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

2.  The comparative effectiveness review (CER) process  Overview of the CER  Introduction  Detailed Results  Direct 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

3.  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

4.  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

5.  To conduct a systematic review and synthesize evidence for differences in:  The accuracy of diagnostic tests  The 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: Objectives Butler M, et al. AHRQ Comparative Effectiveness Review No. XXX. Available at: http://effectivehealthcare.ahrq.gov/index.

6.  Data Sources:  MEDLINE®, the Cochrane Library, and Allied and Complementary Medicine (AMED)  ClinicalTrials.gov and expert consultants  Reference lists from relevant literature  Review Methods:  Standard Evidence-based Practice Center methods  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  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. Overview: Methods

7.  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

8.  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 strain Overview: Results for Treatment of CDI with Standard Antibiotics

9.  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

10.  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

11.  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

12.  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)

13.  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 person’s 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

14.  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

15.  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

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

17.  Cytotoxicity assays  C. difficile culture  Immunoassays for toxins  Toxin gene detection tests Assays Commonly Used in CDI Diagnostics

18. Methods Evaluated for Detecting Toxigenic C. difficile Diagnostic Assays Investigated Number of Studies (n) Toxin A and B Immunoassays Premier Toxin A&B, Meridian7 Tox A/B II, TechLab6 Tox A/B QUIK CHEK, TechLab4 ImmunoCard A&B, Meridian7 Xpect Toxin A/B, Remel4 ProSpecT Toxin A/B, Remel2 VIDAS C. diff Tox A/B, bioMerieux4 Gene Detection Tests GeneOhm, Becton Dickinson3 GeneXpert, Cepheid2

19.  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

20. Comparative Effectiveness of Standard Antibiotic Treatment for CDI FDA-approved antibiotics Other antibiotics

21.  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

22. Nonstandard Interventions to Treat CDI or Reduce the Risk of Recurrence Antibiotics + probiotics Probiotics Oligofructose prebiotic Fecal flora reconstitution C. difficile-specific polyclonal antibody-enriched immune whey Toxin-neutralizing antibodies Toxin absorptive resins IV immunoglobulin

23.  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

24.  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 prebiotic  Toxin-neutralizing antibodies (intravenous infusion of human monoclonal antibodies against C. difficile toxins A (CDA1) and B (CDB1)  Low strength of evidence Nonstandard Interventions to Reduce the Occurrence of Primary CDI

25.  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

26.  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

27.  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

28. Comparative Effectiveness of CDI Prevention Strategies Antibiotic prescribing policies Institutional prevention strategies Bundled intervention strategies Sustainability of prevention strategies CDI risk factors

29.  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

30.  Low strength of evidence suggested that CDI incidence may be reduced by using common contact barriers such as:  Disposable gloves  Tympanic or disposable single-use thermometers  Disinfection 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

31.  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

32.  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 interventions— such as probiotics, prebiotics, toxin-absorbing compounds, and fecal flora reconstitution, among others—can 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

33.  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