Contemporary Diagnosis and Management of Clostridium difficile Infection

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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

<1

1-2

2-3

3-4

>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 <1 wk acquired C difficile, whereas 10 (50%) of 20 patients hospitalized for >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)

<0.001

0

<0.001

<0.001

0

<0.001

1.0

c The P value is for the comparison between current and historic BI/NAP1/027 isolates. d An MIC breakpoint of not more than 2 µg/mLwas used for the definition of susceptibility, on the basis of the recommendations of the Clinical Laboratory Standards Institute for trovafloxacin. From McDonald33

ing nonepidemic strains, were resistant to levofloxacin, 100% of the epidemic strains had a minimum inhibitory concentration (MIC) of >32 µg/mL versus 58% of concurrently obtained nonepidemic strain isolates33 (Figure 1-5). Also, 100% of the BI/NAP1/027 strains were resistant to gatifloxacin and moxifloxacin compared to only 42% of the non-BI/NAP1/027 strains (Table 1-1). Investigators also searched a bank of more than 6,000 C difficile isolates 17

dating back to 1984 and identified 14 BI/NAP1/027 strains. Of note, none of the historical isolates were resistant to gatifloxacin or moxifloxacin (Table 1-1). It has been theorized that a previously uncommon strain of C difficile with several important virulence factors gained a competitive advantage over other strains of C difficile by acquiring high-level resistance to fluoroquinolones.

CDI Outbreaks The BI/NAP1/027 strain has been the predominant strain (when strain typing data were available) of nearly all CDI outbreaks since 2000. Not known at the time, the first report of a CDI outbreak due to this strain occurred at the University of Pittsburgh Medical Center, a 600bed, tertiary-care teaching hospital, when a nearly 2-fold increase in incidence of CDI in 2000 and 2001 compared to 1990 through 1999 was identified.42 In addition, the incidence of patients with CDI in whom life-threatening symptoms developed had increased from 1.6% to 3.2%. Forty-four patients required colectomy and 20 others died from CDI. The study concluded that C difficile was an increasing cause of death, particularly once fulminant disease was evident. The CDC received an increase in the number of reports from health-care facilities of cases of severe CDI. These reports were supported by a nationwide survey of infectious disease physicians in the Emerging Infections Network of the Infectious Diseases Society of America, which found that approximately 39% of respondents noted an increase in the severity of cases of CDI in their patient population. The CDC was also asked to assist in the investigation of several CDI outbreaks at eight health-care facilities in six states between 2000 and 2003. Overall, 187 C difficile isolates were collected, 96 (51%) of which were the BI/NAP1/027 strain. Several outbreaks caused by the BI/NAP1/027 strain have been identified in Canada and Europe as well. 18

Prompted by a marked increase in the incidence of CDI noted at several hospitals in Quebec, Canada, a prospective study was conducted at 12 Quebec hospitals in 2004 to determine the incidence of nosocomial CDI and its complications.31 The study of this simultaneous outbreak showed an overall mean incidence of 22.5 per 1,000 admissions, which was approximately four times the incidence of 6 per 1,000 admissions reported in a 1997 survey of 18 Canadian institutions.43 Molecular typing indicated that this predominant strain was identical to the NAP1 strain identified in the US.36 This strain accounted for 82.2% of the isolates collected. During the latter half of 2002, an increase in the number of patients with severe CDI was noted at the Centre Hospitalier Universitaire de Sherbrooke in Quebec. Investigators conducted a retrospective study of all CDI cases diagnosed at the facility between January 1, 1991 and December 31, 2003.44 During this time, the incidence increased from 35.6 per 100,000 population in 1991 to 156.3 per 100,000 in 2003. The greatest increase was among patients 65 years of age or older, from 102.0 to 866.5 per 100,000, and the proportion of complicated cases increased from 7.1% in 1991-1992 to 18.1% in 2003. Additionally, the proportion of patients who died within 30 days after the diagnosis of CDI increased from 4.7% in 1991-1992 to 13.8% in 2003. By 2008, the epidemic BI/NAP1/027 strain had been reported in 16 European countries.45 It was associated with outbreaks in the United Kingdom, Belgium, Germany, Finland, France, Ireland, Luxembourg, the Netherlands, and Switzerland. In a survey of 38 hospitals from 14 European countries, Barbut et al46 reported a mean CDI incidence of 2.45 cases/10,000 patient-days, with wide variability among the different participating hospitals. The overall prevalence of the epidemic BI/NAP1/027 strain in 2005 was 6.2%, but The Netherlands had a 40% prevalence of the strain and Belgium had 31.4% prevalence.46 19

1

CDI Post-Emergence of the BI/NAP1/027 Strain Since severe outbreaks of CDI associated with the BI/NAP1/027 strain occurred in the first half of this decade, additional CDI surveillance measures have been taken. Although the BI/NAP1/027 strain has caused outbreaks in Europe and North America, it is much more common in North America. An analysis was conducted of 894 C difficile isolates obtained from 2005 to 2007 through a clinical trial of CDI treatment.47 There were 443 C difficile isolates from patients from North America, 308 from Europe, and 24 from Australia. Overall, the BI/NAP1/027 strain was the most common strain, accounting for 24% of isolates. The prevalence of this strain varied by country and by study site. It accounted for 36% of isolates from North America, 8% from Europe, but none from Australia. The BI/NAP1/027 strain was present at 59% of the study sites in North America and 10% of the study sites in Europe. In the 13 European countries where patients were enrolled, the BI/NAP1/027 strain was found in Belgium, Ireland, and the United Kingdom. Thirty-four hospitals across Canada participated in the Canadian Nosocomial Infection Surveillance Program (CNISP) CDI surveillance program from November 2004 to April 2005.48,49 Compared to the last CNISP CDI surveillance program in 1997, the CDI incidence was unchanged (66/100,000 patient-days in 1997 versus 65/100,000 patient days). However, the attributable mortality from CDI increased from 1.5% in 1997 to 5.7% (P <0.001). Clinical information and the infecting strain of C difficile were obtained from 1,008 patients. The most common strain was the BI/NAP1/027 strain, accounting for 31% of isolates. Thirty-nine (12.5%) of the infections caused by the BI/ NAP1/027 strain resulted in a severe outcome, compared with only 41 (5.9%) of infections from the other types (P <0.001). The patient’s age was strongly associated with a severe outcome. Patients ≥60 years of age were approximately twice as likely to experience a severe outcome if 20

Proportion surviving

1.00

Controls

1

0.75

Cases 0.50 0

100

200

300

400

No. of days*

Figure 1-6: Probability of death since diagnosis among inpatients in whom nosocomial CDI developed and among matchedcontrol subjects without CDI. Adapted from Pépin et al.30

the infection was caused by BI/NAP1/027, compared with infections caused by other types. With support from the European Centre for Disease Prevention and Control, a European C difficile surveillance system was created.50 In November 2008, data and C difficile isolates were collected from 106 laboratories in 34 countries from patients who were diagnosed with CDI. The mean incidence of CDI was 4.1 cases per 10,000 patient days (range 0 to 36.3/10,000 patient days). C difficile isolates were available from 389 of 509 patients. Some 65 different PCR ribotypes of C difficile were identified and the prevalence of different strains of C difficile varied by country. Overall, the BI/NAP1/027 strain was the sixth most common strain, accounting for 4.8% of strains, and was found in only six countries.

Outcomes and Costs of CDI CDI has a significant impact on hospital costs and outcomes, even with conservative estimates. Among the poorer 21

Table 1-2: Per Episode and Estimated Annual Hospital Costs Attributable to CDI

Study Kynea

Patient Population 2 medical wards 40 cases: 1998

O’Brienb

MA discharge database 3,692 cases: 2000

Cost per CDI Episode $3,669 1° diagnosis $10,212 2° diagnosis $13,675

Dubberkec

Nonsurgical patients 439 cases: 2003

$2,454 to $3,240

a

Median costs, nonsurgical patients, estimated ~240,000 CDI cases per year in US b

Mean costs, includes all costs during hospitalization, including surgical costs for patients who underwent surgery, estimated ~320,000 CDI cases per year in US

outcomes for hospitalized patients with CDI are longer LOS, risk for admission to a long-term care facility, risk for readmission to hospital, colectomy, and death. Two Canadian studies analyzed data from Quebec hospitals during CDI outbreaks in 2003 and 2004. Loo et al28 reported that among patients with CDI, CDI was the attributable cause of death in 6.9% and contributed to death in another 7.5% of patients. Among the 422 patients with CDI, 110 patients required intensive care and 33 patients required colectomy due to CDI. In their study, Pépin et al30 found an overall attributable mortality due to CDI of 16.7% 22

c

US Cost Estimate $1.1 billion

% Increase in Costs Attributable to CDI 54%

Increase in LOS Attributable to CDI 3.6 days

NA

$3.2 billion

46%

3.0 days

$5,042 to $7,179

$580 million

41%

2.8 days

53%

NA

6-month Costs per Patient NA

Median costs, estimated 178,000 CDI cases per year in the US

From Kyne et al,51 Dubberke et al,52 O’Brien et al53 LOS=length of stay

at 12 months, with all attributable deaths occurring in patients more than 64 years of age (Figure 1-6). In addition, patients with CDI spent an average of 10.7 days longer in hospital than control subjects, 9.9% needed admission to an intensive care unit, and 2.5% required colectomy. Several recent studies evaluated per episode costs of CDI and overall annual costs in the US 51-54 (Table 1-2). Cost estimates vary among the studies because of differences in methodologies used, reported estimates, and patient populations. Estimates of the number of cases in the US and variances in control for confounders also differ. 23

1

But the studies are similar in the percentage increase in costs attributable to CDI and the increase in LOS attributable to CDI. The increased costs appear to be directly related to the increase in LOS.51 The total economic burden of CDI is even greater when additional costs due to CDI are considered. Approximately 20% of patients who acquire CDI will have at least one recurrence of the disease after therapy and as many as 14 episodes.55 Few studies have reported the costs for CDI in long-term care facilities where CDI is relatively common and where hospitalized patients with CDI may be transferred upon discharge. Hospital bed-days are lost due to contact precautions for patients with CDI, and clinic visits and loss of productivity or work days are additional factors that add to the total economic burden of CDI.

Death Certiﬁcate Data United States death certificate data from public health reports show a marked increase in the annual number of deaths attributed to enterocolitis caused by C difficile from 1999 through 2002, the latest period for which public health statistics are available.55 Of a total 2.39 million deaths in 1999, 793 were attributed to C difficile.56 By 2002, 2,195 deaths listed C difficile as the underlying cause of death from a total 2.195 million deaths. This represents a 2.7-fold increase in the age-adjusted rates. Death certificates that mentioned C difficile among their diagnoses as immediate cause, underlying cause, contributing to underlying cause, or as a significant condition not contributing to the underlying cause, increased from 1,545 in 1999 to 3,514 in 2002, a 2.3-fold increase. In the US, the overall rate for females was higher than for males, except in the elderly, who had similar rates. Based on death certificate data from Ohio in 2006, it was estimated that 7,752–20,000 deaths per year in the US are attributable to CDI (Figure 1-7).34 The number of deaths in the UK associated with C difficile infection has also steadily risen since 1999, according 24

to government statistics.57 According to death certificates issued in England and Wales, the number of deaths in which C difficile infection was indicated rose from 3,757 in 2005 to 6,480 in 2006, an increase of 72% (Figure 1-8). Between 2005 and 2006, death rates increased from 37.0 to 65.5 per million population among males and from 38.6 to 64.2 per million population among females, a 77% increase for males and 66% increase for females.

Community-Associated CDI C difficile infection has long been considered primarily a nosocomial disease associated with antibiotic use in hospitals, clustering of susceptible hosts, multiple personto-person contacts, and environmental contamination. However, CDI can occur in patients without any recent health-care exposures (community-associated CDI [CACDI]). Similar to health-care-associated CDI (HA-CDI), there have not been surveillance systems to track CA-CDI, making it difficult to identify trends in CA-CDI over time. Although CA-CDI may be increasing in Canada58 and the United Kingdom,59 CA-CDI rates in the US appear to be stable60-64 (Table 1-3). Of note, while prior antibiotic use is considered the primary risk factor for development of infection with C difficile, there are no obvious recent antibiotic exposures in as many as 53% of CA-CDI cases.58 Severe CDI in low-risk populations and peripartum women in the US In 2005, the CDC reported severe CA-CDI cases from four US states—Pennsylvania, New Jersey, New Hampshire, and Ohio—in populations previously considered at low risk.64 Investigations identified 33 cases of CA-CDI in previously healthy persons and in peripartum women. Ten cases were peripartum women. Transmission from close contacts was seen in four cases: two cases were in children of patients with peripartum CDI, one was an adult caring for a hospitalized parent with CDI, and one was in an adult who visited a parent with CDI in a nursing home. 25

1

26

Number of deaths

1000 900 800 700 600 500 400 300 200 100 0

2000

2001

2002

2003

2004

2005

2006

Year Primary underlying cause of death

112

137

219

246

369

481

528

Any reported cause of death

198

241

365

451

640

782

893

Figure 1-7: Deaths of Ohio residents from 2000 through 2006 for which enterocolitis from C difficile was reported as the primary or any cause of death.34

Number of deaths

7000 6000 5000 4000 3000 2000 1000 0 1999

2000

2001

1999

Underlying cause

2003

2004

2005

2006

Mentions

27

Figure 1-8: Number of death certificates mentioning C difficile, by whether it was the underlying cause of death, England and Wales, 1999-2006. From Health Statistics Quarterly, Spring 2008.57

1

Table 1-3: Community-associated Clostridium difficile Infection Cases per 100,000 Person Years Study Canada Diala,58 UK a Dial59 US Hirschhorn60

1998-2000 2003, 2004

22 58

1994 2004

1 22

1994

7.7

Levy61

1992-1994

12

Frost62

1993-1997

3.3

63

7/2004-6/2005

7.6

64

2006

6.9

CDC CDC a

Year(s)

Cases/100,000 person years

Derived from General Practice Research Database (UK)

One peripartum mother who transmitted C difficile to her child also transmitted C difficile to a family friend. Eight of 33 patients, including five children, had no exposure to antimicrobial agents within 3 months before the CDI onset. Fifteen of the 33 patients required an emergency department visit or hospitalization, and 13 of the 33 had a relapse of CDI and required antimicrobial therapy, including 50% of the peripartum women. Only two C difficile isolates were available for study and neither was the BI/NAP1/027 epidemic strain. But specimens were positive for the binary toxin, which has been associated with increased severity of CDI. This suggests that virulent 28

strains may be responsible for more frequent, severe disease in populations previously at low risk, as well as in high-risk populations. The CDC subsequently received additional reports of CDI in peripartum women and conducted a survey through the Emerging Infections Network (EIN) of the Infectious Diseases Society of America.65 Ten severe cases of CDI in peripartum women were reported (including five cases from the previous report).63 Seven required admission to an intensive care unit or required colectomy. Three infants were stillborn and two women died. Three patients had prior hospitalization and nine had recent antimicrobial exposures. Clostridial DNA was extracted from two of five available colectomy specimens, with evidence of the BI/NAP1/027 strain found in one specimen. C difficile was cultured from an additional patient, and it was identified as the epidemic strain. Four hundred nineteen infectious diseases physicians responded to the EIN survey and 37 (8.8%) reported having seen or were aware of 55 cases of CDI in peripartum women. Twenty-two (40%) cases occurred before delivery, and 16 (30%) occurred ≥1 week after delivery; 21 patients (38%) had a complication due to CDI. A recent case report described a postpartum woman with recurrent CDI. 66 Subsequently, tests confirmed that her infant was asymptomatically colonized with an identical strain of C difficile. The patient was taught how to perform meticulous hand hygiene after changing diapers and how to use a 10% bleach solution for surface disinfection. No further recurrences occurred. This case highlights that infants, who are commonly colonized with C difficile soon after birth, may be a source of transmission to postpartum women.

C difﬁcile in Animals A Canadian study in 2005 67 identified C difficile among fecal samples from 144 calves with diarrhea. 29

1

Toxins were detected in calf feces from 58 of 102 farms. Thirty-one isolates showed eight distinct polymerase chain reaction (PCR) ribotype patterns, seven of which have been identified in humans, two of which have been associated with outbreaks of severe disease. Based on the presence of C difficile in farm animals, another Canadian study68 explored the possibility that retail meat might be contaminated with spores of C difficile. C difficile was isolated from 20% of the total of 60 meat samples: 11 of 53 ground beef samples and 1 of 7 ground veal samples. Among the 12 isolates examined, two were of PCR ribotypes that are recognized as human pathogens and a third was a toxinotype III strain that had many similarities to the epidemic strain, but was genetically distinct. The risk to humans with consumption of C difficile-contaminated meat is unknown. Even though thorough cooking is recommended for meat, C difficile is a spore-forming bacterium and spores are notably difficult to destroy, even at recommended cooking temperatures. CDI caused by toxinotype V strains of C difficile has been reported as a cause of epidemic disease in neonatal pigs and colonization in calves during the past decade.68,69 Other names for this strain include NAP7 (PFGE typing), BK (REA typing), and 078 (PCR ribotyping). A US study70 reviewed a database of patients with C difficile toxinotype V from multiple health-care facilities from 1984 to 2001, as well as isolates sent to the CDC from multiple states from outbreaks of CDI reported from 2001 through 2007. A total of 15 isolates were identified. Seven isolates, representing <0.02% of all isolates, were detected from 1984 to 2000. Seven isolates (1.3%) were identified from 2001 through 2006. Clinical information was available for 13 isolates, and six (46.2%) of the patients with CDI due to this strain had CA-CDI. Like the BI/NAP1/027 strain, the toxinotype V strain was found to have a tcdC mutation, produce more toxin A and B, and produce binary toxin. 30

A study in the Netherlands by Goorhuis et al71 from 2005 to 2008 documented the emergence of CDI caused by PCR ribotype 078, which is the predominant strain in pigs and calves and is analogous to the toxinotype V strain in the US. The incidence of CDI from this strain increased from 3% to 13% of CDI episodes. Compared to patients with CDI due to type 027, patients with type 078 CDI were younger and represented a higher proportion of CA-CDI. Severe diarrhea and mortality were comparable for both 078 and 027 patients. Fewer relapses and complications were seen in patients with the 078 strain compared to the 027 strain. It is unclear what is causing the emergence of the 078 strain in humans, but it is a hypervirulent strain that is genetically indistinguishable from porcine type 078 strains. Few investigations have been conducted on the potential for interspecies transmission of C difficile to humans. In addition, few studies have investigated links between CDI spores in food animals and humans. The appearance of toxinotype V C difficile in humans may suggest a common environmental exposure to C difficile by humans and animals, transmission to humans by direct or indirect contact with infected live animals, or human CDI associated with consumption of products from infected food-producing animals. The study data also suggest that C difficile toxinotype V may be a relatively common cause of CA-CDI and that animal contact is a plausible means of transmission for CA-CDI. Information is limited, however, with respect to possible routes for human CA-CDI, and toxinotype V remains an uncommon cause of human illness.

Key points 1. The incidence and severity of CDI are increasing. This has been associated with the identification of a new, predominant strain of C difficile, the BI/NAP1/027 epidemic strain. 31

1

2. C difficile is an ubiquitous organism, but people are much more likely to become colonized and develop symptomatic CDI while in a health-care setting. 3. It is important to think of CDI as a cause of diarrhea in the community, even in the absence of recent antimicrobial exposures, especially if the patient has persistent diarrhea, blood in the stool, fevers, or a high white count. 4. CDI is rare in neonates, who are commonly colonized with C difficile but may be a source of transmission to the mother. 5. CDI surveillance systems are essential to have a complete understanding of C difficile epidemiology and to identify emerging strains.

References 1. Hall IC, O’Toole E: Intestinal flora in newborn infants with a description of a new pathogenic anaerobe, Bacillus difficilis. Am J Dis Child 1935;49:390-402. 2. Bartlett JG: Historical perspectives of studies of Clostridium difficile and C difficile infection. Clin Infect Dis 2008;46(suppl 1): S4-S11. 3. Tedesco FJ, Barton RW, Alpers DHK: Clindamycin-associated colitis. A prospective study. Ann Intern Med 1974;81:429-433. 4. Keighley MR, Burdon DW, Arabi Y, et al: Randomized controlled trial of vancomycin for pseudomembranous colitis and postoperative diarrhea. Br Med J 1978;2:1667-1669. 5. Lusk RH, Fekety FR Jr, Silva J Jr, et al: Gastrointestinal side effects of clindamycin and ampicillin therapy. J Infect Dis 1977;135(suppl):S111-S119. 6. Bartlett JG, Onderdonk AB, Cisneros RL, et al: Clindamycinassociated colitis due to a toxin-producing species of Clostridium in hamsters. J Infect Dis 1977;136:701-705. 7. Bartlett JG, Chang TW, Gurwith M, et al: Antibiotic-associated pseudomembranous colitis due to toxin-producing clostridia. N Engl J Med 1978;298:531-534. 8. Bartlett JG, Chang T, Taylor NS, et al: Colitis induced by Clostridium difficile. Rev Infect Dis 1979;1;370-378.

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9. Taylor NS, Bartlett JG: Partial purification and characterization of a cytotoxin from Clostridium difficile. Rev Infect Dis 1979;1: 379-385. 10. Teasley DG, Gerding DN, Olson MM, et al: Prospective randomized trial of metronidazole versus vancomycin for Clostridiumdifficile-associated diarrhea and colitis. Lancet 1983;2:1043-1046. 11. Al Saif N, Brazier JS: The distribution of Clostridium difficile in the environment of South Wales. J Med Microbiol 1996;45:133137. 12. Matsuki S, Ozaki E, Shozu M, et al: Colonization by Clostridium difficile of neonates in a hospital, and infants and children in three day-care facilities of Kanmazawa, Japan. Int Microbiol 2005;8:43-48. 13. Cohen SH, Gerding DN, Johnson S, et al: SHEA‐IDSA guideline: Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol 2010;31:431-455. 14. Gould CV, McDonald LC: Bench-to-bedside review: Clostridium difficile colitis. Crit Care 2008;12:203. 15. Viscidi R, Laughon BE, Yolken R, et al: Serum antibody response to toxins A and B of Clostridium difficile. J Infect Dis 1983; 148:93-100. 16. Kelly CP, Pothoulakis C, Orellana J, et al: Human colonic aspirates containing immunoglobulin A antibody to Clostridium difficile toxin A inhibit toxin A-receptor binding. Gastroenterology 1992;102:35-40. 17. Clabots CR, Johnson S, Olson MM: Acquisition of Clostridium difficile by hospital patients: evidence for colonized new admissions as a source of infection. J Infect Dis 1992;166:561-567. 18. McFarland LV, Mulligan ME, Kwok RY, et al: Nosocomial acquisition of Clostridium difficile infection. N Engl J Med 1989;320: 204-210. 19. Riggs MM, Sethi AK, Zabarsky TF, et al: Asymptomatic carriers are a potential source for transmission of epidemic and nonepidemic Clostridium difficile strains among long-term care facility residents. Clin Infect Dis 2007;45:992-998. 20. Johnson S, Gerding DN: Clostridium difficile-associated diarrhea. Clin Infect Dis 1998;26:1027-1036.

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21. Dubberke ER, Reske KA, Olsen MA, et al: Evaluation of Clostridium difficile-associated disease pressure as a risk factor for C. difficile disease. Arch Intern Med 2007;167:1092-1097. 22. Samore MH, Venkataraman L, DeGirolami PC, et al: Clinical and molecular epidemiology of sporadic and clustered cases of nosocomial Clostridium difficile diarrhea. Am J Med 1996;100:32-40. 23. Chang VT, Nelson K: The role of physical proximity in nosocomial diarrhea. Clin Infect Dis 2000;31:717-722. 24. Shaughnessy MK, Micielli RL, DePestel DD, et al: Evaluation of hospital room assignment and acquisition of Clostridium difficile infection. Infect Control Hosp Epidemiol 2011;32:201-206. 25. Dubberke ER, Gerding DN, Classen D, et al: Strategies to prevent Clostridium difficile infections in acute care hospitals. Infect Control Hosp Epidemiol 2008;29(suppl 1):S81-S92. 26. Miller BA, Chen LF, Sexton DJ, Anderson DJ: Comparison of the burdens of hospital-onset, healthcare facility-associated Clostridium difficile infection and of healthcare-associated infection due to methicillin-resistant Staphylococcus aureus in community hospitals. Infect Control Hosp Epidemiol 2011;32:387-390. 27. Zilberberg MD, Shorr AF, Kollef MH: Growth and geographic variation in hospitalizations with resistant infections, United States, 2000-2005. Emerg Infect Dis 2008;14:1756-1758. 28. Redelings MD, Sorvillo F, Mascola L: Increase in Clostridium difficile-related mortality rates, United States, 1999-2004. Emerg Infect Dis 2007;13:1417-1419. 29. McDonald LC, Owings M, Jernigan DB: Clostridium difficile infection in patients discharged from US short-stay hospitals, 19962003. Emerg Infect Dis 2006;12:409-415. 30. Pépin J, Valiquette L, Cossette B: Mortality attributable to nosocomial Clostridium difficile-associated disease during an epidemic caused by a hypervirulent strain in Quebec. CMAJ 2005;173: 1037-1042. 31. Loo VG, Poirier L, Miller MA, et al: A predominantly clonal multi-institutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality. N Engl J Med 2005;353: 2422-2449. 32. Kuijper EJ, Coignard B, Tull P: Emergence of Clostridium difficile-associated disease in North America and Europe. Clin Microbiol Infect 2006;12(suppl 6):2-18.

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33. McDonald LC, Kilgore GE, Thompson A, et al: An epidemic, toxin gene-variant strain of Clostridium difficile. N Engl J Med 2005;353:2433-2441. 34. Ohio Department of Health: Final report for rates of Clostridium difficile for Ohio hospitals and nursing homes, January 1-December 31, 2006. Available at http://www.odh.ohio.gov/alerts/cdiff1.aspx. Accessed January 2009. 35. McDonald LC: Confronting Clostridium difficile in inpatient health care facilities. Clin Infect Dis 2007;45:1274-1276. 36. Zilberberg MD, Shorr AF, Kolleff MH: Increase in adult Clostridium difficile-related hospitalizations and case-fatality rate, United States, 2000-2005. Emerg Infect Dis 2008;929-931. 37. Merrigan M, Venugopal A, Mallozzi M, et al: Human hypervirulent Clostridium difficile strains exhibit increased sporulation as well as robust toxin production. J Bacteriol 2010;192:4904-4911. 38. Burns DA, Heap JT, Minton NP: The diverse sporulation characteristics of Clostridium difficile clinical isolates are not associated with type. Anaerobe 2010;16:618-622. 39. Warny M, Pépin J, Fang A, et al: Toxin production by an emerging strain of Clostridium difficile associated with outbreaks of severe disease in North America and Europe. Lancet 2005;366: 1079-1084. 40. Gonçalves C, Decré D, Barbut F, et al: Prevalence and characterization of a binary toxin (actin-specific ADP-ribosyltransferase) from Clostridium difficile. J Clin Microbiol 2004;42:1933-1939. 41. Geric B, Carman RJ, Rupnik M, et al: Binary toxin-producing, large clostridial toxin-negative Clostridium difficile strains are enterotoxic but do not cause disease in hamsters. J Infect Dis 2006;193:1143-1150. 42. Dallal RM, Harbrecht BG, Boujoukas AJ, et al: Fulminant Clostridium difficile: an under-appreciated and increasing cause of death and complications. Ann Surg 2002;235:363-372. 43. Hyland M, Ofner-Agostini M, Miller M, et al: N-CDAD in Canada: results of the Canadian nosocomial infection surveillance program. 1997 N-CDAD surveillance project. Can J Infect Dis 2001;12:81-88. 44. Pépin J, Valiquette L, Alary M-E, et al: Clostridium difficileassociated diarrhea in a region of Quebec from 1991 to 2003: a changing pattern of disease severity. CMAJ 2004;171:466-472.

