Contemporary Diagnosis and Management of Clostridium difficile Infection

First Edition

Contemporary Diagnosis and Management of

Clostridium difficile Infection ®

Erik R. Dubberke, MD, MSPH Assistant Professor of Medicine Washington University School of Medicine St. Louis, MO

Curtis J. Donskey, MD Associate Professor of Medicine Case Western Reserve University Infectious Diseases Section, Cleveland Veterans Affairs Medical Center Cleveland, OH

Contemporary Diagnosis and Management of

Clostridium difficile Infection ®

Erik R. Dubberke, MD, MSPH Assistant Professor of Medicine Washington University School of Medicine St. Louis, MO

Curtis J. Donskey, MD Associate Professor of Medicine Case Western Reserve University Infectious Diseases Section, Cleveland Veterans Affairs Medical Center Cleveland, OH

First Edition Published by Handbooks in Health Care Co., Newtown, Pennsylvania, USA

This book has been prepared and is presented as a service to the medical community. The information provided reflects the knowledge, experience, and personal opinions of the lead authors, Erik R. Dubberke, MD, MSPH, Assistant Professor of Medicine, Washington University School of Medicine, St. Louis, Missouri, and Curtis J. Donskey, MD, Associate Professor of Medicine, Case Western Reserve University, Infectious Diseases Section, Cleveland Veterans Affairs Medical Center, Cleveland, Ohio. Acknowledgment Dee Simmons, a medical writer, contributed to the research and writing of this book.

International Standard Book Number: 978-1-935103-32-5 PDF eBook ISBN: 978-1-937309-57-2 ePub ISBN: 978-1-937309-58-9 Library of Congress Catalog Card Number: 2009932791 Contemporary Diagnosis and Management of Clostridium difficile Infection®. Copyright© 2011 by Handbooks in Health Care Co., a Division of AMM Co., Inc. All rights reserved. Printed in the United States of America. No part of this book may be used or reproduced in any manner whatsoever, included but not limited to electronic or mechanical means such as photocopying, recording, or using any information storage or retrieval system, without written permission, except in the case of brief quotations embodied in critical articles and reviews. For information, write Handbooks in Health Care, 6 Penns Trail, Suite 215, Newtown, Pennsylvania 18940, (215) 860-9600. Web site: www.HHCbooks.com 2

Table of Contents Chapter 1 Epidemiology .................................................................................5 Chapter 2 Pathogenesis ...............................................................................39 Chapter 3 Diagnosis .....................................................................................62 Chapter 4 Treatment/Management ..........................................................82 Chapter 5 CDI Surveillance ........................................................................122 Chapter 6 Prevention .................................................................................137 Index ..........................................................................................166

3

This book is not intended to replace or to be used as a substitute for the complete prescribing information prepared by each manufacturer for each drug. Because of possible variations in drug indications, in dosage information, in newly described toxicities, in drug/drug interactions, and in other items of importance, reference to such complete prescribing information is definitely recommended before any of the drugs discussed are used or prescribed.

4

Chapter 1 1

Epidemiology

C

lostridium difficile, which is often referred to as C diff, is the most important cause of infectious diarrhea in adults. It can be responsible for symptoms ranging from mild diarrhea to life-threatening colitis. In recent years, C difficile has increased in importance to join the ranks of the so-called “superbugs” that resist antimicrobial therapy and flourish in hospitals and long-term care facilities. C difficile is a gram-positive, anaerobic, spore-forming bacillus. The pathogen was originally described by Hall and O’Toole1 in 1935 as a component of the fecal flora of healthy newborns. Because it was difficult to culture and grew slowly, it was named Bacillus difficilis. Hall and O’Toole showed that C difficile produced a potent toxin that was lethal to rabbits, but initially the bacterium was not considered a human pathogen.

Antibiotic-associated Colitis Soon after antibiotics came into use, pseudomembranous colitis (PMC) became a well-recognized complication of antibiotic treatment. Staphylococcus aureus was commonly suspected of causing enterocolitis, and oral vancomycin was the standard and effective treatment.2 In 1974, Tedesco et al3 reported high rates of PMC among patients treated with clindamycin at Barnes Hospital in St. Louis, Missouri. Of 200 patients given clindamycin, 21% developed diarrhea, and in 10% of these patients 5

