), and then drink the solution immediately.
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IV Zidovudine. Administer IV zidovudine slowly (over 1 hour). Do not mix the solution with biologic or colloidal fluids (eg, blood products, protein solutions). Administer within 8 hours (if stored at room temperature) or within 24 hours (if stored under refrigeration).
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Pharmacology Nursing Care, 7th Edition storedfor at room temperature) or within 24 hours (if stored under refrigeration). 94.1... 94.1... 94.1...
Ongoing Evaluation and Interventions Evaluating Therapeutic Effects Plasma HIV RNA. Success is indicated by a reduction in plasma HIV RNA. With ART, plasma HIV RNA should decline to 10% of baseline within 2 to 8 weeks. After 16 to 20 weeks of treatment, plasma HIV RNA should reach its minimum. Ideally, the minimum will be undetectable with sensitive assays.
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CD4 T-Cell Counts. As viral load decreases, CD4 T-cell counts may rise, indicating some restoration of immune function.
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Minimizing Adverse Effects Anemia and Neutropenia. Zidovudine can cause severe anemia and neutropenia. Determine hematologic status before treatment and at least every 4 weeks thereafter. In the event of severe anemia (hemoglobin below 7.5 gm/dL or down 25% from the pretreatment baseline) or severe neutropenia (granulocyte count below 750 cells/mL or down 50% from the pretreatment baseline), interrupt treatment until there is evidence of bone marrow recovery. If neutropenia and anemia are less severe, a reduction in dosage may be sufficient. Some patients may require multiple transfusions. Granulocyte colonystimulating factors can be used to reverse neutropenia. Epoetin alfa (recombinant erythropoietin) can be given to reduce transfusion requirements in patients with anemia, provided endogenous erythropoietin levels are not already elevated.
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Lactic Acidosis with Hepatic Steatosis. Potentially fatal lactic acidosis and hepatic steatosis can occur with all NRTIs. Inform patients about symptoms—nausea, vomiting, abdominal pain, malaise, fatigue, anorexia, and hyperventilation—and instruct them to report these immediately. Diagnosis is done by measuring lactate in arterial blood. If lactic acidosis is present, the NRTI should be discontinued.
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Pharmacology forshould Nursing Care, 7th Edition the NRTI be discontinued. 94.1...
Pancreatitis. Didanosine can cause potentially fatal pancreatitis. Monitor patients for signs of developing pancreatitis (elevated serum amylase in association with elevated serum triglycerides, decreased serum calcium, and nausea, vomiting, or abdominal pain). If evolving pancreatitis is diagnosed, didanosine should be withdrawn.
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Peripheral Neuropathy. Didanosine and stavudine can cause painful peripheral neuropathy. Inform patients about early signs of neuropathy (numbness, tingling, or pain in hands and feet), and instruct them to report these immediately. Treat pain of severe neuropathy with opioid analgesics. Neuropathy may reverse if these drugs are withdrawn early.
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Hypersensitivity Reactions. Abacavir can cause potentially fatal hypersensitivity reactions. Before using abacavir, screen for HLA-B*5701 (a genetic variant associated with abacavir hypersensitivity), and don't use the drug if the variant is detected. Inform patients of symptoms—fever, rash, myalgia, arthralgia, nausea, vomiting, diarrhea, abdominal pain, pharyngitis, dyspnea, and cough—and instruct them to report these immediately. If a hypersensitivity reaction is diagnosed—or even strongly suspected—abacavir should be discontinued and never used again.
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HIV Transmission. Reduction of plasma HIV RNA may create a false sense of safety. Accordingly, inform patients that, even when HIV RNA is undetectable, they are still infectious, and hence should avoid behaviors that can transmit HIV.
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Minimizing Adverse Interactions Zidovudine. Drugs that are myelosuppressive, nephrotoxic, or directly toxic to circulating blood cells can increase the risk of hematologic toxicity. Drugs of concern include ganciclovir, dapsone, pentamidine, pyrimethamine, trimethoprim/sulfamethoxazole, amphotericin B, flucytosine, vincristine, vinblastine, and doxorubicin.
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Pharmacology for Nursing Care, 7th Edition amphotericin B, flucytosine, vincristine, vinblastine, and doxorubicin. 94.1...
Ribavirin. Ribavirin can increase levels of the active form of didanosine, thereby posing a risk of toxicity. Use the combination with caution.
