C. Difficile : Accurate Testing & Diagnosing New Treatments on the Horizon

1. C. Difficile:Accurate Testing &DiagnosingNew Treatments on the Horizon October 2, 2014 For the Georgia Hospital Association(GHA)/ Georgia Advanced Practice Program (GAPP) Bruce Kalmin, M.D. Board Certified Gastroenterologist

2. Clostridium difficileinfection (CDI) • Objectives: • Participant will be able to identify most accurate C. difficile infection testing and diagnosing recommendations • Participant will become aware of new treatments for C. difficileon the horizon including Fecal Microbial Therapy

3. What’s so important about Clostridium difficile? • Annual hospitalizations in U.S. with CDI as a diagnosis (Agency for Healthcare Research & Quality) • 1993: 85,700 hospitalizations • 2010: 346,800 hospitalizations Kelly & Lamont. N Engl J Med 2008;359:1932-40. Bauer et al. ClinMicrobiol2009;15:1067-79. Cohen et al. Infect Control HospEpidemiol 2010;31:431-55.

4. What’s so important about Clostridium difficile? • Clostridium difficile-related deaths Figure. Yearly Clostridium difficile–related mortality rates per million population, United States, 1999–2004. Redelings MD, Sorvillo F, Mascola L. Increase in Clostridium difficile–related mortality rates, United States, 1999–2004. Emerg Infect Dis [serial on the Internet]. 2007 Sep [date cited].Available from: http://wwwnc.cdc.gov/eid/article/13/9/06-1116

5. What is Clostridium difficile? • C. difficileis a spore-forming, gram-positive anaerobic bacillus that produces two exotoxins: toxin A and toxin B • Common cause of antibiotic-associated diarrhea (AAD) • Accounts for 15-25% of all episodes of AAD

6. What is Clostridium difficile? • First identified in 1935 (Hall and O’Toole) • 60-70% of newborns colonized (Bacillus difficilis) • Possible lack of toxin receptor -> no symptoms • C. difficileidentified as pathogen in 1978 (Tedesco et al. and Bartlett et al.) • Causes pseudomembranous colitis in patients receiving clindamycin Hall EC, E OT. Intestinal flora in new-born infants with a description of a new pathogenic anaerobe, Bacillus difficilis. Am J Dis Child 1935; 49: 12. Bolton RP, Tait SK, Dear PR, Losowsky MS. Asymptomatic neonatal colonisation by Clostridium difficile. Arch Dis Child 1984; 59: 466–472.  Bartlett JG, Chang TW, Moon N, Onderdonk AB. Antibiotic-induced lethal enterocolitis in hamsters: studies with eleven agents and evidence to support the pathogenic role of toxin-producing Clostridia. Am J Vet Res 1978; 39: 1525–1530. Tedesco FJ, Alpers DH. Editorial: pseudomembranous colitis. West J Med 1974; 121: 499–500. Bartlett JG, Moon N, Chang TW, Taylor N, Onderdonk AB. Role of Clostridium difficile in antibiotic-associated pseudomembranous colitis. Gastroenterology 1978; 75: 778–782.

7. Pseudomembranous Colitis

8. Colonization vs. Infection • C. difficilecolonization • Patient exhibits NO clinic symptoms • Patient tests positive for C. difficileorganism and/or its toxin • More common than C. difficileinfection • C. difficileinfection • Patient exhibits clinical symptoms • Patient tests positive for C. difficileorganism and/or its toxin

9. Can Colonization be Protective? • Gerding at al. 2013 • Two different strains of non-toxigenic C. difficileprovided protection against both historic and epidemic (BI/NAP1/O27) strain • Can colonization be protective against CDI? • ViraPharma is conducting Phase I/II trials Gerding at al. Non-toxigenic Clostridium difficilevs. BI/NAP1/O27. Antimicrobial Agents and Chemotherapy, October 2013.