PMC was seen by endoscopy. Because stool cultures were negative for S aureus, this study stimulated further research to determine the cause of antibiotic-associated colitis. Consequently, PMC also came to be termed “clindamycinassociated colitis.” Further studies were performed to define the cause of clindamycin colitis, including work by Keighley et al4 in England, Fekety and Silva5 in Michigan, and Bartlett6 in Massachusetts. C difficile was identified as the causative pathogen in 1978.7 Additional studies during the 1970s revealed that two toxins, toxin A (an enterotoxin) and toxin B (a cytotoxin), were involved in the pathogenesis of C difficile infection (CDI).6,8,9 Within a few years, the cell culture cytotoxicity assay was established as the preferred method for diagnosis of CDI, clinical studies demonstrated that many classes of antibiotics could induce CDI, older age was confirmed as a risk, and acute care and chronic care facilities were found to be sites of high risk. Oral vancomycin was initially the standard treatment, but oral metronidazole became widely used after randomized, controlled trials showed it to be as effective as vancomycin.10

C difficile Acquisition An ubiquitous organism, C difficile has been cultured from rivers, lakes, sea water, soil, tap water, dog feces, farm animal feces, food intended for human consumption, and home environments.11 Colonization with C difficile is common in neonates, with rates as high as 84% in some series,12 but the pathogen appears unable to cause disease in neonates. It is postulated that this is because of a lack of receptors necessary for toxin A and toxin B to bind to the neonatal intestinal tract.13 Most studies demonstrate that only 3% or less of healthy adults, including health-care workers, are colonized with C difficile at any point in time.14 In contrast, 60% to 70% of people have serologic evidence of past C difficile expos6

ure.15,16 Presumably, people in the community are periodically exposed to low levels of C difficile spores, but are healthy enough to stave off symptomatic infection and to mount an antibody defense against C difficile toxin. The data also suggest that C difficile colonization is transient in healthy adults. The scenario is different in health-care settings. Studies demonstrated that about 20% of hospitalized patients, or patients recently discharged from a hospital, are colonized with C difficile.17,18 The same is true for long-term care facilities, where as many as 51% of patients may be colonized with C difficile.19 The risk of becoming colonized with C difficile increases linearly with length of stay (LOS) in the hospital (Figure 1-1).20 Another study demonstrated that CDI pressure, a measure of exposure to other patients with CDI, is a major risk factor for CDI but not LOS.21 This indicates that LOS is likely a marker for exposure to other patients with CDI, antimicrobial exposure, and severity of illness and comorbidities, rather than an independent risk factor for CDI. The primary vector for C difficile in the health-care setting is the hands of health-care workers. One study demonstrated that C difficile could be detected from the hands of health-care workers 59% of the time after being in the room of a patient with CDI. This was the same whether or not the health-care worker had any direct contact with the patient while in the room.18 The risk of health-care worker hand contamination is related to the severity of the patient’s diarrhea.22 Several studies have also found that patients in rooms adjacent to rooms that housed patients colonized with C difficile were at higher risk for acquiring C difficile or developing CDI than were patients who either shared the room with the colonized patient or who were admitted to the room after the colonized patient was discharged.17,18,22,23 A recent study found that being admitted to a room whose prior occupant had CDI was a risk factor for the 7

1

Percentage of patients who acquired C difficile

50 40 30 20 10

4

Length of hospital stay (wk)

Figure 1-1: Rate of Clostridium difficile acquisition as a function of length of hospital stay in weeks. Data are from a prospective surveillance study of one hospital ward where 557 patients initially culture negative for C difficile were monitored by weekly rectal swab cultures. Only 3 (1%) of 323 patients whose hospital stays were 4 wk became stool culture positive. From Johnson et al.20

newly admitted patient to develop CDI. However, 89% of patients in the study who developed CDI did not have that risk factor, indicating that most patients acquired C difficile from a health-care worker.24 Fomites and the hospital environment are other important, secondary sources of C difficile transmission. C difficile has been cultured from thermometers, telephones, tubs, commodes, scales, stethoscopes, blood pressure cuffs, intravenous pumps, and oximeters.11 The hospital environment can be contaminated with C difficile spores, and it may be necessary to enhance cleaning efforts to remove the spores in outbreak settings.22,25 8