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45. Kuijper EJ, Barbut F, Brazier JS, et al: Update of Clostridium difficile infection due to PCR ribotype 027 in Europe, 2008. Euro Surveill 2008;13:pii:18942. 46. Barbut F, Mastrantonio P, Delmée M, et al: Prospective study of Clostridium difficile infections in Europe with phenotypic and genotypic characterization of the isolates. Clin Microbiol Infect 2007;13:1048-1057. 47. Cheknis AK, Sambol SP, Davidson DM, et al: Distribution of Clostridium difficile strains from a North American, European and Australian trial of treatment for C. difficile infections: 2005-2007. Anaerobe 2009;15:230-233. 48. Gravel D, Miller M, Simor A, et al: Health care-associated Clostridium difficile infection in adults admitted to acute care hospitals in Canada: a Canadian Nosocomial Infection Surveillance Program Study. Clin Infect Dis 2009;48:568-576. 49. Miller M, Gravel D, Mulvey M, et al: Health care-associated Clostridium difficile infection in Canada: patient age and infecting strain type are highly predictive of severe outcome and mortality. Clin Infect Dis 2010;50:194-201. 50. Bauer MP, Notermans DW, van Benthem BH, et al: Clostridium difficile infection in Europe: a hospital-based survey. Lancet 2011;377:63-73. 51. Kyne L, Hamel MB, Polavaram R, et al: Health care costs and mortality associated with nosocomial diarrhea due to Clostridium difficile. Clin Infect Dis 2002;34:346-353. 52. Dubberke ER, Reske KA, Olsen MA, et al: Short- and longterm attributable costs of Clostridium difficile-associated disease in nonsurgical patients. Clin Infect Dis 2008;46:497-504. 53. O’Brien JA, Lahue BJ, Caro JJ, et al: The emerging infectious challenge of Clostridium difficile-associated disease in Massachusetts hospitals: clinical and economic consequences. Infect Control Hosp Epidemiol 2007;28:1219-1227. 54. Zerey M, Paton BL, Lincourt AE, et al: The burden of Clostridium difficile in surgical patients in the United States. Surg Infect (Larchmt) 2007;6:557-566. 55. McFarland LV, Surawicz CM, Rubin M, et al: Recurrent Clostridium difficile disease: epidemiology and clinical characteristics. Infect Control Hosp Epidemiol 1999;20:43-50.

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56. Wysowski DK: Increase in deaths related to enterocolitis due to Clostridium difficile in the United States, 1999-2002. Public Health Rep 2006;121:361-362. 57. Office for National Statistics: Reported deaths involving Clostridium difficile rise by 72 per cent. Health Statistics Quarterly 37, spring 2008. Issued by National Statistics, London, SW1V 2QQ. Available at http://www.statistics.gov.uk. 58. Dial S, Kezouh A, Dascal A, et al: Patterns of antibiotic use and risk of hospital admission because of Clostridium difficile infection. CMAJ 2008:179:767-772. 59. Dial S, Delaney JAC, Barkun AN, et al: Use of gastric acidsuppressive agents and the risk of community-acquired Clostridium difficile-associated disease. JAMA 2005;294:2989-2995. 60. Hirschhorn LR, Trnka Y, Onderdonk A, et al: Epidemiology of community-acquired Clostridium difficile-associated diarrhea. J Infect Dis 1994;169:127-133. 61. Levy DG, Stergachis A, McFarland LV, et al: Antibiotics and Clostridium difficile diarrhea in the ambulatory setting. Clin Ther 2000;22:91-102. 62. Frost F, Hurley JS, Petersen HV, et al: Estimated incidence of Clostridium difficile infection. Emerg Infect Dis 1999;5:303-304. 63. Centers for Disease Control and Prevention: Severe Clostridium difficile-associated disease in populations previously at low risk— four states, 2005. MMWR 2005;54:1201-1205. 64. Centers for Disease Control and Prevention: Surveillance for community-associated Clostridium difficile—Connecticut, 2006. MMWR 2008;57:340-343. 65. Rouphael NG, O’Donnell JA, Bhatnager J, et al: Clostridium difficile-associated diarrhea: an emerging threat to pregnant women. Am J Obstet Gynecol 1008;198:635.e1-6. 66. Hecker MT, Riggs MM, Hoyen CK, et al: Recurrent infection with epidemic Clostridium difficile in a peripartum woman whose infant was asymptomatically colonized with the same strain. Clin Infect Dis 2008;15:956-957. 67. Rodriguez-Palacios A, Staempfli HR, Duffield T, et al: Clostridium difficile PCR ribotypes in calves, Canada. Emerg Infect Dis 2006;12:1730-1736.

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68. Rodriguez-Palacios A, Staempfli HR, Duffield, T, et al: Clostridium difficile in retail ground meat, Canada. Emerg Infect Dis 2007;13:485-487. 69. Songer JG, Anderson MA: Clostridium difficile: an important pathogen of food animals. Anaerobe 2006;12:1-4. 70. Jhung MA, Thompson AD, Kilgore GE, et al: Toxinotype V Clostridium difficile in humans and food animals. Emerg Infect Dis 2008;14:1039-1045. 71. Goorhuis A, Bakker D, Corver J, et al: Emergence of Clostridium difficile infection due to a new hypervirulent strain, polymerase chain reaction ribotype 078. Clin Infect Dis 2008;47:1162-1170.

38

Chapter 2

Pathogenesis 2

I

n addition to asymptomatic carriage, Clostridium difficile causes a broad spectrum of human diseases, ranging from mild diarrhea to fulminant colitis and death. The severity of illness and the likelihood of recurrence depend not only on the organism but also on host factors, including the indigenous microflora and the ability to mount an immune response to C difficile toxins. This chapter examines the pathogenesis of C difficile colonization and infection, with an emphasis on those factors that have important implications for the treatment and prevention of C difficile infection (CDI).

Overview of C difﬁcile pathogenesis Figure 2-1 provides a general overview of the pathogenesis of C difficile colonization and infection. Some of the factors that are important in allowing C difficile to colonize and produce toxin are not modifiable, while others are iatrogenic factors that may be amenable to intervention. In particular, disruption of the indigenous intestinal microflora by antibiotic therapy plays a central role in the pathogenesis of CDI. Exposure to C difﬁcile

Patients with CDI shed spores in feces, resulting in contamination of their skin, clothing, and nearby environmental surfaces.1-3 From these sites, spores may be transmitted to susceptible patients on the hands of health39

Exposure spore

1

vegetative cell indigenous colonic microflora

Stomach 2

Small Intestine

3

Germination

No Antibiotics

Antibiotics

Colon BA

5 Primary bile salts

4

Secondary bile salts

A B A

7 Primary bile salts

6 B

AB

8 Environment

Skin Hands

40

care workers or on portable equipment (eg, electronic thermometers), or they may be acquired through direct contact with contaminated environmental surfaces. Increased severity of illness and prolonged duration of hospitalization place patients at increased risk for acquisition of C difficile in part because these factors result in increased opportunities for interaction with health-care workers and contaminated surfaces or devices. The risk of transmission from contaminated surfaces is enhanced by the ability of spores to survive for months on surfaces3 and to resist killing by disinfectants other than bleach. In antibiotic-treated hamsters, fewer than 10 spores are needed to precipitate disease.5 If a similar low number of spores is required to induce CDI in humans, even low levels of environmental contamination could contribute to transmission.

Figure 2-1 (left): Overview of C difficile pathogenesis. (1) Patients ingest C difficile spores transmitted on hands of health-care workers, on portable equipment, or from contaminated environmental surfaces. (2) Spores pass through the stomach unchanged. They are not killed by gastric acid and do not germinate in the stomach. (3) Spores germinate in the small intestines after exposure to bile salts, with glycine as a cogerminant. (4) In the absence of antibiotic therapy, the indigenous microflora of the colon inhibit growth of C difficile. (5) One proposed mechanism is conversion of primary bile salts to secondary bile salts that inhibit growth of C difficile. (6) Suppression of the indigenous microflora by antibiotics allows C difficile to grow and produce toxins A and B. (7) It has been proposed that antibiotics may promote growth of C difficile in part by suppressing microflora that convert primary to secondary bile salts (inhibitory to growth of C difficile). (8) Fecal contamination results in contamination of environmental surfaces and patients’ skin with C difficile. Factors such as diarrhea and fecal incontinence contribute to fecal contamination. Adapted from Donskey.12

41

2

Passage Through the Stomach

Gastric acid may provide an important host defense against some pathogens (eg, vancomycin-resistant enterococci) by reducing the number of ingested organisms that enter the intestinal tract.6 However, C difficile spores are not killed in acidic gastric contents and do not initiate germination in gastric contents of patients receiving proton pump inhibitors.7 Although vegetative cells are killed by gastric acid, this form of the organism is believed to play a relatively minor role in transmission.8 Germination

Germination of C difficile spores is required for disease to occur because only the vegetative form of the organism produces toxins. Wilson and Freter demonstrated that 78% of ingested C difficile spores germinated in the small intestines of hamsters within 1 hr.9 Researchers have postulated that germination of spores is stimulated by exposure to bile salts.9,10 Sorg and Sonenshein recently provided additional evidence that bile salts, specifically cholate derivatives, stimulate germination of C difficile spores in the small intestines, with the amino acid glycine acting as a cogerminant.11 Colonization

The human colon contains as many as 1012 bacteria per gram of contents and more than 100 bacterial species.11 These indigenous bacteria provide an important host defense, termed colonization resistance, by inhibiting the growth of C difficile and other potentially pathogenic microorganisms. Multiple mechanisms may contribute to the inhibition of C difficile, including depletion of nutrients, prevention of access to adherence sites or niches associated with the mucosa, and production of inhibitory substances or conditions (eg, volatile fatty acids).12 Wilson10 and more recently Sorg and Sonenshein11,13 have suggested that the 42

indigenous microflora may inhibit colonization by C difficile in the colon in part through conversion of primary to secondary bile salts (eg, deoxycholate) that are inhibitory to C difficile growth. Based on studies of mice and humans treated with antibiotics and using in vitro models, it has been suggested that obligate anaerobes play a crucial role in inhibition of colonization by pathogens; however, the specific members of the microflora that inhibit colonization by C difficile are not known. Antibiotics, which disturb indigenous flora and thus colonization resistance, are the most important risk factor for CDI. While penicillins, cephalosporins, clindamycin, and, more recently, fluoroquinolones are considered the highest risk agents,14 nearly all antibiotics have been associated with CDI. Other drugs that disturb the indigenous microflora can also cause CDI, such as antineoplastic agents, methotrexate in particular.15 The impact of specific antimicrobials is discussed in further detail below. Disruption of normal host flora exposes potential niches within the intestine to colonization by C difficile. The specific pathogenic mechanisms used by C difficile are being investigated. Several proposed virulence factors include flagella, fimbrae, hydrolytic enzymes, and adhesins such as surface-layer proteins. Extracts of C difficile flagella bind to intestinal mucus from mice; this may represent one strategy used to establish gut infection.16 Denève et al have described increased adherence of C difficile to cultured cells after exposure to subinhibitory concentrations of clindamycin and ampicillin, although not to ofloxacin, moxifloxacin, or kanamycin. The authors relate this to increased expression of genes encoding three different adhesins (two cell surface-associated proteins and the surface layer protein P47) and a cysteine protease, concluding that antibiotics may facilitate CDI not only through depletion of the host microflora but also by inducing expression of colonization factors by C difficile.17 43

2

44 Figure 2-2: Structure of toxin A and toxin B of C difficile. From Jank et al: Glycobiology 2007;17:15R-22R.

tcdR

tcdR

tcdB

tcdE

PaLoc

tcdA

tcdC 2kb

tcdA=toxin A gene; tcdB=toxin B gene; tcdR=accessory gene that activates the gene expression; tcdC=accessory gene that negatively regulates toxin synthesis; tcdE=accessory gene that appears to release of toxins from the cell. Figure 2-3: The pathogenicity locus (PaLoc) of C difficile. From Dupuy et al: J Med Microbiol 2008;57:685-689.

Toxin Production

Disease caused by C difficile has been attributed to production of two large clostridial toxins, toxins A and B (tcdA and tcdB), that cause inflammation and mucosal damage (Figures 2-2, 2-3, 2-4). These toxins have 63% amino acid sequence similarity and act as glycosyltransferases that modify small GTPases within the host cell that are involved in actin polymerization and cytoskeleton structure, resulting in cell death.18 The genes encoding production of C difficile toxins are carried on a short chromosomal segment, the pathogenicity locus (PaLoc), by pathogenic strains of C difficile (Figure 2-3). The PaLoc comprises toxin genes tcdA and tcdB and three accessory genes encoding the proteins tcdR, tcdE, and tcdC. TcdR acts as an alternative RNA polymerase sigma factor that directly activates toxin gene expression. TcdA, tcdB, and tcdR genes are expressed during the stationary growth phase. The tcdC gene, however, is transcribed during the exponential growth phase and could act as a negative regulator of toxin synthesis by interfering with gene expression. This has been proposed as an explanation for the increased severity of disease associated with the epidemic BI/NAP1/027 strains of C difficile that carry deletions in tcdC that result 45

2

46 Figure 2-4: Pathogenesis of C difficile infection in adults. C difficile vegetative cells produce toxins A and B and hydrolytic enzymes (1). Toxin production leads to production of tumor necrosis factor-alfa and proinflammatory interleukins, increased vascular permeability, neutrophil and monocyte recruitment (2) and opening of tight intracellular junctions in the epithelium (3), and epithelial cell necrosis (4). Hydrolytic enzymes cause connective tissue degradation, leading to watery diarrhea, colitis, and pseudomembrane formation. Adapted from Poutanen SM, Simor AE: CMAJ 2004;171:51-58.

in frameshift mutations that are predicted to result in a truncated tcdC protein that is not likely to be functional. Warny et al19 reported that these strains not only produce higher levels of toxin but also initiate toxin production earlier compared to nonepidemic strains, supporting the putative role of tcdC in toxin regulation. However, Merrigan et al20 recently reported that while BI/NAP1/027 strains displayed robust toxin production during stationary phase growth, the amounts were not significantly different from those of the nonepidemic strains tested and production did not begin earlier in the growth phase. These authors suggested that tcdC may have a modulatory rather than a strictly repressive role in regulation of toxin production.20 Additionally, BI/NAP1/027 strains possess the gene for binary toxin cdtB, although its clinical significance is unclear.18 The PCR ribotype 078 strains that have been reported as an emerging cause of CDI in the Netherlands has a 39-base pair deletion in tcdC and a point mutation resulting in a stop codon, but it is not known if these strains produce increased toxin in comparison to other strains.21 These strains not only produce higher levels of toxin but also initiate toxin production earlier compared to nonepidemic strains,19 supporting the putative role of tcdC in toxin regulation. Additionally, they also possess the gene for binary toxin, cdtB, although its clinical significance is unclear.19 Clinical manifestations of CDI are triggered by the effects of toxins A and B, including disruption of tight junctions, decreasing the intestinal barrier function, and causing intraluminal fluid accumulation (Figure 2-4). The ensuing mucosal inflammation is caused largely by an influx of neutrophils and mononuclear cells, although mast cells also release inflammatory mediators when exposed to C difficile exotoxins.22 The resultant pseudomembranes, which are pathognomonic for CDI, are plaques composed of fibrin, mucin, neutrophils, and necrotic debris (Figure 2-4). Based on in vitro models, clinicians previously believed that toxin A might be the major exotoxin responsible for 47

2

disease. Using human colonic mucosal explants, however, Riegler et al demonstrated that toxin B causes 10-fold more damage compared to toxin A.23 This early finding was supported by clinical evidence, which revealed that a toxin A-negative, toxin B-positive strain caused the full spectrum of clinical illness typically observed with toxin A- and B-positive strains.24 Recent data using isogenic mutants producing either toxin A or B can cause fulminant disease in hamsters, supporting a role for both toxins in pathogenesis of infection.25 Shedding

During the acute, diarrheal phase of illness, patients shed large numbers of both vegetative and spore forms of C difficile.8 Spores on skin can easily be acquired on hands of health-care workers.1 The number of organisms decreases significantly with effective therapy,1 but up to half of patients treated with metronidazole or vancomycin may continue to shed spores at the end of therapy.26 In a small study, it was demonstrated that about half of CDI patients continued to harbor C difficile on their skin after their diarrhea had resolved.1 Further research is needed to better define the duration and extent of C difficile shedding during and after completion of treatment. Persistent skin and environmental contamination with C difficile could contribute to recurrences from repeated exposure with ingestion of spores.

Host Factors The host’s health also influences the risk of acquiring CDI, the severity of disease, and the risk of recurrence. Increased underlying severity of illness, as indicated by a modified Horn’s index of 3 or more (severe or extremely severe disease), has been associated with an increased risk of CDI.27 Specific comorbid illnesses, including inflammatory bowel disease, renal failure, cancer (solid organ), and leukemia or lymphoma, have also been associated with an 48

increased risk of CDI.28 In one study, the presence of feeding tubes, particularly postpyloric tubes, was associated with an increased risk of C difficile acquisition and CDI in comparison to matched controls.29 Immunosuppression

The immune system plays an important role in the pathogenesis of C difficile infection. The development of a systemic antibody response to C difficile toxin A protects against development of acute diarrhea.30,31 In addition, Kyne et al demonstrated that patients who were not able to develop increased serum antitoxin A IgG titers in response to an initial episode of CDI were much more likely to develop recurrent CDI compared to those who mounted an adequate immune response.32 Other host factors may also play a role in determining vulnerability to CDI. For example, Jiang et al found that a single neucleotide polymorphism in the IL-8 gene is associated with increased susceptibility to CDI and the presence of increased fecal IL-8 in diarrheal stools.33,34 Age

Elderly populations have the highest rates of CDI and of recurrent disease, and in particular, the increased incidence from the epidemic BI/NAP1/027 strain is most notable in those ≥65 years.35 It is likely that immunosenescence is a major contributor to the increasing risk of CDI with age.34 In addition, the elderly are at increased risk for exposure to spores because of frequent admission to hospitals and long-term care facilities and receive antibiotic therapy more often than younger individuals. Asymptomatic colonization with C difficile is increased among residents of long-term care facilities (LTCFs) (4%-50%)2,36 with several contributing factors, including frequent exposure to antimicrobial agents, incontinence, age-related hypochlorhydria, frailty, underlying disease burden, living in crowded conditions, and sharing bathroom facilities.36 Exposure to antibiotics 49

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is the most important factor predisposing elderly patients to becoming C difficile-toxin positive.37 The severity of disease, however, is not predicted by age but rather by functional disability and cognitive impairment.38 Infection control measures combined with antimicrobial stewardship programs have been effective in controlling CDI outbreaks on elderly care wards.39

Antibiotics and CDI As discussed above, antimicrobials increase the risk of C difficile colonization and infection by disrupting the indigenous microflora of the intestinal tract. Several studies provide a general framework for considering the effects of antimicrobials on C difficile colonization.12,14 During therapy, antimicrobials may potentially inhibit both C difficile and the host’s commensal microorganisms. After completion of therapy, the indigenous microflora recover over a period of days to weeks,12 leaving the gut vulnerable to C difficile colonization and infection. Therefore, when assessing patients with diarrhea for possible CDI, it is important to inquire about antibiotic exposures that occurred several weeks prior to onset of diarrhea. Specific examples of the effects of antibiotics on C difficile colonization derived from mouse model studies are shown in Figures 2-5A and 2-5B. Antimicrobials that disrupt the microflora but lack significant inhibitory activity against C difficile strains (eg, ceftriaxone, a third-generation cephalosporin) may promote CDI when exposure occurs during treatment or during the period of recovery of the microflora (Figures 2-5A and 2-5B). Antimicrobials with inhibitory activity against C difficile strains (eg, oral vancomycin, piperacillin/tazobactam) may prevent colonization during therapy; however, such agents may facilitate colonization if exposure occurs during the period of recovery of the microflora.40-42 Furthermore, antimicrobials that cause minimal disruption of the anaerobic microflora (eg, aztreonam, a monobactam antimicrobial 50

with no appreciable in vitro activity against anaerobes) do not promote C difficile in mice or hamsters.42,43 Even antibiotics that cause relatively minor disruptions of the anaerobic microflora (eg, trimethoprim/sulfamethoxazole, ciprofloxacin) have been associated with CDI in clinical settings.44-49 Antimicrobial resistance in C difficile strains appears to be playing an increasingly important role in the epidemiology of CDI.50 The emergence of clindamycinresistant strains of C difficile has been associated with large outbreaks, probably in part because these organisms may cause disease during or after completion of clindamycin therapy, whereas clindamycin-susceptible strains may be inhibited during therapy.51,52 Similarly, the emergence of high-level fluoroquinolone resistance among the epidemic BI/NAP1/027 strain and nonepidemic C difficile isolates almost certainly contributes to the increase in reports of an association between these fluoroquinolones and CDI. In addition, increasing fluoroquinolone resistance has been observed in nonepidemic strains.53 As shown in Figure 2-6, fluoroquinolone treatment may exert selective pressure favoring proliferation of fluoroquinolone-resistant epidemic strains (ie, inhibition of fluoroquinolone-susceptible nonepidemic strains and promotion of fluoroquinoloneresistant epidemic strains).54 Finally, tigecycline and β-lactam/β-lactamase inhibitors such as piperacillin/ tazobactam may be relatively infrequently associated with CDI because they possess inhibitory activity against many C difficile strains (ie, C difficile may be inhibited during the course of treatment with these agents but not cephalosporins).42,55 Alternatively, it has been proposed that agents such as piperacillin/tazobactam may be infrequently associated with CDI because they stimulate less toxin production than agents such as cefotaxime or because they cause relatively minor changes in the microflora.56,57 As is examined in greater detail in Chapter 6, these data regarding the ecologic impact of antibiotics have im51

2

52

2-5A Log10 CFU/mL of cecal contents

8 7 6 5 4 3

Strain 1

2

Strain 2

1 0 Saline

Aztreonam

Pip/tazobactam

Antibiotic treatment

Ceftriaxone

Log10 CFU/mL of cecal contents

2-5B 8 7 6 5 4 3 2 1 0

Strain 1 Strain 2

Saline

Aztreonam

Pip/tazobactam

Ceftriaxone

Antibiotic treatment

53

Figures 2-5A and 2-5B: Effect of select agents on growth of two C difficile strains in the cecal contents of mice. Cecal contents were collected and inoculated with 104 CFU/mL of the C difficile strains either 2 hr (2-5A) or 3 days (2-5B) after receiving the final dose of the study drug. Samples were incubated anaerobically for 48 hr, and serial dilutions were plated onto selective media for quantification of C difficile. MICs were as follows: aztreonam, >128 µg/mL for strain 2; and ceftriaxone, 64 µg/mL for both strains. Error bars, SDs. Adapted from Pultz NJ, Donskey CJ: Antimicrob Agents Chemother 2005;49:3529-3532.

2

Strain 1 (FQ susceptible) 8

Strain 6 (FQ susceptible)

7 6 5 4 3

& Antibiotic treatment

e on iax ftr Ce

xa flo vo Le

C Le eftr vo iax flo on xa e cin

cin

in ac ifl ox M

Ga

tif

lo

ox

xa

lin

cin

e

2 1

Sa

Log10 CFU/mL of cecal contents

54 Strain 5 (FQ resisitant) Figure 2-6: Effect of antibiotic treatment on growth of C difficile in the cecal contents of mice during treatment. Mice received daily subcutaneous antibiotic treatment for 5 days. Two hours after the final antibiotic dose, cecal contents were collected and inoculated with 104 CFU/mL of the C difficile test strains. Samples were incubated anaerobically for 48 hr, and then serial dilutions were plated onto selective medium for quantification of C difficile. Error bars represent standard errors. FQ=fluoroquinolone. From Adams et al: Antimicrob Agents Chemother 2007; 51:2674-2678.

portant implications for antimicrobial stewardship interventions. Substitution of β-lactam/β-lactamase inhibitor combinations (inhibitory activity against C diffi cile) for extended-generation cephalosporins (no significant inhibitory activity against C difficile) has been associated with reductions in CDI.58 In the setting of outbreaks caused by clindamycin-resistant strains, restriction of clindamycin has been an effective control measure and has been associated with reduction in the proportion of CDI isolates exhibiting clindamycin-resistance.59 In two recent reports, restriction of fluoroquinolones, alone or in combination with other control measures, has been associated with control of outbreaks associated with epidemic BI/NAP1/027 strains and reductions in the proportion of CDI isolates exhibiting fluoroquinoloneresistance.60,61

Key Points 1. The indigenous microflora of the colon provide an important host defense, termed colonization resistance, by inhibiting growth of pathogens such as C difficile. 2. Antibiotics, which disturb indigenous microflora and colonization resistance, are the most important risk factor for CDI. 3. C difficile spores may be transmitted to susceptible patients on the hands of health-care workers or through direct contact with contaminated environmental surfaces or equipment. 4. Proton pump inhibitors (PPIs) have been associated with CDI in clinical studies, but the mechanism by which PPIs might promote disease is unclear because the spores are not killed by gastric acid and do not germinate in the stomach. 5. Clinical manifestations of CDI are due to the effects of toxins A and B. Epidemic strains also produce binary toxin, but the contribution of this toxin to disease pathogenesis is unclear. 55

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6. The host immune response is an important factor in the pathogenesis of CDI. The development of an antibody response to C difficile toxin protects against development of CDI.

References 1. Bobulsky GS, Al-Nassir WN, Riggs MM, et al: Clostridium difficile skin contamination in patients with C. difficile-associated disease. Clin Infect Dis 2008;46:447-450. 2. Riggs MM, Sethi AK, Zabarsky TF, et al: Asymptomatic carriers are a potential source for transmission of epidemic and nonepidemic Clostridium difficile strains among long-term care facility residents. Clin Infect Dis 2007;45:992-998. 3. Louie TJ, Emery J, Krulicki W, et al: OPT-80 eliminates Clostridium difficile and is sparing of Bacteroides species during treatment of C. difficile infection. Antimicrob Agents Chemother 2009;53:261-263. 4. Kim KH, Fekety R, Batts DH, et al: Isolation of Clostridium difficile from the environment and contacts of patients with antibioticassociated colitis. J Infect Dis 1981;143:42-50. 5. Larson HE, Borriello SP: Quantitative study of antibioticinduced susceptibility to Clostridium difficile enterocecitis in hamsters. Antimicrob Agents Chemother 1990;34:1348-1353. 6. Stiefel U, Rao A, Pultz MJ, et al: Suppression of gastric acid production by proton pump inhibitor treatment facilitates colonization of the large intestine by vancomycin-resistant Enterococcus spp. and Klebsiella pneumoniae in clindamycin-treated mice. Antimicrob Agents Chemother 2006;50:3905-3907. 7. Rao A, Jump RL, Pultz NJ, et al: In vitro killing of nosocomial pathogens by acid and acidified nitrite. Antimicrob Agents Chemother 2006;50:3901-3904. 8. Jump RL, Pultz MJ, Donskey CJ: Vegetative Clostridium difficile survives in room air on moist surfaces and in gastric contents with reduced acidity: a potential mechanism to explain the association between proton pump inhibitors and C difficile-associated diarrhea? Antimicrob Agents Chemother 2007;51:2883-2887. 9. Wilson KH, Sheagren JN, Freter R: Population dynamics of ingested Clostridium difficile in the gastrointestinal tract of the Syrian hamster. J Infect Dis 1985;151:355-361.