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All NRTIs. Giving a combination of NRTIs to a pregnant woman may increase the risk of lactic acidosis and hepatic steatosis. Accordingly, it would seem prudent to avoid these combinations during pregnancy.
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NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS Delavirdine Efavirenz Etravirine Nevirapine
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Preadministration Assessment Therapeutic Goals Treatment has five goals: maximal and durable suppression of viral load, restoration and/ or preservation of immune function, improvement of quality of life, reduction of HIVrelated morbidity and mortality, and prevention of HIV transmission.
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Baseline Data Assess the patient's clinical status and obtain a plasma HIV RNA level, CD4 T-cell count, and liver function tests. Perform a pregnancy test prior to giving efavirenz.
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Implementation: Administration Route Oral.
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Pharmacology Oral. for Nursing Care, 7th Edition 94.1...
Administration
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All NNRTIs. Instruct patients to adhere closely to the prescribed dosing schedule.
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Delavirdine. Inform patients that delavirdine may be taken with or without food. Advise patients who cannot swallow delavirdine tablets whole to mix them with 3 or more ounces of water. Advise patients with achlorhydria to take delavirdine with an acidic beverage, such as orange or cranberry juice.
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Efavirenz. Instruct patients to take efavirenz with or without food—but not with a high-fat meal.
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Nevirapine. Inform patients that nevirapine may be taken with or without food.
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Etravirine. Instruct patients to take etravirine after a meal.
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Ongoing Evaluation and Interventions Evaluating Therapeutic Effects See information for NRTIs.
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Minimizing Adverse Effects Rash. Rash is common and may range from mild to severe to life threatening. Risk of a severe reaction is greatest with nevirapine. If rash is mild, treat with an antihistamine or topical glucocorticoid. If rash is severe or associated with signs of toxic epidermal necrolysis or Stevens-Johnson syndrome (fever, blistering, oral lesions, conjunctivitis, muscle pain, joint pain), the NNRTI should be withdrawn. To minimize risk, use a low dosage for the first 14 days of treatment, and then increase the dosage if rash has not
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Pharmacology Nursing 7th should Edition musclefor pain, joint pain),Care, the NNRTI be withdrawn. To minimize risk, use a low dosage for the first 14 days of treatment, and then increase the dosage if rash has not occurred. 94.1...
Hepatotoxicity. NNRTIs can cause hepatotoxicity, which may be severe. Risk is greatest with nevirapine. Perform liver function tests at baseline and periodically thereafter. Interrupt treatment if tests indicate significant liver injury.
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CNS Symptoms. Efavirenz frequently causes CNS symptoms (eg, dizziness, insomnia, impaired consciousness, drowsiness, vivid dreams, nightmares). Inform patients that symptoms typically resolve in 2 to 4 weeks, despite ongoing efavirenz use, and that taking efavirenz at bedtime can minimize CNS effects. If severe symptoms occur (eg, delusions, hallucinations, severe acute depression), efavirenz should be withdrawn.
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Birth Defects. Efavirenz is teratogenic. Inform women about the potential for fetal harm, and instruct them to use a barrier method of birth control (eg, condom) in conjunction with a hormonal method (eg, oral contraceptive). Perform a pregnancy test prior to treatment.
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HIV Transmission. Reduction of plasma HIV RNA may create a false sense of safety. Accordingly, inform patients that, even when HIV RNA is undetectable, they are still infectious, and hence must avoid behaviors that can transmit HIV.
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Minimizing Adverse Interactions Nevirapine. Nevirapine induces cytochrome P450 and can thereby decrease levels of other drugs. Effects on protease inhibitors, oral contraceptives, and methadone are of particular concern.
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Pharmacology for Nursing Care, 7th Edition concern. Combining nevirapine with St. John's wort or rifampin, which also induce P450, can decrease nevirapine levels, and hence these combinations should be avoided. 94.1...
Delavirdine. Delavirdine inhibits P450, and can thereby increase levels of other drugs. To avoid toxicity from excessive drug levels, patients must not take cisapride, alprazolam, midazolam, triazolam, lovastatin, or simvastatin—or astemizole or terfenadine, which are no longer available in the United States. In addition, the following drugs should be used with caution: indinavir, saquinavir, clarithromycin, dapsone, warfarin, quinidine, ergot alkaloids, PDE5 inhibitors (eg, sildenafil [Viagra]), and the dihydropyridine-type calcium channel blockers. Antacids, histamine2-receptor blockers, proton pump inhibitors, and buffered formulations of didanosine can decrease absorption of delavirdine.
