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) ��� Author(s): Stuart H. Cohen , MD, Dale N. Gerding , MD, Stuart Johnson , MD, Ciaran P. Kelly , MD, Vivian G. Loo , MD, L. Clifford McDonald , MD, Jacques Pepin , MD, Mark H. Wilcox , MD Source: Infection Control and Hospital Epidemiology, Vol. 31, No. 5 (May 2010), pp. 431-455 Published by: The University of Chicago Press on behalf of The Society for Healthcare Epidemiology of America Stable URL: http://www.jstor.org/stable/10.1086/651706 . Accessed: 03/02/2011 10:23 Your use of the JSTOR archive indicates your acceptance of JSTOR's Terms and Conditions of Use, available at . http://www.jstor.org/page/info/about/policies/terms.jsp. JSTOR's Terms and Conditions of Use provides, in part, that unless you have obtained prior permission, you may not download an entire issue of a journal or multiple copies of articles, and you may use content in the JSTOR archive only for your personal, non-commercial use. Please contact the publisher regarding any further use of this work. Publisher contact information may be obtained at . http://www.jstor.org/action/showPublisher?publisherCode=ucpress. . Each copy of any part of a JSTOR transmission must contain the same copyright notice that appears on the screen or printed page of such transmission. JSTOR is a not-for-profit service that helps scholars, researchers, and students discover, use, and build upon a wide range of content in a trusted digital archive. We use information technology and tools to increase productivity and facilitate new forms of scholarship. For more information about JSTOR, please contact support@jstor.org. The University of Chicago Press and The Society for Healthcare Epidemiology of America are collaborating with JSTOR to digitize, preserve and extend access to Infection Control and Hospital Epidemiology. http://www.jstor.org

infection control and hospital epidemiology may 2010, vol. 31, no. 5 s h e a - i d s a g u i d e l i n e 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) Stuart H. Cohen, MD Dale N. Gerding, MD Stuart Johnson, MD Ciaran P. Kelly, MD Vivian G. Loo, MD L. Clifford McDonald, MD Jacques Pepin, MD Mark H. Wilcox, MD Since publication of the Society for Healthcare Epidemiology of America position paper on Clostridium difficile infection in 1995, significant changes have occurred in the epidemiology and treatment of this infection. C. difficile remains the most important cause of healthcare- associated diarrhea and is increasingly important as a community pathogen. A more virulent strain of C. difficile has been identified and has been responsible for more-severe cases of disease worldwide. Data reporting the decreased effectiveness of metronidazole in the treatment of severe disease have been published. Despite the increasing quantity of data available, areas of controversy still exist. This guideline updates recommendations regarding epidemiology, diagnosis, treatment, and infection control and environmental management. Infect Control Hosp Epidemiol 2010 31(5):431-455 From the Department of Internal Medicine, Division of Infectious and Immunologic Diseases, University of California Davis Medical Center, Sacramento, California (S.H.C) the Research Service, Edward Hines Jr. Veterans Affairs Hospital, and Infectious Disease Division, Department of Medicine, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois (D.N.G, S.J.) the Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Massachusetts (C.P.K.) the Department of Microbiology, McGill University Health Center, Montreal, Quebec, Canada (V.G.L.) the Division of Healthcare Quality Promotion, National Center for Preparedness, Detection, and Control of Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia (L.C.M.) the Department of Microbiology and Infectious Diseases, University of Sherbrooke, Quebec, Canada (J.P.) and the Department of Microbiology, Leeds Teaching Hospitals National Health Service Trust and Institute of Molecular and Cellular Biology, University of Leeds, Leeds, United Kingdom (M.H.W.). Received February 4, 2010 accepted February 5, 2010 electronically published March 22, 2010. 2010 by The Society for Healthcare Epidemiology of America. All rights reserved. 0899-823X/2010/3105-0001$15.00. DOI: 10.1086/651706 executive summary This guideline is designed to improve the diagnosis and man- agement of Clostridium difficile infection (CDI) in adult pa- tients. A case of CDI is defined by the presence of symptoms (usually diarrhea) and either a stool test positive for C. difficile toxins or toxigenic C. difficile, or colonoscopic or histopath- ologic findings revealing pseudomembranous colitis. In ad- dition to diagnosis and management, recommended methods of infection control and environmental management of the pathogen are presented. The recommendations are based on the best available evidence and practices, as determined by a joint Expert Panel appointed by SHEA and the Infectious Diseases Society of America (IDSA) (the SHEA-IDSA Expert Panel). The use of these guidelines can be impacted by the size of the institution and the resources, both financial and laboratory, available in the particular clinical setting. I. Epidemiology: What are the minimum data that should be collected for surveillance purposes and how should the data be reported? 1. To increase comparability between clinical settings, use available standardized case definitions for surveillance of (1) healthcare facility (HCF)-onset, HCF-associated CDI (2) community-onset, HCF-associated CDI and (3) community-associated CDI (Figure 1) (B-III). 2. At a minimum, conduct surveillance for HCF-onset, HCF-associated CDI in all inpatient healthcare facilities, to detect outbreaks and monitor patient safety (B-III). 3. Express the rate of healthcare-associated CDI as the number of cases per 10,000 patient-days (B-III). 4. If CDI rates are high compared with those at other facilities or if an outbreak is noted, stratify rates by patient location in order to target control measures (B-III). II. Diagnosis: What is the best testing strategy to diagnose CDI in the clinical laboratory and what are acceptable options? 5. Testing for C. difficile or its toxins should be per- formed only on diarrheal (unformed) stool, unless ileus due to C. difficile is suspected (B-II).