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10. Wilson KH: Efficiency of various bile salt preparations for stimulation of Clostridium difficile spore germination. J Clin Microbiol 1983;18:1017-1019. 11. Sorg JA, Sonenshein AL: Bile salts and glycine as cogerminants for Clostridium difficile spores. J Bacteriol 2008;190:2505-2512. 12. Donskey CJ: The role of the intestinal tract as a reservoir and source for transmission of nosocomial pathogens. Clin Infect Dis 2004; 39:219-226. 13. Sorg JA, Sonenshein AL: Chenodeoxycholate is an inhibitor of Clostridium difficile spore germination. J Bacteriol 2009;191:11151117. 14. Owens RC Jr, Donskey CJ, Gaynes RP, et al: Antimicrobialassociated risk factors for Clostridium difficile infection. Clin Infect Dis 2008;46(suppl 1):S19-S31. 15. Anand A, Glatt AE: Clostridium difficile infection associated with antineoplastic chemotherapy: a review. Clin Infect Dis 1993;17: 109-113. 16. Tasteyre A, Barc MC, Collignon A, et al: Role of FliC and FliD flagellar proteins of Clostridium difficile in adherence and gut colonization. Infect Immun 2001;69:7937-7940. 17. Denève C, Delomenie C, Barc MC, et al: Antibiotics involved in Clostridium difficile-associated disease increase colonization factor gene expression. J Med Microbiol 2008;57(pt 6):732-738. 18. Geric B, Carman RJ, Rupnik M, et al: Binary toxin-producing, large clostridial toxin-negative Clostridium difficile strains are enterotoxic but do not cause disease in hamsters. J Infect Dis 2006; 193:1143-1150. 19. Warny M, Pepin J, Fang A, et al: Toxin production by an emerging strain of Clostridium difficile associated with outbreaks of severe disease in North America and Europe. Lancet 2005;366: 1079-1084. 20. Merrigan M, Venugopal A, Mallozzi M, et al: Human hypervirulent Clostridium difficile strains exhibit increased sporulation as well as robust toxin production. J Bacteriol 2010;192:4904-4911. 21. Goorhuis A, Bakker D, Corver J, et al: Emergence of Clostridium difficile infection due to a new hypervirulent strain, polymerase chain reaction ribotype 078. Clin Infect Dis 2008;47:1162-1170. 22. Meyer GK, Neetz A, Brandes G, et al: Clostridium difficile toxins A and B directly stimulate human mast cells. Infect Immun 2007;75:3868-3876.

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23. Riegler M, Sedivy R, Pothoulakis C, et al: Clostridium difficile toxin B is more potent than toxin A in damaging human colonic epithelium in vitro. J Clin Invest 1995;95:2004-2011. 24. Alfa MJ, Kabani A, Lyerly D, et al: Characterization of toxin A-negative, toxin B-positive strain of Clostridium difficile responsible for a nosocomial outbreak of Clostridium difficile-associated diarrhea. J Clin Microbiol 2000;38:2706-2714. 25. Kuehne SA, Cartman ST, Heap JT, et al: The role of toxin A and toxin B in Clostridium difficile infection. Nature 2010;467: 711-713. 26. McFarland LV, Elmer GW, Surawicz CM: Breaking the cycle: treatment strategies for 163 cases of recurrent Clostridium difficile disease. Am J Gastroenterol 2002;97:1769-1775. 27. Kyne L, Sougioultzis S, McFarland LV, et al: Underlying disease severity as a major risk factor for nosocomial Clostridium difficile diarrhea. Infect Control Hosp Epidemiol 2002;23:653-659. 28. Dial S, Delaney JA, Schneider V, et al: Proton pump inhibitor use and risk of community-acquired Clostridium difficile-associated disease defined by prescription for oral vancomycin therapy. CMAJ 2006;175:745-748. 29. Bliss DA, Johnson S, Savik K, et al: Acquisition of Clostridium difficile and Clostridium difficile-associated diarrhea in hospitalized patients receiving tube feeding. Ann Intern Med 1998;129: 1012-1019. 30. Kyne L, Warny M, Qamar A, et al: Asymptomatic carriage of Clostridium difficile and serum levels of IgG antibody against toxin A. N Engl J Med 2000;342:390-397. 31. Shim JK, Johnson S, Samore MH, et al: Primary symptomless colonisation by Clostridium difficile and decreased risk of subsequent diarrhoea. Lancet 1998;351:633-666. 32. Kyne L, Warny M, Qamar A, et al: Association between antibody response to toxin A and protection against recurrent Clostridium difficile diarrhoea. Lancet 2001;357:189-193. 33. Jiang ZD, DuPont HL, Garey K, et al: A common polymorphism in the interleukin 8 gene promoter is associated with Clostridium difficile diarrhea. Am J Gastroenterol 2006;101:1112-1116. 34. Jiang ZD, Garey KW, Price M, et al: Association of interleukin-8 polymorphism and immunoglobulin G anti-toxin A in patients with

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Clostridium difficile-associated diarrhea. Clin Gastroenterol Hepatol 2007;5:964-968. 35. McDonald LC, Owings M, Jernigan DB: Clostridium difficile infection in patients discharged from US short-stay hospitals, 19962003. Emerg Infect Dis 2006;12:409-415. 36. Strausbaugh LJ, Sukumar SR, Joseph CL: Infectious disease outbreaks in nursing homes: an unappreciated hazard for frail elderly persons. Clin Infect Dis 2003;36:870-876. 37. Starr JM, Martin H, McCoubrey J, et al: Risk factors for Clostridium difficile colonisation and toxin production. Age Ageing 2003;32:657-660. 38. Kyne L, Merry C, O’Connell B, et al: Factors associated with prolonged symptoms and severe disease due to Clostridium difficile. Age Ageing 1999;28:107-113. 39. McNulty C, Logan M, Donald IP, et al: Successful control of Clostridium difficile infection in an elderly care unit through use of a restrictive antibiotic policy. J Antimicrob Chemother 1997;40: 707-711. 40. Fekety R, Silva J, Toshniwal R, et al: Antibiotic-associated colitis: effects of antibiotics on Clostridium difficile and the disease in hamsters. Rev Infect Dis 1979;1:386-397. 41. Rolfe RD, Finegold SM: Intestinal beta-lactamase activity in ampicillin-induced, Clostridium difficile-associated ileocecitis. J Infect Dis 1983;147:227-235. 42. Pultz NJ, Donskey CJ: Effect of antibiotic treatment on growth of and toxin production by Clostridium difficile in the cecal contents of mice. Antimicrob Agents Chemother 2005;49:3529-3532. 43. Borriello SP, Welch AR, Barclay FE, et al: Mucosal association by Clostridium difficile in the hamster gastrointestinal tract. J Med Microbiol 1988;25:191-196. 44. Loo VG, Poirier L, Miller MA, et al: A predominantly clonal multi-institutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality. N Engl J Med 2005;353: 2442-2449. 45. Muto CA, Pokrywka M, Shutt K, et al: A large outbreak of Clostridium difficile-associated disease with an unexpected proportion of deaths and colectomies at a teaching hospital following increased fluoroquinolone use. Infect Control Hosp Epidemiol 2005;26: 273-280.

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46. Pepin J, Saheb N, Coulombe MA, et al: Emergence of fluoroquinolones as the predominant risk factor for Clostridium difficileassociated diarrhea: a cohort study during an epidemic in Quebec. Clin Infect Dis 2005;41:1254-1260. 47. McCusker ME, Harris AD, Perencevich E, et al: Fluoroquinolone use and Clostridium difficile-associated diarrhea. Emerg Infect Dis 2003;9:730-733. 48. Vollaard EJ, Clasener HA: Colonization resistance. Antimicrob Agents Chemother 1994;38:409-414. 49. Bignardi GE: Risk factors for Clostridium difficile infection. J Hosp Infect 1998;40:1-15. 50. Gerding DN: Clindamycin, cephalosporins, fluoroquinolones, and Clostridium difficile-associated diarrhea: this is an antimicrobial resistance problem. Clin Infect Dis 2004;38:646-648. 51. Climo MW, Israel DS, Wong ES, et al: Hospital-wide restriction of clindamycin: effect on the incidence of Clostridium difficile-associated diarrhea and cost. Ann Intern Med 1998;128:989-995. 52. Pear SM, Williamson TH, Bettin KM, et al: Decrease in nosocomial Clostridium difficile-associated diarrhea by restricting clindamycin use. Ann Intern Med 1994;120:272-277. 53. McDonald LC, Killgore GE, Thompson A, et al: An epidemic, toxin gene-variant strain of Clostridium difficile. N Engl J Med 2005;353:2433-2441. 54. Adams DA, Riggs MM, Donskey CJ: Effect of fluoroquinolone treatment on growth of and toxin production by epidemic and nonepidemic Clostridium difficile strains in the cecal contents of mice. Antimicrob Agents Chemother 2007;51:2674-2678. 55. Jump RL, Li Y, Pultz MJ, et al: Tigecycline exhibits inhibitory activity against Clostridium difficile in the colon of mice and does not promote growth or toxin production. Antimicrob Agents Chemother 2011;55:546-549. 56. Baines SD, Freeman J, Wilcox MH: Effects of piperacillin/ tazobactam on Clostridium difficile growth and toxin production in a human gut model. J Antimicrob Chemother 2005;55:974-982. 57. Freeman J, Wilcox MH: Antibiotic activity against genotypically distinct and indistinguishable Clostridium difficile isolates. J Antimicrob Chemother 2001;47:244-246.

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58. Wilcox MH, Freeman J, Fawley W, et al: Long-term surveillance of cefotaxime and piperacillin-tazobactam prescribing and incidence of Clostridium difficile diarrhoea. J Antimicrob Chemother 2004;54:168-172. 59. Johnson S, Samore MH, Farrow KA, et al: Epidemics of diarrhea caused by a clindamhycin-resistant strain of Clostridium difficile in four hospitals. N Engl J Med 1999;341:1645-1651. 60. Kallen AJ, Thompson A, Ristaino P, et al: Complete restriction of fluoroquinolone use to control an outbreak of Clostridium difficile infection at a community hospital. Infect Control Hosp Epidemiol 2009;30:264-272. 61. Muto CA, Blank MK, Marsh JW, et al: Control of an outbreak of infection with the hypervirulent Clostridium difficile BI strain in a university hospital using a comprehensive “bundle” approach. Clin Infect Dis 2007;45:1266-1273.

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Chapter 3

Diagnosis

C

lostridium difficile infection (CDI) should be suspected in individuals with diarrhea and recent antimicrobial use, particularly if there has been exposure to a health-care facility. The onset of diarrhea may be as short as 1 day or as long as 6 weeks after exposure to antimicrobials.1,2 Clostridium difficile infection causes stools that are usually watery, but mucoid or soft stools may also occur.3 Gross blood in the stool is uncommon. Diarrhea is commonly defined as three or more unformed stools in 24 hr for 2 days.4 Peterson et al5 have suggested that ≥3 loose stools in a single day should be the minimum clinical criterion for considering CDI. Less frequent passage of stool, in the absence of an ileus, decreases the likelihood that diarrhea is due to C difficile.5 Other clinical features of CDI include fever, lower abdominal cramps, anorexia, nausea, and malaise. Common laboratory abnormalities in CDI patients include leukocytosis, hypoalbuminemia, and presence of leukocytes in feces, but these findings are nonspecific. Some patients with severe CDI do not have diarrhea because of the presence of ileus.6-8 A common scenario is a postoperative patient receiving narcotics for pain control. In addition, it is not uncommon for leukocytosis, fever, and abdominal pain to precede the development of diarrhea by one or more days.9 When CDI is suspected in the absence of diarrhea, computed tomography (CT) imaging of the abdomen is useful to evaluate for findings that suggest 62

CDI and to exclude other intra-abdominal disorders.10,11 Colonoscopy may also be useful to evaluate for pseudomembranous colitis (PMC), but there is a small risk of perforation if fulminant colitis is present.11 A variety of conditions other than CDI may cause antibiotic-associated diarrhea. In hospitalized patients, only 10% to 20% of antibiotic-associated diarrhea is attributable to CDI.12 Most cases of antibiotic-associated diarrhea are probably due to disruption of the intestinal microflora, resulting in osmotic diarrhea from malabsorption of complex carbohydrates that the bacteria normally break down. Other noninfectious causes of diarrhea include laxatives, other medications, tube feedings, and illnesses such as idiopathic inflammatory bowel disease. Other infectious causes of diarrhea include viruses, parasites, or other bacteria, but these are uncommon in patients who have onset of symptoms more than 72 hr after admission. Because the clinical manifestations of CDI are nonspecific, diagnosis requires laboratory testing. Several different tests are used to establish the diagnosis of CDI, and all of them have advantages and disadvantages. Health-care workers should be aware of the characteristics of the test used in their facility. Physicians and nurses should also appreciate that early diagnosis of CDI may reduce the risk for development of complications and prevent transmission. Therefore, health-care facilities should educate health-care workers about risk factors for and clinical manifestations of CDI and develop strategies to expedite collection and testing of stool specimens.

Laboratory Testing for CDI Laboratory testing is recommended for all patients ≥1 year of age who have symptoms compatible with a diagnosis of CDI and a recent history of antibiotic use. A minority of CDI patients do not have prior exposure to antibiotics. Therefore, testing may be indicated in the absence of antibiotic exposure if the clinical presentation 63

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suggests CDI and there is no other explanation for diarrhea. Testing for C difficile should only be performed on unformed stools (defined as stool that conforms to the container it is in).12-14 Performance of a “test of cure” for patients who have responded to therapy should be discouraged. Evaluation of formed stools from asymptomatic patients is not recommended except for research purposes.

Specimen Collection and Transport The standard diagnostic test for CDI is laboratory analysis of unformed stool samples. Rectal swabs are unacceptable as specimens because toxin testing cannot be performed on them. The specimen does not need special transport media or anaerobic transport. Specimens should be transported to the laboratory as soon as possible and stored at 2° to 8° C until tested. Storage at room temperature should be avoided, as well as repeated freezing and thawing, all of which can inactivate toxins and decrease sensitivity of toxin assays. Diagnostic Tests and Assays A variety of laboratory tests may be used, including toxin enzyme immunoassay (EIA), cell culture cytotoxicity assay, polymerase chain reaction (PCR) for toxin B gene, glutamate dehydrogenase (GDH) assay, toxigenic stool culture (ie, culture followed by assessment of toxin production by C difficile isolates), and two-step testing. Sensitivity, specificity, ease of use, turnaround time, and cost vary among the different test methods (Table 3-1). Toxin Enzyme Immunoassay Tests

Enzyme immunoassays (EIAs) for toxins A and/or B are the most commonly used diagnostic tests for C difficile in the United States.3,5 Toxin EIAs are inexpensive, technically easy to perform, and rapid, producing results in a few hours.3 Toxin EIA specificity ranges from 75% to >99%,12,15,16 and sensitivity ranges from 32% to 73%.17 64

Because of the wide range of specificity and sensitivity for toxin EIA tests, which often depend on which reference standard is used for comparison, toxin EIA tests when used alone may not be reliable. In addition, some EIAs detect only toxin A and therefore miss C difficile strains that produce only toxin B. It is preferable to use an assay that detects both toxins A and B, because strains that produce toxin B only are as pathogenic as strains that produce both toxins A and B and cause the same range of severity of illness.18 Cell Culture Cytotoxicity Assay

The cell culture cytotoxicity assay detects the cytopathic effect of toxin B on cultured cell lines. Some studies have reported a specificity of 99% to 100% and sensitivity of 80% to 90% for the cell culture cytotoxicity assay.19-21 Although it is more sensitive than toxin EIAs, some cell culture cytotoxicity assays have reported a sensitivity as low as 67% when compared to stool culture for C difficile.12 Other disadvantages of cell culture cytotoxicity assays include a long turnaround time of 48 to 72 hr, expensive cells and media, the need to maintain cell cultures, and the technical expertise required to perform the assay. Nucleic Acid Ampliﬁcation Tests

Although use of nucleic acid amplification tests (NAATs) to detect C difficile in the stool has been described in the literature for many years,5 commercial NAATs have only recently become available in the US. Three of the commercial NAAT assays (BD GeneOhm™ Cdiff assay, Cepheid Xpert™ C difficile assay, and Prodesse ProGastro™ Cd assay) use the polymerase chain reaction (PCR) to amplify nucleic acid and therefore require the use of a thermocycler.22-30 The Illumigene test (Meridian Illumigene™ C difficile) is based on loop-mediated isothermal amplification (LAMP) technology and does not require a thermocycler.31 65

3

Table 3-1: Comparisons of Different Laboratory-based Diagnostic Tests for CDI Laboratory Test

Advantages

Toxin enzyme immunoassay (EIA)

Inexpensive, rapid

Cell cytotoxicity assay

More sensitive than toxin EIA assays

Glutamate dehydrogenase

Rapid, inexpensive, sensitive, good for initial screening

assay (GDH) Stool culture for C difficile

Most sensitive test, provides C difficile isolates

Real-time polymerase chain reaction (PCR)

Sensitive, specific, rapid

In one study, when compared to stool culture for toxigenic C difficile, the sensitivity, specificity, positive and negative predictive values of the PCR assays were >94%, 99.2%, >94%, and >99%, respectively, compared to 44.4% to 61.1%, 100%, 100%, and 93% to 95%, respectively, for toxin EIAs (Table 3-2). Other comparisons have shown similar results.23-31 Advantages of NAATs include increased sensitivity compared to cytotoxicity cell assays and rapid turnaround time. Disadvantages include higher cost and the need for specialized equipment for the PCRbased tests. 66

Disadvantages Less sensitive than cell cytotoxicity assay, some only test for toxin A, C difficile not isolated Requires specialized equipment, less sensitive than stool culture, 48–72-hr turnaround Not specific (detects nontoxigenic C difficile and other bacteria)

3

Not specific (detects nontoxigenic C difficile), labor intensive, 24–48-hr turnaround, permits molecular typing Expensive, requires specialized equipment, less sensitive than stool culture

Glutamate Dehydrogenase Test

Glutamate dehydrogenase (GDH) is a protein that is constitutively produced by C difficile, and assays are available to detect GDH in stool. Initially, it was thought this assay was specific for C difficile, but it was subsequently demonstrated that other Clostridium species can occasionally produce GDH.32 The original latex agglutination tests for GDH suffered from poor sensitivity (58%–68%)12,33 but the sensitivity of the current EIAs for GDH are much better, ranging from 85% to 100%.34-36 A positive GDH test only indicates the presence of 67

Table 3-2: Performance of C DIFF Quik Chek Complete®, VIDAS®, Xpert™ C difficile PCR, and GeneOhm™ PCR Compared to Those of Toxigenic Culture22

Comparator Test Parameter

C DIFF Quik Chek Complete® for: GDH

CDT

Toxigenic % sensitivity 100 (82.4–100) 61.1 (38.4–79.7) culture % specificity 97.0 (92.5–98.8) 100 (97.3–100) % PPV

81.8 (61.2–92.5) 100 (73.5–100)

% NPV

100 (97.2–100)

95.0 (90.0–97.5)

CDT=C difficile toxin; GDH=glutamate dehydrogenase; CI=confidence interval; NPV=negative predictive value; PPV=positive predictive value Adapted from Swindells et al22

C difficile, not the production of toxins. Because some C difficile strains do not produce toxin, the GDH test is most useful as a sensitive screening test to detect the presence of C difficile. Stool Culture

Under proper conditions, stool culture is the most sensitive method for detecting C difficile. Stool culture is seldom used in US clinical microbiology laboratories because of its cost and long turnaround time of 48 to 72 hr.14 Stool culture does, however, provide isolates that allow for molecular typing of the organism, which is essential in epidemiologic studies, and for antibiotic susceptibility. 68

Performance (95% CI) by: VIDAS *

Xpert™ C difficile PCR

GeneOhm™ PCR

44.4 (24.4–66.5)

100 (82.4–100)

94.4 (74.0–98.7)

100 (97.3–100)

99.2 (95.9–99.8)

99.2 (95.9–99.8)

100 (66.4–100)

94.7 (75.1–98.8)

94.4 (74.0–98.7)

93.0 (87.5–96.1)

100 (97.2–100)

99.2 (95.9–99.8)

®

3

*This test not FDA approved for this use.

Selective media such as cycloserine-cefoxitin-fructose agar (CCFA), or C difficile brucella agar (CDBA) are used to isolate C difficile.37 The agar is prereduced in an anaerobic environment to enhance C difficile recovery. Visual identification by colony morphology and gramstain appearance is usually sufficient for identification of C difficile by experienced personnel. C difficile colonies have a flat, yellow, ground-glass appearance with a surrounding yellow halo (see Figure 6-2). C difficile isolates should be tested for toxin production (ie, toxigenic culture) to establish the diagnosis of CDI because as many as 25% of C difficile isolates do not produce toxin and are incapable of causing CDI.12 69

Two-Step Testing Because of concerns of low sensitivity of toxin EIAs and the cost and time required for more sensitive tests such as cell culture cytotoxicity assays and toxigenic stool culture, several investigators have evaluated two-step testing. The first step is a high-sensitivity, rapid screen test such as the glutamate dehydrogenase (GDH) test (Figure 3-1). A negative result has good to excellent negative predictive value (≥99% predictive of a negative cell culture cytotoxicity assay) and rules out CDI.36 Because GDH is not specific for toxin-producing strains of C difficile, positive tests require additional testing, such as the cell culture cytotoxicity assay or toxigenic stool culture. Stool positive by the cell culture cytotoxicity assay or for a toxigenic strain of C difficile by stool culture is diagnostic for CDI; stool negative by the cytotoxicity cell assay or a toxigenic strain of C difficile is reported as negative. The two-step approach is able to rapidly identify patients who do not have CDI (negative GDH assay) and select patients with possible CDI who require additional testing. This approach may also be more cost-effective than use of the cytotoxicity cell assay alone.36 However, there have been some recent concerns with the use of the GDH test as an initial screen. Some studies have found the GDH test to have a sensitivity as low as 76%.38 This is problematic because for every 1% drop in sensitivity of the screening assay, there will be a resulting 1% increase in the number of true CDI cases missed compared to if the second assay was used alone. This is demonstrated in a recent publication by Novak-Weekley et al.39 Although the sensitivity of the GDH test they used is not provided, the sensitivity of each two-step comparison was lower than when the second test was evaluated alone (58.3% to 55.6% for EIA alone versus GDH then EIA; 94.4% to 86.1% for PCR alone versus GDH then PCR). In the near future, it is likely that there will continue to be debate regarding the use of GDH-based algorithms versus PCR alone for CDI diagnostic testing.40 For example, 70

Goldenberg et al30 recently concluded that screening for GDH is an effective method when used in combination with PCR, whereas Larson et al41 reported that GDH-based algorithm was convenient and rapid but less sensitive than PCR. Tenover et al28 recently provided evidence that GDH algorithms may be less sensitive than PCR for detection of ribotypes other than BI/NAP1/027. This finding could potentially provide an explanation for some of the variability in the sensitivity reported for GDH-based approaches for CDI diagnosis.

Molecular Typing Methods Molecular typing of C difficile requires isolation of the organism by culture and is generally available only through research laboratories for epidemiologic investigation. The use of molecular typing methods has been essential in recent efforts to monitor the emergence and dissemination of epidemic BI/NAP1/027 strains. Several genotypic methods are available, including restriction endonuclease analysis (REA), pulsed-field gel electrophoresis (PFGE), multilocus sequence typing (MLST), amplified fragment-length polymorphism, multilocus variable-number tandem-repeat analysis (MLVA), surface layer protein A gene sequence typing, and polymerase chain reaction ribotyping (PCR ribotyping).42 In a comparative study, all of these methods were shown to be capable of detecting outbreak strains, but only REA and MLVA showed sufficient discrimination to distinguish strains from different outbreaks.42 Binary toxin genes and the 18-base pair tcdC mutation are consistently present in epidemic BI/NAP1/027 strains and less common in other strain types.42 Therefore, analyses to detect binary toxin genes and the tcdC mutation provide valuable supplemental data when studying outbreaks from the epidemic strain.43 Repeat Testing Although repeat testing of stool in patients with negative tests for C difficile is common, there is little data to 71

3

72

Stool specimen for C difficile testing

negative

C difficile specific antigen

positive

(GDH assay)

positive

C difficile toxin A/B

negative

(EIA for A/B)

C difficile antigen not detected

C difficile antigen detected C difficile toxin A/B detected

C difficile antigen detected C difficile toxin A/B not detected

Interpretation: Absence of C difficile No further testing

Interpretation: Nontoxin or toxinproducing C difficile or false-positive antigen result

Interpretation: Toxin-producing C difficile

Cell cytotoxicity assay or culture for toxigenic C difficile identification, optional molecular typing and antimicrobial sensitivity

73

Figure 3-1: Algorithm for Clostridium difficile two-step testing. EIA=enzyme immunoassay, GDH=glutamate dehydrogenase. Adapted from Ticehurst et al.36

3

support this practice. This practice results from the concern of low sensitivity of toxin EIAs, and studies indicate that 10% of patients who initially test negative for C difficile toxin will have a positive test on repeat testing.12 However, these studies, by not performing stool culture for C difficile, have not confirmed that the positive toxin tests on repeat testing were true positives. This is a problem because the prevalence of C difficile colonization is lower in patients with a previous negative test. As prevalence decreases, the positive predictive value of the test also decreases, and the likelihood of a false-positive test increases. Conversely, the negative predictive value of a test with a sensitivity of only 75% and disease prevalence of 10% to 20% (likely true sensitivity of toxin EIAs and typical prevalence of CDI in hospitalized patients with diarrhea) remains high at 94% to 97%. In addition, several studies support the lack of benefit of repeat testing after initial negative test results, since results of repeat testing frequently do not alter management of the patient and clinical outcomes are not different in patients not treated but with subsequent positive tests.44-47 Published guidelines based on these data do not recommend routine repeat testing.12,13 Methods to optimize the sensitivity of toxin tests, such as two-step testing or use of tests with enhanced sensitivity such as PCR or stool culture, may decrease the desire to request repeat testing. If these tests are not available, repeat testing should be reserved for when there is a high index of suspicion for CDI. If there is a concern for a high rate of false-negative tests, stool collection, transport, storage, and testing methodology should be investigated to determine if there are any suboptimal practices that may lead to a decrease in test sensitivity.

Nonlaboratory Based Tests Pseudomembranous colitis (PMC) is considered pathognomonic for CDI, and CDI is the cause of more than 90% of cases of PMC, which can be diagnosed with direct visualization of pseudomembranes by sigmoidoscopy or 74

3 Figure 3-2. Computed tomography scan of patient with pseudomembranous colitis (PMC), demonstrating limited ascites, submucosal edema as indicated by the thickened, low-attenuation colon wall, and the accordion sign in the rectosigmoid colon. The accordion sign is suggestive of PMC, showing oral contrast material with high attenuation in the colonic lumen alternating with an inflamed mucosa with low attenuation, resulting in an image that is similar to an accordion. Used with permission from Kawamoto.11

colonoscopy. Colonoscopy is the preferred method because PMC involves only the right colon in up to one-third of patients, and sigmoidoscopy would not detect such cases.4 Some patients may not have PMC identified by direct visualization, but have evidence of it on histopathology. Although considered diagnostic for CDI, PMC is identified in only 50% of cases of CDI.48 As noted previously, when CDI is suspected in the absence of diarrhea, CT imaging of the abdomen is useful to evaluate for findings suggestive of CDI and for excluding 75

other intra-abdominal disorders.10,11 Common CT findings in CDI include wall thickening, low-attenuation mural thickening corresponding to mucosal and submucosal edema, the “accordion sign,” pericolonic stranding, and ascites (Figure 3-2). However, because of poor sensitivity and specificity (approximately 50% for each), clinicians should not rely on abdominal CT scans to confirm or rule out the diagnosis of CDI.10,48 Furthermore, abdominal CT scans alone do not correlate with severity of CDI.10,49

Key Points 1. C difficile infection should be suspected in individuals with diarrhea (≥3 unformed stools in 24 hr) and recent antimicrobial use, particularly in health-care settings. 2. Common but nonspecific laboratory abnormalities in CDI patients include leukocytosis, hypoalbuminemia, and presence of leukocytes in feces. 3. Patients with severe CDI may not have diarrhea because of the presence of ileus. 4. In some CDI patients, leukocytosis and fever may precede onset of diarrhea (ie, unexplained leukocytosis in a patient who has received antibiotics could be a harbinger of CDI). 5. Laboratory testing is essential to diagnose CDI because only 10%-20% of antibiotic-associated diarrhea is attributable to CDI. 6. Testing for CDI should only be performed on unformed stools (defined as stool that conforms to the container it is in). 7. Toxin enzyme immunoassay (EIA) is the most commonly used diagnostic test in the US because it is easy to perform and low in cost, but it has lower sensitivity than the cell culture cytotoxicity assay, PCR, or toxigenic culture methods. 8. Routine repeat laboratory testing after initial negative assay results is not recommended because of low positive predictive value of results. 76

9. A two-step approach combining an initial screen with a glutamate dehydrogenase EIA with a second test (eg, toxigenic culture, PCR, cell culture cytoxicity assay) for toxin is able to rapidly identify patients who do not have CDI (negative GDH assay) and select patients with possible CDI for additional testing. However, some recent studies suggest that such GDH-based algorithms do not have sufficient sensitivity for detection of CDI. 10. Real-time polymerase chain reaction (PCR) for diagnosis of CDI is sensitive and rapid, but is expensive and requires specialized equipment. 11. When CDI is suspected in the absence of diarrhea, CT imaging of the abdomen is a useful test to evaluate for findings suggestive of CDI and for excluding other intra-abdominal pathology.

