Clostridium difficile Infections: Diagnosis, Treatment, and PreventionPrepared for:Agency for Healthcare Research and Quality (AHRQ)www.ahrq.gov

The comparative effectiveness review (CER) processOverview of the CERIntroductionDetailed ResultsDirect comparisons of available diagnostic assays.Comparative effectiveness and harms of antibiotic treatments.Comparative effectiveness of nonstandard interventions to treat CDI or reduce the risk of recurrence.Effectiveness of prevention strategies.Conclusions

Outline of this CME Activity

Topics are nominated through a public process, which includes submissions from health care professionals, professional organizations, the private sector, policymakers, the public, and others. A systematic review of all relevant clinical studies is conducted by independent researchers, funded by AHRQ, to synthesize the evidence in a report summarizing what is known and not known about the select clinical issue. The research questions and the results of the report are subject to expert input, peer review, and public comment.The results of these reviews are summarized into Clinician and Consumer Research Summaries for use in decisionmaking and in discussions with patients. The research reviews, full report, and a link to the condensed research article in Annals of Internal Medicine are available at: www.effectivehealthcare.ahrq.gov.Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Review (CER) Development

The strength of evidence was classified into four broad categories:High - Further research is very unlikely to change the confidence in the estimate of effect.Moderate - Further research may change the confidence in the estimate of effect and may change the estimate.Low - Further research is likely to change the confidence in the estimate of effect and is likely to change the estimate. Insufficient - Evidence either is unavailable or does not permit estimation of an effect.Rating the Strength of Evidence From the CER

To conduct a systematic review and synthesize evidence for differences in:The accuracy of diagnostic testsThe effects of standard antibiotics to treat Clostridium difficile infection (CDI) in adult patients.Nonstandard interventions to prevent and treat CDI in adult patients. Prevention strategies.Overview: ObjectivesButler M, et al. AHRQ Comparative Effectiveness Review No. XXX. Available at: http://effectivehealthcare.ahrq.gov/index.

Data Sources: MEDLINE, the Cochrane Library, and Allied and Complementary Medicine (AMED)ClinicalTrials.gov and expert consultantsReference lists from relevant literatureReview Methods:Standard Evidence-based Practice Center methodsHigh-quality direct comparison studies were used to examine differences in diagnostic tests.Randomized controlled trials (RCTs) were used to examine comparative effectiveness of antibiotic treatment for CDIQualitative narrative analysis was used to synthesize evidence from all available study types for environmental prevention and nonstandard prevention and treatment, with the exception of probiotics as primary prevention.Overview: Methods

Direct comparisons of commercially available enzyme immunoassays for C. difficile toxins A and B did not find major differences in sensitivity or specificity. (Low strength evidence)Limited evidence suggests that tests for genes related to the production of C. difficile toxins may be more sensitive than immunoassays for toxins A and B while the comparisons of these test specificities were inconsistent.It is unclear whether the potential differences in the accuracy of the diagnostic tests being employed in practice would translate into differences in clinical behaviors or patient outcomes. Overview: Results for Diagnostic Testing

Initial cure rates are similar for oral vancomycin versus metronidazole and vancomycin versus fidaxomicin. (Moderate strength evidence)Recurrence rates were about 10 percent lower after treatment with fidaxomicin when compared with vancomycin (15 percent versus 25 percent; P = 0.005). (Moderate strength evidence)Patients treated with vancomycin for a non-NAP1 strain infection were about 3 times as likely to have a recurrence than patients treated with fidaxomicin, but patients with the NAP1 strain had recurrence rates that did not differ significantly by treatment. (Low strength evidence) NAP1: North American Pulsed Field type 1 strainOverview: Results for Treatment of CDI with Standard Antibiotics

Adding certain probiotics to antibiotics for primary treatment may increase the risk for fungemia-related complications in critically ill patients and adds no known benefit. (Low strength evidence)Probiotics, prebiotics, and toxin-neutralizing antibodies alone do not reduce primary hospital CDI incidence rates. (Low strength evidence)For patients who had one or more relapses in a 3-month time period, CDIW was well-tolerated and the overall response rate was similar to metronidazole. (Low strength evidence)Fecal flora reconstitution via fecal transplantation prevents recurrent infections for up to 1 year. (Low strength evidence)CDI recurrence rates were reduced three-fold when an oligofructose prebiotic (low strength evidence) or toxin-neutralizing antibodies (moderate strength evidence) were added to standard antibiotics.Overview: Results for Nonstandard Interventions to Treat CDI or Reduce the Risk of Recurrence

Appropriate prescribing practices that decrease the use of high-risk antimicrobials are associated with lower CDI incidence rates. (Low strength evidence)CDI incidence may be reduced by using disposable gloves and thermometers and by disinfection with chemicals that kill C. difficile spores. (Low strength evidence)Risk factors for CDI include antibiotic use, severe underlying disease, acid suppression, hospitalization in an ICU, age, and nonsurgical gastrointestinal procedures. (Low strength evidence)Overall, the use of multiple component interventions limits the ability to synthesize evidence in a meaningful way.Overview: Results for Prevention

Limited evidence on the comparisons of immunoassays and genetic tests do not provide guidance to change current diagnostic approaches. Comparisons of oral vancomycin and metronidazole as well as vancomycin and fidaxomicin demonstrate similar initial cure rates. Fidaxomicin is associated with significantly lower recurrence rates than vancomycin for patients infected with non-NAP1 strains of C. difficile. For patients with the NAP1 strain, recurrence rates did not differ by treatment. For patients with multiple recurrences, use of C. difficile immune whey or fecal flora reconstitution show promise, but evidence is low. Limited evidence supports current practices for prevention, including appropriate antibiotic stewardship to reduce the use of broad-spectrum antibiotics.Overview: Conclusions

Important healthcare-associated infection and growing health care problem.Estimated at 6.5 cases per 10,000 patient days in hospital.About 250,000 hospitalizations were associated with CDI in 2005.Elderly people in hospitals account for the majority of severe morbidity and mortality.Residents of long-term care facilities are also at higher risk.Incidence rates may increase by four or five-fold during outbreaks.Incidence and severity may be increasing due to the emergence of a hypervirulent strain of C. difficile.

Introduction:Incidence of C. difficile Infection (CDI)

C. difficile is a Gram-positive, spore-forming, anaerobic bacterium that can cause CDI when a toxigenic strain is ingested by a susceptible person.Toxigenic C. difficile strains produce toxin B (a cytotoxin) +/- toxin A (an enterotoxin).Asymptomatic colonization of a healthy persons colon is common; if colonic flora is disturbed (e.g., through antibiotic use), toxigenic C. difficile can cause disease. Risk factors include antibiotic use, increasing age, female gender, comorbidities, gastrointestinal procedures, and use of gastric acid suppression medications.C. difficile is also common in the community, being easily isolated from soil and water samples.New, more virulent strains have emerged since 2000 that put a larger population at risk.

Introduction: C. difficile Etiology

CDI symptoms can include varying levels of diarrhea severity, pseudomembranous colitis, or toxic megacolon.CDI recurs in about 20 percent of patients.A subset of recurrent patients spiral into several subsequent recurrences.

Introduction: Symptoms of CDI

Standard Antibiotic Treatment:Oral vancomycin and fidaxomicin are the only FDA-approved antibiotics to treat CDI.Other antibiotics such as metronidazole are commonly used to treat mild-to-moderate CDI.Only 11 trials were identified that evaluated different antimicrobials for treatment of CDI.Antibiotic Treatment for Recurrent/Refractory CDI:There was insufficient data to determine the most effective regimen and therefore not addressed in this research review.Nonstandard Interventions for Primary and Recurrent CDI:CER authors consolidated the evidence for alternative or nonstandard/nonantibiotic interventions that clinicians are using to treat primary and recurrent or refractory CDI patients.

Introduction: Current State of the Research on Antibiotic Therapy for CDI

Comparative Effectiveness of Diagnostic Assays for C. difficileImmunoassays for toxins A and B Toxin gene detection tests

Cytotoxicity assaysC. difficile cultureImmunoassays for toxinsToxin gene detection tests

Assays Commonly Used in CDI Diagnostics

Methods Evaluated for Detecting Toxigenic C. difficile

Diagnostic Assays InvestigatedNumber of Studies (n)Toxin A and B ImmunoassaysPremier Toxin A&B, Meridian7Tox A/B II, TechLab6Tox A/B QUIK CHEK, TechLab4ImmunoCard A&B, Meridian7Xpect Toxin A/B, Remel4ProSpecT Toxin A/B, Remel2VIDAS C. diff Tox A/B, bioMerieux4Gene Detection Tests GeneOhm, Becton Dickinson3GeneXpert, Cepheid2

16 paired comparisons of seven commonly used immunoassays for toxins A and B could not determine if significant differences existed in test sensitivities or specificities. (Low level of confidence)Tests that detect fragments of toxin-related genes may increase sensitivity, but may lose specificity. (Low level of confidence)There was insufficient evidence to determine whether any differences in sensitivity or specificity between diagnostic tests depend on patient or specimen characteristics or the clinical scenarios that lead to testing for toxigenic C. difficile.

