Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile

1. Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile Els van Nood, M.D., Anne Vrieze, M.D., Max Nieuwdorp, M.D., Ph.D., et al. N Engl J Med Volume 368(5):407-415 January 31, 2013

2. Background • C. difficile infection can be life-threatening • 15-26% do not respond to initial treatment • No effective treatment for recurrences • Vancomycin: 60% response in 1st recurrence (lower in multiple recurrences)

3. Persistence of spores, diminished antibody response, altered microbiota • Reports that fecal infusion is effective (>300 cases) • No RCT

4. Method • RCT • 3 Therapies (donor infusion after BL and vanc, standard vanc, standard vanc with BL) • 1 center: AMC Amsterdam

6. Population • > 18 years old • Life expectancy > 3 months • C diff relapse after appropriate AB course • Exclusion criteria: • immunocompromized (post chemo, HIV with CD4 <240) • steroid use • pregnancy • other antibiotics • ICU, pressors

7. Treatment • Group 1 • Abbreviated vanc: 4 days 500 mg Q6 • Bowel lavage (4 ltrs macrogol) on day 4 • Duodenal infusion of feces day 5 • Group 2 • Standard vanc (14 days 500 mg Q6) • Group 3 • Standard vanc with bowel lavage day 4-5

8. Infusion • Donors <60 yrs, volunteers • Feces screened for parasites, c. diff, enteropathogenic bacteria • Collected same day, diluted 500 cc NS, stirred, strained and collected. • Nasoduodenal tube, 50 ml/2-3 mins • Tube removed after 30 mins

9. Endpoints • Primary: cure (without relapse) within 10 weeks. • Secondary: cure (without relapse) within 5 weeks • Blinded adjucation committee • Stool diary • Interview day 7, 14, 21, 35, 70 • Stool tested day 14, 21, 35, 70

10. Statistics • Assumed 90% cure for infusion, 60% for AB • Planned 40 patients per treatment group

11. Results • Jan 2008 – April 2010 • Total 43 patients • After interim analysis was performed

12. Baseline demographics

13. Enrollment and Outcomes

14. Outcomes • Infusion (N=16): 94% cured • 13 (81%) cured after 1 infusion • 2 (13%) cured after 2 infusions • Vanc alone (N=13) • 4 (31%) cured • Vanc and BL (N=13) • 3 (23%) cured • Cure rate ratio • 3.05 (99.9% CI 1.08-290) as compared to vanc alone • 4.05 (99.9% CI 1.21-290) as compared to vanc and BL

15. Cure without Relapse

16. Recurrence at 5 weeks • Infusion: • 1/16 (6%) • Vanc alone: • 8/13 (62%) • Vanc and BL: • 7/13 (54%) • After initial AB off label infusion cured 15/18 (83%)

17. Microbiota Diversity

18. Adverse events

19. Conclusion • The infusion of donor feces was significantly more effective for the treatment of recurrent C. difficile infection than the use of vancomycin.

20. Discussion • High risk groups not studied: immunodeficiency, critically ill, pts requiring other AB • Prolonged vancomycin taper not compared • 56% of patients did have this before inclusion • Only 8/43 patients included had 1st recurrence when randomized • Reluctance to infusion • Other promising strategies • fidaxomycin • infusion of antibodies

21. No clear protocol for infusion yet • How much feces? • Upper or lower endoscopy? Enema? • Bowel lavage needed?

22. Critical appraisal • Randomized – Yes • Similar groups – Yes • Groups equally treated – Yes • All patients accounted for – Yes • Objective/Blind – Only outcome • Treatment effect large – Yes (small population, large CI) • Not clearly reported • Lasting? • External validity: unclear after which recurrence to be used, role of vanc taper/fidaxomycin, certain groups excluded.