References 1. Kelly CP, Pothoulakis C, LaMont JT: Clostridium difficile colitis. N Engl J Med 1994;330:257-262. 2. Mylonakis E, Ryan ET, Calderwood SB: Clostridium difficileassociated diarrhea: a review. Arch Intern Med 2001;161:525-533. 3. Bartlett JG, Gerding DN: Clinical recognition and diagnosis of Clostridium difficile infection. Clin Infect Dis 2008;46(suppl 1): S12-S18. 4. McFarland LV, Mulligan M, Kwok RY, et al: Nosocomial acquisition of Clostridium difficile infection. N Engl J Med 1989;320: 204-210. 5. Peterson LR, Manson RU, Paule SM, et al: Detection of toxigenic Clostridium difficile in stool samples by real-time polymerase chain reaction for the diagnosis of C difficile-associated diarrhea. Clin Infect Dis 2007;45:1152-1160. 6. Longo WE, Mazuski JE, Virgo KS, et al: Outcome after colectomy for Clostridium difficile colitis. Dis Colon Rectum 2004;47: 1620-1626. 7. Sheikh R, Yasmeen S, Pauly MP, et al: Pseudomembranous colitis without diarrhea presenting clinically as acute intestinal pseudo-obstruction. J Gastroenterol 2001;36:629-632.

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8. Triadafilopoulos G, Hallstone AE: Acute abdomen as the first presentation of pseudomembranous colitis. Gastroenterology 1991;101:685-691. 9. Bulusu M, Narayan S, Shetler K, et al: Leukocytosis as a harbinger and surrogate marker of Clostridium difficile infection in hospitalized patients with diarrhea. Am J Gastroenterol 2000;95:3137-3141. 10. Ash L, Baker ME, O’Malley CM Jr, et al: Colonic abnormalities on CT in adult hospitalized patients with Clostridium difficile colitis; prevalence and significance of findings. AJR Am J Roentgenol 2006;186:1393-1400. 11. Kawamoto S, Horton KM, Fishman EK: Pseudomembranous colitis: spectrum of imaging findings with clinical and pathologic correlation. Radiographics 1999;19:887-897. 12. Cohen SH, Gerding DN, Johnson S, et al: SHEA‐IDSA guideline: Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol 2010;31:431-455. 13. Dubberke ER, Gerding DN, Classen D, et al: Strategies to prevent Clostridium difficile infections in acute care hospitals. Infect Control Hosp Epidemiol 2008;29(suppl 1):S81-S92. 14. McDonald LC, Coignard B, Dubberke E, et al: Recommendations for surveillance of Clostridium difficile-associated disease. Infect Control Hosp Epidemiol 2007;28:140-145. 15. Vanpoucke H, De Baere T, Claeys G, et al: Evaluation of six commercial assays for the rapid detection of Clostridium difficile toxin and/ or antigen in stool specimens. Clin Microbiol Infect 2001;7:55-64. 16. Barbut F, Kajzer C, Planas N, et al: Comparison of three enzyme immunoassays, a cytotoxicity assay, and toxigenic culture for diagnosis of Clostridium difficile-associated diarrhea. J Clin Microbiol 1993; 3:963-967. 17. Peterson, LR, and Robicsek, A:. Does my patient have Clostridium difficile infection? Ann Intern Med. 2009;151(3):176-179. 18. Johnson S, Kent SA, O’Leary KJ, et al: Fatal pseudomembranous colitis associated with a variant Clostridium difficile strain not detected by toxin A immunoassay. Ann Intern Med 2001;135: 434-438. 19. Wilkins TD, Lyerly DM: Clostridium difficile testing: after 20 years, still challenging. J Clin Microbiol 2003;4:531-534.

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20. Delmée M: Laboratory diagnosis of Clostridium difficile disease. Clin Microbiol Infect 2001;7:411-416. 21. Poutanen SM, Simor AE: Clostridium difficile-associated diarrhea in adults. CMAJ 2004;171:51-58. 22. Swindells J, Brenwald N, Reading N, et al: Evaluation of diagnostic tests for Clostridium difficile infection. J Clin Microbiol 2010;48(2):606-608. 23. Stamper PD, Alcabasa R, Aird D, et al: Comparison of a commercial real-time PCR assay for tcdB detection to a cell culture cytotoxicity assay and toxigenic culture for direct detection of toxinproducing Clostridium difficile in clinical samples. J Clin Microbiol 2009;47:373-378. 24. BD GeneOhm™ Cdiff Assay [package insert]: Ste-Foy, Qc, Canada: BD Diagnostics, 2009. 25. Xpert® C. difficile assay [package insert]: Sunnyvale, CA: Cepheid Corporation; 2011. 26. Kvach EJ, Ferguson D, Riska PF, et al: Comparison of BD GeneOhm C diff real-time PCR assay with a two-step algorithm and a toxin A/B enzyme-linked immunosorbent assay for diagnosis of toxigenic Clostridium difficile infection. J Clin Microbiol 2010;48:109-114. 27. Babady NE, Stiles J, Ruggiero P, et al: Evaluation of the Cepheid Xpert Clostridium difficile Epi assay for diagnosis of Clostridium difficile infection and typing of the NAP1 strain at a cancer hospital. J Clin Microbiol 2010;48:4519-4524. 28. Tenover FC, Novak-Weekle S, Woods CW, et al: Impact of strain type on detection of toxigenic Clostridium difficile: comparison of molecular diagnostic and enzyme immunoassay approaches. J Clin Microbiol 2010;48:3719-3724. 29. Knetsch CW, Bakker D, de Boer RF, et al: Comparison of realtime PCR techniques to cytotoxigenic culture methods for diagnosing Clostridium difficile infection. J Clin Microbiol 2011;49:227-231. 30. Goldenberg SD, Cliff PR, Smith S, et al: Two-step glutamate dehydrogenase antigen real-time polymerase chain reaction assay for detection of toxigenic Clostridium difficile. J Hosp Infect 2010;74: 48-54. 31. Lalande V, Barrault L, Wadel S, et al: Evaluation of a loopmediated isothermal amplification (LAMP) assay for the diagno-

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sis of Clostridium difficile infections. J Clin Microbiol 2011;49: 2714-2716. 32. Wongwanich S, Kusum M, Phan-Urai R: Reactivity of the Cd D-1 latex test with Clostridium difficile and other bacteria. Southeast Asian J Trop Med Public Health 1994;25:321-323. 33. Staneck JL, Weckbach LS, Allen SD, et al: Multicenter evaluation of four methods for Clostridium difficile detection: immunoCard C. difficile, cytotoxin assay, culture, and latex agglutination. J Clin Microbiol 1996;34:2718-2721. 34. Snell H, Ramos M, Longo S, et al: Performance of the TechLab C. DIFF CHEK-60 enzyme immunoassay (EIA) in combination with the C. difficile Tox A/B II EIA kit, the Triage C. difficile panel immunoassay, and a cytotoxin assay for diagnosis of Clostridium difficile-associated diarrhea. J Clin Microbiol 2004;42:4863-4865. 35. Zheng L, Keller SF, Lyerly DM, et al: Multicenter evaluation of a new screening test that detects Clostridium difficile in fecal specimens. J Clin Microbiol 2004;42:3837-3840. 36. Ticehurst JR, Aird DZ, Dam LM, et al: Effective detection of toxigenic Clostridium difficile by a two-step algorithm including tests for antigen and cytotoxin. J Clin Microbiol 2006;44:1145-1149. 37. Nerandzic MM, Donskey CJ: Effective and reduced-cost modified selective medium for isolation of Clostridium difficile. J Clin Microbiol 2009;47:397-400. 38. Sloan LM, Duresko BJ, Gustafson DR, Rosenblatt JE: Comparison of real-time PCR for detection of the tcdC gene with four toxin immunoassays and culture in diagnosis of Clostridium difficile infection. J Clin Microbiol 2008;46:1996–2001. 39. Novak-Weekley SM, Marlowe EM, Miller JM, et al: Clostridium difficile testing in the clinical laboratory by use of multiple testing algorithms. J Clin Microbiol 2010;48:889-893. 40. Wilcox MH, Planche T, Fang FC, et al: What is the current role of algorithmic approaches for diagnosis of C difficile infection? J Clin Microbiol 2010;48:4347-4353. 41. Larson AM, Fung AM, Fang FC: Evaluation of tcdB real-time PCR in a three-step diagnostic algorithm for detection of toxigenic Clostridium difficile. J Clin Microbiol 2010;48:124-130. 42. Killgore G, Thompson A, Johnson S, et al: Comparison of seven techniques for typing international epidemic strains of Clostridium difficile: restriction endonuclease analysis, pulsed-field gel electro-

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phoresis, PCR-ribotyping, multilocus sequence typing, multilocus variable-number tandem-repeat analysis, amplified fragment length polymorphism, and surface layer protein A gene sequence typing. J Clin Microbiol 2008;46:431-437. 43. McDonald LC, Killgore GE, Thompson A, et al: An epidemic, toxin gene-variant strain of Clostridium difficile. N Engl J Med 2005; 353:2433-2441. 44. Mohan SS, McDermott BP, Parchuri S, et al: Lack of value of repeat stool testing for Clostridium difficile toxin. Am J Med 2006; 119:356.e7-8. 45. Cardona DM, Rand KH: Evaluation of repeat Clostridium difficile enzyme immunoassay testing. J Clin Microbiol 2008;46: 3686-3689. 46. Aichinger E, Schleck CD, Harmsen WS, et al: Nonutility of repeat laboratory testing for detection of Clostridium difficile by use of PCR or enzyme immunoassay. J Clin Microbiol 2008;46: 3795-3797. 47. El-Gammal A, Scotto V, Malik S, et al: Evaluation of the clinical usefulness of C difficile toxin testing in hospitalized patients with diarrhea. Diagn Microbiol Infect Dis 2000;36:169-173. 48. Gerding DN, Olson MM, Peterson LR, et al: Clostridium difficile-associated diarrhea and colitis in adults. A prospective casecontrolled epidemiologic study. Arch Intern Med 1986;146:95-100. 49. Boland GW, Lee MJ, Cats AM, et al: Clostridium difficile colitis: correlation of CT findings with severity of clinical disease. Clin Radiol 1995;50:153-156.

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Chapter 4

Treatment/Management

T

here had been no new therapies approved for the treatment of Clostridium difficile infection (CDI) in the United States since oral vancomycin was approved by the Food and Drug Administration (FDA) for the treatment of CDI in 1986. In May 2011, fidaxomicin became only the second therapeutic approved by the FDA for the treatment of CDI as a result of phase III studies demonstrating fidaxomicin had a superior sustained clinical response compared to oral vancomycin.1 In addition, several other novel therapeutics are being investigated for the treatment and prevention of CDI. These, as well as fidaxomicin, are discussed later in this chapter. But except for the mildest cases,2 discontinuing the offending antibiotic without prescribing therapy for CDI is not recommended because of the increasing severity of CDI. Although there are no data to support switching the offending antibiotic to an antibiotic associated with a lower risk of CDI, this is often done. It is prudent to continue the first-line therapy for the underlying infection if there are no alternative antibiotics associated with a lower risk of CDI, if the alternate antibiotics are not are equally effective for treating the underlying infection, or if the alternate antibiotics do not have an acceptable safety profile. Another recent recommendation is to avoid antiperistaltic agents, including antidiarrheals and opiates. This is based on observations that these agents are associated with worse outcomes for invasive bacterial enteropathogens, such as Salmonella, Shigella, and Campylobacter.3,4 There 82

are less data on the use of these agents when managing patients with CDI. A recent systematic review identified 55 patients with CDI who also received an antiperistaltic agent.5 Overall, 19 (35%) patients improved and 17 (31%) clinically deteriorated and developed toxic megacolon or colonic dilation. Of the 15 patients with a known outcome after clinical deterioration, 6 (40%) died. None of the patients who developed clinical deterioration was on active treatment for CDI when the antiperistaltic agent was initiated. In the largest cohort of patients who received an antiperistaltic agent after active treatment for CDI was started (n=23), no patients clinically deteriorated.5 All CDI cases were mild, and antiperistaltic agents were not associated with a reduction in duration of diarrhea. In light of these data, it seems prudent to withhold antiperistaltic agents for CDI patients because there may be risk without any apparent benefit.6

CDI Speciﬁc Therapies: Historical Overview The two first-line treatments for CDI in the US are oral metronidazole (Flagyl®) and oral vancomycin (Vancocin®). Oral vancomycin is approved by the FDA for treatment of CDI, whereas metronidazole is not. Oral metronidazole is preferred over intravenous (IV) metronidazole because only the oral formulation has been evaluated in prospective, randomized trials. However, oral metronidazole is almost 100% absorbed before it reaches the colon. Levels of metronidazole in the stool for oral and IV metronidazole are comparable, and appear to depend on the degree of colonic inflammation present.7 Intravenous vancomycin does not achieve sufficient levels in the stool to treat CDI, so it should not be used as a treatment for CDI.8 Although oral metronidazole does not have an FDA indication for the treatment of CDI,9,10 treatment recommendations have historically suggested oral metronidazole over oral vancomycin in the US. This is because prospective, randomized studies indicate similar efficacy 83

4

Table 4-1: Selected Randomized Trials for the Treatment of CDI Study

Drug

Keighley et al, 1978

Placebo Vancomycin

Number of Response Relapse Patients 22% 92%

44%* 0

7 16

Teasley et al, Metronidazole 1983 Vancomycin

95% 100%

5% 11%

42 56

Dudley et al, Bacitracin 1986 Vancomycin

80% 93%

33% 20%

17 23

Wenisch et al, 1996

94% 94%

16% 16%

21 31

Metronidazole Vancomycin

Emergence of new strain of CDI in 2004 Musher et al, 2006

Nitazoxanide Metronidazole

89% 82%

14% 24%

44 98

Lagrotteria et al, 2006

Metronidazole Metronidazole plus Rifampin

65% 63%

38% 42%

20 19

Louie et al, 2007

Metronidazole Vancomycin

72% 81%

27% 23%

143 134

*P <0.05

for oral vancomycin and oral metronidazole (Table 4-1). The primary reason is that oral metronidazole costs less than oral vancomycin.11,12 There is also the theoretical risk that oral vancomycin will increase selective pressure 84

Table 4-2: Reports of Metronidazole Treatment Failures Reference

Response Rate

Relapse Rate

Fernandez et al, 2004

61/99 (62%)

NR

Musher et al, 2005

161/207 (78%)

47/161 (22%)

Pépin et al, 2005

323/435 (74%)

109/323 (34%)

Belmares et al, 2007

72/102 (71%)

NR

NR=not reported

4 for vancomycin-resistant enterococci (VRE), although metronidazole appears equally effective at selecting for VRE.13-16

Reports of Increase in Metronidazole Treatment Failures Since 2004, several publications have described failure rates of oral metronidazole up to 33% higher than previously reported (Table 4-2).17-20 Of three retrospective studies,17,19,20 two were conducted to assess risk factors associated with metronidazole treatment failures and excluded patients with other potential causes of diarrhea. These two studies reported a 29% to 38% failure rate of oral metronidazole.17,20 The third retrospective study was an analysis of data related to a BI/NAP1/027 epidemic strain outbreak in Quebec, Canada, and reported a 26% 85

oral metronidazole failure rate.19 Musher et al conducted a prospective study to specifically assess whether or not there was an increase in metronidazole failures, and they identified a 22% failure rate.18 Subsequently, several randomized trials for treatment of CDI suggested that the decrease in treatment response is not limited to metronidazole. Rather, there appears to be a global decrease in response to CDI treatments, with a nonsignificant trend toward more treatment failures with oral metronidazole versus the comparator drug (Table 4-1). However, two recent studies demonstrated that treatment of CDI with oral vancomycin may result in a more rapid resolution of diarrhea in comparison to metronidazole.4,20 In one of the studies, vancomycin-treated patients were more likely to develop undetectable levels of C difficile in stool during the first 5 days of treatment, suggesting that some metronidazole treatment failures may be attributable to a slower and less consistent microbiologic response than that with oral vancomycin treatment.20 The increase in metronidazole failure rates does not appear to be directly attributable to the BI/NAP1/027 epidemic strain of C difficile. Pépin et al did a follow-up study on treatment responses to metronidazole and vancomycin in relation to the BI/NAP1/027 epidemic strain outbreak in Sherbrook, Quebec.21 Although initial treatment with vancomycin was associated with a decreased risk of developing severe, complicated CDI compared to metronidazole before the emergence of the epidemic strain (odds ratio [OR] 0.21, 95% confidence interval [CI] 0.05–0.99), this association was lost after the emergence of the epidemic strain (OR 0.90, 95% CI 0.53–1.55). Hu and colleagues compared data collected in 1998 with data collected from 2004 to 2006.22 Treatment failure rates were no different between the two time periods (35% for both), and the frequency of the BI/NAP1/027 strain in patients with or without metronidazole failure was not significantly different (26% vs 21%, P=0.67). 86

Patient Stratiﬁcation by Severity of CDI Because the incidence and severity of C difficile appear to be increasing and because prompt treatment is important for severe CDI, identification of patients with severe CDI is the key to timely, appropriate therapy. In addition, emerging data indicate that treatment choice should be based on the clinical severity of CDI. Outcomes of complicated or severe CDI are not difficult to identify: death directly or indirectly due to CDI, need for admission to the intensive care unit (ICU), development of hypotension or shock, or development of megacolon, perforation, or another condition that requires emergency colectomy.23 Several studies have identified factors associated with worse outcomes from CDI, including advanced age, fever, hypoalbuminemia, leukocytosis, acute renal failure, altered mental status, high severity of underlying illness, hypotension requiring vasopressors, frequency of diarrhea, ileus, peritoneal signs, and immunocompromised status.24 There is a need for validated clinical severity score indices that clinicians can use to stratify patients by CDI severity at the time of diagnosis. Fujitani et al performed a prospective observational study to compare 8 published severity score indices for CDI.25 Infection was considered severe if patients had at least one of the following clinical events during their hospitalization: (1) death attributed to CDI within 30 days after diagnosis, (2) colectomy necessitated by CDI, or (3) intensive care unit admission for management of complications attributed to CDI. Of 184 patients with CDI who were evaluated, 19 had severe cases. Sensitivities of the 8 severity score indices ranged from 63% to 84%, and specificities ranged from 59% to 94%. The Hines VA index had the highest kappa score (0.69). This index included 5 risk factors, each assigned a score of 0-2, with a total score of 3 or more meeting the definition of severe CDI. The factors included age, presence of fever, albumin level, WBC count, and endoscopic findings. 87

4

Table 4-3: ATLAS Score Parameter

0 points

1 point

2 points

<60 years

60-79 years

≥80 years

Temperature

≤37.5º

37.6-38.5º

≥38.6º

Leukocytosis

<16,000

16,00025,000

>25,000

Albumin

>35

26-35

≤25

Systemic concomitant antibiotics

No

Age

Yes

Minimum score=0 Maximum score=10 From Zar et al32

Miller et al developed the ATLAS Bedside Scoring System as another strategy to predict severity and likelihood of clinical cure.26 The ATLAS score uses 5 clinical parameters (Table 4-3) that are easily obtained at the bedside, including age, temperature, leukocytosis, albumin, and systemic concomitant antibiotics. ATLAS scores range from 0 to 10. In a cohort of 516 CDI patients enrolled in a North American trial comparing fidaxomicin to vancomycin, the ATLAS scores calculated at the time of diagnosis correlated well with the clinical cure rate. Patients with an ATLAS score of 0 had a 98% cure rate and the rate dropped with higher scores (eg, ATLAS score of 7 corresponded to a cure rate of 55%). In another study, the ATLAS score was 88

shown to correlate well with increased risk for mortality due to CDI.27

Treatment of Mild/Moderate CDI While CDI will resolve in up to 23% of patients by discontinuing the offending antibiotic alone, this approach is no longer advised, except in the mildest of cases,3,4 because of the increasing severity in CDI cases and the rapidity of fulminant disease. The Society for Healthcare Epidemiology (SHEA) and the Infectious Diseases Society of America (IDSA) recently published clinical practice guidelines for management of CDI in adults.28 These guidelines recommend oral metronidazole for treatment of initial episodes or first recurrences of mild/moderate CDI28 (Table 4-4). The criteria used for defining mild-moderate disease include a white blood cell count of 15,000 cells per μL or lower and a serum creatinine level less than 1.5 times the baseline level. These criteria were based on expert opinion and they are likely to be revised on publication of prospectively validated severity scores. For treatment of adults with mild/moderate CDI, metronidazole is usually given orally in doses of 250 mg four times per day or 500 mg three times per day for 10 to 14 days. The current practice guidelines recommend a dose of 500 mg three times per day.28 For children, a dosage of 35–50 mg/kg/d divided into three doses has been used.29 Clinicians should be aware that metronidazole can be associated with significant interactions with warfarin, leading to increased warfarin concentrations and increased international normalized ratio (INR); in a recent report, this interaction was associated with intracerebral hemorrhage in a 78-year-old woman.30 Metronidazole may also interact with tacrolimus, leading to increased tacrolimus trough concentrations and toxicity.31 In patients receiving these medications, careful monitoring of INR and tacrolimus levels is indicated, or oral vancomycin can be used. 89

4

Table 4-4: Recommended Treatment of CDI for Adults by CDI Severity28 CDI Severity*

Treatment Regimen

Mild/moderate CDI

Oral metronidazole 500 mg 3 times per day for 10 to 14 d Fidaxomicin** 200 mg twice a day with or without food

Severe CDI, no ileus

Oral vancomycin 125 mg 4 times per day for 10 to 14 d Fidaxomicin** 200 mg twice a day with or without food

*Criteria for severe disease include leukocytosis with a white blood cell count of 15,000 cells/μL or higher or a serum creatinine level greater than or equal to 1.5 times the premorbid level. Criteria for severe, complicated CDI include hypotension or shock, ileus, or megacolon.

90

CDI Severity*

Treatment Regimen

Fulminant/severe, complicated CDI

IV metronidazole 500 mg 4 times per day for 14 d and oral or nasogastric tube vancomycin 500 mg 4 times per day and If complete ileus, consider adding rectal instillation of vancomycin 125 to 500 mg 4 times a day and Surgical consult and Oral vancomycin 125 mg to 500 mg q.i.d. (if tolerated) and Surgical consult ***

**Fidaxomicin was not recommended in the 2010 SHEA/IDSA guidelines, but this agent received FDA approval in May 2011 and is now available as a treatment option. ***IVIG 250-500 mg/kg x 1 is sometimes given. Although there is some anecdotal experience, there is little supporting evidence for its use.

91

4

Treatment of Severe CDI Oral vancomycin is recommended for treatment of severe CDI (Table 4-4).28 This recommendation from the SHEA and the IDSA clinical practice guidelines for CDI is based on results of 2 recent randomized trials in which vancomycin was superior to metronidazole for treatment of severe CDI.32,33 The recommended dose of oral vancomycin is 125 mg four times per day.4 Higher doses should not be necessary because this dose was found to be equivalent to 500 mg four times per day, and the concentration of oral vancomycin in feces at the low dose is 100- to 1000-fold higher than the minimum inhibitory concentration of vancomycin for C difficile.15,34 Vancomycin should not be given IV for CDI because therapeutic levels of the drug do not accumulate within the colonic lumen when it is administered IV. Treatment of Severe, Complicated CDI Clostridium difficile causes fulminant colitis in 3% to 8% of patients with CDI.31 Severe, complicated CDI is defined in the recent SHEA/IDSA treatment guidelines as a case complicated by hypotension or shock, ileus, or toxic megacolon (Figure 4-1).28 These criteria for defining complicated CDI are based on expert opinion and are likely to be revised in the future upon publication of prospectively validated severity scores for CDI. For severe, complicated CDI, it is recommended that vancomcyin 500 mg 4 times per day be administered by mouth or by nasogastric tube in combination with metronidazole 500 mg every 8 hr intravenously. The rationale for giving higher doses of vancomycin and adding IV metronidazole is that it is unclear if a sufficient quantity of vancomycin reaches the colon in the setting of abnormal GI motility or outright ileus when standard doses are given. There are no data to indicate a synergistic effect against C difficile for the combination of IV metronidazole and oral vancomycin, but the IV metronidazole is added to 92

Figure 4-1: Acute toxic megacolon in a patient with fulminant pseudomembranous colitis. Note the thickened and edematous bowel wall (arrow). From Adams et al,34 reprinted with permission from the American Medical Association.

ensure that sufficient levels of anti-C difficile treatment will be delivered to the colon as quickly as possible in these extremely sick patients. When severe adynamic ileus is evident or severe nausea and/or vomiting preclude the use of oral vancomycin, alternate methods of intraluminal vancomycin delivery to the colon must be considered.28 Delivery of vancomycin can be accomplished through a nasogastric tube, a long catheter in the small intestine, or rectally through an enema.3,4,35 The largest case series and review of the literature of patients with fulminant CDI who received vancomycin enemas found that 28 out of 33 patients (85%) responded.30 The vancomycin enemas were given in conjunction with other treatments for CDI. A wide range of dosages (total 2-3 g/d of vancomycin) and frequency of dosing (2-6 times/d) were noted. 93

4

In a recent case series, four patients with severe, refractory CDI were successfully treated with adjunctive or alternative therapy with IV tigecylcine.36 Tigecycline is a glycylcycline antibiotic that is approved for the treatment of complicated skin and soft-tissue infections. Tigecycline has excellent activity against C difficile strains, achieves significant concentrations in bile, and inhibits establishment of C difficile colonization in mice.37 Further studies are needed to determine whether tigecycline is beneficial as an adjunctive therapy for severe, complicated CDI. Colectomy

The surgical procedure of choice for medically unresponsive patients is total abdominal colectomy and end ileostomy.3,4,38,39 Up to 20% of cases of fulminant infection require surgery, but mortality is high, ranging from 35% to 80%.40-42 The need for vasopressors, changes in mental status, and prolonged length of medical treatment are all predictive of mortality after colectomy. Surgical consultation should be obtained for all patients with fulminant/severe, complicated CDI (Table 4-4). Once medical management has failed, prompt surgical intervention may reduce mortality after colectomy. A retrospective observational study of CDI patients who required ICU admission or prolonged ICU stay indicated that colectomy was more beneficial for patients who were 65 years of age or older, were immunocompetent, or had a leukocytosis of 20 x 109/L or greater or lactate between 2.2 and 4.9 mmol/L43 (Table 4-5). Another study found that a delay in the colectomy was an independent predictor of inhospital mortality among patients undergoing colectomy for CDI.40 Intravenous Immunoglobulin

A poor immune response has been shown to be an important risk factor in the development of CDI, prompting some to use IV immunoglobulin (IVIG) as an adjunctive 94

Table 4-5: Thirty-day Mortality According to Whether a Colectomy Was Performed in Patients with Fulminant Clostridium difficileassociated Disease (CDAD) Had a Colectomy (died/total)

Did Not Have Colectomy (died/total) P

3/10 (30%) 6/14 (43%) 4/14 (29%)

9/28 (32%) 19/31 (61%) 46/68 (68%)

0.90 0.25 0.006

6/27 (22%) 7/11 (64%)

45/89 (51%) 29/38 (76%)

0.001 0.41

Characteristic Age 39-64 yr 65-74 yr ≥75 yr Immunosuppression* No Yes Shock requiring vasopressor amines No Yes

1/11 (9%) 12/27 (44%)

25/61 (41%) 49/66 (74%)

0.04 0.006

Peak white cell count (x 109/L) <20 20.0-49.9 ≥50

2/2 (100%) 6/28 (21%) 5/8 (63%)

14/34 (41%) 39/71 (55%) 21/22 (95%)

0.11 0.002 0.02

Peak lactate (mmol/L) ≤2.1 2.2-4.9 ≥5 Not done

3/8 (38%) 3/18 (17%) 6/7 (86%) 1/5 (20%)

13/29 (45%) 23/46 (50%) 33/35 (94%) 5/17 (29%)

1.00 0.03 0.43 1.00

4

*Systemic corticosteroids for at least 1 month, leukemia, lymphoma, organ transplant, neutropenia, or any combination thereof. Adapted from Lamontagne et al43

95

treatment for severe, complicated CDI. Some case reports suggest that IVIG may be effective for severe, complicated CDI.44,45 Abougergi and Kwon46 reviewed 6 published reports of IVIG infusion for severe CDI, including 2 case reports, 3 case series, and 1 retrospective case-control study. The most frequently used dose was 400 mg/kg (range: 75-400 mg/kg), with 1 to 5 doses being administered.46 Of 51 total CDI patients treated with IVIG, 32 (67%) survived their illness. In the retrospective, case-control study, 18 patients with severe CDI who received IVIG were compared to 18 patients with severe CDI who did not receive IVIG.47 This study found no benefit to adjunctive use of IVIG for severe CDI. Limitations of this study include the retrospective study design, use of a CDI severity grading score that has not been validated to identify patients with severe CDI, use of a lower dose of IVIG (200-300 mg/kg), and not controlling for duration of symptoms before administration of IVIG. Overall, the evidence supporting use of IVIG for treatment of severe, complicated CDI is limited and current treatment guidelines do not recommend use of this agent for severe CDI.28

Recurrent CDI A recurrent CDI case is defined as an episode of CDI that occurs 8 wk or less after the onset of a previous episode, provided that CDI symptoms from the earlier episode resolved with or without therapy. Most recurrences occur in the first 2 wk after CDI treatment is stopped.1 After an initial episode of CDI, the incidence of a recurrence is between 15% and 35%, but that rate increases to 45% to 65% in patients who have had multiple prior episodes of CDI.3,4,29,48,49 The frequency of recurrence is similar whether metronidazole or vancomycin was used for treatment of the initial episode or subsequent episodes, and neither the dosage nor duration of therapy appear to affect the frequency of recurrence if treatment is stopped abruptly. Symptomatic recurrence is rarely due to treat96

ment failure or antimicrobial resistance to metronidazole or vancomycin. The risk for recurrence of CDI after metronidazole and vancomycin treatment is related in part to the fact that these agents are nonselective and inhibit the normal colonic microflora in addition to C difficile, thereby predisposing to regrowth or reacquisition of spores after completion of therapy.