Results of Direct Comparisons of Available Diagnostic Assays

Comparative Effectiveness of Standard Antibiotic Treatment for CDIFDA-approved antibioticsOther antibiotics

Initial cure rates are similar for oral vancomycin versus metronidazole and vancomycin versus fidaxomicin. (Moderate strength of evidence)Similarly, none of the other head-to-head trials demonstrated superiority of any single antimicrobial for initial clinical cure, recurrence, or mean days to resolution of diarrhea.Recurrence rates were about 10 percent lower after treatment with fidaxomicin when compared with vancomycin (P = 0.005). (Moderate strength of evidence)Patients treated with vancomycin for a non-NAP1 strain infection were about 3 times as likely to have a recurrence than patients treated with fidaxomicin, but patients with the NAP1 strain had recurrence rates that did not differ significantly by treatment. (Low strength of evidence)Comparative Effectiveness Results for Treating CDI With Antibiotics

Nonstandard Interventions to Treat CDI or Reduce the Risk of RecurrenceAntibiotics + probioticsProbioticsOligofructose prebioticFecal flora reconstitutionC. difficile-specific polyclonal antibody-enriched immune wheyToxin-neutralizing antibodiesToxin absorptive resinsIV immunoglobulin

Adjunctive therapy added to standard antibiotic therapy in the included studies consisted of:Probiotic containing Saccharomyces boulardii was added to oral vancomycin, metronidazole, or both.Probiotic containing Lactobacillus plantarum was added to metronidazole.Overall conclusions:Probiotics administered as an adjunct to antibiotic treatment were not more effective than treatment with antibiotics alone. (Low strength of evidence)Adding probiotics containing Saccharomyces spp. to antibiotics for primary treatment may increase the risk for fungemia-related complications in critically ill patients and adds no known benefit. (Low strength of evidence)

Comparative Effectiveness Results for Treatment of CDI With Antibiotics + Adjunctive Therapy

Primary hospital CDI incidence rates were not reduced in response to these individual treatments:Probiotics (Saccharomyces boulardii, Lactobacillus GG, L. acidophilus + Bifidobacterium bifidum, L. casei + L. bulgaris + Streptococcus thermophilus, L. plantarum)An oligofructose prebioticToxin-neutralizing antibodies (intravenous infusion of human monoclonal antibodies against C. difficile toxins A (CDA1) and B (CDB1)Low strength of evidenceNonstandard Interventions to Reduce the Occurrence of Primary CDI

For patients who had one or more relapses in a 3-month time period, CDIW was well-tolerated and the overall response rate was similar to metronidazole. (Low strength of evidence)Six case studies or case series indicated that fecal flora reconstitution via fecal transplantation prevented recurrent infections for up to 1 year. (Low strength of evidence)

Nonstandard Interventions for Treatment of Multiple Recurrences of CDI

CDI recurrence rates decreased 3-fold when an oligofructose prebiotic (low strength of evidence) or toxin-neutralizing antibodies (moderate strength of evidence) were added to standard antibiotics.

Nonstandard Interventions to Reduce CDI Recurrence Rates

C. difficile immune whey is well tolerated and may prevent recurrence of CDI at rates similar to metronidazole. (Low Strength of Evidence)Fecal flora reconstitution via fecal transplantation may prevent recurrent infections for up to 1 year. (Low Strength of Evidence)Probiotics, prebiotics, and toxin-neutralizing antibodies alone may not reduce CDI incidence rates. (Low Strength of Evidence)Oligofructose prebiotic (Low Strength of Evidence) and toxin-neutralizing antibodies (Moderate Strength of Evidence) have the potential to help reduce the risk of recurrent infections.Overall Conclusions: Nonstandard Interventions to Treat CDI or Reduce the Risk of Recurrence

Comparative Effectiveness of CDI Prevention StrategiesAntibiotic prescribing policiesInstitutional prevention strategiesBundled intervention strategiesSustainability of prevention strategiesCDI risk factors

Appropriate prescribing practices that decrease the use of high-risk antimicrobials may be associated with lower CDI incidence rates. (Low strength of evidence)The studies reviewed did not evaluate the cost, toxicities, or other related outcomes from the implementation of antibiotic stewardship policies.

Prevention Strategies for CDI Focusing on Antibiotic Prescribing Policies

Low strength of evidence suggested that CDI incidence may be reduced by using common contact barriers such as:Disposable glovesTympanic or disposable single-use thermometersDisinfection with chemicals, including hypochlorite solutions, aldehydes, and liquid vapor hydrogen peroxide, that kill C. difficile spores may lower CDI incidence. (Low strength of evidence)No studies determined if hand washing was more effective than alcohol gels; however, C. difficile spores are known to be resistant to alcohol-based hand rubs and other routinely used antiseptics.Institutional Prevention Strategies for CDI

They mainly evaluated effectiveness of CDI prevention during an epidemic or in a hyperendemic environment.Studies did not evaluate the sustainability of the interventions beyond the study period. The potential negative impact these interventions would have on the institutional environment other than cost was not evaluated in these studies but may include:Time needed to perform disinfection;Possible harm to surfaces or equipment from harsh decontamination chemicals;Failure of vapor disinfection systems; Exposure of patients and personnel to toxic chemicals; Rates of recontamination after hand washing that results from touching equipment or surfaces in patient rooms contaminated with C. difficile spores, which may persist on some surfaces for up to 5 months;The reduction in direct patient-care contact due to isolation.

Limitations of Research on CDI Prevention

Newer DNA-based diagnostic C. difficile assays have given promising initial results; however, it is not clear how differences in diagnostic test sensitivity and specificity affect clinical decisions and patient outcomes. Research is needed to determine the optimal institution-wide CDI-prevention strategies for addressing multiple potential routes of transmission and for reducing patient susceptibility. Research is still needed to determine if nonantibiotic interventionssuch as probiotics, prebiotics, toxin-absorbing compounds, and fecal flora reconstitution, among otherscan be effective in preventing primary or recurrent CDI. More research is needed to determine if oral vancomycin may provide higher initial cure rates for severely ill CDI patients; however, more research is necessary in this patient population. A consensus needs to be reached between clinical and research-oriented definitions of CDI with regard to diarrhea, that is, the number and consistency of stools.Gaps in Knowledge

What risk factors they may have that makes them or someone they care for susceptible to CDI. If they or someone they care for has CDI, how they can help prevent the spread of the infection. Which antibiotic treatment is appropriate for their CDI. Whether or not nonstandard interventions would be beneficial especially considering their availability and potential costs to the patient.What To Discuss With Your Patients

Clostridium difficile Infections: Diagnosis, Treatment, and Prevention This slide set is based on the research presented in a comparative effectiveness review (CER), Effectiveness of Early Diagnosis, Prevention, and Treatment of Clostridium difficile Infection, that was developed by the Minnesota Evidence-based Practice Center for the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. 290-02-0009-EPC2). The findings and conclusions in this document are those of the author(s), who are responsible for its contents; the findings and conclusions do not necessarily represent the views of AHRQ. Therefore, no statement in this report should be construed as an official position of AHRQ or of the U.S. Department of Health and Human Services. The information presented here is intended to help health care decision makersclinicians, health system leaders, and policymakers, among othersmake well-informed decisions and thereby improve the quality of health care services. This information is not intended to be a substitute for the application of clinical judgment. Anyone who makes decisions concerning the provision of clinical care should consider this report in the same way as any medical reference and in conjunction with all other pertinent information, that is, in the context of available resources and circumstances presented by individual patients.

Several electronic databases (through August 2011), grey literature, trial registries, and reference lists were searched for relevant material. The methods used to develop this CER followed version 1.0 of the Methods Reference Guide for Effectiveness and Comparative Effectiveness Reviews published by AHRQ. (Draft available at: http://effectivehealthcare.ahrq.gov/repFiles/2007_10DraftMethodsGuide.pdf.)

References:Agency for Healthcare Research and Quality. Methods Reference Guide for Effectiveness and Comparative Effectiveness Reviews, Version 1.0. Rockville, MD: Agency for Healthcare Research and Quality; Draft Posted October 2007. Available at: effectivehealthcare.ahrq.gov/repFiles/2007_10DraftMethodsGuide.pdf.

Butler M, Bliss D, Drekonja D, Filice G, Rector T, MacDonald R, Wilt T. Effectiveness of Early Diagnosis, Prevention, and Treatment of Clostridium difficile Infection. Comparative Effectiveness Review No. 31 (Prepared by the Minnesota Evidence-based Practice Center under Contract No. 290-02-0009.) AHRQ Publication No. 11(12)-EHC051-EF. Rockville, MD. Agency for Healthcare Research and Quality. December 2011. Available at: http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=772.

Outline of this CME ActivityThis slide set is based on the research presented in a comparative effectiveness review (CER), Effectiveness of Early Diagnosis, Prevention, and Treatment of Clostridium difficile Infection, that was developed by the Minnesota Evidence-based Practice Center for the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. 290-02-0009-EPC2). CERs represent systematic reviews of the literature and usually compare two or more types of treatments, such as different drugs, devices, or procedures for the same disease. The methods used to develop this CER followed version 1.0 of the Methods Reference Guide for Effectiveness and Comparative Effectiveness Reviews published by AHRQ . (Draft available at: http://effectivehealthcare.ahrq.gov/repFiles/2007_10DraftMethodsGuide.pdf).

This activity will cover the current evidence from several electronic databases (through August 2011), grey literature, trial registries, and reference lists. The comparative effectiveness review process will be discussed briefly, including the specific questions addressed in this CER and the results from this research. Finally, the data that is most applicable to clinicians and policy decisionmakers are presented.

References:Agency for Healthcare Research and Quality. Methods Reference Guide for Effectiveness and Comparative Effectiveness Reviews, Version 1.0. Rockville, MD: Agency for Healthcare Research and Quality; Draft Posted October 2007. Available at: http://effectivehealthcare.ahrq.gov/repFiles/2007_10DraftMethodsGuide.pdf.Butler M, Bliss D, Drekonja D, Filice G, Rector T, MacDonald R, Wilt T. Effectiveness of Early Diagnosis, Prevention, and Treatment of Clostridium difficile Infection. Comparative Effectiveness Review No. 31 (Prepared by the Minnesota Evidence-based Practice Center under Contract No. 290-02-0009.) AHRQ Publication No. 11(12)-EHC051-EF. Rockville, MD. Agency for Healthcare Research and Quality. December 2011. Available at: www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=772Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Review (CER) Development

Topics are nominated through a public process, which includes submissions from health care professionals, professional organizations, the private sector, policymakers, the public, and others. A systematic review of all relevant clinical studies is conducted by independent researchers, who are funded by AHRQ, to synthesize the evidence in a report summarizing what is known and not known about the select clinical issue. The research questions and the results of the report are subject to expert input, peer review, and public comment. The results of these reviews are summarized into Clinician and Consumer Research Summaries for use in decisionmaking and in discussions with patients. The research reviews and the full report, with references for included and excluded studies, are available at www.effectivehealthcare.ahrq.gov. After the CER was finalized, a condensed version of the research titled Comparative Effectiveness of Clostridium difficile Treatments: A Systematic Review was published in the Annals of Internal Medicine (available at: http://www.annals.org).