432 infection control and hospital epidemiology may 2010, vol. 31, no. 5 6. Testing of stool from asymptomatic patients is not clinically useful, including use as a test of cure. It is not recommended, except for epidemiological studies. (B-III) 7. Stool culture is the most sensitive test and is essential for epidemiological studies (A-II). 8. Although stool culture is not clinically practical be- cause of its slow turnaround time, the sensitivity and spec- ificity of stool culture followed by identification of a tox- igenic isolate (ie, toxigenic culture), as performed by an ex- perienced laboratory, provides the standard against which other clinical test results should be compared (B-III). 9. Enzyme immunoassay (EIA) testing for C. difficile toxin A and B is rapid but is less sensitive than the cell cytotoxin assay, and it is thus a suboptimal alternative ap- proach for diagnosis (B-II). 10. Toxin testing is most important clinically, but is hampered by its lack of sensitivity. One potential strategy to overcome this problem is a 2-step method that uses EIA detection of glutamate dehydrogenase (GDH) as initial screening and then uses the cell cytotoxicity assay or tox- igenic culture as the confirmatory test for GDH-positive stool specimens only. Results appear to differ based on the GDH kit used therefore, until more data are available on the sensitivity of GDH testing, this approach remains an interim recommendation. (B-II) 11. Polymerase chain reaction (PCR) testing appears to be rapid, sensitive, and specific and may ultimately address testing concerns. More data on utility are necessary before this methodology can be recommended for routine testing. (B-II) 12. Repeat testing during the same episode of diarrhea is of limited value and should be discouraged (B-II). III. Infection Control and Prevention: What are the most important infection control measures to implement in the hospital during an outbreak of CDI? A. Measures for Healthcare Workers, Patients, and Visitors 13. Healthcare workers and visitors must use gloves (A-I) and gowns (B-III) on entry to a room of a patient with CDI. 14. Emphasize compliance with the practice of hand hygiene (A-II). 15. In a setting in which there is an outbreak or an increased CDI rate, instruct visitors and healthcare workers to wash hands with soap (or antimicrobial soap) and water after caring for or contacting patients with CDI (B-III). 16. Accommodate patients with CDI in a private room with contact precautions (B-III). If single rooms are not available, cohort patients, providing a dedicated commode for each patient (C-III). 17. Maintain contact precautions for the duration of diarrhea (C-III). 18. Routine identification of asymptomatic carriers (pa- tients or healthcare workers) for infection control purposes is not recommended (A-III) and treatment of such iden- tified patients is not effective (B-I). B. Environmental Cleaning and Disinfection 19. Identification and removal of environmental sources of C. difficile, including replacement of electronic rectal thermometers with disposables, can reduce the incidence of CDI (B-II). 20. Use chlorine-containing cleaning agents or other sporicidal agents to address environmental contamination in areas associated with increased rates of CDI (B-II). 21. Routine environmental screening for C. difficile is not recommended (C-III). C. Antimicrobial Use Restrictions 22. Minimize the frequency and duration of antimicro- bial therapy and the number of antimicrobial agents pre- scribed, to reduce CDI risk (A-II). 23. Implement an antimicrobial stewardship program (A-II). Antimicrobials to be targeted should be based on the local epidemiology and the C. difficile strains present, but restricting the use of cephalosporin and clindamycin (except for surgical antibiotic prophylaxis) may be partic- ularly useful (C-III). D. Use of Probiotics 24. Administration of currently available probiotics is not recommended to prevent primary CDI, as there are limited data to support this approach and there is a po- tential risk of bloodstream infection (C-III). IV. Treatment: Does the choice of drug for CDI matter and, if so, which patients should be treated and with which agent? 25. Discontinue therapy with the inciting antimicrobial agent(s) as soon as possible, as this may influence the risk of CDI recurrence (A-II). 26. When severe or complicated CDI is suspected, ini- tiate empirical treatment as soon as the diagnosis is sus- pected (C-III). 27. If the stool toxin assay result is negative, the decision to initiate, stop, or continue treatment must be individ- ualized (C-III). 28. If possible, avoid use of antiperistaltic agents, as they may obscure symptoms and precipitate toxic megacolon (C-III). 29. Metronidazole is the drug of choice for the initial episode of mild-to-moderate CDI. The dosage is 500 mg orally 3 times per day for 10���14 days. (A-I) 30. Vancomycin is the drug of choice for an initial ep- isode of severe CDI. The dosage is 125 mg orally 4 times per day for 10���14 days. (B-I) 31. Vancomycin administered orally (and per rectum, if ileus is present) with or without intravenously adminis- tered metronidazole is the regimen of choice for the treat-