Relapse Versus Reacquisition Recurrent CDI may be due to relapse resulting from regrowth of spores that persist in the colon after completion of therapy or reacquisition of the same or a different strain from the environment. Using molecular typing, Wilcox et al50 found that 56% of clinical recurrences of infection were due to reinfection rather than relapse. Another larger study found that about 48% of clinical recurrences were reinfections with a different strain.51 In both studies, recurrences occurred within 2 months. Normal colonic flora provides colonization protection, but antimicrobial treatment for CDI disrupts protective flora and can predispose to CDI after the treatment is stopped. Patients with CDI can contaminate their homes after discharge from the hospital.52 The patient is vulnerable to reinfection while alteration of intestinal flora persists, even in the home environment. Risk Factors for Recurrent CDI Risk factors for recurrent CDI include increasing age, renal impairment, immunocompromised status, previous CDI, multiple comorbidities, severe underlying illness, continued or repeated exposure to antibiotics, gastric acid suppression, and increasing number of prior episodes of CDI.53-56 Age-related changes in fecal flora and host immune defenses contribute to the vulnerability of older patients to recurrent CDI. Persistent use of antimicrobials inhibits the return of the normal intestinal flora that protect against pathogens. A good immune response to the initial episode of CDI has been shown to result in an 97

4

Table 4-6: Risk of Recurrent C difficile Infection by a Clinical Prediction Rule One point is assigned for each of the following predictors: age >65 years, severe or fulminant underlying illness (by Horn’s index), and additional antibiotic use.

Recurrence Predicted (derivation cohort) (n=44)

Observed (validation cohort) (n=64)

Score

n

%

n

%

0

0/7

0

0/9

0

1

5/15

33.3

6/36

16.7

2

10/14

71.4

5/16

31.3

3

7/8

87.5

2/3

66.7

Note: Patients with scores ≥2 were classified as high risk. From Hu57

anamnestic response to toxin A with increased serum levels of IgG antibody on subsequent CDI episodes. A poor antibody response contributes to the risk of recurrence.55 While severe comorbid disease and decreased quality-oflife scores put the patient at high risk for recurrence of CDI, severity of initial CDI episode is not associated with increased risk of recurrence. Hu and colleagues recently validated a clinical risk prediction tool for recurrent CDI.57 One point is assigned for each of the following predictors: age >65 years, severe or fulminant underlying illness (by Horn’s index), and additional antibiotic use. In the derivation cohort, 87% of 98

patients with a score of 3, 71% with a score of 2, 33% with a score of 1, and 0 with a score of 0 developed recurrent CDI (Table 4-6). In the validation cohort, 67%, 31%, 17%, and 0 patients with a score of 3, 2, 1, and 0, respectively, developed recurrent CDI. Since there were only 13 cases of recurrent CDI in the validation cohort, additional study is needed to determine how useful this tool may be at predicting which patients are at greatest risk for CDI.

First Recurrence The first recurrence of CDI usually begins with a return of diarrhea within a few days to 2 months after successful antimicrobial therapy. This is a time when antimicrobial therapy has been discontinued and normal intestinal flora have not yet returned.58 Diagnosis should again be confirmed. The fact that the antimicrobial was successful in treating the initial episode indicates that the recurrence was not due to failure of the initial treatment, and it should work again. Therapy should be based on severity of the recurrence, but if the recurrence is severe, vancomycin should be used even if metronidazole was successful for the initial episode (Table 4-4 and Table 4-7). The patient should be monitored for response to therapy. Subsequent Recurrences A number of strategies to manage subsequent recurrences after the first recurrence of CDI have been published. Most data involve single-center experience with a small number of cases, and are of relatively poor quality. In general, the few randomized trials have not demonstrated significant benefit of the approach intended to reduce the risk of recurrence. If a patient is on the third episode of CDI, vancomycin should be provided in a tapered or pulsed fashion (Table 4-7). This approach should be attempted several times before trying other, less proven methods for preventing recurrences. It is also important to remember that not all episodes of diarrhea will be caused by CDI, 99

4

Table 4-7: Management of Recurrent C difficile Colitis All Recurrences • Confirm diagnosis: patients can often distinguish whether diarrhea is from CDI • Consider supportive treatment alone if symptoms are mild • Adopt general recurrence avoidance measures: avoid unnecessary antibiotics, antimotility agents, gastric acid suppression • Decontaminate home environment: patient should clean bathroom with 1:10 dilution of household bleach First Relapse • Treat based on CDI severity (Table 4-4) Subsequent Relapses • Attempt vancomycin taper or pulse several times before trying other adjunctive measures – Vancomycin taper 125 mg every 6 hr for 14 d 125 mg every 8 hr for 7 d 125 mg every 12 hr for 7 d 125 mg daily for 7 d 125 mg every other day for 7 d 125 mg every 3 d for 14 d

and often patients will be able to tell you if they think the diarrhea is CDI-based. This is because treatments for CDI will predispose to CDI once they are stopped, so it is prudent to avoid them if the diarrhea is not due to CDI. Whenever possible, other medications associated with recurrent CDI should be discontinued, and the patient should be instructed to clean the bathroom at home with a 1:10 100

Subsequent Relapses (continued) – Vancomycin pulse 125 mg every 6 hr for 14 d 125 mg every 3 d for 2 to 3 mo Additional Measures if Continued Recurrences • Rifaximin “chaser” 400 mg b.i.d. x 14 d after 2 wk of vancomycin 125 mg q.i.d. • Adjunctive Saccharomyces boulardii 500 mg b.i.d. while on vancomycin, plus 4 wk • IV immunoglobulin (IVIG) 200-500 mg/kg for 1 to 3 doses • Fecal flora restoration • Vancomycin, 125 mg 4 times daily and rifampin, 600 mg twice daily, for 7 d • Nitazoxanide 500 mg b.i.d. x 10 d

4

dilution of household bleach (Table 4-7) (Caution: bleach can be corrosive, especially to chrome fixtures). Also, it is not recommended to give prolonged or tapered/pulsed courses of metronidazole. Metronidazole does not reach therapeutic levels in stool in the absence of diarrhea, and prolonged courses of metronidazole are associated with the development of peripheral neuropathy.59 101

Vancomycin Tapering/Pulse Dosing

The strongest evidence to support a method that may decrease the risk of recurrent CDI in patients with a history of CDI involves use of an oral vancomycin taper or pulse.4 The theory behind tapered or pulsed oral vancomycin is that increasing the interval between doses of oral vancomycin allows the intestinal flora to regenerate. At the same time, periodic dosing of vancomycin keeps any residual C difficile suppressed while waiting for the intestinal flora to regenerate. McFarland et al did a secondary analysis of patients enrolled in the placebo arm of two trials originally designed to evaluate the use of Saccharomyces boulardii to prevent CDI recurrences.59 In these studies, patients were randomized to placebo or S boulardii. The active treatment for CDI, vancomycin or metronidazole, was left to the discretion of the treating physician in the first trial, including dose and duration. In the second trial, active treatment was again at the discretion of the treating physician, but the dose and duration were limited to one of three options (metronidazole 1 g/day for 10 days, vancomycin 500 mg/d for 10 days, or vancomycin 2 g/day for 10 days). The analysis included 163 patients. Overall, 10/36 (28%) of patients who received a tapered or pulsed course of oral vancomycin had a recurrence compared to 45/83 (54%) of patients whose vancomycin was stopped abruptly (relative risk [RR] 0.51, 95% CI 0.29–0.90) and 16/38 (42%) of patients who received metronidazole (RR 0.66, 95% CI 0.35–1.26). Adjunctive Therapies

A variety of empiric management strategies are available and each has advantages and disadvantages. Ion Exchange Resins

Use of ion exchange resins, such as cholestyramine and colestipol, has been suggested for adjunctive treatment 102

of recurrent CDI when standard treatment has failed.60 Cholestyramine binds C difficile toxins A and B in vitro. Several case reports indicate a possible decrease in the risk of recurrent CDI with doses of 4 g given 3 or 4 times daily for 1 to 2 wk. Two small, randomized trials have been conducted with colestipol for treatment of CDI. In one trial, colestipol was inferior to oral vancomycin.61 In the other trial, the response rate to colestipol was no different than the response rate to placebo.62 In addition to data indicating that ion exchange resins are no better than placebo, they bind vancomycin and should be taken at least 2 or 3 hr apart from vancomycin. Based on the available evidence, current SHEA/IDSA practice guidelines do not recommend the use of ion exchange resin. Probiotics

Probiotics are live organisms that are postulated to enhance re-establishment of the normal intestinal flora, compete for nutrients and binding sites of pathogenic organisms, and stimulate the host immune response. Although a popular and the best-studied approach for preventing CDI recurrences, current data indicate that probiotics are not effective at preventing CDI.4 Three randomized controlled trials of lactobacillus versus placebo for the prevention of recurrent CDI have been published.63-65 Lactobacillus was no better than placebo at reducing the risk of recurrent CDI in any of the studies. Two studies evaluated the use of lactobacillus-based probiotic formulations for the prevention of diarrhea and CDI in hospitalized patient on antibiotics.66,67 Plummer enrolled 150 consecutive patients, 138 of whom completed the trial; 22% of patients in both the placebo and probiotic arms developed diarrhea, and 7.3% versus 2.9% of patients in each group developed CDI, respectively (P=0.44).66 The study by Hickson et al found the probiotic formulation was associated with a lower risk of diarrhea (12% vs 34%, P=0.007) and CDI (0 vs 17%, 103

4

P=0.001).67 The results by Hickson should be interpreted with caution. Only 7.6% of patients screened for the study were actually enrolled into the study. In addition, the incidence of CDI in the placebo arm of patients who developed diarrhea (47%) was significantly higher than the incidence of CDI typically observed in hospitalized patients with diarrhea (20%). Two randomized trials examined the use of S boulardii for the prevention of recurrent CDI.68,69 In the first trial, all patients with CDI were eligible, regardless if it was an initial episode of CDI or a recurrent episode of CDI.68 Overall, use of S boulardii resulted in a significant reduction in CDI (RR 0.43, 95% CI 0.20–0.97). However, on subgroup analysis there was no reduction in CDI if it was the first episode (rate 19.3% compared with 24.2% on placebo; P=0.86), but there was a significant reduction in CDI if it was a recurrent episode (recurrence rate 34.6%, compared with 64.7% on placebo; P=0.04). A second trial was conducted in which only patients with recurrent CDI were enrolled. Overall, S boulardii was not associated with a decrease in additional recurrences of CDI (RR 0.91, 95% CI 0.66–1.27). A review of 60 cases of Saccharomyces fungemia in the literature found that not only were 46% of cases on a Saccharomyces probiotic at the time of the fungemia, but 8% of cases were themselves not on a probiotic but were near a patient on a Saccharomyces probiotic.70 In addition, 17% of patients developed endocarditis or a disseminated infection and 28% of cases died. In summary, probiotics do not appear to be effective in preventing CDI or recurrent CDI. Because of increased risk of infection from the probiotic strain while hospitalized due to the presence of vascular access devices and increased acuity of illness, probiotics should be used sparingly in the inpatient setting. Probiotics are well tolerated in the outpatient setting. Because there are data to indicate a possible trend toward a decreased risk of CDI recurrence with S boulardii in patients with multiple prior episodes 104

of CDI, it is not unreasonable to consider S boulardii for patients who have failed several vancomycin tapers/pulses (Table 4-7). Immune-based Therapy

Immune response to C difficile toxins plays a major role in determining host susceptibility to CDI. Normal pooled human gamma globulin contains antitoxin IgG antibodies that are capable of neutralizing C difficile. Abougergi and Kwon46 reviewed 11 published reports of IVIG infusion for protracted or relapsing CDI, including 6 case reports and 5 case series. IVIG doses ranged from 150 to 500 mg/kg, with 1-6 doses being administered. Of 46 total patients treated with IVIG, 40 (87%) had clinical resolution of diarrhea. Of 41 evaluable patients, 6 (15%) had recurrent diarrhea over a follow-up period of 3 to 24 months. Thus, although IVIG appears promising, randomized, controlled trials are needed to determine optimal anti-C difficile antibody levels, dose, and duration. Disadvantages associated with IVIG therapy include high cost and frequent shortages of human gamma globulin, marginal efficacy, and lack of data regarding optimal dose. Fortunately, vaccines and monoclonal antibodies against C difficile are being studied. Fecal Flora Restoration

Several case reports of replacing fecal flora to treat CDI and to prevent recurrences of CDI have been reported in the literature, with a success rate of ≥90%.71,72 Various methods for restoring fecal flora have been described, including fecal enemas, administering feces through a nasogastric tube, and administering feces throughout the colon under colonoscopic visualization. Aas and coworkers describe the most aesthetic method for administering fecal flora to the recipient and named the procedure a “fecal transplant.”71 Before the procedure, patients were given a course of 250 mg oral vancomycin every 8 hr for 4 days or longer to diminish the C difficile load. The 105

4

Table 4-8: Preparation of Donor Stool Sample Before Stool Transplantation • Obtain stool sample ≤6 hr before the transplantation procedure. • Select a stool specimen (preferably a soft specimen) with a weight of ~30 g or a volume of ~2 cm3 • Add 50-70 mL of sterile 0.9 N NaCl to the stool sample and homogenize with a household blender. Initially use the low setting until the sample breaks up, and then advance the speed gradually to the highest setting. Continue for 2-4 min until the sample is smooth. • Filter the suspension using a paper coffee filter. Allow adequate time for slow filtration to come to an end. • Refilter the suspension, again using a paper coffee filter. As before, allow adequate time for slow filtration. From Aas72

vancomycin was discontinued the night before stool transplantation, and 20 mg omeprazole was given that evening and on the morning of the procedure. Stool was collected from a donor on the morning of the procedure (Table 4-8). The stool was homogenized in a blender with nonbacteriostatic, sterile normal saline and filtered twice, and then 25 mL of the suspension was injected into the stomach through a nasogastric tube. The nasogastric tube was flushed with 25 mL normal saline and then removed. In most instances, the patients had fewer symptoms and felt significantly better within 12–24 hr. The cure rate was 94%. 106

Combination Treatments for Recurrent CDI

The combination of oral vancomycin plus rifampin has been studied as a treatment for CDI (Table 4-7). A case series of vancomycin 125 mg q.i.d plus rifampin 600 mg b.i.d. demonstrated a modest reduction in CDI recurrence, with 5 of 7 (71%) patients having no additional recurrences.71 Because rifampin has many significant drug-drug interactions, careful review for potential interactions is indicated before considering use of rifampin. In addition, a randomized trial of metronidazole versus metronidazole plus rifampin demonstrated no difference in treatment response or risk of recurrent CDI, although overall mortality was higher in the group that received rifampin.73 In addition to combination therapy, sequential therapy with oral vancomycin followed by a rifaximin “chaser” has also recently been reported as a strategy to manage patients with multiple recurrences.74,75 This approach is described in more detail in the section on new and investigational agents.

New and Investigational Agents The increasing incidence and severity of CDI during the past decade have led to increased efforts to develop new therapies for CDI. One new agent, fidaxomicin (Dificid™), recently received approval by the FDA for the treatment of CDI. Two other agents, rifaximin and nitazoxanide, are approved by the FDA for other indications and have been studied for the treatment of CDI. Several other agents are in earlier stages of investigation. Fidaxomicin

Fidaxomicin, formerly known as OPT-80 or difimicin, is a new class of antibiotic, a macrocycle agent in the macrolide group, that is highly active against C difficile and against anaerobic gram-positive species. A potential benefit of fidaxomicin is that it has no activity against gramnegative obligate anaerobes, which allows more selective 107

4

killing of C difficile while not harming a large portion of the normal intestinal flora.76 An open-label, randomized, phase II trial showed fidaxomicin at doses of 50, 100, or 200 mg orally every 12 hr for 10 days was well tolerated in patients with mild to moderately severe CDI.77 Resolution of diarrhea within 10 days was achieved in 10/14 (71%), 12/15 (80%), and 15/16 (94%) patients, respectively, and the clinical cure rate across all groups was 41/45 (91%). Of patients who responded to therapy, there were only 2 (5%) CDI recurrences. Subsequent analyses of the stool specimens collected for this study demonstrated a significant reduction in the concentration of Bacteroides species per gram of feces during vancomycin treatment (P=0.03), whereas no reduction occurred during fidaxomicin treatment.77 Fidaxomicin-treated subjects also had lower spore counts after completion of treatment than vancomycintreated subjects.1 A subsequent analysis by Tannock et al76 demonstrated that fidaxomicin had minimal effect on the major phylogenetic clusters in feces. Notably, clostridial clusters XIVa and and IV and bifidobacteria were much less affected by fidaxomicin compared to vancomycin treatment. The preservation of the anaerobic microflora during fidaxomicin therapy provides a biologic rationale why fidaxomicin may be associated with a decreased risk of recurrent CDI. Results of the North American phase III trial comparing fidaxomicin and vancomycin for treatment of CDI were recently published.1 The study included 265 patients who received fidaxomicin and 283 patients who received oral vancomycin in the per protocol population. As shown in Figure 4-2, patients treated with fidaxomicin were as likely as vancomycin-treated patients to achieve clinical cure, but significantly less likely to experience recurrence (13% vs 24%; P=0.004). Overall, fidaxomicin was associated with an improved likelihood of sustained clinical response (ie, cure with no recurrence in 25 days78) compared to vancomycin. 108

100 90

88.2 85.8

Fidaxomicin

92.1 89.8

Vancomycin

Patients (%)

80 70

P=0.006

P=0.006 77.7

74.6 64.1

67.1

60 50 40

P=0.005

P=0.004

30

25.3

24.0

20

15.4

13.3

10 0

mITT

PP

Clinical Cure

mITT

PP

Recurrence

mITT

PP

Sustained Clinical Response

109

Figure 4-2: For the primary outcome of clinical cure, the lower boundary of the 97.5% confidence interval for the difference in cure rates between fidaxomicin and vancomycin was -3.1 percentage points in the modified intention-to-treat (mITT) analysis and -2.6 percentage points in the per-protocol (PP) analysis. Adapted and used with permission from Louie et al.1

4

The adverse event profile was similar for the two therapies. In a subanalysis, fidaxomicin-treated patients were significantly less likely than vancomycin-treated patients to acquire colonization with vancomycin-resistant enterococci (7% vs 31%; P<0.001) or Candida species (19% vs 29%; P=0.03) colonization during therapy.79 These results suggest that fidaxomicin is a promising new agent for treatment of CDI that is as initially effective as vancomycin but with a superior sustained clinical response over 25 d, less recurrences, and lower risk for acquisition of colonization by nosocomial pathogens. Rifaximin

Rifaximin (Xifaxan®) is a poorly absorbed rifamycin derivative that is highly active against C difficile in vitro and may be more active against C difficile than other bowel flora.80 In addition, rifaximin was associated with a lower risk of recurrent CDI than vancomycin in a hamster model of CDI.81 A rifaximin “chaser” was studied in a case series of 8 women who each had repeated episodes of CDI. A two-week course of rifaximin was administered immediately after completion of the last course of oral vancomycin or metronidazole treatment for CDI when the patients were asymptomatic and before recurrence of symptoms.74 Seven of the 8 patients had no further recurrence of CDI in this small study. A concern with rifamycin antibiotics is the ability of bacteria to develop resistance, and resistance to rifaximin was documented in the one patient who had an additional episode of CDI. Also, a large outbreak of CDI due to the BI/NAP1/027 strain of C difficile documented that 81.5% of recovered isolates were resistant to rifampin.82 However, data are conflicting as to whether rifampin resistance translates directly to rifaximin resistance.83,84 Until additional data become available on the likelihood that C difficile may develop resistance to rifaximin, it is prudent to use rifaximin sparingly for recurrent CDI and to use the “chaser” approach to minimize the C difficile load before initiation of rifaximin. 110

Nitazoxanide

Nitazoxanide is a nitrothiazolide used to treat intestinal infestation with Cryptosporidium or Giardia species. In vitro nitazoxanide and its primary breakdown product, tizoxanide, inhibit C difficile at low concentrations. In a prospective, randomized, double-blind, phase II study, nitazoxanide was shown to be at least as effective as metronidazole in treating C difficile colitis.85 There was also a trend toward fewer recurrences in patients who received 500 mg b.i.d. for 10 days (23.5% vs 13.9%). A phase III trial comparing nitazoxanide to vancomycin was discontinued early due to slow enrollment, and treatment response and recurrence rates were equivalent.86 Monoclonal Antibody Therapy

Studies are underway to evaluate if the addition of monoclonal antibodies to standard treatment for CDI reduces the risk of severe or recurrent CDI. Based on animal data indicating that monoclonal antibodies neutralize C difficile toxins A and B,87 two antibodies are being investigated in clinical trials: CDA1, which is being tested against toxin A, and MDX-1388, which is being tested against toxin B. In the hamster model, CDA1 alone reduced mortality at day 2 after C difficile challenge from 94% to 45% (P <0.001), and the combination of MDX1388 and CDA1 further reduced mortality to 6% (P <0.001). Recurrent CDI was reduced from 62% to 44% for CDA1 alone (P=0.02), and further reduced to 32% with the combination (P<0.01). A phase 2 trial, published in the New England Journal of Medicine, studied the efficacy of CDA1 plus CDB1, fully human monoclonal antibodies, in preventing recurrence of CDI. 88 Researchers also explored the safety of this therapy and its effects on duration and severity of initial episodes of the infection on duration of hospitalization. Antibodies were administered at 10 mg/kg of body weight, together as a single infusion. Participants were ≤18 years of age, taking metronidazole or vancomycin, and symptomatic for CDI. 111

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Two hundred patients from 30 participating centers were enrolled (101 CDA1-CDB1 antibodies vs 99 placebo). Laboratory-documented recurrence of infection, during the 84 days after administration of antibodies or placebo served as the primary outcome. Thirty-two patients saw recurrence of CDI: 7% in the antibodies group and 25% in the placebo group (95% CI, 7-29; P <0.001). Among patients with more than one previous episode of CDI, recurrence rates were 7% and 38%, respectively. Although further study is warranted, this trial showed that administration of combined CDA1 and CDB1 human monoclonal antibodies, in addition to metronidazole or vancomycin significantly reduces the recurrence of CDI. Vaccine

An anti-C difficile toxoid consisting of formalin-detoxified C difficile toxins A and B has been developed with the goal of inducing an immune response in patients with multiple episodes of recurrent CDI.89 Three patients who had been treated long-term with vancomycin for multiple episodes of recurrent CDI were vaccinated with the toxoid. Two of the 3 showed an increase in both serum IgG antitoxin A and B antibodies, and all 3 patients discontinued oral vancomycin treatment without further recurrences. A phase II secondary prevention trial is now underway. Nontoxigenic Clostridium difﬁcile

Several investigators have postulated that nontoxigenic strains of C difficile might prevent CDI by inhibiting colonization by toxigenic strains.90-92 The observation that hospitalized patients with asymptomatic colonization by C difficile (either toxigenic or nontoxigenic) are at reduced risk of CDI provided suggestive evidence that colonization by nontoxigenic strains might indeed be protective.93 In hamsters, prior colonization with nontoxigenic C difficile strains selected on the basis of their high frequency of 112

asymptomatic colonization of hospitalized patients was effective in preventing CDI after challenge with toxigenic strains.94,95 Based on these findings, nontoxigenic C difficile spores are being developed as a potential biotherapeutic agent to prevent CDI in patients. A phase II trial is now enrolling patients.

Key Points 1. If the patient develops multiply recurrent CDI, alternative methods include include adjunctive Saccharomyces, IVIG, fecal flora restoration, vancomycin plus rifampin, nitazoxanide, or a rifaximin chaser. 2. If possible, discontinue the antibiotic that precipitated the episode of CDI. 3. Intravenous vancomycin does not reach adequate levels in the colon for treatment of CDI. 4. Treatment of an initial episode of CDI and first recurrence of CDI is based on CDI severity (Table 4-4). 5. Use vancomycin taper or pulse therapy to treat subsequent recurrences (Table 4-7). 6. Seek surgical consultation for patients with fulminant CDI. 7. Fidaxomicin is a new FDA-approved agent for treatment of CDI that was as effective as vancomcyin in clinical trials but with less recurrences (ie, improved global cure or cure without recurrence). References 1. Louie TJ, Miller MA, Mullane KM, et al: Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med 2011;364:422-431. 2. Teasley DG, Gerding DN, Olson MM, et al: Prospective randomized trial of metronidazole versus vancomycin for Clostridium difficile-associated diarrhea and colitis. Lancet 1983;2(8358): 1043-1046. 3. Gerding DN, Muto CA, Owens RC Jr: Treatment of Clostridium difficile infection. Clin Infect Dis 2008;46:S32-S42.

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4. Cohen SH, Gerding DN, Johnson S, et al: SHEA‐IDSA guideline: Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol 2010;31:431-455. 5. Koo HL, Koo DC, Musher DM, et al: Antimotility agents for the treatment of Clostridium difficile diarrhea and colitis. Clin Infect Dis 2009;48:598-605. 6. Wilcox MH, Howe R: Diarrhoea caused by Clostridium difficile: response time for treatment with metronidazole and vancomycin. J Antimicrob Chemother 1995;36:673-679. 7. Gerding DN: Antimotility agents for the treatment of Clostridium difficile infection: is the juice worth the squeeze? Clin Infect Dis 2009;48:606-608. 8. Bolton RP, Culshaw MA: Faecal metronidazole concentrations during oral and intravenous therapy for antibiotic associated colitis due to Clostridium difficile. Gut 1986;27:1169-1172. 9. Currie BP, Lemos-Filho L: Evidence for biliary excretion of vancomycin into stool during intravenous therapy: potential implications for rectal colonization with vancomycin-resistant enterococci. Antimicrob Agents Chemother 2004;48:4427-4429. 10. Guerrant RL, Van Gilder T, Steiner TS, et al: Practice guidelines for the management of infectious diarrhea. Clin Infect Dis 2001;32: 331-351. 11. The American Society of Health-System Pharmacists: ASHP therapeutic position statement on the preferential use of metronidazole for the treatment of Clostridium difficile-associated disease. Am J Health Syst Pharm 1998;55:1407-1411. 12. Teasley DG, Gerding DN, Olson MM, et al: Prospective randomized trial of metronidazole versus vancomycin for Clostridium difficileassociated diarrhea and colitis. Lancet 1983;2(8358):1043-1046. 13. Miller MA, Hyland M, Ofner-Agostini M, et al: Morbidity, mortality, and healthcare burden of nosocomial Clostridium difficile-associated diarrhea in Canadian hospitals. Infect Control Hosp Epidemiol 2002;23:137-140. 14. Sethi AK, Al-Nassir WN, Nerandzic MM, et al: Skin and environmental contamination with vancomycin-resistant Enterococci in patients receiving oral metronidazole or oral vancomycin treatment for Clostridium difficile-associated disease. Infect Control Hosp Epidemiol 2009;30:13-17.