References:Butler M, Bliss D, Drekonja D, Filice G, Rector T, MacDonald R, Wilt T. Effectiveness of Early Diagnosis, Prevention, and Treatment of Clostridium difficile Infection. Comparative Effectiveness Review No. 31 (Prepared by the Minnesota Evidence-based Practice Center under Contract No. 290-02-0009.) AHRQ Publication No. 11(12)-EHC051-EF. Rockville, MD. Agency for Healthcare Research and Quality. December 2011. Available at: http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=772.

Butler M, Bliss D, Drekonja D, et al. Comparative Effectiveness of Clostridium difficile Treatments: A Systematic Review Ann Intern Med 2011 Dec. Available at: http://www.annals.org.Rating the Strength of Evidence From the CER The EPC GRADE approach, based on the standard GRADE approach, was used to assess the quality of the body of evidence for each outcome. The overall strength of evidence was graded as high (further research is very unlikely to change the confidence in the estimate of effect), moderate (further research may change the confidence in the estimate of effect and may change the estimate), low (further research is likely to change the confidence in the estimate of effect and is likely to change the estimate), or insufficient (evidence either is unavailable or does not permit estimation of an effect). The authors also independently evaluated the applicability to real-world practice of the total body of evidence within a given clinical indication using the PICOTS framework (population, intervention, comparator, outcome, timing, and setting).

References:Agency for Healthcare Research and Quality. Methods reference guide for effectiveness and comparative effectiveness reviews, Version 1.0. Rockville, MD: Agency for Health Care Research and Quality; Draft Posted October 2007. Available at: http://www.effectivehealthcare.ahrq.gov/repFiles/2007_10DraftMethodsGuide.pdf.

Butler M, Bliss D, Drekonja D, Filice G, Rector T, MacDonald R, Wilt T. Effectiveness of Early Diagnosis, Prevention, and Treatment of Clostridium difficile Infection. Comparative Effectiveness Review No. 31 (Prepared by the Minnesota Evidence-based Practice Center under Contract No. 290-02-0009.) AHRQ Publication No. 11(12)-EHC051-EF. Rockville, MD. Agency for Healthcare Research and Quality. December 2011. Available at: http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=772.Overview: ObjectivesThe objective of the comparative effectiveness review was to conduct a systematic review and synthesize evidence for differences in the accuracy of diagnostic tests, and the effects of interventions to prevent and treat C. difficile associated infection (CDI) in adult patients.

Reference:Butler M, Bliss D, Drekonja D, Filice G, Rector T, MacDonald R, Wilt T. Effectiveness of Early Diagnosis, Prevention, and Treatment of Clostridium difficile Infection. Comparative Effectiveness Review No. 31 (Prepared by the Minnesota Evidence-based Practice Center under Contract No. 290-02-0009.) AHRQ Publication No. 11(12)-EHC051-EF. Rockville, MD. Agency for Healthcare Research and Quality. December 2011. Available at: http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=772.Overview: MethodsSearching for relevant literature was conducted in MEDLINE, the Cochrane Library, and Allied and Complementary Medicine (AMED). ClinicalTrials.gov and expert consultants provided leads to additional studies. Reference lists from relevant literature were also manually searched. Standard Evidence-based Practice Center methods were employed. Screening of abstracts and full text articles to identify studies meeting inclusion/exclusion criteria was performed by two independent reviewers. High-quality direct comparison studies were used to examine differences in diagnostic tests. Randomized controlled trials (RCTs) were used to examine comparative effectiveness of antibiotic treatment for CDI. Quality of data extraction was checked by separate reviewers. Quality ratings and strength of evidence grading was performed on included studies. Evidence on diagnostic tests was quantitatively synthesized focusing on differences between test sensitivities and specificities. Evidence on antibiotic treatment was quantitatively examined using pooled analysis. Qualitative narrative analysis was used to synthesize evidence from all available study types for environmental prevention and nonstandard prevention and treatment, with the exception of probiotics as primary prevention.

Reference:Butler M, Bliss D, Drekonja D, Filice G, Rector T, MacDonald R, Wilt T. Effectiveness of Early Diagnosis, Prevention, and Treatment of Clostridium difficile Infection. Comparative Effectiveness Review No. 31 (Prepared by the Minnesota Evidence-based Practice Center under Contract No. 290-02-0009.) AHRQ Publication No. 11(12)-EHC051-EF. Rockville, MD. Agency for Healthcare Research and Quality. December 2011. Available at: http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=772.

Overview: Results for Diagnostic TestingOverall, literature was sparse and strength of evidence was generally low due to small sample sizes or lack of adequate controls. For diagnostic testing, direct comparisons of commercially available enzyme immunoassays for C. difficile toxins A and B did not find major differences in sensitivity or specificity. Limited evidence suggests that tests for genes related to the production of C. difficile toxins may be more sensitive than immunoassays for toxins A and B while the comparisons of these test specificities were inconsistent. It is not clear how differences in diagnostic test sensitivity and specificity will in turn affect clinical decisions and patient outcomes.

Reference:Butler M, Bliss D, Drekonja D, Filice G, Rector T, MacDonald R, Wilt T. Effectiveness of Early Diagnosis, Prevention, and Treatment of Clostridium difficile Infection. Comparative Effectiveness Review No. 31 (Prepared by the Minnesota Evidence-based Practice Center under Contract No. 290-02-0009.) AHRQ Publication No. 11(12)-EHC051-EF. Rockville, MD. Agency for Healthcare Research and Quality. December 2011. Available at: http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=772.Overview: Results for Treatment of CDI with Standard AntibioticsFor standard antibiotic treatment, no antimicrobial is clearly superior for the initial cure of CDI. There is moderate strength evidence that vancomycin has similar initial cure rates as metronidazole as well as fidaxomicin. Moderate strength evidence also suggests that recurrence is reduced by 10 percent when patients were treated with fidaxomicin when compared with vancomycin. This reduction is most likely due to infections with a non-NAP1 (non-North American Pulsed Field type 1) strain of C. difficile. There is low strength evidence that patients treated with vancomycin for a non-NAP1 strain infection were about 3 times as likely to have a recurrence than patients treated with fidaxomicin, but patients with the NAP1 strain had recurrence rates that did not differ significantly by treatment.

Reference:Butler M, Bliss D, Drekonja D, Filice G, Rector T, MacDonald R, Wilt T. Effectiveness of Early Diagnosis, Prevention, and Treatment of Clostridium difficile Infection. Comparative Effectiveness Review No. 31 (Prepared by the Minnesota Evidence-based Practice Center under Contract No. 290-02-0009.) AHRQ Publication No. 11(12)-EHC051-EF. Rockville, MD. Agency for Healthcare Research and Quality. December 2011. Available at: http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=772.Overview: Results for Nonstandard Interventions to Treat CDI or Reduce the Risk of RecurrenceNumerous potential new forms of treatment are being examined in placebo controlled RCTs, case series, and case reports. There is low strength evidence that adding probiotics containing Saccharomyces cerevisiae or Saccharomyces boulardii to antibiotics for primary treatment may increase the risk for fungemia-related complications in critically ill patients and adds no known benefit. Probiotics, prebiotics, and toxin-neutralizing antibodies alone do not reduce primary hospital CDI incidence rates. C. difficile immune whey (CDIW) is well-tolerated and the overall response rate was similar to metronidazole. Fecal flora reconstitution via fecal transplantation prevents recurrent infections for up to 1 year. CDI recurrence rates were reduced three-fold when an oligofructose prebiotic or toxin-neutralizing antibodies were added to standard antibiotics.

Reference:Butler M, Bliss D, Drekonja D, Filice G, Rector T, MacDonald R, Wilt T. Effectiveness of Early Diagnosis, Prevention, and Treatment of Clostridium difficile Infection. Comparative Effectiveness Review No. 31 (Prepared by the Minnesota Evidence-based Practice Center under Contract No. 290-02-0009.) AHRQ Publication No. 11(12)-EHC051-EF. Rockville, MD. Agency for Healthcare Research and Quality. December 2011. Available at: http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=772.Overview: Results for PreventionLow strength of evidence in favor of antibiotic restriction policies for prevention was found. Environmental preventive interventions such as glove use and disposable thermometers reduce CDI incidence, but have limited evidence. Identified risk factors for CDI include antibiotic use, severe underlying disease, acid suppression, hospitalization in an ICU, age, and nonsurgical gastrointestinal procedures. However, this literature is largely based on controlling outbreaks. Use of multiple component interventions further limits the ability to synthesize evidence in a meaningful way.

Reference:Butler M, Bliss D, Drekonja D, Filice G, Rector T, MacDonald R, Wilt T. Effectiveness of Early Diagnosis, Prevention, and Treatment of Clostridium difficile Infection. Comparative Effectiveness Review No. 31 (Prepared by the Minnesota Evidence-based Practice Center under Contract No. 290-02-0009.) AHRQ Publication No. 11(12)-EHC051-EF. Rockville, MD. Agency for Healthcare Research and Quality. December 2011. Available at: http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=772.