CDI Incidence and Severity For two decades, CDI was viewed as a relatively benign disease, a nuisance of antimicrobial exposure, except for the occasional patient with multiply recurrent CDI or toxic megacolon. Death caused by CDI was uncommon, with several studies unable to find any attributable mortality from CDI. In the last decade, however, a resurgence of CDI has occurred, with increases in incidence and severity. C difficile now rivals, and in some cases surpasses, methicillinresistant Staphylococcus aureus (MRSA) as the most common cause of nosocomial infection in the United States26,27 (Figure 1-2). In fact, CDI is responsible for more deaths in the US than all other intestinal infections combined.28 CDI rates in the US more than doubled between 2000 and 200328 and quadrupled between 1999 and 200429 (Figure 1-3). CDI incidence has also increased in Canada and Europe.30-32 Reports of severe CDI, such as toxic megacolon, perforation, colectomy, and death, have also increased.30-33 These increases in incidence and severity have been associated with a new, predominant strain of C difficile that is known by many names: BI by restriction-enzyme analysis (REA), NAP1 by pulsed-field gel electrophoresis, or 027 by polymerase chain reaction ribotyping. CDI Prevalence In addition to recent well-publicized outbreaks, the overall prevalence of CDI appears to be increasing as well. Historically, there have been no CDI surveillance systems in the US, Canada, or Europe that prospectively track CDI prevalence. Therefore, data on changes in CDI prevalence often depend on analysis of administrative data or comparison of several different studies that may not have used identical definitions for CDI. This has hampered efforts to understand the true extent of CDI. Another limitation of the current available data is that the data are focused on the acute care setting and may miss more than 50% of all health-care–associated CDI. In 2006, the Ohio Department 9

1

Northeast Midwest South West

Incidences/100,000 population

A 160 140 120 100 80 60 40 20 0

2000

2001

2002

2003

2004

2005

2000

2001

2002

2003

2004

2005

2000

2001

2002

2003

2004

2005

Incidences/100,000 population

B 160 140 120 100 80 60 40 20 0

Incidences/100,000 population

C

10

160 140 120 100 80 60 40 20 0

Northeast Midwest South West

Incidences/100,000 population

D 160 140 120 100 80 60 40 20 0

1

2000

2001

2002

2003

2004

2005

2000

2001

2002

2003

2004

2005

Incidences/100,000 population

E 160 140 120 100 80 60 40 20 0

Figure 1-2: Population incidence of resistant infections in the US, by region, 2000-2005. A=Clostridium difficileassociated disease; B=methicillin-resistant Staphylococcus aureus (MRSA); C=vancomycin-resistant Enterococcus (VRE); D=Pseudomonas aeruginosa; E=Candida species. From Zilberberg et al.36

11

120 100 80 60 40 20 0 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 Year

Figure 1- 3: National estimates of US short-stay hospital discharges with Clostridium difficile listed as primary or as any diagnosis. Adapted from McDonald et al,29 plus unpublished data from McDonald.

of Health mandated CDI reporting for acute care hospitals and long-term care facilities. More than half of all CDI cases had onset in a long-term care facility.34 Data from the National Hospital Discharge Survey (NHDS), which is conducted annually by the National Center for Health Statistics, Centers for Disease Control and Prevention (CDC), indicate that the number of patients discharged from acute-care facilities in the US who were assigned the International Classification of Diseases (ICD-9) code for CDI (008.45) was stable between 1996 and 2000, with approximately 78,000 to 98,000 cases of CDI per yr, for a rate of approximately 31 cases per 100,000 population.29 The data demonstrated a steady increase in CDI prevalence between 2000 and 2003, when the estimated number of CDI cases was 178,000, for a rate of 61 per 100,000 population. Patients over 65 years of age experienced the greatest increase in rate and number of CDI 12

cases, several-fold higher than in the 45-to-64 age group. The rate of increase was similar across all regions of the country and all hospitals, regardless of bed size. Unpublished estimates by the CDC indicate a further increase, to >250,000 hospitalizations in 2005.35 Our own analysis of the Agency for Healthcare Research and Quality (AHRQ) Nationwide Inpatient Sample (NIS) data shows that CDI incidence has continued to increase, with almost 350,000 cases in 2008, the most recent year for which data are available (from http://www.hcupnet. ahrq.gov, accessed April 24, 2011). Zilberberg et al36 identified CDI-related hospitalizations for 2000-2005 from the National Inpatient Sample (NIS) data, which is a stratified 20% sample of US community hospitals that is weighted to provide national estimates. The analysis showed a 23% annual increase in CDI hospitalizations over the 6-year period from 2000 through 2005. And the absolute number of CDI hospitalizations more than doubled for all but the youngest age group (18-44), for which a 74.1% increase was seen over the study period. Also, the estimated unadjusted case-fatality rate increased from 1.2% in 2000 to 2.3% in 2004, which likely reflects the effects of increased virulence of the organism.