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15. Al-Nassir WN, Sethi AK, Li Y, et al: Both oral metronidazole and oral vancomycin promote persistent overgrowth of vancomycin-resistant enterococci during treatment of Clostridium difficile-associated disease. Antimicrob Agents Chemother 2008;52:2403-2406. 16. Donskey CJ, Chowdhry TK, Hecker MT, et al: Effect of antibiotic therapy on the density of vancomycin-resistant enterococci in the stool of colonized patients. N Engl J Med 2000;343:1925-1932. 17. Fernandez A, Anand G, Friedenberg F: Factors associated with failure of metronidazole in Clostridium difficile-associated disease. J Clin Gastroenterol 2004;38:414-418. 18. Musher DM, Aslam S, Logan N, et al: Relatively poor outcome after treatment of Clostridium difficile colitis with metronidazole. Clin Infect Dis 2005;40:1586-1590. 19. Pépin J, Alary M-E, Valiquette L, et al: Increasing risk of relapse after treatment of Clostridium difficile colitis in Quebec, Canada. Clin Infect Dis 2005;40:1591-1597. 20. Belmares J, Gerding DN, Parada JP, et al: Outcome of metronidazole therapy for Clostridium difficile disease and correlation with a scoring system. J Infect 2007;55:495-501. 21. Pépin J, Valiquette L, Gagnon S, et al: Outcomes of Clostridium difficile-associated disease treated with metronidazole or vancomycin before and after the emergence of NAP1/027. Am J Gastroenterol 2007;102:2781-2788. 22. Hu MY, Maroo S, Kyne KL, et al: A prospective study of risk factors and historical trends in metronidazole failure for Clostridium difficile infection. Clin Gastroenterol Hepatol 2008;6:1354-1360. 23. Pépin J: Vancomycin for the treatment of Clostridium difficile infection: for whom is this expensive bullet really magic? Clin Infect Dis 2008;46:1493-1498. 24. Belmares J, Gerding DN, Tillotson G, et al: Measuring the severity of Clostridium difficile infection: implications for management and drug development. Expert Rev Anti Infect Ther 2008;6:897-908. 25. Fujitani S, George WL, Murthy AR: Comparison of clinical severity score indices for Clostridium difficile infection. Infect Control Hosp Epidemiol 2011;32:220-228. 26. Miller M, Louie T, Mullane K, et al: Categorization of patients in a large multicenter study of Clostridium difficile infection (CDI) using the ATLAS Bedside Scoring System, and correlation with both

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cure and recurrence. Infectious Diseases Society of America Annual Meeting, Vancouver, BC, 2010, abstract 1411. 27. Chopra T, Miller M, Louie T, et al: ATLAS-A Bedside scoring system—predicting mortality due to Clostridium difficile infection (CDI) in elderly hospitalized patients. Infectious Diseases Society of America Annual Meeting, Vancouver, BC 2010, abstract 449. 28. Cohen SH, Gerding DN, Johnson S, et al: Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hospital Epidemiol 2010;31:431-455. 29. Fekety R: Guidelines for the diagnosis and management of Clostridium difficile-associated diarrhea and colitis. Am J Gastroenterol 1997;92:739-750. 30. Apisarnthanarak A, Razavi B, Mundy LM: Adjunctive intracolonic vancomycin for severe Clostridium difficile colitis: case series and review of the literature. Clin Infect Dis 2002;35:690-696. 31. Olson MM, Shanholtzer CJ, Lee JT Jr, et al: Ten years of prospective Clostridium difficile-associated disease surveillance and treatment at the Minneapolis VA Medical Center, 1982-1991. Infect Control Hosp Epidemiol 1994;15:371-381. 32. Zar FA, Bakkanagari SR, Moorthi KM, et al: A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis 2007;45:302-307. 33. Louie T, Gerson M, Grimard D, et al, for the Polymer Alternative for CDAD Treatment (PACT) Investigators: Results of a phase III trial comparing tolevamer, vancomycin and metronidazole in patients with Clostridium difficile-associated diarrhea (CDAD). In Programs and Abstracts of the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy; Chicago IL. American Society for Microbiology; September 17-20, 2007. 34. Adams SD, Mercer DW: Fulminant Clostridium difficile colitis. Curr Opin Crit Care 2007;13(4):450-455. 35. Silva J Jr. Update on pseudomembranous colitis. West J Med 1989;151:644-648. 36. Herpers BL, Vlaminckx B, Burkhardt O, et al: Intravenous tigecycline as adjunctive or alternative therapy for severe refractory Clostridium difficile infection. Clin Infect Dis 2009;48:1732-1735.

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37. Jump RL, Li Y, Pultz MJ, et al: Tigecycline exhibits inhibitory activity against Clostridium difficile in the colon of mice and does not promote growth or toxin production. Antimicrob Agents Chemother 2011;55:546-549. 38. Bartlett JG: Historical perspectives on studies of Clostridium difficile and C difficile infection. Clin Infect Dis 2008;46: S4-S11. 39. Dallal RM, Harbrecht BG, Boujoukas AJ, et al: Fulminant Clostridium difficile: an underappreciated and increasing cause of death and complications. Ann Surg 2002;235:363-372. 40. Byrn JC, Maun DC, Gingold DS, et al: Predictors of mortality after colectomy for fulminant Clostridium difficile colitis. Arch Surg 2008;143:150-154. 41. Koss K, Clark MA, Sanders DS, et al: The outcome of surgery in fulminant Clostridium difficile colitis. Colorectal Dis 2006; 8:149-154. 42. Klipfel AA, Schein M, Fahoum B, et al: Acute abdomen and Clostridium difficile colitis: still a lethal combination. Dig Surg 2000;17:160-163. 43. Lamontagne F, Labbe A-C, Haeck O, et al: Impact of emergency colectomy on survival of patients with fulminant Clostridium difficile colitis during an epidemic caused by a hypervirulent strain. Ann Surg 2007;245:267-272. 44. Salcedo J, Keates S, Pothoulakis C, et al: Intravenous immunoglobulin therapy for severe Clostridium difficile colitis. Gut 1997; 41:366-370. 45. Hassoun A, Ibrahim F: Use of intravenous immunoglobulin for the treatment of severe Clostridium difficile colitis. Am J Geriatr Pharmacother 2007;5:48-51. 46. Abougergi MS, Kwon JH: Intravenous immunoglobulin for the treatment of Clostridium difficile infection: a review. Dig Dis Sci 2011;56:19-26. 47. Juang P, Skledar SJ, Zqheib NK, et al: Clinical outcomes of intravenous immune globulin in severe Clostridium difficile-associated diarrhea. Am J Infect Control 2007;35:131-137. 48. Wenisch C, Parschalk B, Hasenhündl M, et al: Comparison of vancomycin, teicoplanin, metronidazole, and fusidic acid for the treatment of Clostridium difficile-associated diarrhea. Clin Infect Dis 1996;22:813-818.

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49. Johnson S, Adelmann A, Clabots CR, et al: Recurrences of Clostridium difficile diarrhea not caused by the original infecting organism. J Infect Dis 1989;159:340-343. 50. Wilcox MH, Fawley WN, Settle CD, et al: Recurrence of symptoms in Clostridium difficile infection—relapse or reinfection? J Hosp Infect 1998;38:93-100. 51. Barbut F, Richard A, Hamadi K, et al: Epidemiology of recurrences or reinfections of Clostridium difficile-associated diarrhea. J Clin Microbiol 2000;38:2386-2388. 52. Kim KH, Fekety R, Batts DH, et al: Isolation of Clostridium difficile from the environment and contacts of patients with antibioticassociated colitis. J Infect Dis 1981;143:42-50. 53. Fekety R, McFarland LV, Surawicz CM, et al: Recurrent Clostridium difficile diarrhea: characteristics of and risk factors for patients enrolled in a prospective, randomized, double-blinded trial. Clin Infect Dis 1997;24:324-333. 54. McFarland LV, Surawicz CM, Rubin M, et al: Recurrent Clostridium difficile disease: epidemiology and clinical characteristics. Infect Control Hosp Epidemiol 1999;20:43-50. 55. Kyne L, Warny M, Qamar A, et al: Association between antibody response to toxin A and protection against recurrent Clostridium difficile diarrhea. Lancet 2001;357:189-193. 56. Do AN, Fridkin SK, Yechouron A, et al: Risk factors for early recurrent Clostridium difficile-associated diarrhea. Clin Infect Dis 1998;26:954-959. 57. Hu MY, Katchar K, Kyne L, et al: Prospective derivation and validation of a clinical prediction rule for recurrent Clostridium difficile infection. Gastroenterology 2009;136:1206-1214. 58. Pashby NL, Bolton RP, Sherriff RJ: Oral metronidazole in Clostridium difficile colitis. Br Med J 1979;1:1605-1606. 59. McFarland LV, Elmer GW, Surawicz CM: Breaking the cycle: treatment strategies for 163 cases of recurrent Clostridium difficile disease. Am J Gastroenterol 2002;97:1769-1775. 60. Kyne L, Farrell RJ, Kelly CP: Clostridium difficile. Gastroenterol Clin North Am 2001;30:753-777. 61. Mogg GA, Arabi Y, Youngs D, et al: Therapeutic trials of antibiotic associated colitis. Scand J Infect Dis Suppl 1980;41-45.

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62. Mogg GA, George RH, Youngs D, et al: Randomized controlled trial of colestipol in antibiotic-associated colitis. Br J Surg 1982;69:137-139. 63. Pochapin M: The effect of probiotics on Clostridium difficile diarrhea. Am J Gastroenterol 2000;95:S11-S13. 64. Wullt M, Hagslatt ML, Odenholt I: Lactobacillus plantarum 299v for the treatment of recurrent Clostridium difficile-associated diarrhoea: a double-blind, placebo-controlled trial. Scand J Infect Dis 2003;35:365-367. 65. Lawrence SJ, Korzenik JR, Mundy LM: Probiotics for recurrent Clostridium difficile disease. J Med Microbiol 2005;54:905-906. 66. Plummer S, Weaver MA, Harris JC, et al: Clostridium difficile pilot study: effects of probiotic supplementation on the incidence of C difficile diarrhoea. Int Microbiol 2004;7:59-62. 67. Hickson M, D’Souza AL, Muthu N, et al: Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised double blind placebo controlled trial. BMJ 2007;335:80. 68. McFarland LV, Surawicz CM, Greenberg RN, et al: A randomized placebo-controlled trial of Saccharomyces boulardii in combination with standard antibiotics for Clostridium difficile disease. JAMA 1994;271;1913-1918. 69. Surawicz CM, McFarland LV, Greenberg RN, et al: The search for a better treatment for recurrent Clostridium difficile disease: use of high-dose vancomycin combined with Saccharomyces boulardii. Clin Infect Dis 2000;31:1012-1017. 70. Munoz P, Bouza E, Cuenca-Estrella M, et al: Saccharomyces cerevisiae fungemia: an emerging infectious disease. Clin Infect Dis 2005;40:1625-1634. 71. McFarland LV: Alternative treatments for Clostridium difficile disease: what really works? J Med Microbiol 2005;54:101-111. 72. Aas J, Gessert CE, Bakken JS: Recurrent Clostridium difficile colitis: case series involving 18 patients treated with donor stool administered via nasogastric tube. Clin Infect Dis 2003;36:580-585. 73. Lagrotteria D, Holmes S, Smieja M, et al: Prospective, randomized inpatient study of oral metronidazole versus oral metronidazole and rifampin for treatment of primary episode of Clostridium difficile-associated diarrhea. Clin Infect Dis 2006;43:547-552.

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74. Johnson S, Schriever C, Galang M, et al: Interruption of recurrent Clostridium difficile-associated diarrhea episodes by serial therapy with vancomycin and rifaximin. Clin Infect Dis 2007;44: 846-848. 75. Johnson S, Schriever C, Patel U, et al: Rifaximin redux: treatment of recurrent Clostridium difficile infections with rifaximin immediately post-vancomycin treatment. Anaerobe 2009;15:290-291. 76. Tannock G, Munro K, Taylor C, et al: A new macrocycle antibiotic, fidaxomicin (OPT-80) causes less alteration to the bowel microbiota of Clostridium difficile-infected patients than does vancomycin. Microbiology 2010;156:3354-3359. 77. Louie T, Miller M, Donskey C, et al: Clinical outcomes, safety, and pharmacokinetics of OPT-80 in a phase 2 trial with patients with Clostridium difficile infection. Antimicrob Agents Chemother 2009;53:223-228. 78. Dificid [package insert]: San Diego, CA, Optimer Pharmaceuticals, Inc, 2011. 79. Nerandzic MM, Mullane KM, Miller MA, et al: Acquisition and overgrowth of vancomycin-resistant enterococci in patients treated with either fidaxomicin or vancomycin for Clostridium difficile infection. Interscience Conference on Antimicrobial Agents and Chemotherapy, 2009. 80. Dupont HL, Jiang ZD, Okhuysen PC, et al: A randomized, double-blind, placebo-controlled trial of rifaximin to prevent travelers’ diarrhea. Ann Intern Med 2005;142:805-812. 81. Kokkotou E, Moss AC, Michos A, et al: Comparative efficacies of rifaximin and vancomycin for treatment of Clostridium difficileassociated diarrhea and prevention of disease recurrence in hamsters. Antimicrob Agents Chemother 2008;52:1121-1126. 82. Curry SR, Marsh JW, Shutt KA, et al: High frequency of rifampin resistance identified in an epidemic Clostridium difficile clone from a large teaching hospital. Clin Infect Dis 2009;15:425-429. 83. Jiang ZD, Dupont HL, La Rocco M, et al: In vitro susceptibility of Clostridium difficile to rifaximin and rifampin in 359 consecutive isolates at a university hospital in Houston, Texas. J Clin Pathol 2010; 63:355-358. 84. O’Connor JR, Galang MA, Sambol SP, et al: Rifampin and rifaximin resistance in clinical isolates of Clostridium difficile. Antimicrob Agents Chemother 2008;52:2813-2817.

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85. Musher DM, Logan N, Hamill RJ, et al: Nitazoxanide for the treatment of Clostridium difficile colitis. Clin Infect Dis 2006;43: 421-427. 86. Musher DM, Logan N, Bressler AM, et al: Nitazoxanide versus vancomycin in Clostridium difficile infection: a randomized, doubleblind study. Clin Infect Dis 2009;15:e41-e46. 87. Babcock GJ, Broering TJ, Hernandez HJ, et al: Human monoclonal antibodies directed against toxins A and B prevent Clostridium difficile-induced mortality in hamsters. Infect Immun 2006;74: 6339-6347. 88. Lowy I, Molrine DC, Leav BA, et al: Treatment with monoclonal antibodies against Clostridium difficile toxins. N Engl J Med 2010;362(3):197-205. 89. Sougioultzis S, Kyne L, Drudy D, et al: Clostridium difficile toxoid vaccine in recurrent C difficile-associated diarrhea. Gastroenterology 2005;128:764-770. 90. Wilson KH, Sheagren JN: Antagonism of toxigenic Clostridium difficile by nontoxigenic C difficile. J Infect Dis 1983;147: 733-736. 91. Seal D, Borriello SP, Barclay F, et al: Treatment of relapsing Clostridium difficile diarrhoea by administration of a non-toxigenic strain. Eur J Clin Microbiol 1987;6:51-53. 92. Sambol SP, Merrigan MM, Tang JK, et al: Colonization for the prevention of Clostridium difficile disease in hamsters. J Infect Dis 2002;186:1781-1789. 93. Shim J, Johnson S, Samore M, et al: Primary symptomless colonization by Clostridium difficile and decreased risk of subsequent diarrhoea. Lancet 1998;351:633-636. 94. Sambol SP, Merrigan MM, Tang JK, et al: Colonization for the prevention of Clostridium difficile disease in hamsters. J Infect Dis 2002;186:1781-1789. 95. Merrigan MM, Sambol SP, Johnson S, et al: Prevention of fatal Clostridium difficile-associated disease during continuous administration of clindamycin in hamsters. J Infect Dis 2003;188: 1922-1927.

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Chapter 5

CDI Surveillance

S

ince 2000, the rate of Clostridium difficile infection (CDI) has increased so rapidly (Figure 5-1) that CDI now rivals, and in some areas surpasses, methicillinresistant Staphylococcus aureus (MRSA) as the most common agent to cause health-care–related infections in the United States.1-4 Existing data suggest there may be more than 1 million cases of CDI annually and between 15,000 and 30,000 deaths associated with CDI in the US.4-6 In addition to the increasing rate of CDI, a more virulent strain of C difficile, designated as BI/NAP1/027, has emerged and has spread globally. This epidemic strain is associated with a more severe course of disease, high relapse rate, and significant mortality. Increases in incidence and severity of CDI underscore the importance of both hospital-based surveillance and sentinel surveillance, which can detect clustering of cases in time and space and monitor for newly emerging virulent strains. Surveillance is valuable in providing a timely guide for the implementation of interventions aimed at controlling CDI within health-care facilities (HCFs) and assessment of the effect of such interventions. Surveillance in the community serves public health purposes by tracking the emergence of community-onset CDI, the severity of the disease, and its incidence in previously low-risk populations. 122

80 Any diagnosis Primary

Discharges per 100,000 population

70 60 50 40 30 20 10 0 1996

1997

1998

1999

2000

2001

2002

2003

Figure 5-1: National estimates of US short-stay hospital discharges with Clostridium difficile listed as primary or as any diagnosis. Isobars represent 95% confidence intervals. From McDonald et al.4

Hospital-based Surveillance Surveillance can be performed as a measure of CDI in an entire health-care facility or in a specific ward or unit. The CDI rate can be expressed as the number of CDI case patients per 10,000 patient-days, which is calculated this way: the number of case patients/number of patient-days x 10,000. Laboratories that perform C difficile testing should report results to infection prevention and control staff daily. Standardized case definitions are needed to properly identify and compare CDI trends and outbreaks both in HCFs and in the community. Data are lacking to determine the ideal definition for health-care–associated CDI. Until recently, standardized surveillance definitions for CDI were lacking.7,8 The Ad Hoc Clostridium difficile Surveillance Working Group recently made recommendations for surveillance of CDI, which include definitions for a 123

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CDI case, for recurrent CDI, and for severe CDI.9 Clostridium difficile case patients were further defined by their exposures according to this classification: as HCF-onset, HCF-associated CDI; community-onset, HCF-associated CDI; community-associated CDI; indeterminate exposure; and unknown exposure (Table 5-1). At a minimum, it is recommended that all acute-care facilities track HCF-onset, HCF-associated CDI.8

Deﬁnitions CDI Case

The Ad Hoc Clostridium difficile Surveillance Working Group has defined a CDI case as diarrhea (unformed stool that conforms to the shape of a specimen collection container) or toxic megacolon (a radiologically identified abnormal dilation of the large intestine) without other known etiology that meets one or more of the following criteria: (1) the stool specimen is positive for C difficile toxin A and/or B by laboratory assay or is identified as toxigenic C difficile by culture or other testing; (2) pseudomembranous colitis is seen by endoscopy or surgery; and (3) pseudomembranous colitis is identified during histopathological examination.9 Recurrent CDI

A recurrent CDI case is one that meets the criteria for a CDI case and occurs 8 wk or less after the onset of the previous episode that was successfully resolved either with or without therapy. A recurrent CDI case is one for which an additional positive result of a laboratory test is found in a specimen collected 2 to 8 wk after the last specimen that tested positive. If an additional laboratory test is positive for a specimen collected 2 wk or less after the last positive specimen, the case is considered a continuation of the previous CDI case. If an additional laboratory test is positive for a specimen collected more than 8 wk after the last positive specimen, it represents a new CDI case.9 124

Severe CDI

A case is considered severe CDI if any of the following occurs within 30 days after onset of symptoms, or within 30 days after the index laboratory test for laboratory-based reporting: (1) intensive care unit (ICU) admission from complications of CDI, such as shock, requiring vasopressor therapy; (2) colectomy, surgery for toxic megacolon or perforation, or refractory colitis; and (3) death attributed to CDI within 30 days after symptom onset as recorded on death certificate or as recorded in the medical record by the attending physician.9 Exposure Setting

Clostridium difficile case patients are also defined according to exposure setting (Table 5-1, Figure 5-2). HCF-onset, HCF-associated CDI is defined as a patient with CDI symptom onset more than 48 h after admission to an HCF. A patient with CDI symptom onset in the community or 48 h or less after admission to an HCF is defined as having community-onset, HCF-associated CDI, provided that the symptom onset was less than 4 wk after the last discharge from an HCF. If the symptom onset was more than 12 wk after the last discharge from an HCF and symptom onset occurred in the community or 48 h or less after admission to an HCF, the patient is classified as having community-associated CDI. A patient who does not fit any of these criteria is said to have indeterminate exposure. If insufficient data are available to determine the exposure setting, the patient is classified as having unknown disease exposure.9

Outbreak Detection Although there is a lack of published data on CDI surveillance using standardized definitions and similar case-finding methods, identification of what constitutes an “outbreak” can be defined as an increase in CDI rate in time and/or place believed to be greater than that expected 125

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Table 5-1: Clostridium difficile Infection (CDI) Surveillance Definitions CDI Case Type

Definition

Health-care facility onset

Symptom onset >48 h after admission to a health-care facility

Health-care facilityassociated community onset

Symptom onset in the community or ≤48 h after admission, provided that symptom onset was < 4 wk after the last discharge from a health-care facility

Community associated

Symptom onset in the community or ≤48 h after admission to a health-care facility, provided that symptom onset was >12 wk after the last discharge from a health-care facility

Indeterminate onset

Case does not fit any of the previously mentioned criteria for an exposure setting (eg, onset in the community >4 wk but <12 wk after the last discharge from a health-care facility)

by chance alone. If a CDI rate is persistently elevated when compared to past rates or compared to rates in other, similar facilities, it can be considered a “hyperendemic” rate.7,8 The primary function of health-care–based infection surveillance is for timely identification of abnormal increases in infections, or outbreaks. As previously noted, the data necessary to create the “ideal” surveillance definitions for CDI are lacking. This lack of data has led to the creation of the many surveillance definitions for CDI. At a minimum, it 126

CDI Case Type

Definition

Unknown

Exposure setting cannot be determined because of lack of available data

Recurrent

Episode occurred ≤8 wk after the onset of a previous episode, provided that CDI symptoms from the earlier episode resolved

Note: When laboratory-based surveillance is used, the date and time of stool specimen collection can be used as a surrogate for symptom onset. If data on the time a patient was admitted (in addition to date) and/or the time stool was collected for testing are not available, CDI can be considered to be health-care facility onset if stool is positive for toxigenic C difficile or a C difficile toxin after the third calendar day after hospital admission, where the first day is the day of admission (ie, a patient admitted on Monday with stool first positive for C difficile toxin on Thursday or later is considered to have health-care facility–onset CDI). Adapted from Dubberke et al,7 McDonald et al,9 Kutty et al10

is recommended that health-care facilities track HCF-onset, HCF-associated CDI. However, studies have demonstrated that significantly more HCF-associated cases of CDI will be identified if community-onset, HCF-associated CDI cases are identified in addition to HCF-onset, HCF-associated CDI.10 Tracking community-onset, HCF-associated CDI is resource intensive, and many infection prevention and control departments are not adequately staffed to conduct this additional surveillance. 127

5

128 Admission

Discharge

48 h

4 wk

8 wk Symptom onset

(*)

HO-HCFA

CO-HCFA

indeterminate

CA-CDAD

Figure 5-2: Timeline for definitions of Clostridium difficile infection (CDI) exposures. Case patients with symptom onset during the window of hospitalization marked by an asterisk (*) would be classified as having community-onset, health-care facility–associated disease (CO-HCFA), if patient was discharged from a health-care facility within the previous 4 wk; would be classified as having indeterminant disease, if the patient was discharged from a health-care facility between the previous 4-12 wk; or would be classified as having community-associated CDAD (CA-CDAD), if the patient was not discharged from a health-care facility in the previous 12 wk, HO-HCFA, health-care facility-onset, health-care facility–associated CDAD. Used with permission from McDonald et al.9

Recent data indicate that tracking community-onset, HCF-associated CDI may not be necessary to identify outbreaks of CDI within a health-care facility.11,12 In a multicenter study, significantly more cases of HCF-associated CDI were found when surveillance for community-onset, HCF-associated cases were conducted in addition to surveillance for HCF-onset CDI, compared to surveillance for HCF-onset CDI alone.12 However, the agreement between the two surveillance definitions for identifying CDI outbreaks was 0.899 when allowing a 1-month lag between definitions for identifying an outbreak. This indicates that although more cases of CDI will be identified if surveillance for community-onset, HCF-associated CDI is conducted in addition to HCF-onset CDI, health-care facilities should not worry about missing a CDI outbreak if they are unable to conduct surveillance for community-onset, HCF-associated CDI.