Overview: ConclusionsGiven the frequency and severity of CDI and the fact that future reimbursement policy may withhold payment for hospital-acquired infections, this is an under-researched topic. More precise estimates of the magnitude of differences in test sensitivities and specificities are needed. More importantly, studies have not established that any of the possible differences in test accuracy would lead to substantially different patient outcomes in clinical practice. Therefore, limited evidence on the comparisons of immunoassays and genetic tests do not provide guidance to change current diagnostic approaches. More research on effective treatment and unintended consequences of treatment, such as resistance, is needed. Gut flora may be important, but improved understanding of healthy gut ecology and the complex interactions is necessary before continuing to pursue probiotics. Comparisons of oral vancomycin and metronidazole as well as vancomycin and fidaxomicin demonstrate similar initial cure rates. Fidaxomicin is associated with significantly lower recurrence rates than vancomycin for patients infected with non-NAP1 strains of C. difficile. For patients with the NAP1 strain, recurrence rates did not differ by treatment. For patients with multiple recurrences, use of C. difficile immune whey or fecal flora reconstitution show promise, but evidence is low. Limited evidence supports current practices for prevention, including appropriate antibiotic stewardship to reduce the use of broad-spectrum antibiotics.

Reference:Butler M, Bliss D, Drekonja D, Filice G, Rector T, MacDonald R, Wilt T. Effectiveness of Early Diagnosis, Prevention, and Treatment of Clostridium difficile Infection. Comparative Effectiveness Review No. 31 (Prepared by the Minnesota Evidence-based Practice Center under Contract No. 290-02-0009.) AHRQ Publication No. 11(12)-EHC051-EF. Rockville, MD. Agency for Healthcare Research and Quality. December 2011. Available at: http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=772.Introduction: Incidence of C. difficile Infection (CDI)Clostridium difficile infection (CDI) is a serious healthcare-associated infection and a growing health care problem. CDI incidence is estimated at 6.5 cases per 10,000 patient days in hospital. About 250,000 hospitalizations were associated with CDI in 2005. Direct attributable mortality from CDI has been reported to be as high as 6.9 percent of cases. Elderly people in hospitals account for the vast majority of severe morbidity and mortality. Residents of long-term care facilities are also at higher risk. Incidence rates may increase by four-fold or five-fold during outbreaks. The increase in incidence and severity of C. difficile infection may be attributed to the emergence of a hypervirulent C. difficile strain, known as the North American Pulsed Field type 1 (NAP1) strain.

References:Brandt LJ, Kosche KA, Greenwald DA, et al. Clostridium difficile-associated diarrhea in the elderly. Am J Gastroenterol 1999 Nov; 94(11):32636. http://www.ncbi.nlm.nih.gov/pubmed/10566727 Butler M, Bliss D, Drekonja D, Filice G, Rector T, MacDonald R, Wilt T. Effectiveness of Early Diagnosis, Prevention, and Treatment of Clostridium difficile Infection. Comparative Effectiveness Review No. 31 (Prepared by the Minnesota Evidence-based Practice Center under Contract No. 290-02-0009.) AHRQ Publication No. 11(12)-EHC051-EF. Rockville, MD. Agency for Healthcare Research and Quality. December 2011. Available at: http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=772. 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. Clinical Infect Dis 2009 Mar 1; 48(5):56876. www.ncbi.nlm.nih.gov/pubmed/19191641 Hebuterne X. Gut changes attributed to ageing: effects on intestinal microflora. Curr Opin Clin Nutr Metab Care 2003 Jan; 6(1):4954. www.ncbi.nlm.nih.gov/pubmed/12496680 Jarvis WR, Schlosser J, Jarvis AA, et al. National point prevalence of Clostridium difficile in US health care facility inpatients, 2008. Am J Infect Control 2009 May; 37(4):263-70. www.ncbi.nlm.nih.gov/pubmed/19278754 Kim J, Smathers SA, Prasad P, et al. Epidemiological features of Clostridium difficile-associated disease among inpatients at children's hospitals in the United States, 2001-2006. Pediatrics 2008 Dec; 122(6):126670. www.ncbi.nlm.nih.gov/pubmed/19047244 Laffan AM, Bellantoni MF, Greenough WB, 3rd, et al. Burden of Clostridium difficile-associated diarrhea in a long-term care facility. J Am Geriatr Soc 2006 Jul; 54(7):106873. www.ncbi.nlm.nih.gov/pubmed/16866677 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 Dec 8; 353(23):24429. www.ncbi.nlm.nih.gov/pubmed/16322602 Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011 Feb 3; 364(5):422-31. www.ncbi.nlm.nih.gov/pubmed/21288078. Donald LC. Confronting Clostridium difficile in inpatient health care facilities. Clin Infect Dis 2007 Nov 15; 45(10):12746. www.ncbi.nlm.nih.gov/pubmed/17968820 Simor AE, Bradley SF, Strausbaugh LJ, et al. Clostridium difficile in long-term-care facilities for the elderly. Infect Control Hosp Epidemiol 2002 Nov; 23(11):696703. www.ncbi.nlm.nih.gov/pubmed/12452300Introduction: C. difficile Etiology

Clostridium difficile is a Gram-positive, spore-forming, anaerobic bacterium that can cause CDI when a toxigenic strain is ingested by a susceptible person. In order for CDI to develop, a person must be infected with a strain of C. difficile capable of making toxin in the persons colon. Toxigenic strains are those that make toxin B (a cytotoxin), with or without toxin A (an enterotoxin). Approximately 12 percent of healthy individuals are colonized with C. difficile. If these people have usual, healthy colonic flora, the risk of developing CDI is very low. There is a small risk of CDI if the colon flora becomes disturbed, commonly through antibiotic use, if the person is colonized with a toxigenic strain. The immune status of the patient also contributes to the risk of developing CDI and the experienced severity. Other risk factors include increasing age, female gender, comorbidities, gastrointestinal procedures, and use of gastric acid suppression medications. Risk profiles for recurrent CDI are similar. In addition to institutional care environments, C. difficile is also common in the community, being easily isolated from soil and water samples. New, more virulent strains have emerged since 2000. Characteristics associated with hypervirulent strains can include increased toxin production, an additional binary toxin, hypersporulation, and high-level resistance to fluoroquinolone antibiotics. These new strains affect a wider population, often people with a lack of established risk factors for CDI and include children, pregnant women, and other healthy adults.

References:Aseeri M, Schroeder T, Kramer J, et al. Gastric acid suppression by proton pump inhibitors as a risk factor for Clostridium difficile-associated diarrhea in hospitalized patients. Am J Gastroenterol 2008 Sep; 103(9):230813. www.ncbi.nlm.nih.gov/pubmed/18702653

Aslam S, Musher DM. An update on diagnosis, treatment, and prevention of Clostridium difficile-associated disease. Gastroenterol Clin North Am 2006 Jun; 35(2):31535. www.ncbi.nlm.nih.gov/pubmed/16880068

Bignardi GE. Risk factors for Clostridium difficile infection. J Hosp Infect 1998 Sep; 40(1):115. www.ncbi.nlm.nih.gov/pubmed/9777516

Butler M, Bliss D, Drekonja D, Filice G, Rector T, MacDonald R, Wilt T. Effectiveness of Early Diagnosis, Prevention, and Treatment of Clostridium difficile Infection. Comparative Effectiveness Review No. 31 (Prepared by the Minnesota Evidence-based Practice Center under Contract No. 290-02-0009.) AHRQ Publication No. 11(12)-EHC051-EF. Rockville, MD. Agency for Healthcare Research and Quality. December 2011. Available at: www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=772

Centers for Disease Control and Prevention. Severe Clostridium difficile-associated disease in populations previously at low risk: four states, 2005. MMWR Morb Mortal Wkly Rep 2005 Dec 2; 54(47):12015. www.ncbi.nlm.nih.gov/pubmed/16319813

Cunningham R, Dial S. Is over-use of proton pump inhibitors fuelling the current epidemic of Clostridium difficile-associated diarrhea? J Hosp Infect 2008 Sep; 70(1):16. www.ncbi.nlm.nih.gov/pubmed/18602190

Dial S, Alrasadi K, Manoukian C, et al. Risk of Clostridium difficile diarrhea among hospital inpatients prescribed proton pump inhibitors: cohort and case-control studies. CMAJ 2004 Jul 6; 171(1):338. www.ncbi.nlm.nih.gov/pubmed/15238493

Dial S, Delaney JAC, Barkun AN, et al. Use of gastric acid-suppressive agents and the risk of community-acquired Clostridium difficile-associated disease. JAMA 2005 Dec 21; 294(23):298995. Available at: www.ncbi.nlm.nih.gov/pubmed/16414946

Garey KW, Sethi S, Yadav Y, et al. Meta-analysis to assess risk factors for recurrent Clostridium difficile infection. J Hosp Infect 2008 Dec; 70(4):298304. www.ncbi.nlm.nih.gov/pubmed/18951661

Gerding DN, Muto CA, Owens RC, Jr. Measures to control and prevent Clostridium difficile infection. Clin Infect Dis 2008 Jan 15; 46 Suppl 1:S439. www.ncbi.nlm.nih.gov/pubmed/18177221

Howell MD, Novack V, Grgurich P, et al. Iatrogenic gastric acid suppression and the risk of nosocomial Clostridium difficile infection. Arch Intern Med 2010 May 10; 170(9):78490. www.ncbi.nlm.nih.gov/pubmed/20458086

Jarvis WR, Schlosser J, Jarvis AA, et al. National point prevalence of Clostridium difficile in US health care facility inpatients, 2008. Am J Infect Control 2009 May; 37(4):26370. www.ncbi.nlm.nih.gov/pubmed/19278754

Kim KH. Isolation of Clostridium difficile from the environment and contacts of patients with antibiotic-associated colitis. J Infect Dis 1981 Jan; 143(1):4250.www.ncbi.nlm.nih.gov/pubmed/7217711

Leonard J, Marshall JK, Moayyedi P. Systematic review of the risk of enteric infection in patients taking acid suppression. Am J Gastroenterol 2007 Sep; 102(9):204756; quiz 57. www.ncbi.nlm.nih.gov/pubmed/17509031

Linsky A, Gupta K, Lawler EV, et al. Proton pump inhibitors and risk for recurrent Clostridium difficile infection. Arch Intern Med 2010 May 10; 170(9):7728. www.ncbi.nlm.nih.gov/pubmed/20458084

McFarland LV. Renewed interest in a difficult disease: Clostridium difficile infections--epidemiology and current treatment strategies. Curr Opin Gastroenterol 2009 Jan; 25(1):2435. www.ncbi.nlm.nih.gov/pubmed/19114771

Thibault A, Miller MA, Gaese C. Risk factors for the development of Clostridium difficile-associated diarrhea during a hospital outbreak. Infect Control Hosp Epidemiol 1991 Jun; 12(6):3458. www.ncbi.nlm.nih.gov/pubmed/2071877

Viscidi R, Willey S, Bartlett JG. Isolation rates and toxigenic potential of Clostridium difficile isolates from various patient populations. Gastroenterol 1981 Jul; 81(1):59. www.ncbi.nlm.nih.gov/pubmed/7239125Introduction: Symptoms of CDISymptoms of CDI can include varying levels of diarrhea severity, pseudomembranous colitis, or even toxic megacolon. CDI recurs in about 20 percent of patients; a subset of recurrent patients spiral into several subsequent recurrences.