practice guidelines for c. difficile infection in adults 433 ment of severe, complicated CDI. The vancomycin dosage is 500 mg orally 4 times per day and 500 mg in approx- imately 100 mL normal saline per rectum every 6 hours as a retention enema, and the metronidazole dosage is 500 mg intravenously every 8 hours. (C-III) 32. Consider colectomy for severely ill patients. Moni- toring the serum lactate level and the peripheral blood white blood cell count may be helpful in prompting a decision to operate, because a serum lactate level rising to 5 mmol/L and a white blood cell count rising to 50,000 cells per mL have been associated with greatly increased perioperative mortality. If surgical management is neces- sary, perform subtotal colectomy with preservation of the rectum. (B-II) 33. Treatment of the first recurrence of CDI is usually with the same regimen as for the initial episode (A-II) but should be stratified by disease severity (mild-to-moderate, severe, or severe complicated), as is recommended for treatment of the initial CDI episode (C-III). 34. Do not use metronidazole beyond the first recur- rence of CDI or for long-term chronic therapy because of potential for cumulative neurotoxicity (B-II). 35. Treatment of the second or later recurrence of CDI with vancomycin therapy using a tapered and/or pulse reg- imen is the preferred next strategy (B-III). 36. No recommendations can be made regarding pre- vention of recurrent CDI in patients who require continued antimicrobial therapy for the underlying infection (C-III). introduction Summary Definition of CDI A case definition of CDI should include the presence of symp- toms (usually diarrhea) and either a stool test result positive for C. difficile toxins or toxigenic C. difficile, or colonoscopic findings demonstrating pseudomembranous colitis. Definition of CDI The diagnosis of CDI should be based on a combination of clinical and laboratory findings. A case definition for the usual presentation of CDI includes the following findings: (1) the presence of diarrhea, defined as passage of 3 or more un- formed stools in 24 or fewer consecutive hours1-8 (2) a stool test result positive for the presence of toxigenic C. difficile or its toxins or colonoscopic or histopathologic findings dem- onstrating pseudomembranous colitis. The same criteria should used to diagnose recurrent CDI. A history of treatment with antimicrobial or antineoplastic agents within the pre- vious 8 weeks is present for the majority of patients.9 In clinical practice, antimicrobial use is often considered part of the operative definition of CDI, but it is not included here because of occasional reports of CDI in the absence of an- timicrobial use, usually in community-acquired cases.10 A re- sponse to specific therapy for CDI is suggestive of the di- agnosis. Rarely (in fewer than 1% of cases), a symptomatic patient will present with ileus and colonic distension with minimal or no diarrhea.11 Diagnosis in these patients is dif- ficult the only specimen available may be a small amount of formed stool or a swab of stool obtained either from the rectum or from within the colon via endoscopy. In such cases, it is important to communicate to the laboratory the necessity to do a toxin assay or culture for C. difficile on the nondi- arrheal stool specimen. Background The vast majority of anaerobic infections arise from endog- enous sources. However, a number of important clostridial infections and intoxications are caused by organisms acquired from exogenous sources. It is the ability of these organisms to produce spores that explains how C. difficile, a fastidiously anaerobic organism in its vegetative state, can be acquired from the environment. C. difficile is recognized as the pri- mary pathogen responsible for antibiotic-associated colitis and for 15%���25% of cases of nosocomial antibiotic-associ- ated diarrhea.12-14 C. difficile can be detected in stool specimens of many healthy children under the age of 1 year15,16 and a few percent of adults.17,18 Although these data support the potential for endogenous sources of human infection, there was early cir- cumstantial evidence to suggest that this pathogen could be transmissible and acquired from external sources. Cases often appear in clusters and outbreaks within institutions.19,20 An- imal models of disease also provide evidence for transmis- sibility of C. difficile.21,22 Subsequently, many epidemiologic studies of CDI confirm the importance of C. difficile as a transmissible nosocomial pathogen.1,9,23-25 Clinical Manifestations The clinical manifestations of infection with toxin-producing strains of C. difficile range from symptomless carriage, to mild or moderate diarrhea, to fulminant and sometimes fatal pseu- domembranous colitis.13,14,26 Several studies have shown that 50% or more of hospital patients colonized by C. difficile are symptomless carriers, possibly reflecting natural immunity.1, 3,5,27 Olson et al28 reported that 96% of patients with symp- tomatic C. difficile infection had received antimicrobials within the 14 days before the onset of diarrhea and that all had received an antimicrobial within the previous 3 months. Symptoms of CDI usually begin soon after colonization, with a median time to onset of 2���3 days.1,5,23,27 C. difficile diarrhea may be associated with the passage of mucus or occult blood in the stool, but melena or hemato- chezia are rare. Fever, cramping, abdominal discomfort, and a peripheral leukocytosis are common but found in fewer than half of patients.11,13,14,29 Extraintestinal manifestations, such as arthritis or bacteremia, are very rare.30-33 C. difficile ileitis or pouchitis has also been rarely recognized in patients who have previously undergone a total colectomy (for com- plicated CDI or some other indication).34 Clinicians should

