1. Clostridium difficile infection (CDI) in the ICU and Clostridium difficile outcomes in the PROSPECT Main Trial Erick Duan MD FRCPC Presented at the CCCTG Halifax, NS, June 2016

2. Burden of C. difficile Most common nosocomial cause of diarrhea More common nosocomial infection than MRSA In 2011 (US surveillance data): 453,000 cases of CDI 29,000 CDI associated deaths Increased health care cost of $1.5 billion USD Canadian point prevalence study: In 2002: 0.8% of all admissions In 2009: 1.2% of all admissions Leffler NEJM 2015 Taylor Antimicrob Res Inf Cont 2016

3. And it’s getting worse Since 2002: more common more severe more refractory to treatment more recurrent infection Emergence of hypervirulent strain: 027/BI/NAP1 15-20x toxin production, production of binary toxin Outbreak in Sherbrooke, PQ (2002) Increased attributable mortality: 17% Increased rate of colectomy: 23% Pepin CMAJ 2005

4. PatientsOutcomes Hospital pts Hospital pts ICU pts ICU pts ICU- acquired CDI pre-ICU CDI Risk Factors colonization with CD Prevention of CDI Prevention of CDI Morbidity Mortality renal failure shock colectomy length of stay renal failure shock colectomy length of stay Prognostic Factors Treatment of CDI Treatment of CDI Exposures/Interventions Incidence Outbreaks Attributable Cost Hospital pts with CDI Hospital pts with CDI pre-ICUICU Recurrent CDI Recurrent CDI Treatment of CDI Recurrence Treatment of CDI Recurrence severe, complicated or fulminant CDI Clostridium difficle in the ICU Diagnosis of CDI Prevalence Recurrent CDI Recurrent CDI Attributable Morbidity and Mortality ICU patients with CDI

5. Burden of C. difficile in ICU Prevalence of ICU-acquired CDI varies greatly 80 835 pts in 22 studies Pooled estimate: prevalence of 2% (95%CI 1-2%) Karanika et al Open Forum Infectious Diseases 2016

6. Burden of C. difficile in ICU With limitations, there is some signal that ICU acquired C. difficile infection increases hospital mortality and hospital LOS Also, increases ICU LOS with no difference in ICU mortality Karanika et al Open Forum Infectious Diseases 2016 Hospital mortality Hospital LOS 32%24% 50 vs 30 days 26-39%14-36%95%CI

7. Studies of C. difficile in ICU Largely retrospective studies Low event rate Variable definitions of C. difficile infection Severity unknown (and criteria never validated) Complications poorly and inconsistently reported Treatment poorly described

8. What’s coming down the pipeline for CDI?

9. Fecal microbiota transplantation Antibiotics: fidaxomicin, teicoplanin, tigecycline surtomycin, cadazolid IVIG Monoclonal antibodies Vaccine

10. What’s coming down the pipeline for CDI? Fecal microbiota transplantation Antibiotics: fidaxomicin, teicoplanin, tigecycline surtomycin, cadazolid IVIG Monoclonal antibodies Vaccine

11. Fecal microbiota transplantation 89% cure rate in observational studies (273 CDI patients) no adverse effects reported compared to 18% treatment failures with metronidazole 60% chance of recurrence after 2 prior episodes Kassam Am J Gastroenterol 2013

12. The trouble with fecal microbiota transplantation typically stool donors are family members stool collected within 6 hours of transplant stool screening process is extensive, and not standardized reported but not well studied in critically ill patients concern about delaying surgical intervention in critically ill patients

13. JAMA 2014 JAMA 2016 232 patients with recurrent CDI Cure rates: 83.5% frozen 85.1% fresh Frozen as good as fresh

14. Coming sometime to an ICU near you???

15. Back to

16. C. difficile data collection and outcome adjudication in PROSPECT

17. Studies of C. difficile in ICU largely retrospective studies low event rate highly variable definitions of C. difficile infection severity unknown (and criteria never validated) complications poorly and inconsistently reported treatment poorly described

18. C. difficile Data collection CRF

19. C. difficile data collection

20. C. difficile Adjudication patients with possible CDI randomly allocated to a pair of adjudicators ED DJC JD JJ independent blind adjudication consensus consensus on CDI and CDI related outcomes consensus

22. C. difficile Adjudication in PROSPECT

23. Strengths: duplicate adjudication standard definition of CDI (Public Health Ontario) application of multiple severity criteria systematic collection of complications + treatments rich patient baseline and daily data Limitations: event rate is likely to be low results in a selected RCT population C. difficile outcomes in PROSPECT