References:Butler M, Bliss D, Drekonja D, Filice G, Rector T, MacDonald R, Wilt T. Effectiveness of Early Diagnosis, Prevention, and Treatment of Clostridium difficile Infection. Comparative Effectiveness Review No. 31 (Prepared by the Minnesota Evidence-based Practice Center under Contract No. 290-02-0009.) AHRQ Publication No. 11(12)-EHC051-EF. Rockville, MD. Agency for Healthcare Research and Quality. December 2011. Available at: http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=772 Fekety R. Guidelines for the diagnosis and management of Clostridium difficile-associated diarrhea and colitis. American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol 1997 May; 92(5):739-50. www.ncbi.nlm.nih.gov/pubmed/9149180 van Nood E, Speelman P, Kuijper EJ, et al. Struggling with recurrent Clostridium difficile infections: is donor faeces the solution? Euro Surveill 2009; 14(34). www.ncbi.nlm.nih.gov/pubmed/19712646.

Introduction: Current State of the Research on Antibiotic Therapy for CDI FDA-approved antibiotics for the treatment of CDI include oral vancomycin and fidaxomicin. However, concerns about antibiotic overuse, increasing pathogen resistance, and cost have led to the use of other antibiotics such as metronidazole to treat mild-to-moderate CDI. Metronidazole and vancomycin are the two most commonly used treatments, but they are ineffective in 8 to 36 percent of patients with primary CDIs, and there are no antibiotics that kill C. difficile spores. Also, relapse or recurrence occurs in 20 to 25 percent of patients. For these reasons, there is interest in a comprehensive review of the comparative effectiveness of current antibiotic treatments for CDI and the use of nonstandard interventions for multiple recurrences.

Reference:Butler M, Bliss D, Drekonja D, Filice G, Rector T, MacDonald R, Wilt T. Effectiveness of Early Diagnosis, Prevention, and Treatment of Clostridium difficile Infection. Comparative Effectiveness Review No. 31 (Prepared by the Minnesota Evidence-based Practice Center under Contract No. 290-02-0009.) AHRQ Publication No. 11(12)-EHC051-EF. Rockville, MD. Agency for Healthcare Research and Quality. December 2011. Available at: http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=772.Comparative Effectiveness of Diagnostic Assays for C. difficileThe included studies used clinical stool specimens from patients suspected to have CDI. Also included were those studies that concurrently compared at least two diagnostic tests in the same laboratory using the same stool samples and using the same reference standard to reduce heterogeneity in the estimates. Studies must have used toxigenic culture, cell cytotoxicity assay, or combinations of tests as the reference test for toxigenic CDI. Direct comparisons of diagnostic tests without a reference test were not included. Studies that included patient outcomes or outcomes related to changes in therapy were identified. The results are presented in positive terms, that is, true positives (sensitivity) and false positives (1 minus specificity). Comparisons of diagnostic tests in terms of differences in their sensitivity (true positives for toxigenic C. difficile) and specificity (true negatives for toxigenic C. difficile) are provided as these statistics are the most relevant to clinical decisionmakers. Studies focus on the comparative diagnostic accuracy of commonly used rapid tests, such as immunoassays for C. difficile toxin and toxin gene detection tests, which may reduce the time lapse between the onset of symptoms and laboratory confirmation of CDI and treatment decisions. Repeat testing of selected specimens does not provide good comparative information about test accuracy and therefore is not covered in the focused review of diagnostic test accuracy.

Reference:Butler M, Bliss D, Drekonja D, Filice G, Rector T, MacDonald R, Wilt T. Effectiveness of Early Diagnosis, Prevention, and Treatment of Clostridium difficile Infection. Comparative Effectiveness Review No. 31 (Prepared by the Minnesota Evidence-based Practice Center under Contract No. 290-02-0009.) AHRQ Publication No. 11(12)-EHC051-EF. Rockville, MD. Agency for Healthcare Research and Quality. December 2011. Available at: http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=772Assays Commonly Used in CDI DiagnosticsCytotoxicity assay. The cultured cell cytotoxicity assay often has been used as a reference test for evaluating new diagnostic tests for toxigenic C. difficile. Briefly, a diluted and filtered aliquot of a stool sample is mixed with cultured test cells. The test cells are examined for toxin effects (cell rounding) that are not seen in comparator test cells where an excess amount of antitoxin is present. A cytotoxicity assay requires up to 48 hours for the toxin effects to appear. Cytotoxicity testing is not a perfectly accurate gold standard. Methodological differences in the time to process and dilution of stool samples, the age and type of cultured test cells being used for the test, the antitoxins, and the interpretation of results all can cause cytotoxicity assay results to vary. Culturing C. difficile organisms. Culturing C. difficile by anaerobic incubation of fecal aliquots on selective cycloserine-cefoxitin, fructose agar, or other media can be more sensitive than the cytotoxicity assay for detecting the presence of C. difficile organisms. However, C. difficile culture techniques also are not standardized, are susceptible to methodological variation, and require expertise, equipment, and several days to complete. Cultured C. difficile organisms also have to test positive for disease-causing toxins. Therefore, culture of C. difficile from stool samples followed by a toxin-detection assay is considered the most sensitive method for detecting toxigenic C. difficile; however, the time it takes to complete these tests are not practical for clinical decisionmaking. Immunoassays for toxins. A variety of faster (within a few hours), less costly commercial immunoassays for C. difficile toxins are available. Initially, most immunoassays detected only toxin A. More recently it was discovered that a small but increasing number of clinically significant C. difficile strains produced only toxin B. When the performance of a diagnostic test depends on the level of toxins in test specimens and most organisms produce both toxins A and B, immunoassays that detect both toxins might be more sensitive if other critical factors such as dilution of the specimens are equal. Therefore, experts have recommended using immunoassays that can detect both toxins A and B. A highly sensitive and specific immunoassay for these toxins may be used as a second test after the stool culture. Data from the College of American Pathology proficiency testing program for C. difficile toxin detection indicated that 90 percent of labs used an immunoassay for toxins A and B in June 2009. The most commonly used tests were the Immunocard and Premier A & B test kits manufactured by Meridian, the TechLab Tox AB II and Toxin A/B QUIK CHEK kits, and the Remel ProSpecT and Xpect Toxin A/B tests. Toxin gene detection tests. Three tests of stool specimens for the presence of genes involved in the production of C. difficile toxins have recently become commercially available. These tests use the polymerase chain reaction to amplify targeted gene fragments to detect the presence of a gene or genes involved in the production of toxins, not the actual toxins. The target of the assays can be the genes that produce toxin B and a gene C that negatively regulates the production of toxins A and B. A mutation in gene C has been detected in an increasingly common hypervirulent strain of C. difficile that produces large amounts of toxins A and B. One concern about using the tests based on amplification of toxin gene fragments is that very small, clinically unimportant genetic residue or specimen contamination may be detected. Clinically speaking these would be false positives that would reduce test specificity. Therefore, some experts have recommended using this type of test only when a patient has clinical signs and symptoms suggestive of CDI.

Reference:Butler M, Bliss D, Drekonja D, Filice G, Rector T, MacDonald R, Wilt T. Effectiveness of Early Diagnosis, Prevention, and Treatment of Clostridium difficile Infection. Comparative Effectiveness Review No. 31 (Prepared by the Minnesota Evidence-based Practice Center under Contract No. 290-02-0009.) AHRQ Publication No. 11(12)-EHC051-EF. Rockville, MD. Agency for Healthcare Research and Quality. December 2011. Available at: http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=772.Methods Evaluated for Detecting Toxigenic C. difficileOverall, the reports included data on seven immunoassays for toxins A and B, one two-stage method where an immunoassay for glutamate dehydrogenase was combined with an immunoassay for toxins A and B, and two tests to detect gene fragments involved in the production of toxin B. Only three comparative studies included one of the recently FDA-approved toxin gene detection tests. Thus, the number and type of paired (within study) comparisons available for each diagnostic test varied considerably, and not all possible comparisons were available.

Reference:Butler M, Bliss D, Drekonja D, Filice G, Rector T, MacDonald R, Wilt T. Effectiveness of Early Diagnosis, Prevention, and Treatment of Clostridium difficile Infection. Comparative Effectiveness Review No. 31 (Prepared by the Minnesota Evidence-based Practice Center under Contract No. 290-02-0009.) AHRQ Publication No. 11(12)-EHC051-EF. Rockville, MD. Agency for Healthcare Research and Quality. December 2011. Available at: http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=772.Results of Direct Comparisons of Available Diagnostic AssaysTen studies directly compared at least two immunoassays for toxins A and B, providing 16 pair wise comparisons of seven different immunoassays. Comparative data were not found for many currently used tests. There were no statistical differences between the sensitivities of immunoassays that were compared; however, the estimates of the differences in sensitivity were not very precise and could not rule out substantial differences. Substantial differences in false positives, that is, specificity, were not found among the tests that were compared. Four studies compared at least one toxin gene detection test to at least one immunoassay for toxins A and B, providing a total of nine direct comparisons. Comparative data were not always available for the three currently available gene detection tests. The gene detection tests could be substantially more sensitive than many immunoassays for toxins A and B, but may lose specificity. Therefore, better studies are needed. Insufficient patient information was provided in reports of comparative data.