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Efavirenz. Efavirenz competes with other drugs for metabolism by P450, and can thereby increase their levels. To avoid toxicity from excessive drug levels, the patient must not take astemizole, terfenadine, cisapride, midazolam, triazolam, dihydroergotamine, or ergotamine. Efavirenz induces P450, and can thereby accelerate metabolism of other drugs, including two PIs: saquinavir and indinavir. Avoid combined use with saquinavir. Increase indinavir dosage. St. John's wort induces P450, and can thereby reduce levels of efavirenz. The combination should not be used.
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Etravirine. Etravirine competes with other drugs for metabolism by P450 and can thereby increase their levels. The plasma concentration of etravirine is lowered by use of St. John's wort, anticonvulsants, darunavir/ritonavir, systemic dexamethasone, rifampin, rifapentine, ritonavir, saquinavir/ritonavir, and tipranavir/ritonavir.
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Pharmacology forsaquinavir/ritonavir, Nursing Care,and 7thtipranavir/ritonavir. Edition ritonavir, 94.1...
PROTEASE INHIBITORS Amprenavir Atazanavir Darunavir Fosamprenavir Indinavir Lopinavir/Ritonavir Nelfinavir Ritonavir Saquinavir Tipranavir
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Preadministration Assessment Therapeutic Goals Treatment has five goals: maximal and durable suppression of viral load, restoration and/ or preservation of immune function, improvement of quality of life, reduction of HIVrelated morbidity and mortality, and prevention of vertical HIV transmission.
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Baseline Data Assess the patient's clinical status and obtain a plasma HIV RNA level and CD4 T-cell count. Measure serum transaminases and blood glucose.
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Pharmacology for Nursing Care, 7thandEdition count. Measure serum transaminases blood glucose. 94.1...
Identifying High-Risk Patients Amprenavir oral solution is contraindicated for pregnant women, children less than 4 years old, patients with renal or hepatic failure, and patients taking disulfiram or metronidazole.
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Implementation: Administration Route All protease inhibitors are taken orally.
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Administration and Storage All Protease Inhibitors. Instruct patients to adhere closely to the prescribed dosing schedule.
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Atazanavir, Darunavir, Tipranavir, Lopinavir/Ritonavir. Instruct patients to take these products with food.
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Amprenavir. Inform patients they can take amprenavir without food or with food—as long as the food is low fat.
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Indinavir. Instruct patients to administer indinavir (1) with water but on an empty stomach (ie, 1 hour before a meal or 2 hours after); or (2) with skim milk, coffee, tea, or a low-fat meal (eg, corn flakes with skim milk and sugar), but not with a large meal. Instruct patients to store indinavir at room temperature in the package supplied by the manufacturer.
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Nelfinavir. Instruct patients to take nelfinavir with food. Instruct patients to mix the powder formulation with a small amount of water, milk, formula, soy formula, soy milk, or dietary supplement, but not with acidic foods or juices (eg, applesauce, apple
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Pharmacology for Nursing Care, 7thofEdition formulation with a small amount water, milk, formula, soy formula, soy milk, or dietary supplement, but not with acidic foods or juices (eg, applesauce, apple juice, orange juice). 94.1...
Ritonavir. Advise patients to take ritonavir with food. Instruct patients to mix the oral solution with chocolate milk, Ensure, or Advera (within 1 hour of administration) to improve the taste. Instruct patients to store ritonavir refrigerated (2°C to 8°C; 36°F to 46°F) and protected from light.
94.1...
Saquinavir. Instruct patients to take saquinavir tablets or capsules with a ritonavir boost; dosing may be done with or without food.
94.1... 94.1...
Ongoing Evaluation and Interventions Evaluating Therapeutic Effects See information for NRTIs.
94.1... 94.1...
Minimizing Adverse Effects Hyperglycemia/Diabetes. All PIs can cause hyperglycemia and diabetes. Instruct patients to report any symptoms (eg, polydipsia, polyphagia, polyuria). In patients with existing diabetes, monitor blood glucose closely. To detect new-onset diabetes, measure blood glucose at baseline, every 3 to 4 months during the first year of treatment, and less frequently thereafter. Diabetes can be treated with insulin and oral antidiabetic agents (eg, metformin).