10. Symptoms of CDI • Watery diarrhea • Fever • Loss of appetite • Nausea • Abdominal pain/tenderness

11. At-Risk Populations • Patients with: • Antibiotic exposure • Proton pump inhibitors • Gastrointestinal surgery/manipulation • Long length of stay in healthcare settings • Serious underlying illness • Immunocompromising conditions • Advanced age

12. Laboratory Testing • Stool culture • Most sensitive but most often associated with false-positive results due to presence of non-toxigenic strains • False positivity can be overcome by testing isolates for toxin production • Labor intensive • Slow turn-around time (48-96 hours)

13. Laboratory Testing • Molecular Tests • FDA-approved PCR assays • Test for gene encoding toxin B • Highly sensitive and specific • Antigen detection (latex agglutination or immunochromatographic assay) • Rapid test (<1 hour) • Non-specific but used in combination with toxin detection, PCR, or toxigenic culture

14. Laboratory Testing • Toxin testing • Tissue culture cytotoxicity assay • Detects toxin B only • Costly • Slow turn-around time (24-48hrs) • Historical gold standard but replaced by PCR or toxigenic culture • Enzyme immunoassay • Detects toxin A, toxin B, or toxin A and B • Concerns over A-/B+ strains causing disease • Same-day assay • Relatively insensitive • Less than tissue culture cytotoxicity and much less than PCR or toxigenic culture

15. Laboratory Testing • Important Note!!! • C. difficiletoxin is VERY unstable • Degrades at room temperature • May be undetectable within 2 hours after collection of a stool specimen • Specimens can be kept refrigerated

16. When can you repeat PCR Testing for C. difficile? • PCR has high sensitivity (~90%) and specificity (~90%) with high negative predictive value • Summary of literature review(8 studies: 2008-2013) • PCR testing is reliable; no need to repeat when initial results are negative • If C. difficileis suspected (persistent symptoms) but initial negative test, repeat from days 8-14 or after day 10 http://www.stmarysmadison.com/physicianfocus/Documents/Sept.2013/link-C%20Diff%20testing%20summary%20mar%202013.pdf

17. When can you repeat PCR Testing for C. difficile? • If initial test was positive, may remain positive. May represent asymptomatic colonization or false positives due to PCR sensitivity. If retesting is done, wait for 7 days. • Most studies look at retesting after initial negative test and not if initial test was positive. • “Test of cure” is NOT recommended. http://www.stmarysmadison.com/physicianfocus/Documents/Sept.2013/link-C%20Diff%20testing%20summary%20mar%202013.pdf

18. CDI Prevention • Use antibiotics judiciously • Contact Precautions • Private rooms or (if not available) cohorted with other patients with C. difficileinfection • Gloves/Gowns • Wash hands with SOAP and WATER • Alcohol-based hand rubs are not as effective • Removal of C. difficilespores is challenging, even with soap and water

19. CDI Prevention • Dedicate or clean any shared equipment • Use EPA-registered disinfectant with sporicidal claim or hypochlorite (bleach) • Standard EPA-registered hospital disinfectants are NOT effective against C. difficilespores • Continue precautions until diarrhea ceases • Most institutions will routinely continue isolation for either several days beyond symptom resolution or until discharge

20. The “New” C. difficileStrain • BI/NAP1/O27 • Outbreaks • Pittsburgh (2000) • Atlanta (2001-2) • Montreal (2003) • More virulent • Increased production of toxins A and B • Additional toxin: binary toxin • Resistant to fluoroquinolones Additional info: Read Bench-to-Bedside review: Clostridium difficilecolitis at http://www.cdc.gov/HAI/pdfs/cdiff/Gould_CritCare2008.pdf

21. The “New” C. difficileStrain • Detection • Any of the current tests will detect BI/NAP1/O27 • None of them differentiate between the various strains of C. difficile • Treatment • Same as standard therapy • Controversial • Metronidazole first: prevents VRE • Vancomycin first: strain may be resistant to metronidazole

22. Management of CDI Stratified by Disease Severity Cohen SH, et al. Clinical Practice Guidelines, IDSA & SHEA. ICHE 2010;31(5):431-455.

23. Management of CDI • Vancomycin is more effective than metronidazole in treating severe CDI1 • Severe complicated CDI (refractory/fulminant) • Early surgical consultation2 • WBC >20K, creatinine >1.5 baseline, lactate >5mmol/L • In addition to vancomycinpo/enema & metronidazole IV, consider • Tigecycline IV? • IVIG 400 mg/kg? • Fidaxomicin? • Colectomy vs. loop ileostomy3 • 93% of colon can be preserved with intraoperative colonic lavage via ileostomy and post-op antegradevancomycin installation via ileostomy • 1 Zaret al. Clin Infect Dis 2007; 45:302-7 • 2LamontagneF, et al. Ann Surg 2007; 245:267-272. Pepin J, et al. Can Med J Assoc 2004; 171:466-472. Miller MA. Clin Infect Dis 2007;45:S122-S128. • 3Neal MD, et al. Ann Surg 2001;254:423-429.