Reference:Butler M, Bliss D, Drekonja D, Filice G, Rector T, MacDonald R, Wilt T. Effectiveness of Early Diagnosis, Prevention, and Treatment of Clostridium difficile Infection. Comparative Effectiveness Review No. 31 (Prepared by the Minnesota Evidence-based Practice Center under Contract No. 290-02-0009.) AHRQ Publication No. 11(12)-EHC051-EF. Rockville, MD. Agency for Healthcare Research and Quality. December 2011. Available at: http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=772.Comparative Effectiveness of Standard Antibiotic Treatment for CDIThe target patient population was of adult patients with clinical signs consistent with CDI in hospital, outpatient, or long-term care settings. Studies that examined the comparative effectiveness of the antimicrobial treatments by organism strain were included. The interventions that were included consisted of vancomycin, metronidazole, bacitracin, nitazoxanide, rifaximin, fidaxomicin, and rifampin. As fusidic acid and teicoplanin are not currently approved for use in the United States, these treatments were excluded. Fidaxomicin was added as an intervention because FDA approval was granted May, 2011. Desired outcomes included initial cure, recurrence (variably defined by symptoms with or without a positive test for C. difficile), and mortality, which are outcomes of interest to clinicians and are reported in most studies. Also included were time to resolution of diarrhea, which may be important because of effects on patient comfort, duration of hospitalization, and for infection control purposes. Reported harms data to patients using any of the standard antimicrobial treatments were also included.

References:Dudley MN, McLaughlin JC, Carrington G, et al. Oral bacitracin vs vancomycin therapy for Clostridium difficile-induced diarrhea. A randomized double-blind trial. Arch Intern Med 1986 Jun; 146(6):11014. www.ncbi.nlm.nih.gov/pubmed/3521518 Fekety R, Silva J, Kauffman C, et al. Treatment of antibiotic-associated Clostridium difficile colitis with oral vancomycin: comparison of two dosage regimens. Am J Med 1989 Jan; 86(1):159. www.ncbi.nlm.nih.gov/pubmed/2910090 Keighley MR, Burdon DW, Arabi Y, et al. Randomised controlled trial of vancomycin for pseudomembranous colitis and postoperative diarrhoea. BMJ 1978 Dec 16; 2(6153):16679. www.ncbi.nlm.nih.gov/pubmed/367509 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 Sep 1; 43(5):54752. www.ncbi.nlm.nih.gov/pubmed/16886144. Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011 Feb 3; 364(5):422-31. Available at: www.ncbi.nlm.nih.gov/pubmed/21288078. Musher DM, Logan N, Bressler AM, et al. Nitazoxanide versus vancomycin in Clostridium difficile infection: a randomized, double-blind study. Clin Infect Dis 2009 Feb 15; 48(4):e416. www.ncbi.nlm.nih.gov/pubmed/19133801. Musher DM, Logan N, Hamill RJ, et al. Nitazoxanide for the treatment of Clostridium difficile colitis. Clin Infect Dis 2006 Aug 15; 43(4):4217. www.ncbi.nlm.nih.gov/pubmed/16838229. Teasley DG, Gerding DN, Olson MM, et al. Prospective randomised trial of metronidazole versus vancomycin for Clostridium-difficile-associated diarrhoea and colitis. Lancet 1983 Nov 5; 2(8358):10436. www.ncbi.nlm.nih.gov/pubmed/6138597. Wenisch C, Parschalk B, Hasenhundl M, et al. Comparison of vancomycin, teicoplanin, metronidazole, and fusidic acid for the treatment of Clostridium difficile-associated diarrhea. Clin Infect Dis 1996 May; 22(5):8138. www.ncbi.nlm.nih.gov/pubmed/8722937. Young GP, Ward PB, Bayley N, et al. Antibiotic-associated colitis due to Clostridium difficile: double-blind comparison of vancomycin with bacitracin. Gastroenterol 1985 Nov; 89(5):103845. www.ncbi.nlm.nih.gov/pubmed/4043661. 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 Aug 1; 45(3):3027. www.ncbi.nlm.nih.gov/pubmed/17599306.Comparative Effectiveness Results for Treating CDI With AntibioticsThere was moderate strength evidence that initial cure rates were similar for oral vancomycin versus metronidazole and vancomycin versus fidaxomicin. Similarly, none of the other head-to-head trials demonstrated superiority of any single antimicrobial for initial clinical cure, recurrence, or mean days to resolution of diarrhea. Antibiotic comparisons included: vancomycin versus metronidazole, vancomycin versus fidaxomicin, vancomycin versus nitazoxanide, bacitracin, and high-dose vancomycin; and metronidazole versus nitazoxanide. Metronidazole was also compared to metronidazole plus rifampin with no evidence of superiority but with a statistically significant higher mortality associated with the combination (5% versus 32%; P = 0.04). One RCT comparing vancomycin to metronidazole, using a prespecified subgroup analysis of 69 patients, found a small but significant increase in the proportion of subjects with severe CDI who achieved initial clinical cure with vancomycin, using a treatment-received analysis. This difference was not significant using a strict intention-to-treat analysis. There was also moderate strength evidence that recurrence rates were about 10 percent lower after treatment with fidaxomicin when compared with vancomycin (15 percent versus 25 percent; P = 0.005). Low strength evidence suggested that patients treated with vancomycin for a non-NAP1 (non-North American Pulsed Field type 1) strain infection were about 3 times as likely to have a recurrence than patients treated with fidaxomicin, but patients with the NAP1 strain had recurrence rates that did not differ significantly by treatment.

References:Butler M, Bliss D, Drekonja D, Filice G, Rector T, MacDonald R, Wilt T. Effectiveness of Early Diagnosis, Prevention, and Treatment of Clostridium difficile Infection. Comparative Effectiveness Review No. 31 (Prepared by the Minnesota Evidence-based Practice Center under Contract No. 290-02-0009.) AHRQ Publication No. 11(12)-EHC051-EF. Rockville, MD. Agency for Healthcare Research and Quality. December 2011. Available at: http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=772

Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011 Feb 3; 364(5):422-31. Available at: www.ncbi.nlm.nih.gov/pubmed/21288078.Teasley DG, Gerding DN, Olson MM, et al. Prospective randomised trial of metronidazole versus vancomycin for Clostridium-difficile-associated diarrhoea and colitis. Lancet 1983 Nov 5; 2(8358):10436. www.ncbi.nlm.nih.gov/pubmed/6138597

Wenisch C, Parschalk B, Hasenhundl M, et al. Comparison of vancomycin, teicoplanin, metronidazole, and fusidic acid for the treatment of Clostridium difficile-associated diarrhea. Clin Infect Dis 1996 May; 22(5):8138. www.ncbi.nlm.nih.gov/pubmed/8722937

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 Aug 1; 45(3):3027. www.ncbi.nlm.nih.gov/pubmed/17599306Nonstandard Interventions to Treat CDI or Reduce the Risk of RecurrenceThe clinical question of interest in this part of the study was what nonstandard treatments are currently being utilized and their efficacy, particularly for recurrent CDI. Patients with relapsing or recurrent CDI are of special concern due to the demonstrated difficulty with permanent cure of the infectious organism, and are often the stated targeted patient population for nonstandard treatments. Likewise, preventing recurrence is an important clinical goal. A total of five RCTs on nonstandard adjunctive treatments of CDI and 13 studies that addressed prevention of CDI formed the basis of this analysis. The target patient population was adults with clinical signs consistent with CDI in hospital, outpatient, or long-term care settings. Nonstandard interventions to improve a patients resistance to CDI or CDI recurrence included probiotics, oligofructose prebiotic, C. difficile-specific polyclonal antibody-enriched immune whey, toxin-neutralizing antibodies, toxin-absorbing resins, and intravenous immunoglobulin. Probiotics and prebiotics aim to modify the patients intestinal microbioecology to better resist CDI. Probiotics delivers nonpathogenic microorganisms thought to compete with or inhibit C. difficile, while prebiotics aim to promote the growth of beneficial organisms. Fecal flora reconstitution instills donor feces into the patient with CDI to normalize the intestinal flora. The procedure has been variously termed in the literature, including fecal bacteriotherapy, fecal transplantation, and donated stool. The C. difficile-immune whey is a nonantibiotic modality, which is based on orally ingested specific C. difficile-enriched bovine immunoglobulins. The toxin neutralizing antibodies are monoclonal antibodies to C. difficile toxins A and B.