The BI/NAP1/027 Strain of C difficile The epidemic strain, BI/NAP1/027, has been the predominant strain in almost all outbreaks reported in the US, Canada, and Europe since 2000. Many, but not all, of the outbreaks associated with this strain have had an increase in CDI severity in addition to CDI incidence. This epidemic strain is characterized by restriction fragment-length polymorphism changes within the pathogenicity locus for the toxin A and B genes (toxinotype III); a deletion in the putative negative regulator for toxin production (tcdC); the presence of binary toxin, cytolethal distending toxin (CDT), genes; and high-level resistance to fluoroquinolone antibiotics.33 Recent statistics from the CDC indicate that 13

1

DC

AK

PR HI

with strain

without strain

Figure 1-4: The 40 states in the US with reports of the BI/NAP1/027 strain of Clostridium difficile, 2008. From the CDC. Available at: http://www.cdc.gov/HAI/organisms/cdiff/ Cdiff_infect.html. Accessed April 2011.

the BI/NAP1/027 strain has been reported in 40 states in the US (Figure 1-4). Some studies have found this strain produces more spores, possibly contributing to spread of the organism in health-care facilities; but other studies have not found that this strain produces more spores.37,38 tcdC Mutation

The BI/NAP1/027 strain of C difficile has a nonsense mutation and 18 base-pair deletion in the tcdC gene. Production of C difficile toxins A and B appears to be negatively regulated by the tcdC-encoded protein. Warny et al39 measured in vitro production of toxins A and B by isolates of the epidemic strain and of the nonepidemic strains. BI/NAP1/027 strains containing the tcdC deletion produced 16 times more toxin A and 23 more times toxin 14

50

Non-B1/NAP1/027

BI/NAP1/027

No. of Isolates

25

1

20 15 10 5 0 2

4

8

16

>32

Minimum Inhibitory Concentration (µg/mL)

Figure 1-5: Distribution of minimum inhibitory concentrations of levofloxacin for current (obtained after 2000) BI/NAP1/027 and non-BI/NAP1/027 Clostridium difficile isolates. From McDonald.33

B than toxinotype 0 strains. For BI/NAP1/027 strains, the bulk of toxin production occurred during the logarithmic phase, whereas toxinotype 0 strains did not produce significant amounts of toxin until the stationary phase.39 Binary Toxin

Another feature of the epidemic strain of C difficile is production of a third toxin, the recently identified binary toxin CDT. The prevalence of binary toxin genes in human clinical isolates varies from 1.6% to 20.8%,40 but the BI/NAP1/027 C difficile strain uniformly carries the genes for binary toxin.39 The role of binary toxin in C difficile pathogenesis is not known. In hamsters, strains with binary toxin but lacking toxins A and B colonized but did not cause diarrhea or death.41 However, the same strains caused marked fluid accumulation in a rabbit ileal loop model.41 It has been proposed that binary toxin alone may not be 15

Table 1-1: Resistance of Current BI/NAP1/027 Clostridium difficile isolates, Current Non-BI/NAP1/027 Isolates, and Historic BI/NAP1/027 Isolates to Clindamycin and Fluoroquinolonesa

Antimicrobial Agent

Current BI/NAP1/027 Isolates

Current NonBI/NAP1/027 Isolates

Clindamycin

(n=24) (n=24) No. with intermediate resistance or resistant (%) d 19 (79) 19 (79)

Levofloxacin

24 (100)

23 (96)

Gatifloxacin

24 (100)

10 (42)

Moxifloxacin

24 (100)

10 (42)

a The fluoroquinolones are levofloxacin, moxifloxacin, and gatifloxacin. Current BI/NAP1/027 isolates are those obtained since 2001, and historic BI/NAP1/027 isolates are those obtained before 2001. b The P value is for the comparison between BI/NAP1/027 and non-BI/NAP1/027 isolates.

sufficient to cause disease but that this toxin may play an adjunctive role in the pathogenesis of disease caused by strains producing toxins A and B.41 Fluoroquinolone Resistance

The CDC conducted susceptibility testing of C difficile isolates obtained as part of the investigation of several CDI outbreaks. Although nearly all strains collected, includ16

1 Historic BI/NAP1/027 Isolates P Valueb

1.0

(n=14) P Valuec No. with intermediate resistance or resistant (%) d 10 (71) 0.7

1.0

14 (100)