434 infection control and hospital epidemiology may 2010, vol. 31, no. 5 table 1. Definitions of the Strength of Recommendations and the Quality of the Evidence Supporting Them Category and grade Definition Strength of recommendation A Good evidence to support a recommendation for or against use B Moderate evidence to support a recommendation for or against use C Poor evidence to support a recommendation Quality of evidence I Evidence from at least 1 properly randomized, controlled trial II Evidence from at least 1 well-designed clinical trial without randomization, from cohort or case-con- trolled analytic studies (preferably from more than 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 and reproduced from the Canadian Task Force on the Periodic Health Examination,39 with the permission of the Minister of Public Works and Government Services Canada, 2009. consider the possibility of CDI in hospitalized patients who have unexplained leukocytosis, and they should request stool be sent for diagnostic testing.35,36 Patients with severe disease may develop a colonic ileus or toxic dilatation and present with abdominal pain and distension but with minimal or no diarrhea.11,13,14 Complications of severe C. difficile colitis in- clude dehydration, electrolyte disturbances, hypoalbumine- mia, toxic megacolon, bowel perforation, hypotension, renal failure, systemic inflammatory response syndrome, sepsis, and death.11,24,25 Clinical Questions for the 2010 Update In 1995, the Society for Healthcare Epidemiology of America (SHEA) published a clinical position paper on C. difficile��� associated disease and colitis.37 For the current update, the epidemiology, diagnosis, infection control measures, and in- dications and agents for treatment from the 1995 position paper were reviewed by a joint Expert Panel appointed by SHEA and the Infectious Diseases Society of America (IDSA). The previous document is a source for a more detailed review of earlier studies. The SHEA-IDSA Expert Panel addressed the following clin- ical questions in this update: I. What are the minimum data that should be collected for surveillance purposes, and how should the data be re- ported? Have the risk factors for CDI changed? II. What is the best testing strategy to diagnose CDI in the clinical laboratory and what are acceptable options? III. What are the most important infection control mea- sures to implement in the hospital during an outbreak of CDI? IV. Does the choice of drug for treatment of CDI matter and, if so, which patients should be treated and with which agent? practice guidelines definition ���Practice guidelines are systematically developed statements to assist practitioners and patients in making decisions about appropriate health care for specific clinical circum- stances.38(p8) Attributes of good guidelines include validity, reliability, reproducibility, clinical applicability, clinical flex- ibility, clarity, multidisciplinary process, review of evidence, and documentation.���38(p8) update methodology Panel Composition The SHEA Board of Directors and the IDSA Standards and Practice Guidelines Committee convened a panel of experts in the epidemiology, diagnosis, infection control, and clini- cal management of adult patients with CDI to develop these practice guidelines. Literature Review and Analysis For the 2010 update, the SHEA-IDSA Expert Panel completed the review and analysis of data published since 1994. Com- puterized literature searches of PubMed were performed. The searches of the English-language literature from 1994 through April 2009 used the terms ���Clostridium difficile,��� ���epidemiol- ogy,��� ���treatment,��� and ���infection control��� and focused on hu- man studies. Process Overview In evaluating the evidence regarding the management of CDI, the Expert Panel followed a process used in the development of other SHEA-IDSA guidelines. The process included a sys- tematic weighting of the quality of the evidence and the strength of each recommendation (Table 1).39 Guidelines and Conflict of Interest All members of the Expert Panel complied with the SHEA and IDSA policy on conflicts of interest, which requires dis- closure of any financial or other interest that might be con- strued as constituting an actual, potential, or apparent con- flict. Members of the Expert Panel were provided with the SHEA and IDSA conflict of interest disclosure statement and