94.1...
Fat Maldistribution. Forewarn patients that all PIs may cause accumulation of fat on the waist, stomach, breasts, and back of the neck, and loss of fat from the face, arms, buttocks, and legs. Drug withdrawal may cause symptoms to resolve, but is not recommended. Injections of Sculptra can be used to compensate for loss of facial fat.
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Pharmacology for Nursing Care, 7th Edition recommended. Injections of Sculptra can be used to compensate for loss of facial fat. 94.1...
Hyperlipidemia. All PIs can elevate cholesterol and triglycerides, thereby posing a risk of cardiovascular events and pancreatitis. Monitoring plasma cholesterol and triglycerides every 3 to 4 months may be wise. If drugs are given to lower lipid levels, two agents— lovastatin and simvastatin—should be avoided.
94.1...
Increased Bleeding in Patients with Hemophilia. Protease inhibitors may increase the risk of bleeding in patients with hemophilia. Higher doses of coagulation factors may be needed.
94.1...
Increased Transaminase Levels. Protease inhibitors can increase serum levels of transaminases. Exercise caution in patients with chronic liver disease (eg, hepatitis B or C, cirrhosis). Measure serum transaminases before treatment and periodically thereafter.
94.1...
Nephrolithiasis. Indinavir can cause nephrolithiasis. Management consists of hydration and interruption of indinavir for 1 to 3 days. To decrease the risk of nephrolithiasis, instruct patients to consume at least 48 ounces (1.5 L) of water daily.
94.1...
Bone Loss. Protease inhibitors may promote bone loss. To reduce risk, encourage patients to ensure adequate intake of calcium and vitamin D. Osteoporosis can be treated with bisphosphonates, raloxifene, calcitonin, or teriparatide.
94.1...
Diarrhea. Nelfinavir causes diarrhea in 20% to 32% of patients. Diarrhea can usually be managed with loperamide or some other over-the-counter antidiarrheal drug.
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Propylene Glycol Toxicity. Amprenavir oral solution contains a large amount of propylene glycol, which can accumulate to toxic levels in certain patients. Accordingly, this formulation must not be given to pregnant women, children less than 4 years old, patients with renal or hepatic failure, and patients taking disulfiram or metronidazole. Advise patients to
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Pharmacology fortoNursing Care,children 7th Edition be given pregnant women, less than 4 years old, patients with renal or hepatic failure, and patients taking disulfiram or metronidazole. Advise patients to avoid alcohol. 94.1...
Atrioventricular Block. Atazanavir prolongs the PR interval, and can thereby promote AV block. Use with caution in patients with cardiac conduction disturbances.
94.1...
Indirect Hyperbilirubinemia. Atazanavir and indinavir can raise plasma levels of unconjugated bilirubin (indirect bilirubin). Be alert for jaundice (yellowing of the skin) and icterus (yellowing of the eyes), which reverse upon drug withdrawal.
94.1...
HIV Transmission. Reduction of plasma HIV RNA may create a false sense of safety. Accordingly, inform patients that, even when HIV RNA is undetectable, they may still be infectious, and hence should avoid behaviors that can transmit HIV.
94.1... 94.1...
Minimizing Adverse Interactions Interactions Resulting from Inhibition of P450. All PIs inhibit cytochrome P450, and can thereby increase levels of other drugs. To avoid serious toxicity from excessive drug levels, patients must not take cisapride, alprazolam, triazolam, midazolam, ergot alkaloids, lovastatin, or simvastatin—or astemizole or terfenadine, which are no longer available in the United States.
94.1...
Ritonavir Boosting. Because ritonavir is a powerful inhibitor of P450, the drug is often combined with other PIs to raise their blood levels, and thereby boost antiviral effects.
94.1...
Didanosine. Buffered formulations of didanosine decrease absorption of indinavir and ritonavir. Accordingly, buffered didanosine should be administered 1 or 2 hours apart from these drugs.
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Pharmacology drugs.for Nursing Care, 7th Edition 94.1...
Rifampin. Rifampin induces P450, and can thereby reduce levels of the PIs. Concurrent use with all PIs should be avoided.
94.1...
Oral Contraceptives. Ritonavir, nelfinavir, and amprenavir can reduce levels of ethinyl estradiol, a component of many oral contraceptives. Advise patients to use an alternative form of birth control.