References:Bakken JS. Fecal bacteriotherapy for recurrent Clostridium difficile infection. Anaerobe 2009 Dec; 15(6):285-9. www.ncbi.nlm.nih.gov/pubmed/19778623 Can M, Besirbellioglu BA, Avci IY, et al. Prophylactic Saccharomyces boulardii in the prevention of antibiotic-associated diarrhea: a prospective study. Med Sci Monit 2006 Apr; 12(4):P19-22. www.ncbi.nlm.nih.gov/pubmed/16572062 Food and Agriculture Organization of the United Nations, World Health Organization. Health and Nutritional Properties of Probiotics in Food including Powder Milk with Live Lactic Acid Bacteria. Report of a Joint FAO/WHO Expert Consultation on Evaluation of Health and Nutritional Properties of Probiotics in Food Including Powder Milk with Live Lactic Acid Bacteria. Cordoba, Argentina; 2001. Available at: www.who.int/foodsafety/publications/fs_management/en/probiotics.pdf. 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 Jul 14; 335(7610):80. www.ncbi.nlm.nih.gov/pubmed/17604300 Lewis S, Burmeister S, Brazier J. Effect of the prebiotic oligofructose on relapse of Clostridium difficile-associated diarrhea: a randomized, controlled study. Clin Gastroenterol Hepatol 2005 May; 3(5):442-8. www.ncbi.nlm.nih.gov/pubmed/15880313 Lewis S, Burmeister S, Cohen S, et al. Failure of dietary oligofructose to prevent antibiotic-associated diarrhoea. Aliment Pharmacol Ther 2005 Feb 15; 21(4):469-77. www.ncbi.nlm.nih.gov/pubmed/15709999 Lewis SJ, Potts LF, Barry RE. The lack of therapeutic effect of Saccharomyces boulardii in the prevention of antibiotic-related diarrhoea in elderly patients. J Infect 1998 Mar; 36(2):171-4. www.ncbi.nlm.nih.gov/pubmed/9570649 Lowy I, Molrine DC, Leav BA, et al. Treatment with monoclonal antibodies against Clostridium difficile toxins. N Engl J Med 2010 Jan 21; 362(3):197-205. www.ncbi.nlm.nih.gov/pubmed/20089970. MacConnachie AA, Fox R, Kennedy DR, et al. Faecal transplant for recurrent Clostridium difficile-associated diarrhoea: a UK case series. QJM 2009 Nov; 102(11):781-4. www.ncbi.nlm.nih.gov/pubmed/19726581 Mattila E, Anttila VJ, Broas M, et al. A randomized, double-blind study comparing Clostridium difficile immune whey and metronidazole for recurrent Clostridium difficile-associated diarrhoea: efficacy and safety data of a prematurely interrupted trial. Scand J Infect Dis 2008; 40(9):702-8. www.ncbi.nlm.nih.gov/pubmed/19086244 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 Jun 22-29; 271(24):1913-8. www.ncbi.nlm.nih.gov/pubmed/8201735 McFarland LV, Surawicz CM, Greenberg RN, et al. Prevention of beta-lactam-associated diarrhea by Saccharomyces boulardii compared with placebo. Am J Gastroenterol 1995 Mar; 90(3):439-48. www.ncbi.nlm.nih.gov/pubmed/7872284 Mogg GA, George RH, Youngs D, et al. Randomized controlled trial of colestipol in antibiotic-associated colitis. Br J Surg 1982 Mar; 69(3):137-9. Available at: www.ncbi.nlm.nih.gov/pubmed/7039758. Persky SE, Brandt LJ. Treatment of recurrent Clostridium difficile-associated diarrhea by administration of donated stool directly through a colonoscope. Am J Gastroenterol 2000 Nov; 95(11):3283-5. www.ncbi.nlm.nih.gov/pubmed/11095355 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 Mar; 7(1):59-62. www.ncbi.nlm.nih.gov/pubmed/15179608

Rohlke F, Surawicz C, Stollman N. Fecal flora reconstitution for recurrent clostridium difficile infection: results and methodology. J Clin Gastroenterol 2010; 44(8):567-70. www.ncbi.nlm.nih.gov/pubmed/20485184

Silverman MS, Davis I, Pillai DR. Success of self-administered home fecal transplantation for chronic Clostridium difficile infection. Clin Gastroenterol Hepatol 2010 May; 8(5):471-3. www.ncbi.nlm.nih.gov/pubmed/20117243

Surawicz CM, Elmer GW, Speelman P, et al. Prevention of antibiotic-associated diarrhea by Saccharomyces boulardii: a prospective study. Gastroenterol 1989 Apr; 96(4):981-8. www.ncbi.nlm.nih.gov/pubmed/2494098

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 Oct; 31(4):1012-7. www.ncbi.nlm.nih.gov/pubmed/11049785 Thomas MR, Litin SC, Osmon DR, et al. Lack of effect of Lactobacillus GG on antibiotic-associated diarrhea: a randomized, placebo-controlled trial. Mayo Clin Proc 2001 Sep; 76(9):883-9. www.ncbi.nlm.nih.gov/pubmed/11560298 Tvede M, Rask-Madsen J. Bacteriotherapy for chronic relapsing Clostridium difficile diarrhoea in six patients. Lancet 1989 May 27; 1(8648):1156-60. Available at: www.ncbi.nlm.nih.gov/pubmed/2566734. 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(6-7):365-7. www.ncbi.nlm.nih.gov/pubmed/12953945 Yoon S, Brandt L. Treatment of refractory/recurrent C. difficile-associated disease by donated stool transplanted via colonoscopy: a case series of 12 patients. J Clin Gastroenterol 2010; 44(8):562-6. www.ncbi.nlm.nih.gov/pubmed/20463588.Comparative Effectiveness Results for Treatment of CDI With Antibiotics + Adjunctive TherapyProbiotics are a very active area of discussion for CDI. Probiotics are live microorganisms, including bacteria or yeast, which, when administered in adequate amounts, confer a health benefit on the host. Probiotics are believed to replenish nonpathogenic microorganisms to GI flora that has become altered by antibiotic therapy. It is important that the effectiveness of probiotics and related substances are evaluated specifically for their effect on CDI and not rely on the more broadly defined antibiotic-associated diarrheal disease, which includes a much broader set of potential disease etiology. Although probiotics may have been intended solely for prevention of recurrent CDI in some studies, they were included among treatments for recurrent CDI because the probiotic was administered concurrently with a standard antibiotic during treatment and not after recurrent CDI was cured.Probiotics were the only intervention administered as an adjunct to standard antibiotic treatment for CDI. The probiotic in two studies contained Sacchromyces boulardii and in one it contained Lactobacillus plantarum. In the studies analyzed here, probiotics administered as an adjunct to antibiotic treatment were not more effective than treatment with antibiotics alone. Additionally, administration of a probiotic containing Saccharomyces spp. to treat CDI in critically ill patients only increased the risk for greater morbidity and mortality from fungemia without showing any benefit.

References: Butler M, Bliss D, Drekonja D, Filice G, Rector T, MacDonald R, Wilt T. Effectiveness of Early Diagnosis, Prevention, and Treatment of Clostridium difficile Infection. Comparative Effectiveness Review No. 31 (Prepared by the Minnesota Evidence-based Practice Center under Contract No. 290-02-0009.) AHRQ Publication No. 11(12)-EHC051-EF. Rockville, MD. Agency for Healthcare Research and Quality. December 2011. Available at: www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=772.

Food and Agriculture Organization of the United Nations, World Health Organization. Health and Nutritional Properties of Probiotics in Food including Powder Milk with Live Lactic Acid Bacteria. Report of a Joint FAO/WHO Expert Consultation on Evaluation of Health and Nutritional Properties of Probiotics in Food Including Powder Milk with Live Lactic Acid Bacteria. Cordoba, Argentina; 2001. Available at: www.who.int/foodsafety/publications/fs_management/en/probiotics.pdf

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 Jun 22-29; 271(24):1913-8. www.ncbi.nlm.nih.gov/pubmed/8201735

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 Oct; 31(4):1012-7. www.ncbi.nlm.nih.gov/pubmed/11049785

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 Iinfect Dis 2003; 35(6-7):3657. www.ncbi.nlm.nih.gov/pubmed/12953945Nonstandard Interventions to Reduce the Occurrence of Primary CDIThere is limited, low-strength evidence that when probiotics, prebiotics, or toxin-neutralizing antibodies were used as nonstandard prevention interventions, they were not more effective than placebo for primary prevention of CDI.

References:Butler M, Bliss D, Drekonja D, Filice G, Rector T, MacDonald R, Wilt T. Effectiveness of Early Diagnosis, Prevention, and Treatment of Clostridium difficile Infection. Comparative Effectiveness Review No. 31 (Prepared by the Minnesota Evidence-based Practice Center under Contract No. 290-02-0009.) AHRQ Publication No. 11(12)-EHC051-EF. Rockville, MD. Agency for Healthcare Research and Quality. December 2011. Available at: www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=772.

Can M, Besirbellioglu BA, Avci IY, et al. Prophylactic Saccharomyces boulardii in the prevention of antibiotic-associated diarrhea: a prospective study. Med Sci Monit 2006 Apr; 12(4):P1922. www.ncbi.nlm.nih.gov/pubmed/16572062

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 Jul 14; 335(7610):80. www.ncbi.nlm.nih.gov/pubmed/17604300

Lewis S, Burmeister S, Brazier J. Effect of the prebiotic oligofructose on relapse of Clostridium difficile-associated diarrhea: a randomized, controlled study. Clin Gastroenterol Hepatol 2005 May; 3(5):442-8.Lewis SJ, Potts LF, Barry RE. The lack of therapeutic effect of Saccharomyces boulardii in the prevention of antibiotic-related diarrhoea in elderly patients. J Infect 1998 Mar; 36(2):1714. www.ncbi.nlm.nih.gov/pubmed/9570649

Lowy I, Molrine DC, Leav BA, et al. Treatment with monoclonal antibodies against Clostridium difficile toxins. N Engl J Med 2010 Jan 21; 362(3):197-205. Available at: www.ncbi.nlm.nih.gov/pubmed/20089970.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 Mar; 7(1):5962. www.ncbi.nlm.nih.gov/pubmed/15179608

Surawicz CM, Elmer GW, Speelman P, et al. Prevention of antibiotic-associated diarrhea by Saccharomyces boulardii: a prospective study. Gastroenterol 1989 Apr; 96(4):9818. www.ncbi.nlm.nih.gov/pubmed/2494098

Thomas MR, Litin SC, Osmon DR, et al. Lack of effect of Lactobacillus GG on antibiotic-associated diarrhea: a randomized, placebo-controlled trial. Mayo Clin Proc 2001 Sep; 76(9):8839. www.ncbi.nlm.nih.gov/pubmed/11560298Nonstandard Interventions for Treatment of Multiple Recurrences of CDIIn one study of 38 patients who had one or more recurrences in a 3-month period, C. difficile immune whey had an overall relapse-free response rate that was similar to metronidazole. There was not a placebo arm in this study, the sample size was not achieved, and the trial ended prematurely due to the bankruptcy of the sponsor.Another approach under investigation for treatment of recurrent or refractory CDI is fecal flora reconstitution, which instills feces from a healthy donor into the colon of a patient with CDI. Six case studies/series have been published, four within the last 2 years. Of a total of 60 patients, 52 patients (87 percent) resolved diarrhea and experienced no further relapse during followup. Two studies reported relapse of diarrhea in 7 of 34 patients (21 percent). Followup periods ranged from 3 weeks to 8 years. Overall, there is limited low-strength evidence from 6 case studies/series with 60 patients that fecal flora reconstitution is effective in treating recurrent CDI for up to 1 year.