24. Management of CDI • Fidaxomicin vs. Vancomycin • No significant difference in initial response • 88.2% fidaxomicin vs. 85.8% vancomycin (modified ITT) • 92.1% fidaxomicin vs. 89.8% vancomycin (per protocol) • Fidaxomicin is superior in preventing recurrence • 15.4% fidaxomicin vs. 25.3% vancomycin (modified ITT) • P=0.005 • 13.3% fidaxomicin vs. 24.0% vancomycin (per protocol) • P=0.004 Louie TJ, et al. New EnglJ Med 2011; 364:422-431.

25. Management of CDI • Fidaxomicin (Dificid) vs. Vancomycin • Fidaxomicin superior to vancomycin for preventing a first recurrence of CDI but not long-lasting Comely, OA et al. CID 2012;55 (Suppl 2); 154-61.

26. Management of CDI • Taper & pulsed dosing of oral vancomycin • 125mg QID x10-14d • 125mg BID x7d • 125mg daily x7d • 125mg every 2nd day x8d • 125mg every 3rd day x15d • Recurrence rates were lower • Vancomycin ≤ 1g 54.2% • Vancomycin > 1g 54.3% • Vancomycin taper 31.0% (P=0.01) • Vancomycin pulsed 14.3% (P=0.02) • Metronidazole ≤ 1g 44.6% • Metronidazole > 1g 40.0% Tedesco et al. Am J Gastroenterol 1985;80:867-868. McFarland et al. Am J Gastroenterol 2002;97:1769-1775.

27. Management of CDI • Rifaximin “chaser” in recurrent CDI • Standard therapy (metronidazole 82% or vancomycin 18%) PLUS placebo vs. rifaximin 400mg po TID x20d • Standard therapy + placebo = 31% recurrence within 6 months • Standard therapy + rifaximin = 15% recurrence within 6 months • Recurrence = proportion not experiencing recurrent diarrhea Garey, et al. J AntimicrobChemother, 2011;66:2850-5.

28. Management of CDI Summary Cohen SH, et al. IDSA & SHEA Guidelines, ICHE 2010;31(5):431-455. Surawicz, et al. ACG Guidelines. Am J Gastroenterol, 2013. Kelly & LaMont. “Uptodate” accessed Apr 24, 2013.

29. Fecal Microbial Therapy • Concept originated in China millennia ago • 'Yellow soup' was made of fecal matter and water, which was drunk by the patient. • The first description of FMT was published in 1958 by Ben Eiseman and colleagues, a team of surgeons from Colorado, who treated four critically ill patients with fulminant pseudomembranous colitis (before C. difficile was the known cause) using fecal enemas, which resulted in a rapid return to health. • At the Centre for Digestive Diseases in Sydney, Australia, FMT has been offered as a treatment option for more than 20 years. Eiseman B, et al. (1958). "Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis". Surgery44 (5): 854–859.

30. Fecal Microbial Therapy • Duodenal Infusion of Donor Feces for Recurrent Clostridium difficileinfection • First infusion of donor feces resulted in 81.3% cure rate without relapse (N=16) • Vancomycin resulted in 30.2% cure rate without relapse (N=13) • Vancomycin with bowel lavage resulted in 25.1% cure rate without relapse (N=13) • Conclusion: The infusion of donor feces was significantly more effective for the treatment of recurrent C. difficile infection than the use of vancomycin van Nood et al. N Engl J Med, 2013;368(5):407-413.

31. Fecal Microbial Therapy • Multiple methods of administration • From below: ~75% by colonoscopy or retention enema • From above: ~25% by nasogastric tube or upper GI endoscopy • Reported efficacy: From below >90%, from above ~80% Bakken et al. ClinGastroenterol & Hepatol 2001;9:1044-9. Hamilton et al. Am J Gastroenterol, 2012;107:761-7. Kelly CP, N Engl J Med 2013;368:474-5.

32. Fecal Microbial Therapy • The Future of FMT • Stool banking? • “Poop pill”? • Isolation of “protective” microbes • Bacteroidetes and Firmicutes • Treatment of other disorders • Ulcerative colitis? • Crohn’s disease?

33. Summary • Test early with PCR • Stop all non-C. difficileantibiotics ASAP • Give oral vancomycin as first line in severe disease • For recurrent disease, consider • Fidaxomicin? • Vancomycin taper/pulse? • Rifaximin “chaser”? • FMT?

34. Questions?