94.1...
Vitamin E. Amprenavir formulations contain a large amount of vitamin E. Warn patients not to take vitamin E supplements.
94.1...
St. John's Wort. St. John's wort induces P450, and can thereby reduce levels of PIs. Warn patients not to use St. John's wort.
94.1... 94.1... 94.1...
ENFUVIRTIDE, AN HIV FUSION INHIBITOR Preadministration Assessment Therapeutic Goals Enfuvirtide is indicated for HIV infection that is resistant to traditional antiretroviral drugs. Treatment has five goals: maximal and durable suppression of viral load, restoration and/ or preservation of immune function, improvement of quality of life, reduction of HIVrelated morbidity and mortality, and prevention of vertical HIV transmission.
94.1...
Baseline Data Assess the patient's clinical status and obtain a plasma HIV RNA level and CD4 T-cell count.
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Pharmacology count. for Nursing Care, 7th Edition 94.1...
Identifying High-Risk Patients Use enfuvirtide with caution in patients who have pneumonia risk factors: low initial CD4 cell counts, high initial viral load, IV drug use, smoking, and a history of lung disease.
94.1... 94.1...
Implementation: Administration Route Subcutaneous.
94.1...
Preparation and Storage Teach patients to reconstitute powdered enfuvirtide with 1.1 mL of sterile water for injection, and advise them to either (1) inject the solution immediately or (2) store it cold (2°C to 8°C; 36°F to 46°F) for up to 24 hours. Inform patients that powdered enfuvirtide may be stored at room temperature.
94.1...
Administration Educate patients on aseptic injection technique, and instruct them to • Make injections into the upper arm, thigh, or abdomen (but not the navel) • Rotate the injection site • Avoid sites where there is an ongoing injection-site reaction or tissue that is scarred or bruised Instruct patients that, before using stored enfuvirtide solution, they should bring it to room temperature and make sure it is clear, colorless, and free of bubbles and particulate matter.
94.1... 94.1...
Ongoing Evaluation and Interventions Evaluating Therapeutic Effects See information for NRTIs.
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Pharmacology for Nursing Care, 7th Edition See information for NRTIs. 94.1...
Minimizing Adverse Effects
94.1...
Injection-Site Reactions. Inform patients about manifestations of ISRs—pain, tenderness, erythema, induration, nodules, cysts, pruritus, and ecchymosis—and forewarn them that these occur in nearly everyone. Inform patients that they can reduce the risk of a severe ISR by rotating the injection site, avoiding sites with an active ISR, and avoiding unnecessarily deep injections. Instruct patients to seek immediate medical attention if a severe ISR occurs or if local infection develops.
94.1...
Pneumonia. Enfuvirtide may increase the risk of bacterial pneumonia. Inform patients about signs of pneumonia—cough, fever, and breathing difficulties—and instruct them to report these immediately. Use enfuvirtide with caution in patients who have pneumonia risk factors.
94.1...
1130 1131
Hypersensitivity Reactions. Enfuvirtide may cause hypersensitivity reactions, manifesting as rash, fever, nausea, vomiting, chills, rigors, hypotension, or elevated serum transaminases, or possibly as respiratory distress, glomerulonephritis, Guillain-Barré syndrome, or primary immune complex reaction. Inform patients about signs of hypersensitivity, and advise them to report them immediately. If a systemic hypersensitivity reaction occurs, enfuvirtide should be discontinued and never used again.
94.1...
HIV Transmission. Reduction of plasma HIV RNA may create a false sense of safety. Accordingly, inform patients that, even when HIV RNA is undetectable, they are still infectious, and hence must avoid behaviors that can transmit HIV.
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Pharmacology for Nursing Care, 7thbehaviors Editionthat can transmit HIV. infectious, and hence must avoid 94.1... 94.1... 94.1...
MARAVIROC, A CCR5 ANTAGONIST Preadministration Assessment Therapeutic Goals Maraviroc, in combination with other antiretroviral, is indicated for treatmentexperienced adults infected with CCR5-tropic strains of HIV that are resistant to multiple other drugs. Treatment has five goals: maximal and durable suppression of viral load, restoration and/ or preservation of immune function, improvement of quality of life, reduction of HIVrelated morbidity and mortality, and prevention of vertical HIV transmission.
94.1...