Sentinel Surveillance Sentinel surveillance for C difficile involves collecting C difficile isolates, often with relevant clinical information. Molecular typing is then conducted on the isolates to detect if there are any important changes in the predominant strains present. These data can then be correlated with clinical information to determine if changes in strain types causing infection are associated with important changes in clinical presentation or epidemiology. Although speculative, it is possible a C difficile sentinel surveillance system may have identified increases in incidence and severity of CDI associated with the BI/NAP1/027 strain before it became so widespread. Canada The Canadian Hospital Epidemiology Committee (CHEC) is a joint initiative by the Canadian Infectious Diseases Society and the Canadian Nosocomial Infection Surveillance Program, which is part of Health Canada. 129

5

A laboratory-based surveillance was conducted from January to April 1997 for C difficile toxin in stool among 19 Canadian hospitals that participate in CHEC in 8 provinces.13 Liquid or semiformed stools from patients meeting the case definition of CDI were submitted at each participating hospital for screening for the presence of C difficile cytotoxin, using the method then in use at that hospital (cytotoxin assay or culture with evidence of toxin production). Testing was performed for 6 continuous weeks or until 200 consecutive diarrhea stool samples had been tested at each site. Data obtained for each case included patient demographics; length of hospital stay; duration of diarrhea; complications of CDI; and necessary interventions, patient outcomes, and details of death. During the surveillance period, 269 patients met the case definition for nosocomial CDI. The overall incidence of CDI was 6.6 cases per 10,000 patient-days. Complications (including dehydration, hypokalemia, mild gastrointestinal bleeding or ileus, need for transfusion, bowel perforation, and secondary sepsis) related to CDI occurred in 21 patients (8%), and 4 (1.5%) patients died directly or indirectly from CDI. Surveillance data showed that nosocomial CDI was a common and serious infection in Canada, associated with substantial morbidity and mortality. And because the cytotoxin assay, which was used alone in some hospitals, is less sensitive than stool culture for C difficile with follow-up investigation for toxin production, it is likely that the burden of nosocomial CDI was underestimated. A follow-up study was conducted from November 2004 through April 2005.14 During this surveillance period, stool samples were sent to a centralized laboratory for C difficile culture. A total of 1,430 adults with HCF-associated CDI were identified at 29 hospitals during the 6-month surveillance period. The incidence of CDI was 6.5 per 10,000 patient-days. Complications related to CDI occurred in 104 patients (7.3%), and 82 patients (5.7%) died directly or indirectly from CDI. Compared to the previous surveillance 130

period, the overall incidence of HCF-associated CDI was unchanged, but the proportion of patients who died from CDI increased significantly (5.7% vs 1.5%, P <0.001). Although strain typing data of the C difficile isolates were not in this published report, there were significant correlations between the prevalence of the BI/NAP1/027 strain and higher CDI incidence and CDI severity.15

Europe The European Study Group on Clostridium difficile (ESGCD) conducted the first European-wide survey of C difficile isolates from patients suspected of having CDI during a 2-month prospective study in 2005.16 Only hospital-acquired CDI was studied and no data were collected on the severity or outcome of the cases. Thirty-eight hospitals from 14 European countries participated in the survey to document the phenotypic and genotypic features of clinical isolates of C difficile during the study period. Four major toxinotypes were identified (type O, V, VIII, and III) and 66 different polymerase chain reaction (PCR) ribotypes were characterized. Although incidence of CDI varied greatly among the European countries studied, the mean incidence of CDI in the study (2.45/10,000 patient-days) was much lower than that of the US and Canada (4-25/10,000 admissions).17-20 The study found an increased proportion of toxin-variant strains (24.3%) compared with that reported from the US (12%), England (7.7%), and France (6%). The first European-wide survey of C difficile identified the BI/NAP1/027 strain in CDI outbreaks in Belgium, France, the UK, and the Netherlands in 2005 and 2006.21-23 The virulent, epidemic 027 strain accounted for 6.2% of isolates overall in the study, but the Netherlands had a 40% prevalence of the 027 strain, and the prevalence reached 31.4% for the epidemic strain in Belgium. After outbreaks of CDI in the Netherlands in 2005, national surveillance was initiated to investigate the spread and epidemiology of CDI.24 Clostridium difficile infection 131

5

of ribotype 027 was found in 20 of 109 (18.3%) hospitals in the Netherlands. Three separate surveillance studies in the Netherlands also found a new CDI strain, PCR type 078, among hospitalized patients with CDI.25 This emerging strain has mechanisms for the hyperproduction of toxins similar to type 027. In 2005, PCR type 078 was found in 5 of 67 (7.5%) CDI patients in a 17-hospital surveillance study; in 2006, surveillance in a 982-bed hospital found type 078 in 3 of 105 (3.9%) CDI patients, and in 2007, another surveillance study found 5 of 47 (10.6%) CDI patients had infection with the 078 strain. The 078 pathogen was determined to be mainly a community-onset agent and has also been identified in pigs.25,26 In addition to the Netherlands, the 078 strain has also been reported in Belgium, Northern Ireland, Scotland, and possibly Spain.27 A follow-up European-wide surveillance study was conducted in November, 2008. A total of 65 different PCR ribotypes were identified. Similar to the first surveillance study in 2005, the 027 strain represented 4.8% of isolates collected and it was identified in only 6 countries. The most common PCR ribotypes were 014/020, 001, and 078.28

United States There is no national surveillance system for CDI in the US at present, but a 2010 report from the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA) indicates that the BI/NAP1/027 strain has been identified in 40 states.8 In Congressional Testimony before the US Senate Committee on Health, Education, Labor, and Pensions in June 2008, Fred C. Tenover, PhD, Director, Office of Antimicrobial Resistance of the CDC US Department of Health and Human Services, stated that the CDC would begin to collect data from health-care institutions to track C difficile infections using the National Healthcare Services Network (NHSN).5 The NHSN serves as both a system for 132

tracking health-care-associated infections and as a sentinel warning system for unusual, resistant organisms.

Key Points 1. Surveillance for cases of CDI is important to detect clusters of cases by time and place, to identify emerging strains, and to implement and assess interventions aimed at controlling CDI within health-care facilities. 2. Standardized case definitions are needed to properly identify and compare CDI trends and outbreaks. 3. At a minimum, health-care facilities should track HCF-onset CDI to identify outbreaks and track trends over time. 4. Surveillance and molecular typing studies have documented the dissemination of the epidemic BI/NAP1/027 strain of C difficile in North America and Europe. 5. A new C difficile strain, type 078, has emerged in Europe and has characteristics similar to the BI/NAP1/027 strain. References 1. Miller BA, Chen LF, Sexton DJ, Anderson DJ: Comparison of the burdens of hospital-onset, healthcare facility-associated Clostridium difficile infection and of healthcare-associated infection due to methicillin-resistant Staphylococcus aureus in community hospitals. Infect Control Hosp Epidemiol 2011;32:387390. 2. Zilberberg MD, Shorr AF, Kollef MH: Growth and geographic variation in hospitalizations with resistant infections, United States, 2000-2005. Emerg Infect Dis 2008;14:1756-1758. 3. US Department of Health and Human Services: Potentially deadly infection doubled among hospital patients over last 5 years. AHRQ 2008;334:22. Available at: www.hcupnet.ahrq.gov, accessed June 6, 2011. 4. McDonald LC, Owings M, Jernigan DB: Clostridium difficile infection in patients discharged from US short-stay hospitals, 19962003. Emerg Infect Dis 2006;12:409-415. 5. Tenover FC: CDC Congressional Testimony. Washington, DC. United States Senate Committee on Health, Education, Labor and

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Pensions. June 24, 2008. Available at: http://www.cdc.gov/print. do?url=http%3A//www.cdc.gov/washington/testimony/2008/ t20080624.htm. Accessed March 24, 2009. 6. Campbell RJ, Giljahn L, Machesky K, et al: Clostridium difficile infection in Ohio hospitals and nursing homes during 2006. Infect Control Hosp Epidemiol. 2009;30:526-533. 7. Dubberke ER, Gerding DN, Classen D, et al: Strategies to prevent Clostridium difficile infections in acute care hospitals. Infect Control Hosp Epidemiol 2008;29(suppl 1):S81-S92. 8. Cohen SH, Gerding DN, Johnson S, et al: SHEA‐IDSA guideline: Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol 2010;31:431-455. 9. McDonald LC, Coignard B, Dubberke E, et al: Recommendations for surveillance of Clostridium difficile-associated disease. Infect Control Hosp Epidemiol 2007;28:140-145. 10. Kutty PK, Benoit SR, Woods CW, et al: Assessment of Clostridium difficile-associated disease surveillance definitions, North Carolina 2005. Infect Control Hosp Epidemiol 2008;29:197-202. 11. Dubberke ER, McMullen KM, Mayfield JL, et al: Hospital-associated Clostridium difficile infection: is it necessary to track community-onset disease? Infect Control Hosp Epidemiol 2009;30:332-337. 12. Dubberke ER, Butler AM, Hota B, et al: Multicenter study of the impact of community-onset Clostridium difficile infection on surveillance for C. difficile infection. Infect Control Hosp Epidemiol 2009;30:518-525. 13. Miller MA, Hyland M, Ofner-Agostini M, et al: Morbidity, mortality, and healthcare burden of nosocomial Clostridium difficile-associated diarrhea in Canadian hospitals. Infect Control Hosp Epidemiol 2002;23:137-140. 14. Gravel D, Miller M, Simor A, et al: Health care-associated Clostridium difficile infection in adults admitted to acute care hospitals in Canada: a Canadian Nosocomial Infection Surveillance Program Study. Clin Infect Dis 2009;48:568-576. 15. Miller MA: The Canadian experience with Clostridium difficile: tracking a pathogen. Paper presented at: Association for Professionals

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in Infection Control, Clostridium difficile: A Call to Action Conference, November 10-11, 2008; Orlando, FL. 16. Barbut F, Mastrantonio P, Delmée M, et al: The European Study Group on Clostridium difficile (ESGCD). Prospective study of Clostridium difficile infections in Europe with phenotypic and genotypic characterisation of the isolates. Clin Microbiol Infect 2007;13:1048-1057. 17. Pépin J, Valiquette L, Alary ME, et al: Clostridium difficileassociated diarrhea in a region of Quebec from 1991 to 2003; a changing pattern of disease severity. Can Med Assoc J 1991;171: 466-472. 18. Loo VG, Poirier L, Miller MA, et al: A predominantly clonal multi-institutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality. N Engl J Med 2005;353:2442-2449. 19. Sohn S, Climo M, Diekema D, et al: Varying rates of Clostridium difficile-associated diarrhea at prevention epicenter hospitals. Infect Control Hosp Epidemiol 2005;26:676-679. 20. Kuijper EJ, Coignard B, Tull P: Emergence of Clostridium difficile-associated disease in North America and Europe. Clin Microbiol Infect 2006;12(suppl 6):2-18. 21. Joseph R, Demeyer D, Vanrenterghem D, et al: First isolation of Clostridium difficile PCR ribotype 027, toxinotype III in Belgium. Euro Surveill 2005;10:E051020.4. 22. Kuijper EJ, Van den Berg RJ, Debast S, et al: Clostridium difficile ribotype 027, toxinotype III, the Netherlands. Emerg Infect Dis 2006;12:827-830. 23. Tachon M, Cattoen C, Blanckaert K, et al: First cluster of C difficile toxinotype III, PCR-ribotype 027 associated disease in France: preliminary report. Euro Surveill 2006;11:E060504.1. 24. Goorhuis A, Van der Kooi T, Vaessen N, et al: Spread and epidemiology of Clostridium difficile polymerase chain reaction ribotype 027/toxinotype III in the Netherlands. Clin Infect Dis 2007;45:695-703. 25. Goorhuis A, Debast SB, van Leengoed LA, et al: Clostridium difficile PCR ribotype 078: an emerging strain in humans and in pigs? J Clin Microbiol 2008;46:1157-1158.

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26. Keel K, Brazier JS, Post KW, et al: Prevalence of PCR ribotypes among Clostridium difficile isolates from pigs, calves, and other species J Clin Microbiol 2007;45:1963-1964. 27. Kuijper EJ, Barbut F, Brazier JS, et al: Update of Clostridium difficile infection due to PCR ribotype 027 in Europe, 2008. Euro Surveill 2008;13:pii:18942. 28. Bauer MP, Notermans DW, Benthem BHB, et al, for the ECDIS Study Group: Clostridium difficile infection in Europe: a hospitalbased survey. Lancet 2011;377:63-73.

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Chapter 6

Prevention

C

lostridium difficile, methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant Enterococcus (VRE) have common epidemiologic characteristics. But C difficile has a survival advantage that the other gram-positive organisms do not have—the ability to form spores. C difficile spores are resistant to the disinfectants and alcohol used in most hospitals, making hand hygiene and environmental cleaning more challenging. The Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA) have published a compendium on preventing health-care-associated infections, including C difficile infection (CDI) in acute-care facilities.1 Strategies to control CDI have included contact precautions, diligent hand hygiene, environmental decontamination, and antimicrobial restriction and stewardship.2

Transmission/Acquisition Patients with CDI shed spores in feces, resulting in contamination of their skin, clothing, and nearby environmental surfaces.3-8 The hands of health-care workers serve as an important mode of transmission from these sites of contamination to susceptible patients. As shown in Figure 6-1, C difficile spores are frequently acquired on hands after contact with commonly examined skin sites. Figure 6-2 illustrates hand contamination after examination of the groin of a CDI patient.7 A subsequent study demonstrated 137

6

% positive

138 100 90 80 70 60 50 40 30 20 10 0 Hand

Forearm

Chest

Abdomen

Groin

Skin Site

Figure 6-1: Frequency of acquisition of C difficile on hands after contact with skin sites of patients with CDI. From Bobulsky et al.7

Figure 6-2: Illustration of acquisition of C difficile on sterile gloves after contact with a CDI-affected patient’s groin. The larger colonies outlining the fingers are C difficile. Note: the patient had showered one hour before collection of the culture specimen. From Bobulsky et al.7

that contamination of hands was as likely after contact with commonly touched environmental sites (ie, bed rail, bedside table, telephone, and call button) in CDI patients’ rooms as after contact with commonly examined skin sites (54% vs 50%, respectively) (unpublished data, Donskey CJ). Others have also demonstrated that health-care workers are as likely to acquire C difficile on hands after contacting environmental surfaces in CDI patients’ rooms as after direct patient contact.3 Samore et al5 found a positive correlation between the proportion of contaminated environmental sites in CDI patients’ rooms and isolation of C difficile from hands of hospital personnel (Table 6-1). These studies suggest that both CDI patients and heavily 139

6

Table 6-1: Correlation Between Proportion of Positive Environmental Sites and Isolation of Clostridium difficile From Hands of Hospital Personnel Environmental Sites Positive (%)

No. of Index Cases With Environmental Sites and Personnel Cultured

0

12

1-25

5

26-50

5

>50

6

contaminated environmental surfaces are important sources for acquisition of spores on health-care workers’ hands. Fomites that are taken from patient to patient are another potential source of C difficile transmission. For example, electronic rectal thermometers that are used on multiple patients may become contaminated with spores and serve as a source for transmission.9 Substitution of single-use disposable thermometers or tympanic thermometers for electronic thermometers has been associated with reductions in CDI.10,11 Another study also found that portable equipment such as pulse oximetry machines, medication carts, and computers on wheels (COWS) were frequently contaminated with spores.12 Further studies are needed to determine whether contamination of portable equipment other than electronic thermometers plays an important role in transmission. Patients can also acquire C difficile through direct contact with contaminated surfaces. C difficile spores can 140

No. of Positive Personnel/ No. of Personnel Cultured (%) 0/25 0/11 1/12 (8) 9/25 (36)* *Chi-square test for linear trend in proportions: P <0.01. From Samore et al5 )

survive for 5 months or more on environmental surfaces,13-15 and environmental cleaning is often inadequate in healthcare facilities.16,17 However, some studies suggest that direct acquisition from contaminated rooms may be relatively uncommon. For example, Clabots et al6 found that only 2 of 15 patients admitted to a contaminated room acquired the same strain found in the room. In addition, only 1 of 54 patients who acquired C difficile shared a room with a patient colonized with the same strain. A study of mathematical modeling of C difficile transmission suggested that a doubling in the degree of C difficile environmental contamination would result in only a 3% increase in CDI incidence.18 However, the importance of the environment as a source of C difficile transmission appears to be higher in CDI outbreak settings, possibly because of an increase in the amount of contamination and subsequently an increase in the number of CDI patients.1,2 141

6

About two-thirds of hospitalized patients who acquire C difficile colonization become asymptomatic carriers.8 In general, asymptomatic carriers are believed to be a less important source for transmission than are patients with CDI. The concentration of C difficile in the stool and the extent of environmental and skin contamination are greater in CDI patients compared to asymptomatic carriers.5,7,8,19 In addition, the hands of health-care workers are more likely to become contaminated after exposure to CDI patients than to asymptomatic carriers.3-6 However, some studies suggest that asymptomatic carriers could play an underappreciated role in the transmission of C difficile.6,8 For example, the Clabots et al study6 found that 16 of 19 (84%) episodes of nosocomial acquisition of CDI were epidemiologically linked to transmission from new admissions to the study ward, and 15 of 16 (94%) admissions who introduced a strain type to the ward were asymptomatic carriers. Further research is needed to clarify the role of asymptomatic carriers in transmission of C difficile.

Preventing CDI There are two main concepts to preventing CDI in a health-care facility: preventing transmission of C difficile and decreasing the risk of developing CDI if C difficile transmission occurs. The former involves adherence to infection prevention and control recommendations, the latter involves antimicrobial stewardship. The SHEA/IDSA compendium to prevent CDI provides basic recommendations for all acute-care facilities (Table 6-2) and special approaches if there are ongoing problems with controlling CDI despite good practice of the basic recommendations (Table 6-3).1,2 The compendium also assigns grades for the strength of recommendations (from A to C) and the quality of evidence (I to III) (Table 6-4). In addition, the compendium lists who is accountable to ensure implementation of a successful CDI prevention program, practices that should be discouraged, and unresolved issues. All recommenda142

Table 6-2: Basic Recommendations for Preventing CDI From the SHEA/IDSA Compendium Basic Recommendation

Grade

Implement contact precautions for patients with CDI

AI gloves BIII gowns BIII for singlepatient room

Ensure adequate disinfection of equipment and environment

BIII equipment

Design system to alert clinical and infection prevention and control personnel when patient diagnosed with CDI

BIII

Conduct CDI surveillance and feedback data to units and hospital administrators

BIII

Educate health-care personnel, housekeeping personnel, and hospital administration about CDI

BIII

Measure hand hygiene and contact precaution compliance

BIII

BII environment

6

From Dubberke et al2

tions need to have a strength of at least ‘B’ to be included as a basic recommendation or special approach. The following provides an overview behind the core recommendations for CDI prevention—contact precautions and antimicrobial stewardship—as well as some of the more controversial recommendations, including why the preferred method of 143

Table 6-3: Special Approaches to Preventing CDI From the SHEA/IDSA Compendium Special Approach

Grade

Intensify efforts at hand hygiene and contact precaution compliance

BIII

Preferentially use soap and water when performing hand hygiene after caring for a patient with CDI

BIII

Place patients in contact precautions while C difficile testing is pending

BIII

Prolong contact precautions until discharge

BIII

Assess the adequacy of room cleaning

BIII

Use diluted sodium hypochlorite for environmental disinfection if current practices are deemed inadequate

BII

Initiate an antimicrobial stewardship program

AII

From Dubberke et al2

hand hygiene with soap and water and environmental decontamination with bleach are under the special approaches and not the basic recommendations. Readers of this book are encouraged to also read the SHEA/IDSA compendium for preventing CDI, which is available for free at http:// www.shea-online.org/about/compendium.cfm.

Contact Precautions Placing patients with CDI into contact precautions helps reduce patient-to-patient transmission of C difficile. Contact precautions involve placing patients in private rooms, requir144

Table 6-4: Grading of the Strength of Recommendations and Quality of Evidence for the SHEA/IDSA Compendium Category/grade

Definition

Strength of Recommendation A

Good evidence to support a recommendation for use

B

Moderate evidence to support a recommendation for use

C

Poor evidence to support a recommendation for use

Quality of Evidence I

Evidence from ≥1 properly randomized, controlled trial

II

Evidence from ≥1 well-designed clinical trial, without randomization; from cohort or case-control analytic studies (preferably from >1 center); from multiple time series; or from dramatic results from uncontrolled experiments

III

Evidence from opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

Note: Adapted from the Canadian Task Force on the Periodic Health Examination36 and from Dubberke et al2

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Table 6-5: C difficile Diarrhea Incidence and Carriage Prevalence Before and After Institution of Vinyl Glove Use for All Body Substance Contact on the Glove Wards 6 Months Before

Wards

CDI Incidence

CD Carriage Prevalence

Glove Wards A

5/488

5/14

B

4/683

5/23 10/37

Total Total

9/1,171

Control Wards C

3/438

1/11

D

4/792

4/19 5/30

Total Total

7/1,230

CD=C difficile; NS=not significant Adapted from Johnson et al20

ing health-care workers to don gowns and gloves before entering the room, removing gowns and gloves before leaving the room, and having dedicated patient-care equipment. Private rooms are preferable for patients with CDI, especially for those with stool incontinence. Cohorting of patients is acceptable when single, private rooms are not available, but should be avoided if possible. Patients with 146

6 Months After

CDI Incidence

CD Carriage Prevalence

1/473

1/16

1/892

3/27 4/43

2/1,365

0.029 0.015

2/339

1/18

3/853

4/31 5/49

5/1,192

P Value

NS NS

6 discordant status of infection or colonization with other epidemiologically important organisms, such as VRE or MRSA, should not be cohorted. Of the recommended measures to prevent CDI, only glove use has a strength and quality grading of ‘AI.’ In a study conducted before the development of universal and contact precautions, investigators at the Minneapolis VA 147

Medical Center randomized 4 wards to standard of care (control wards) or an educational intervention promoting the use of gloves for all body substance contact (glove wards).20 In addition to education, boxes of gloves were placed at each patient’s bedside. The CDI incidence on the control and glove wards was identical before the intervention (Table 6-5). Both the CDI incidence and C difficile asymptomatic carriage rates declined significantly on the glove wards after the intervention, but there were no changes on the control wards (Table 6-5). Although few studies have evaluated its effectiveness in preventing transmission of C difficile, gown use is recommended as part of contact precautions.1,2,4,13 A study of health-care workers caring for patients with MRSA and VRE, which have an epidemiology that is similar to that of C difficile, found that the gloves and gowns worn during even routine patient care became contaminated with the organisms.21 Contact with a patient with CDI and with objects and materials in the patient’s environment provides opportunities to transfer the organism to clothing and the potential for spreading it to other patients. In addition, studies have found that the use of gowns and gloves is superior to gloves alone for preventing transmission of VRE and MRSA.22 Gloves and a gown should be donned whenever a health-care worker enters the room of a patient with CDI, even if patient contact is not anticipated. And before leaving the room, the gloves and gown should be removed, properly disposed of, and hand hygiene should be performed. Ideally, noncritical patient-care items, such as blood pressure cuffs, thermometers, and stethoscopes, should be dedicated to a single patient with CDI. When this is not possible, the equipment should be cleaned and disinfected after each use and between patient encounters, using the manufacturers’ recommendations. Health-care workers should be observed for compliance and proper hand-washing techniques and for adherence to isolation precautions. Education of patients and their 148

families can also aid compliance with contact precautions. Providing general information about CDI, colonization versus infection, the components and rationale for contact precautions, and the risk for transmission to family and visitors while in the hospital and after discharge may improve compliance and help alleviate patient fears about isolation precautions as well. How long a patient with CDI must remain in contact precautions is not clear. The Centers for Disease Control and Prevention (CDC) recommends that contact precautions can be discontinued after diarrhea resolves, with some experts recommending discontinuation 48 h after diarrhea resolves.1,2 These recommendations are based on epidemiologic data that patients with symptomatic CDI are significantly more likely to be a source of C difficile transmission than patients who are asymptomatically colonized with C difficile. No studies have evaluated the impact that duration of contact precautions for CDI has on CDI incidence. However, recent studies have documented persistent C difficile contamination of the environment and patient skin after diarrhea resolves.7,8 Because of these conflicting data, a special approach to consider if CDI incidence remains unacceptably high is the SHEA/IDSA CDI recommendation to extend contact precautions until discharge from the hospital (Table 6-3).1,2

Hand Hygiene Alcohol versus soap and water

Despite the fact that good hand hygiene is acknowledged as the best way to prevent transmission of infectious agents,23-25 many studies have shown that compliance with hand hygiene is poor.20,26 In 2002, the CDC suggested that alcohol-based hand rubs (ABHRs) should be the primary choice for hand decontamination, with antimicrobial soaps an acceptable alternative.23 ABHRs are available as low-viscosity rinses, gels, and foams, and take less time to use than does hand washing. Hospitals noted a dramatic improvement in hand hygiene compliance after the introduction of ABHRs. 149

6

However, studies showed that while ABHRs are effective against VRE and MRSA, they are ineffective at inactivating or removing spores, and controversy arose over their use in CDI cases.25,27 The Guideline for Hand Hygiene in Health Care published in 2002 by the CDC reports that none of the agents used in antiseptic handwash or antiseptic handrub preparations is reliably sporicidal against Clostridium species.23 This includes alcohols, chlorhexidine, hexachlorophene, iodophors, chloroxylenol (PCMX), and triclosan. Some have suggested that because of their lack of sporicidal activity, ABHRs may actually contribute to the increase in the spread of C difficile.4,28 Two separate studies, however, found no evidence of an association between an increase in CDI incidence and an increased use of ABHRs.29,30 Another study found significantly improved hand hygiene adherence when hand gel was available, with no change in the rate of CDI.31 There are several potential reasons for a lack of increase in CDI with use of ABHRs. First, if gloves are worn when caring for known or suspected CDI patients, it is unlikely that significant numbers of spores will be acquired on hands, and the method of hand hygiene after removal of gloves may be irrelevant. Second, if soap and water are used there is a risk of recontamination of hands after washing, as health-care workers often rely on the same sink the patient used after his or her last C difficile bowel movement. Third, overall compliance with use of soap and water for hand hygiene is typically much lower than compliance with ABHRs. Finally, large numbers of spores are typically inoculated on hands of volunteers in studies that have demonstrated poor removal of spores with ABHRs; it is possible that ABHRs could have greater efficacy in clinical settings if only a few spores are acquired on hands. The recent SHEA/IDSA compendium to prevent CDI recommended diligent hand hygiene with soap and water or an ABHR in routine settings or settings of endemicity.1,2 However, in outbreak settings or settings of CDI hyper150

3.0

Log10 Reduction

2.5 2.0 1.5 1.0 0.5 0 -0.5

Non2% Chlorine antimicrobial Chlorhexidine Towel soap Gluconate

61% Ethyl Alcohol

Figure 6-3: Removal of Bacillus atrophaeus spores after different methods of hand hygiene. From Weber et al.32

endemicity, soap and water were considered preferable to ABHRs for hand hygiene when caring for a patient with CDI (Table 6-3). This recommendation is supported by data demonstrating that soap and water are much more effective than ABHR in removing spores of Bacillus atrophaeus from hands (Figure 6-3).32 However, Edmonds et al33 recently demonstrated relatively poor removal (ie, ~1 log reduction) of C difficile spores from hands of volunteers with a variety of handwash products. These data further reinforce the recommendation of the SHEA/IDSA guideline that wearing gloves is the most important measure to prevent transmission when caring for patients with CDI. After gloves are removed, the method of hand hygiene should conform to your facility policies, and if hand washing with soap and water is recommended, ensure proper technique and rinse for at least 15 sec.1,2 151

6

Environmental Decontamination Another area where concerns based on in vitro data have not always translated to increases (or decreases) in CDI is the use of sporicidal agents to decontaminate the environment of C difficile spores. Proper environmental cleaning is especially critical for spore-forming pathogens such as C difficile because spores resist desiccation and can survive on hard surfaces for as long as 5 months.13-15 However, it does not appear that agents that kill C difficile spores are always necessary when cleaning the environment. Various studies have compared use of diluted sodium hypochlorite (bleach, 500 to 5,000 ppm available chlorine) in water versus commonly used hospital cleaning agents, such as quaternary ammonium-based detergents and other surfactant-based detergents, for environmental cleaning to prevent CDI.34-37 A problem with several of these studies is that they were in response to a CDI outbreak and several interventions were conducted in addition to using a sporicidal cleaning agent.34,35 In this setting, it is difficult to discern whether the interventions had an impact on the outbreak, and, if they did, which component of the interventions had any effect. Two commonly cited studies on the efficacy of diluted bleach as a sole intervention to prevent CDI actually had conflicting results. A before-after study was conducted on three units at a large tertiary-care facility. The only intervention was to replace the standard quarternary ammonium disinfectant with a 1:10 dilution of household bleach (1 part bleach, 9 parts water, 5,000 ppm available chlorine). There was a dramatic reduction in CDI incidence on the bone marrow transplant unit from 8.6 cases to 3.3 cases per 1,000 patient-days.36 However, the results were not reproducible for the two other units involved in the study, a neurosurgical intensive care unit (ICU) and a medical ward. The CDI incidence on the ICU went from 3.0 cases to 2.7 cases per 1,000 patient-days, and the CDI incidence on the medical ward went from 1.3 cases to 1.5 cases per 1,000 patient-days. 152

The other study compared the effectiveness of a detergent-based cleaning solution to a hypochlorite solution (1000 ppm available chlorine) in a cross-over study involving two geriatric wards (wards X and Y).37 The study reported a significant reduction in the CDI rate when the hypochlorite solution was used versus the detergent-based solution on ward X from 8.9 cases to 5.3 cases per 100 admission (P<.05). Conversely, there was a trend toward a higher CDI incidence on ward Y when bleach was used compared to the detergent (4.7 cases vs 3.5 cases per 100 admissions). There are several explanations why the use of a sporicidal environmental decontaminant may not always translate into a decrease in CDI. First, it is possible that use of a sporicidal agent is important in outbreak settings due to an increase in contamination of the environment, but less essential in nonoutbreak settings. In the two studies cited with inconsistent results, use of bleach had an impact only on the wards with the higher baseline CDI incidence. Second, although the environment is an important source of C difficile transmission, it may be less important than transmission via hands of health-care workers. Finally, it is likely that practice is as important as product when disinfecting the hospital environment. If a sporicidal product is not properly applied, it does not have the opportunity to kill the spores. Several studies have demonstrated that housekeeping staff may not adequately disinfect commonly touched surfaces unless monitoring and feedback are provided.16,17 Figure 6-4 shows an illustration of gross contamination of a call button with VRE after completion of cleaning by housekeeping staff following patient discharge. Carling et al17 demonstrated that dramatic improvements in cleaning can be achieved in multiple hospitals with the use of a simple fluorescent targeting method to monitor cleaning and provide feedback. Even if sporicidal products are not used, it is possible that good cleaning practices may result in adequate reduction of C difficile spores due to physical 153

6

Figure 6-4: Culture plate showing gross contamination of a call button with vancomycin-resistant Enterococcus (VRE) after completion of cleaning by housekeeping staff. The same button yielded C difficile by broth enrichment culture. From Eckstein et al.16

removal with wiping of surfaces. Use of products such as vaporized hydrogen peroxide may result in excellent disinfection of surfaces without the need for a person to apply the product.38 However, the high cost and the amount of time required for available systems limit their routine use in health-care facilities.