References:Bakken JS. Fecal bacteriotherapy for recurrent Clostridium difficile infection. Anaerobe 2009 Dec; 15(6):285-9. www.ncbi.nlm.nih.gov/pubmed/19778623

Butler M, Bliss D, Drekonja D, Filice G, Rector T, MacDonald R, Wilt T. Effectiveness of Early Diagnosis, Prevention, and Treatment of Clostridium difficile Infection. Comparative Effectiveness Review No. 31 (Prepared by the Minnesota Evidence-based Practice Center under Contract No. 290-02-0009.) AHRQ Publication No. 11(12)-EHC051-EF. Rockville, MD. Agency for Healthcare Research and Quality. December 2011. www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=772

MacConnachie AA, Fox R, Kennedy DR, et al. Faecal transplant for recurrent Clostridium difficile-associated diarrhoea: a UK case series. QJM 2009 Nov; 102(11):781-4. www.ncbi.nlm.nih.gov/pubmed/19726581

Mattila E, Anttila VJ, Broas M, et al. A randomized, double-blind study comparing Clostridium difficile immune whey and metronidazole for recurrent Clostridium difficile-associated diarrhoea: efficacy and safety data of a prematurely interrupted trial. Scand J Infect Dis 2008; 40(9):702-8. www.ncbi.nlm.nih.gov/pubmed/19086244

Persky SE, Brandt LJ. Treatment of recurrent Clostridium difficile-associated diarrhea by administration of donated stool directly through a colonoscope. Am J Gastroenterol 2000 Nov; 95(11):3283-5. www.ncbi.nlm.nih.gov/pubmed/11095355

Rohlke F, Surawicz C, Stollman N. Fecal flora reconstitution for recurrent clostridium difficile infection: results and methodology. J Clin Gastroenterol 2010; 44(8):567-70. Available at: www.ncbi.nlm.nih.gov/pubmed/20485184

Silverman MS, Davis I, Pillai DR. Success of self-administered home fecal transplantation for chronic Clostridium difficile infection. Clin Gastroenterol Hepatol 2010 May; 8(5):471-3. Available at: www.ncbi.nlm.nih.gov/pubmed/20117243

Tvede M, Rask-Madsen J. Bacteriotherapy for chronic relapsing Clostridium difficile diarrhoea in six patients. Lancet 1989 May 27; 1(8648):1156-60. www.ncbi.nlm.nih.gov/pubmed/2566734

Yoon S, Brandt L. Treatment of refractory/recurrent C. difficile-associated disease by donated stool transplanted via colonoscopy: a case series of 12 patients. J Clin Gastroenterol 2010; 44(8):562-6. www.ncbi.nlm.nih.gov/pubmed/20463588Nonstandard Interventions to Reduce CDI Recurrence RatesA significantly lower rate of CDI recurrence was reported in two studies following administration of the prebiotic oligofructose or a monoclonal antibody to C. difficile toxins A and B. In both studies, the recurrence rate of CDI was approximately three times as great in subjects on placebo compared with the intervention.

References:Butler M, Bliss D, Drekonja D, Filice G, Rector T, MacDonald R, Wilt T. Effectiveness of Early Diagnosis, Prevention, and Treatment of Clostridium difficile Infection. Comparative Effectiveness Review No. 31 (Prepared by the Minnesota Evidence-based Practice Center under Contract No. 290-02-0009.) AHRQ Publication No. 11(12)-EHC051-EF. Rockville, MD. Agency for Healthcare Research and Quality. December 2011. Available at: http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=772.

Lewis S, Burmeister S, Brazier J. Effect of the prebiotic oligofructose on relapse of Clostridium difficile-associated diarrhea: a randomized, controlled study. Clin Gastroenterol Hepatol 2005 May; 3(5):442-8. www.ncbi.nlm.nih.gov/pubmed/15880313

Lowy I, Molrine DC, Leav BA, et al. Treatment with monoclonal antibodies against Clostridium difficile toxins. N Engl J Med 2010 Jan 21; 362(3):197-205. www.ncbi.nlm.nih.gov/pubmed/20089970Overall Conclusions: Nonstandard Interventions to Treat CDI or Reduce the Risk of RecurrenceThe conclusions for nonstandard interventions to treat CDI and/or reduce the risk of recurrent infections are limited by the lack of comparative studies available and generally have a low strength of evidence. Current research suggests that:C. difficile immune whey is well tolerated and may prevent recurrence of CDI at rates similar to metronidazole. Fecal flora reconstitution via fecal transplantation may prevent recurrent infections for up to 1 year. Probiotics, prebiotics, and toxin-neutralizing antibodies alone may not reduce CDI incidence rates.An oligofructose prebiotic (low strength of evidence) and toxin-neutralizing antibodies (moderate strength of evidence) have the potential to help reduce the risk of recurrent infections.

References:Butler M, Bliss D, Drekonja D, Filice G, Rector T, MacDonald R, Wilt T. Effectiveness of Early Diagnosis, Prevention, and Treatment of Clostridium difficile Infection. Comparative Effectiveness Review No. 31 (Prepared by the Minnesota Evidence-based Practice Center under Contract No. 290-02-0009.) AHRQ Publication No. 11(12)-EHC051-EF. Rockville, MD. Agency for Healthcare Research and Quality. December 2011. Available at: www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=772.

Lewis S, Burmeister S, Brazier J. Effect of the prebiotic oligofructose on relapse of Clostridium difficile-associated diarrhea: a randomized, controlled study. Clin Gastroenterol Hepatol 2005 May; 3(5):442-8. www.ncbi.nlm.nih.gov/pubmed/15880313.

Lowy I, Molrine DC, Leav BA, et al. Treatment with monoclonal antibodies against Clostridium difficile toxins. N Engl J Med 2010 Jan 21; 362(3):197-205. www.ncbi.nlm.nih.gov/pubmed/20089970.MacConnachie AA, Fox R, Kennedy DR, et al. Faecal transplant for recurrent Clostridium difficile-associated diarrhoea: a UK case series. QJM 2009 Nov; 102(11):781-4. www.ncbi.nlm.nih.gov/pubmed/19726581

Mattila E, Anttila VJ, Broas M, et al. A randomized, double-blind study comparing Clostridium difficile immune whey and metronidazole for recurrent Clostridium difficile-associated diarrhoea: efficacy and safety data of a prematurely interrupted trial. Scand J Infect Dis 2008; 40(9):702-8. www.ncbi.nlm.nih.gov/pubmed/19086244

Persky SE, Brandt LJ. Treatment of recurrent Clostridium difficile-associated diarrhea by administration of donated stool directly through a colonoscope. Am J Gastroenterol 2000 Nov; 95(11):3283-5. www.ncbi.nlm.nih.gov/pubmed/11095355

Rohlke F, Surawicz C, Stollman N. Fecal flora reconstitution for recurrent clostridium difficile infection: results and methodology. J Clin Gastroenterol 2010; 44(8):567-70. www.ncbi.nlm.nih.gov/pubmed/20485184

Silverman MS, Davis I, Pillai DR. Success of self-administered home fecal transplantation for chronic Clostridium difficile infection. Clin Gastroenterol Hepatol 2010 May; 8(5):471-3. www.ncbi.nlm.nih.gov/pubmed/20117243

Tvede M, Rask-Madsen J. Bacteriotherapy for chronic relapsing Clostridium difficile diarrhoea in six patients. Lancet 1989 May 27; 1(8648):1156-60. www.ncbi.nlm.nih.gov/pubmed/2566734. Yoon S, Brandt L. Treatment of refractory/recurrent C. difficile-associated disease by donated stool transplanted via colonoscopy: a case series of 12 patients. J Clin Gastroenterol 2010; 44(8):562-6. www.ncbi.nlm.nih.gov/pubmed/20463588Comparative Effectiveness of CDI Prevention StrategiesEnvironments of hospitals and outpatient and long-term care facilities involve complex interactions among patients, health care professionals, caregivers, and visitors. CDI-prevention strategies are often implemented or added to existing bundles of infection-control strategies with minimal available evidence. The studies on CDI prevention that were evaluated usually included bundled infection-control interventions making it hard to ascertain the contribution of individual components to the effectiveness of the bundle. Studies that were included examined the effects of prevention strategies aimed at breaking routes of transmission within institutional settings or reducing susceptibility to CDI through antibiotic prescribing practices. Ten studies have examined bundled multiple interventions using before/after study designs. Data was insufficient to draw conclusions. Accurately identifying risk factors associated with CDI can also assist in the implementation of effective prevention strategies.

Reference:Butler M, Bliss D, Drekonja D, Filice G, Rector T, MacDonald R, Wilt T. Effectiveness of Early Diagnosis, Prevention, and Treatment of Clostridium difficile Infection. Comparative Effectiveness Review No. 31 (Prepared by the Minnesota Evidence-based Practice Center under Contract No. 290-02-0009.) AHRQ Publication No. 11(12)-EHC051-EF. Rockville, MD. Agency for Healthcare Research and Quality. December 2011. Available at: www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=772.Prevention Strategies for CDI Focusing on Antibiotic Prescribing PoliciesAvailable research found that changes in antimicrobial education, policies, or formularies, which result in decreasing use of high-risk antimicrobials, may be associated with decreased CDI incidence. It was not possible to clearly isolate the impact of the antibiotic-related interventions in the studies examining multiple interventions. In the individual studies, which were usually done in response to outbreaks, interventio