Baseline Data Assess the patient's clinical status and obtain the following laboratory data: HIV RNA level, CD4 T-cell count, serum transaminases, and proof that the infecting HIV strain is CCR5 tropic.
94.1...
Identifying High-Risk Patients Patients with elevated liver function and cardiovascular disease must be monitored carefully.
94.1... 94.1...
Implementation: Administration Route Oral.
94.1...
Administration Inform patients that dosing may be done with or without food. Advise patients that, if they forget to take a dose, to take the missed dose as soon as possible, and take the next scheduled dose at its regular time. If the time to the next dose is less than 6 hours, the patient should skip the missed dose and take the next dose as scheduled.
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Pharmacology Nursing Care, 7th Edition dose as for scheduled. 94.1... 94.1...
Ongoing Evaluation and Interventions Evaluating Therapeutic Effects See information for NRTIs.
94.1... 94.1...
Minimizing Adverse Effects Hepatotoxicity. Liver injury has been seen in some patients, and may be preceded by evidence of an allergic reaction. Inform patients about signs of an evolving reaction (itchy rash, yellow skin, dark urine, vomiting and/or abdominal pain), and instruct them stop maraviroc and seek medical attention.
94.1...
Cardiovascular Events. During clinical trials, a few patients experienced cardiovascular events, including myocardial ischemia and myocardial infarction. Exercise caution in patients with cardiovascular risk factors.
94.1...
HIV Transmission. Inform patients that maraviroc is not a cure for HIV infection; it does not reduce the risk of transmission of HIV to others through sexual contact, sharing needles, or blood contamination.
94.1... 94.1... 94.1...
RALTEGRAVIR, AN INTEGRASE INHIBITOR Preadministration Assessment Therapeutic Goals Raltegravir is used for treatment-experienced adults infected with HIV-1 strains resistant to multiple antiretroviral agents. Treatment has five goals: maximal and durable suppression of viral load, restoration and/ or preservation of immune function, improvement of quality of life, reduction of HIVrelated morbidity and mortality, and prevention of vertical HIV transmission.
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Pharmacology for Nursing Care,and 7th Edition related morbidity and mortality, prevention of vertical HIV transmission. 94.1...
Baseline Data Assess the patient's clinical status and obtain a plasma HIV RNA level and CD4 T-cell count.
94.1...
Implementation: Administration
94.1...
Route Oral.
94.1...
Administration Advise patients that dosing may be done with or without food.
94.1...
Ongoing Evaluation and Interventions
94.1...
Evaluating Therapeutic Effects See information for NRTIs.
94.1...
Minimizing Adverse Effects
94.1...
HIV Transmission. Inform patients that raltegravir is not a cure for HIV infection; it does not reduce the risk of transmission of HIV to others through sexual contact, sharing needles, or blood contamination. *
Patient education information is highlighted as blue text.
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95
CHAPTER 94 Drug Therapy of Sexually Transmitted Diseases Sexually transmitted diseases (STDs), also known as sexually transmitted infections, are infectious diseases transmitted primarily through sexual contact. STDs are very common in the United States and constitute a major public health problem. In 2003, the Centers for Disease Control and Prevention (CDC) received more than 1.2 million reports of STDs, including 877,478 cases of genital Chlamydia trachomatis infection and 335,104 cases of gonorrhea. However, because most STDs go unreported, the actual incidence is much higher, estimated at 19 million new infections a year, 50% of which occur in people under the age of 25. According to the CDC, Americans now have a 25% lifetime risk of contracting an STD. Our objective in this chapter is to describe the principal STDs and provide an overview of their treatment. Table 94-1 presents a summary of the common STDs, causative organisms, and drugs of choice for treatment. The basic pharmacology of these drugs is discussed in other chapters. In 2006, the CDC revised its “Sexually Transmitted Diseases Treatment Guidelines,” updating the 2002 version. Most of the treatment recommendations presented in this chapter reflect the 2006 guidelines, which are available online at www.cdc.gov/std/treatment. This site also contains any adjustments to the guidelines (eg, the 2007 changes regarding gonococcal infection), and hence should be consulted for the most current recommendations.