Antimicrobial Stewardship The major risk factor for the development of CDI in the health-care setting is prior exposure to antimicrobials, and 154

virtually all antimicrobials have been associated with CDI. Antimicrobial stewardship has the potential to be the most effective method for preventing CDI. Not only does antimicrobial stewardship decrease the risk of CDI by minimizing the inappropriate use of antimicrobials and improving antimicrobial selection if C difficile transmission occurs, but it also decreases C difficile transmission by decreasing the number of patients that develop CDI. Unfortunately, it is difficult to develop a successful antimicrobial stewardship program.39 Two forms of antimicrobial stewardship have proven successful at preventing CDI: restricting use of a single high-risk antimicrobial and decreasing overall antimicrobial use. Active restriction of a high-risk antimicrobial has resulted in reduction of CDI incidence.2,40,41 Historically, clindamycin, third-generation cephalosporins, and penicillins have commonly been associated with a high risk of CDI, and fluoroquinolone use has more recently been implicated in CDI cases. Several studies have documented decreases in CDI with restriction of clindamycin, cephalosporins, or fluoroquinolones40,42,43 (Figure 6-5, Table 6-6). When barrier precautions, educational programs, and enhanced terminal cleaning of patient rooms did not reduce the incidence of nosocomial CDI in a VA medical center during a 1993 outbreak, clindamycin use was identified as a significant risk factor.40 Analysis of C difficile isolates identified a predominant strain that was highly clindamycin resistant. After hospitalwide restriction of clindamycin was instituted, the number of CDI cases decreased (Figure 6-5). Subsequent investigation also found a sustained decrease in the proportion of C difficile isolates resistant to clindamycin—from 91% at the peak of the outbreak to 39% after nearly 2 years. Although cost savings realized after restriction of clindamycin were offset by the increased costs with the use of other, more expensive antibiotics, the substantial decrease in CDI cases resulted in an overall cost 155

6

156

60 50

Frequency of 50/55 (91%) 30/40 (75%) clindamycin resistance among isolates Clindamycin restriction

9/23 (39%)

Cases, n

40 30 20 10 0

Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 1992 1993 1994 1995 1996 Year by Quarters

Figure 6-5: Control of an outbreak of clindamycin-resistant C difficile by restriction of clindamycin. From Pear SM, et al: Ann Intern Med 1994;120:272-277; Climo MW, et al: Ann Intern Med 1998;128:989-995; Johnson S, et al: N Engl J Med 1999;341:16451651.

Table 6-6: Studies Demonstrating Reductions in CDI After Restriction of Cephalosporins Effect on CDI Rate

Restricted Agents

Substituted Agents

Cefuroximea

Narrow-spectrum agents

Decreased

3rd-generation cephalosporins (↓92%)b

Ciprofloxacin

Decreased 50% (no decrease on control ward)

Ceftriaxonec

Levofloxacin

Decreased

Cefotaximed

Piperacillin/ tazobactam

Decreased 52%

3rd-generation cephalosporinse

Not specified

Decreased

Cefotaximef

Not specified

Decreased

a

McNulty C et al: J Antimicrob Chemother 1997;40:707-711. Ludlam H et al: Age Ageing 1999;28:578-580. c Khan R, Cheesbrough J: J Hosp Infect 2003;54:10-4-108. d Wilcox MH et al: J Antimicrob Chemother 2004;54:168-172. e Thomas E et al: Clin Infect Dis 2002;35:457-462. f Impallomeni M, Galletly NP: BMJ 1995;311:1345-1346. b

savings for the hospital. Two other studies documented a similar decrease in CDI after hospital formulary restriction of clindamycin.44,45 Similarly, complete restriction of fluoroquinolones resulted in a significant reduction in CDI in a community hospital, and in the proportion of isolates that were epidemic BI/NAP1/027 strains.42 A more comprehensive approach is to improve antimicrobial prescribing practices rather than restrict a single antimicrobial. A study by Fowler et al41 found that intro157

6

158

CDAD

3.5

Implementation of infection control measures

Targeted Abx 250

Abx optimization intervention 200

3 2.5

150

2 100

1.5 1

50

Patient-days of antibiotic use/1,000 patient-days

0.5 0

1 Jan 2003 1 Apr 2003

0 Sep 2003

Incidence of CDAD/1,000 patients-days

4

1 Apr 2004

1 Apr 2005

1 Apr 2006

Four-week period

Figure 6-6: Effect of antibiotic stewardship on epidemic C difficile infection. From Valiquette L et al.46

duction of a narrow-spectrum antibiotic policy in three wards of a teaching hospital, reinforced by feedback, was associated with significant changes in target antibiotics and a significant reduction in CDI. The hospital was not experiencing a CDI outbreak at the time. Cephalosporins and amoxicillin/clavulanate were targeted for decreased use and benzyl penicillin, trimethoprim, and amoxicillin were targeted for increased use. A reduction in the antibiotics targeted for reduction was significant for both sudden change and long-term trend after the intervention. After the intervention, antibiotics targeted for increased use showed a significant increase in the long-term trend for benzyl penicillin and in sudden and long-term change for amoxicillin. The shift in antimicrobial prescribing practices was associated with a significant reduction in CDI (rate ratio 0.35, 95% confidence interval 0.17–0.73). A nonrestrictive antimicrobial stewardship program was implemented in a hospital in Quebec to help control an epidemic strain outbreak of CDI.46 Guidelines were developed by infectious diseases physicians and pharmacists that aimed to decrease the use of antibiotics most commonly associated with CDI in the literature: second- and third-generation cephalosporins, ciprofloxacin, clindamycin, and macrolides. No formal restrictions were instituted, but pharmacists provided reinforcement of the guidelines through telephone feedback, with suggestions for alternative antibiotics when possible. From 2003-2004 to 2005-2006, total and targeted antibiotic consumption decreased by 23% and 54%, respectively, and the incidence of CDI decreased by 60% (P=0.007) (Figure 6-6). Because of the antimicrobial stewardship program, and despite an overall reduction in antimicrobial prescribing, there was an increase in moxifloxacin use (Table 6-7). This is notable because subsequent analyses identified moxifloxacin as the greatest risk factor for CDI during the outbreak.47 This finding highlights the impact 159

6

Table 6-7: Use of Specific Antibiotics, 2003-2006 20032004a

20042005

Change Between 2005- 2003-2004 and 2006 2005-2006, %

Firstgeneration

47.0

35.9

37.1

-21

Secondgeneration

32.8

8.0

2.4

-93

Thirdgeneration

19.4

6.7

4.1

-79

Clindamycin

10.6

3.3

1.8

-87

8.6

3.3

1.9

-78

87.5

63.6

62.4

-29

Respiratory 15.6 fluoroquinolonesb

33.5

28.0

+79

Piperacillin/ tazobactam

29.4

42.0

+114

Antibiotic Cephalosporins

Macrolides Ciprofloxacin

19.6

Note: Data are patient-days of use per 1,000 patient-days of hospitalization, unless otherwise indicated. a Includes 3 additional fiscal periods (January-March 2003), for a total of 16 periods. b

Moxifloxacin was introduced in June 2004.

From Valiquette et al46

160

that decreasing overall antimicrobial use can have on prevention of CDI.

Key Points 1. The primary mode of transmission of C difficile in healthcare facilities is from the hands of health-care workers. 2. Contact precautions help reduce transmission of C difficile. Private rooms are preferable, especially for patients with diarrhea, but cohorting is acceptable when single, private rooms are unavailable. Dedicated equipment is recommended. 3. Full barrier precautions—gloves and gowns—are part of contact precautions for CDI. 4. Although ABHRs are not sporicidal, no studies have linked ABHR use to an increase in CDI. Consider preferred hand hygiene with soap and water after caring for patients with CDI if CDI is not controlled by other measures. 5. Data on the use of a sporicidal disinfectant (eg, diluted bleach) to reduce CDI have been inconsistent. Use of a sporicidal agent to disinfect the environment should be considered if CDI is not controlled by other measures. 6. Monitoring of cleaning practices by housekeeping staff with regular feedback on performance can result in significant improvements in cleaning 7. Antimicrobial stewardship is an important part of reducing the incidence of CDI. References 1. Cohen SH, Gerding DN, Johnson S, et al: SHEA‐IDSA guideline: Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol 2010;31:431-455. 2. Dubberke ER, Gerding DN, Classen D, et al: Strategies to prevent Clostridium difficile infections in acute care hospitals. Infect Control Hosp Epidemiol 2008;29(suppl 1):S81-S92.

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3. McFarland LV, Mulligan ME, Kwok RY, et al: Nosocomial acquisition of Clostridium difficile infection. N Engl J Med 1989; 320:204-210. 4. Gerding DN, Muto CA, Owens RC Jr: Measures to control and prevent Clostridium difficile infection. Clin Infect Dis 2008;46: S43-S49. 5. Samore MH, Venkataraman L, DeGirolami PC, et al: Clinical and molecular epidemiology of sporadic and clustered cases of nosocomial Clostridium difficile diarrhea. Am J Med 1996;100:32-40. 6. Clabots CR, Johnson S, Olson MM, et al: Acquisition of Clostridium difficile by hospitalized patients: evidence for colonized new admissions as a source of infection. J Infect Dis 1991;166:561-567. 7. Bobulsky GS, Al-Nassir WN, Riggs MM, et al: Clostridium difficile skin contamination in patients with C difficile-associated disease. Clin Infect Dis 2008;46:447-450. 8. Riggs MM, Sethi AK, Zabarsky TF, et al: Asymptomatic carriers are a potential source for transmission of epidemic and nonepidemic Clostridium difficile strains among long-term care facility residents. Clin Infect Dis 2007;45:992-998. 9. Brooks SE, Veal RO, Kramer M, et al: Reduction in the incidence of Clostridium difficile-associated diarrhea in an acute care hospital and a skilled nursing facility following replacement of electronic thermometers with single-used disposables. Infect Control Hosp Epidemiol 1992;13:98-103. 10. Brooks S, Khan A, Stoica D, et al: Reduction in vancomycinresistant Enterococcus and Clostridium difficile infections following change to tympanic thermometers. Infect Control Hosp Epidemiol 1998;19:333-336. 11. Jernigan JA, Siegman-Igra Y, Guerrant RC, et al: A randomized crossover study of disposable thermometers for prevention of Clostridium difficile and other nosocomial infections. Infect Control Hosp Epidemiol 1998;19:494-499. 12. Dumford DM 3rd, Nerandzic MM, Eckstein BC, et al: What is on that keyboard? Detecting hidden environmental reservoirs of Clostridium difficile during an outbreak associated with North American pulsed-field gel electrophoresis type 1 strains. Am J Infect Control 2009;37:15-19. 13. Fekety R, Kim KH, Brown D, et al: Epidemiology of antibioticassociated colitis: isolation of Clostridium difficile from the hospital environment. Am J Med 1981;70:906-908.

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14. Fordtran JS: Colitis due to Clostridium difficile toxins: underdiagnosed, highly virulent, and nosocomial. PROC (Bayl Univ Med Cent) 2006;19:3-12. 15. Owens RC: Clostridium difficile-associated disease: an emerging threat to patient safety: insights from the Society of Infectious Diseases Pharmacists. Pharmacotherapy 2006;26:299-311. 16. Eckstein BC, Adams DA, Eckstein EC, et al: Reduction of Clostridium difficile and vancomycin-resistant Enterococcus contamination of environmental surfaces after an intervention to improve cleaning methods. BMC Infect Dis 2007;7:61. 17. Carling PC, Parry MM, Rupp ME, et al: Healthcare Environmental Hygiene Study Group. Improving cleaning of the environment surrounding patients in 36 acute care hospitals. Infect Control Hosp Epidemiol 2008;29:1035-1041. 18. Starr JM, Campbell A, Renshaw E, et al: Spatio-temporal stochastic modeling of Clostridium difficile. J Hosp Infect 2009;71: 49-56. 19. McFarland LV: The epidemiology of Clostridium difficile infections. Viewpoints on Digestive Diseases 1990;4:82-85. 20. Johnson S, Gerding DN, Olson MM, et al: Prospective controlled study of vinyl glove use to interrupt Clostridium difficile nosocomial transmission. Am J Med 1990;88:137-140. 21. Snyder GM, Thom KA, Furuno JP, et al: Detection of methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci on the gowns and gloves of healthcare workers. Infect Control Hosp Epidemiol 2008;29:583-589. 22. Puzniak LA, Leet T, Mayfield J, et al: To gown or not to gown: the effect on acquisition of vancomycin-resistant enterococci. Clin Infect Dis 2002;35:18-25. 23. Centers for Disease Control and Prevention: Guideline for hand hygiene in health-care settings: recommendations of the healthcare infection control practices advisory committee and the HICPAC/ SHEA/APIC/IDSA hand hygiene task force. MMWR 2002;51 (RR-16):1-45. 24. Larson EL: APIC guideline for hand washing and hand antisepsis in health care settings. Am J Infect Control 1995:23:251-269. 25. Rao GG, Jeanes A, Osman M, et al: Marketing hand hygiene in hospitals—a case study. J Hosp Infect 2002;50:42-47.

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26. Pittet D, Mourouga P, Perneger TV, et al: Compliance with handwashing in a teaching hospital. Ann Intern Med 1999;130:126-130. 27. Gordin FM, Schultz ME, Huber RA, et al: Reduction in nosocomial transmission of drug-resistant bacteria after introduction of an alcohol-based handrub. Infect Control Hosp Epidemiol 2005;26: 650-653. 28. Bartlett JG: Narrative review: the new epidemic of Clostridium difficile-associated enteric disease. Ann Intern Med 2006;145:758-764. 29. Boyce JM, Ligi C, Kohan C, et al: Lack of association between the increased incidence of Clostridium difficile-associated disease and the increasing use of alcohol-based hand rubs. Infect Control Hosp Epidemiol 2006;27:479-483. 30. Vernaz N, Sax H, Pittet D, et al: Temporal effects of antibiotic use and hand rub consumption on the incidence of MRSA and Clostridium difficile. J Antimicrob Chemother 2008;62:601-607. 31. Rupp ME, Fitzgerald T, Puumala S, et al: Prospective, controlled, cross-over trial of alcohol-based hand gel in critical care units. Infect Control Hosp Epidemiol 2008;29:8-15. 32. Weber DJ, Sickbert-Bennett E, Gergen MF, et al: Efficacy of selected hand hygiene agents used to remove Bacillus atrophaeus (a surrogate of Bacillus anthracis) from contaminated hands. JAMA 2003;289:1274-1277. 33. Edmonds S, Kasper D, Zapka C, et al: Clostridium difficile and hand hygiene: spore removal effectiveness of handwash products. Presented at the 19th Annual Scientific Meeting of the Society for Healthcare Epidemiology of America, San Diego, CA, March 2009. 34. McMullen KM, Zack J, Coopersmith CM, et al: Use of hypochlorite solution to decrease rates of Clostridium difficile-associated diarrhea. Infect Control Hosp Epidemiol 2007;28:205-207. 35. Kaatz GW, Gitlin SD, Schaberg DR, et al: Acquisition of Clostridium difficile from the hospital environment. Am J Epidemiol 1988;127:1289-1294. 36. Mayfield JL, Lee T, Miller J, et al: Environmental control to reduce transmission of Clostridium difficile. Clin Infect Dis 2000;31:995-1000. 37. Wilcox MH, Fawley WN, Wigglesworth N, et al: Comparison of the effect of detergent versus hypochlorite cleaning on environmental

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contamination and incidence of Clostridium difficile infection. J Hosp Infect 2003;54:109-114. 38. Barbut F, Menuet D, Verachten M, et al: Comparison of the efficacy of a hydrogen peroxide dry-mist disinfection system and sodium hypochlorite solution for eradication of Clostridium difficile spores. Infect Control Hosp Epidemiol 2009;30:507-514. 39. Dellit TH, Owens RC, McGowan JE Jr, et al: Infectious Diseases Society of American and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis 2007;44:159-177. 40. Climo MW, Israel DS, Wong ES, et al: Hospital-wide restriction of clindamycin: effect on the incidence of Clostridium difficile-associated diarrhea and cost. Ann Intern Med 1998;128:989-995. 41. Fowler S, Webber A, Cooper BS, et al: Successful use of feedback to improve antibiotic prescribing and reduce Clostridium difficile infection: a controlled interrupted time series. J Antimicrob Chemother 2007;59:990-995. 42. Kallen AJ, Thompson A, Ristaino P, et al: Complete restriction of fluoroquinolone use to control an outbreak of Clostridium difficile infection at a community hospital. Infect Control Hosp Epidemiol 2009;30:264-272. 43. Gerding DN: Clindamycin, cephalosporins, fluoroquinolones, and Clostridium difficile-associated diarrhea: this is an antimicrobial resistance problem. Clin Infect Dis 2004;38:646-648. 44. Brown E, Talbot GH, Axelrod P, et al: Risk factors for Clostridium difficile toxin-associated diarrhea. Infect Control Hosp Epidemiol 1990;11:283-290. 45. Pear SM, Williamson TH, Bettin KM, et al: Decrease in nosocomial Clostridium difficile-associated diarrhea by restricting clindamycin use. Ann Intern Med 1994;120:272-277. 46. Valiquette L, Cossette B, Garant M-P, et al: Impact of a reduction in the use of high-risk antibiotics on the course of an epidemic of Clostridium difficile-associated disease caused by the hypervirulent NAP1/027 strain. Clin Infect Dis 2007;45:S112-S121. 47. Pépin J, Saheb N, Coulombe MA, et al: Emergence of fluoroquinolones as the predominant risk factor for Clostridium difficileassociated diarrhea: a cohort study during an epidemic in Quebec. Clin Infect Dis 2005;41:1254-1260.

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Index A abdominal cramps 62 Ad Hoc Clostridium difficile Surveillance Working Group 123, 124 Agency for Healthcare Research and Quality (AHQR) 13 alcohol-based hand rubs (ABHRs) 149-151, 161 altered mental status 87 ammonium disinfectant 152 amoxicillin 159 amoxicillin/clavulanate 159 ampicillin 43 amplified fragment-length polymorphism 71 anorexia 62 antibiotics 5, 6, 13, 40, 41, 43, 49-51, 54, 55, 63, 68, 76, 82, 89, 97, 98, 100, 103, 110, 155, 158-160 antibiotic therapy 39, 41 antidiarrheals 82 antimicrobial soaps 149 antimicrobial stewardship 50, 55, 137, 142-144, 154, 155, 158, 159, 161 antimicrobial stewardship program 50, 144, 159 166

antimotility agents 100 antineoplastic agents 43 antiperistaltic agents 82, 83 ascites 75, 76 ATLAS Bedside Scoring System 88 aztreonam 52, 53

B Bacillus atrophaeus 151 Bacillus difficilis 5 bile salts 40-43 bleach 29, 41, 100, 101, 144, 152, 153, 161 bleach solution 29 bowel perforation 9, 63, 87, 125, 130

C Campylobacter 82 Canadian Nosocomial Infection Surveillance Program (CNISP) 20 cancer 48 Candida 11 CDA1 and CDB1 human monoclonal antibodies 111, 112 cefotaxime 51, 157 ceftriaxone 50, 52-54, 157 cefuroxime 157

cell culture cytotoxicity assay 6, 64, 65, 67, 70, 73, 76, 77 Centers for Disease Control and Prevention (CDC) 12-14, 16, 18, 25, 28-30, 132, 149, 150 cephalosporins 43, 50, 51, 55, 155, 157, 159, 160 chlorhexidine 150, 151 chlorine 152, 153 chloroxylenol (PCMX) 150 cholestyramine 102, 103 ciprofloxacin (Cipro®) 51, 157, 159, 160 clindamycin 5, 6, 16, 17, 43, 51, 55, 155-157, 159, 160 Clinical Laboratory Standards Institute 17 Clostridium difficile 5-9, 11, 12, 14-18, 20, 21, 24-32, 39, 41-51, 53-56, 62, 64-74, 86, 87, 92, 93, 95, 97, 98, 100-103, 105, 107, 110-112, 122-133, 137-142, 144, 146, 148156, 158, 161 BI/NAP1/027 epidemic strain 13, 14, 16-21, 28-31, 49, 51, 71, 85, 86, 110, 122, 129, 131-133, 157 in animals 29, 30, 31 Clostridium difficile brucella agar (CDBA) 69

Clostridium difficile infection (CDI) 6-9, 12, 13, 16, 18-25, 2832, 39, 41, 43, 47-51, 55, 56, 62-64, 66, 6971, 74, 76, 77, 82-84, 86, 87, 89, 90, 92-94, 96-100, 102-105, 107, 108, 110-113, 122-133, 137-144, 146-150, 152155, 157-159, 161 community-associated CDI (CA-CDI) 25, 28, 30, 31 health-care-associated CDI (HA-CDI) 25 Clostridium species 67, 150 cognitive impairment 50 colectomy 9, 18, 22, 23, 29, 87, 94, 95, 125 colestipol 102, 103 colitis 5, 6, 39, 46, 63, 74, 75, 92, 93, 100, 111, 124, 125 fulminant colitis 39, 63, 92 colonization 7, 30, 39, 42, 43, 49, 50, 55, 74, 97, 142, 147, 149 colonoscopy 63, 75 computed tomography (CT) 62, 75-77 corticosteroids 95 Cryptosporidium sp 111 cycloserine-cefoxitinfructose agar (CCFA) 69 cytotoxin 6, 130 167

D dehydration 130 diarrhea 5, 7, 15, 29, 31, 32, 39, 41, 46, 48-50, 6264, 74-76, 83, 85-87, 99, 100, 101, 103, 108, 124, 130, 146, 149, 161

fluoroquinolones 13, 16, 18, 43, 51, 54, 55, 155, 157, 160 Food and Drug Administration (FDA) 83 frailty 49 fungemia 104

E

G

edema 75, 76 Emerging Infections Network (EIN) 29 endocarditis 104 endoscopy 6, 124 enema 93 Enterocolitis 5, 24, 26 pseudomembranous enterocolitis (PMC) 5, 6, 63, 74, 75, 93, 124 enterotoxin 6 enzyme immunoassay (EIA) 64-66, 73, 74, 76, 77 European Centre for Disease Prevention and Control 21 European Study Group on Clostridium difficile (ESGCD) 131

gastric acid suppression 97, 100 gastrointestinal bleeding 130 gatifloxacin 16, 17, 18, 54 Giardia sp 111 gloves 139, 143, 146, 148, 150, 151, 161 glutamate dehydrogenase (GDH) 67, 71 GDH algorithms 70, 71 glutamate dehydrogenase (GDH) assay 64, 66, 68, 70, 72, 73, 77 gowns 143, 146, 148, 161

F fecal flora restoration 105, 113 fever 62, 76, 87 fidaxomicin (OPT-80) (Dificid™) 82, 88, 107, 108, 110, 120 Flagyl® 83 168

H hand hygiene 29, 137, 143, 144, 148-151, 161 health-care facilities (HCFs) 14, 122-133, 142, 154 health-care workers 6, 7, 39, 41, 48, 55, 63, 137, 139, 140, 142, 146, 148, 150, 153, 161 hexachlorophene 150 Horn’s index 48, 98 hydrogen peroxide 154 hypoalbuminemia 62, 76, 87

hypochlorhydria 49 hypochlorite solution 153 hypokalemia 130 hypotension 87

I ileostomy 94 ileus 62, 76, 87, 90, 93, 130 immunoglobulin 94, 101, 113 incontinence 41, 49, 146 infection control measures 50 Infectious Diseases Society of America (IDSA) 18, 29, 89, 137, 142-145, 149, 150, 151 inflammatory bowel disease 48, 63 intracerebral hemorrhage 89 iodophors 150 ion exchange resins 102, 103

K kanamycin 43

L laboratory testing 63, 76 lactobacillus 103 laxatives 63 leukemia 48, 95 leukocytes 62, 76 leukocytosis 62, 76, 87, 88, 94 levofloxacin (Levaquin®) 15-17, 54, 157 lymphoma 48, 95

M macrolides 159, 160 malaise 62 methicillin-resistant Staphylococcus aureus (MRSA) 9, 11, 122, 137, 147, 148, 150 methotrexate 43 metronidazole (Flagyl®) 6, 48, 83, 84-86, 89-92, 96, 97, 99, 101, 102, 107, 110-112 monoclonal antibody therapy 111, 112 moxifloxacin (Avelox®) 16, 17, 18, 43, 54, 159, 160 multilocus sequence typing (MLST) 71 multilocus variable-number tandem-repeat analysis (MLVA) 71

N National Center for Health Statistics 12 National Healthcare Services Network (NHSN) 132 Nationwide Inpatient Sample (NIS) 13 nausea 62, 93 neuropathy 101 neutropenia 95 nitazoxanide (Alinia®) 84, 101, 111, 113 nucleic acid amplification tests (NAATs) 65, 66 169

O

S

ofloxacin 43 omeprazole 106 opiates 82

Saccharomyces boulardii 101, 102, 104, 105 Saccharomyces sp 104, 113 Salmonella 82 sepsis 130 Shigella 82 shock 87, 125 sigmoidoscopy 74, 75 Society for Healthcare Epidemiology of America (SHEA) 89, 137, 142-145, 149-151 SHEA/IDSA guidelines 89, 92 sodium hypochlorite 144, 152 sporicidal disinfectants 152, 161 Staphylococcus aureus 5, 6, 9, 11, 122, 137 stool culture 8, 64-68, 70, 74, 130 stool incontinence 146 surface layer protein A gene sequence typing 71

P penicillins 43, 155, 159 pericolonic stranding 76 peripartum women 25, 28, 29 piperacillin/tazobactam (Zosyn®) 50-53, 157, 160 polymerase chain reaction (PCR) 65 polymerase chain reaction (PCR) assay 64, 66, 70, 74, 76, 77 polymerase chain reaction (PCR) ribotypes 9, 21, 30, 31, 71, 131, 132 probiotics 103, 104 proton pump inhibitors (PPIs) 42, 55 pulsed-field gel electrophoresis (PFGE) 30, 71

R renal failure 48, 87 restriction-enzyme analysis 9 restriction endonuclease analysis (REA) 71 REA typing 30 rifampin 84, 101, 107, 110, 113 rifaximin (Xifaxan®) 101, 110, 113 170

T tacrolimus 89 tcdB gene 45 tcdC gene 14, 30, 47, 71 tolevamer 111 toxic megacolon 9, 83, 93, 124, 125

toxigenic stool culture 64, 70, 77 toxin A 6, 13, 14, 16, 30, 44-47, 49, 55, 64, 65, 67, 72, 98, 111, 124 toxin B 13, 14, 16, 30, 44-46, 55, 64, 65, 72, 111, 124 toxins 5-7, 13, 15, 16, 28, 30, 39, 44, 45, 47, 49, 50, 51, 55, 56, 64-69, 71, 74, 77, 98, 111, 124, 127, 130, 131 triclosan 150 trimethoprim 51, 159 trimethoprim/ sulfamethoxazole 51 tumor necrosis factor-alfa 46

V vaccine 112 Vancocin® 83 vancomycin (Vancocin®) 5, 6, 11, 42, 48, 50, 82-86, 89, 90, 92, 93, 96, 97, 99-103, 105-108, 110-113, 137, 154 vancomycin-resistant enterococci (VRE) 11, 42, 85, 137, 147, 148, 150, 153, 154 vasopressors 87, 94, 95, 125

W warfarin 89 white blood cell (WBC) count 95

X Xifaxan® 110

171

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