95.1
CHLAMYDIA TRACHOMATIS INFECTIONS
95.1.1
Characteristics Chlamydia trachomatis is the most common cause of bacterial STD in the United States (Fig. 94-1), infecting about 2.8 million people annually. The various strains of Chlamydia can cause genital tract infections, proctitis, conjunctivitis, and lymphogranuloma venereum (LGV), as well as ophthalmia and pneumonia in infants. Infection is frequently asymptomatic in women, and may also be asymptomatic in men. In women, untreated infection can cause pelvic inflammatory disease (PID), ectopic pregnancy, and infertility. The CDC estimates that chlamydial infections cause sterility in up to 50,000 women each year, primarily from fallopian tube scarring. Because infection is often asymptomatic in women, and because sequelae can be serious, the CDC now recommends annual screening for all sexually active women under age 25. Screening is also recommended for women over age 25 who have a new sex partner or multiple partners.
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Pharmacology forwomen Nursing Care, 7th Edition recommended for over age 25 who have a new sex partner or multiple partners. 95.1.2
Treatment
95.1.2.1
Adults and Adolescents. For uncomplicated urethral, cervical, or rectal infections in adults or adolescents, two treatments are recommended: (1) a single 1-gm oral dose of azithromycin [Zithromax] or (2) 100 mg of doxycycline [Vibramycin, others] PO twice daily for 7 days.
95.1.2.2
Infection in Pregnancy. Preferred treatments for C. trachomatis infection during pregnancy are (1) a single 1-gm oral dose of azithromycin or (2) 500 mg of amoxicillin PO 3 times daily for 7 days. Although doxycycline and other tetracyclines are active against C. trachomatis, these drugs are contraindicated because they can damage fetal teeth and bones. Similarly, sulfisoxazole and other sulfonamides are active, but are contraindicated near term because they can promote kernicterus in the infant.
95.1.2.3
Infants. About half the infants born to women with cervical C. trachomatis acquire the infection during delivery, putting them at risk for pneumonia and conjunctivitis (ophthalmia neonatorum). Pneumonia is generally not severe and lasts about 6 weeks. Conjunctivitis does not result in blindness and spontaneously resolves in 6 months. The preferred treatment for both infections is oral erythromycin base or erythromycin succinate, 12.5 mg/kg 4 times daily for 14 days. Although topical erythromycin, tetracycline, or silver nitrate may be given to prevent conjunctivitis, these
Figure 94-1 Incidence of sexually transmitted diseases.
drugs are not completely effective—and they have no effect on pneumonia. CHAPTER 94 Drug Therapy of Sexually Transmitted Diseases
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Pharmacology for Nursing Care, 7th Edition drugs are not completely effective—and they have no effect on pneumonia.
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Pharmacology Nursing Care, 7th drugs are not for completely effective—and theyEdition have no effect on pneumonia.
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TABLE 94-1 Drug Therapy of Sexually Transmitted Diseases* Disease or Syndrome
Recommended Treatment
Chlamydial Infections Adults and adolescents
Azithromycin, 1 gm PO once or
Causative Organism(s) Chlamydia trachomatis
Doxycycline, 100 mg PO 2 times/day × 7 days
Children 8 yr and >45 kg: 100 mg every 12 hr
or
>8 yr and ≤45 kg: 2.2 mg/kg every 12 hr
Doxycycline (for young children):
≤8 yr: 2.2 mg/kg every 12 hr
60 days total (IV and PO combined)
As with adults, all patients should get 1 or 2 >8 yr and >45 kg: 100 mg every 60 days 12 hr additional antibiotics. total (IV and PO >8 yr and ≤45 kg: 2.2 mg/kg combined) every 12 hr ≤8 yr: 2.2 mg/kg every 12 hr
Pregnant
Same as nonpregnant adults
Same as nonpregnant adults
Data from Inglesby TV, et al: Anthrax as a biological weapon, 2002: Updated recommendations for management. JAMA 287:2236–2252, 2002.
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Pharmacology for Nursing Care, 7th Edition TABLE 109-3 Therapy of Inhalational Anthrax in the Mass Casualty Setting
Patient Group
Preferred Initial Oral Therapy
Adults
Ciprofloxacin, 500 mg every 12 hr
Alternative Oral Therapy (if Strain Is Proved Susceptible) Duration Doxycycline, 100 mg every 12 hr
60 days
Amoxicillin, 500 mg every 8 hr Children
Ciprofloxacin, 10–15 mg every 12 hr, but no more than 1 gm/day
≥20 kg: amoxicillin, 500 mg 60 days every 8 hr