Fecal Microbiota Transplantation (FMT)

1. Fecal Microbiota Transplantation (FMT) Spencer A. Wilson, MD Northside Gastroenterology September 14, 2013

3. Overview • Intestinal microbiome and host physiology • Dysbiosis of the microbiome and C. difficile infection (CDI) • “Standard” Rx of CDI • FMT for restitution of “colonization resistance” • Rx of recurrent/refractory CDI • The future of FMT

4. Intestinal Microbiota • Includes bacteria, archea (single-celled prokaryotes), viruses, fungi and parasites • > 50 bacterial phyla described • Majority anaerobic • Constitute 60% of dry weight of feces • Bacteroides, Firmicutes, Actinobacteria, Proteobacteria • 1014 bacterial cells  10 times greater than number of human cells in our body Eckburg, PB et al. Science 2005:308;1635-8

5. Intestinal Microbiota:Role in Health and Disease De Vos, WM. SelfCare 2012;3(S1):1-68

6. Intestinal Microbiota:Alterations During Human Life Cycle Ottman, N. Front Cell Infect Microbiol. 2012;2:104

7. Intestinal Microbiota:Environmental Influence and Immune Response

8. Microbiota and Host Physiology

9. C. difficile Infection (CDI) • 1996 – 2009 in U.S., rates of CDI doubled • 3 million cases per year • Unadjusted fatality rate • 1.2 % (2000)  2.3% (2004) • Majority > 65 y/o • ~ 3.2 billion dollars excess cost of care

10. C. difficile Manifestations • Carrier state • C. difficile - associated diarrhea (CDAD) • C. difficile colitis • Pseudomembranous colitis • Fulminant Colitis / Toxic megacolon • Atypical (e.g., sepsis, ascites) • Recurrent disease

11. Recurrent CDI • 15-20% of patients • Relapse • Re-infection • Post-CDI irritable bowel syndrome • 2nd recurrence: 40%; 3rd recurrence 60% • Rx failure before 2003 < 10%; after 2003 ~ 20% • Relapses can continue for years • No universal Rx algorithm

12. Why Do We Get Recurrent CDI ? • Impaired host-response • Altered intestinal microbiome • “Dysbiosis” = decreased microbiota diversity

13. Host Immune Response to C. difficile Infection • IgG anti-toxin A protects against diarrhea and colitis

14. Decreased Diversity of Fecal Microbiome in Recurrent CDI Decreased phylogenic richness in recurrent CDI Bacteroidetesreduced in recurrent but not single episode CDI Chang JY, et al. J Infect Dis 2008:197;435-8

15. ACG Rx Guidelines 2013

16. Fecal Microbiota Transplantation (FMT) Brandt LJ ACG Meeting Oct. 2012 Definition: Instillation of stool from a healthy person into a sick person to cure a certain disease Rationale: A perturbed imbalance in our intestinal microbiota (dysbiosis) is associated with or causes disease and can be corrected with re-introduction of donor feces

17. Recurrent CDI: Rationale for FMT Avoid prolonged, repeated courses of antibiotics Re-establish normal diversity of the intestinal microbiome, thus restoring “colonization resistance”

18. Early History of FMT • 4th Century: • Oral human fecal suspension (“yellow soup”) for severe diarrheal illnesses • 17th Century: Veterinary medicine • Fecal transfer for horses with diarrhea • 1958: FMT enema • Eismann, et al. 4 patients with pseudomembranous colitis • “Dramatic” response within 48 hours

19. Protocol for FMT in Recurrent CDI • Choose donor • Spouse/partner • 1st degree relative • Household contact • Universal donor • Donor exclusions • Antibiotic use within 3 months • Diarrhea, constipation, IBS, IBD, colorectal CA, immunocompromised, anti-neoplastic drugs, obesity, metabolic syndrome, atopy, high-risk behaviors • Donor testing • Stool: culture, listeria, O&P, C. diff, H. pylori Ag, Giardia Ag, cryptosporium Ag, acid-fast stain (cyclospora, isospora), Rotavirus • Blood: Hep A, Hep B, Hep C, syphilis, HIV Brandt LJ ACG Meeting Oct. 2012

20. Protocol for FMT in Recurrent CDI • Recipient • D/C antibiotics 2-3 days prior to procedure • Large volume bowel prep evening before FMT • Loperamide before procedure • Donor • Gentle laxative (e.g. MOM) evening before FMT • Freshly passed stool is used within 6-8 hours • Stool need not be refrigerated Brandt LJ ACG Meeting Oct. 2012

21. Protocol for FMT in Recurrent CDI • Stool Transplant • Donor stool  suspension with non-bacteriostatic saline • Filtered through gauze into canister • Use of hood (level 2 biohazard) • 60 cc catheter tip syringe connected to “suction” tubing • Volume of ~ 300 mL instilled into ileum and/or ascending colon • Patient to hold stool for 4-6 hours Brandt LJ ACG Meeting Oct. 2012

22. Current History of FMT in Recurrent C. difficile infection Kleger, A; Schnell, J; Essig, A; Wagner, M; Bommer, M; Seufferlein, T; Härter, G Fecal Transplant in Refractory Clostridium difficile Colitis Dtsch Arztebl Int 2013; 110(7): 108-15;

23. FMT in Recurrent CDI: 1st RCT of FMT vs Oral Vanco Van Nood N et. al. NEJM 2013

24. FMT in Recurrent CDI: 1st RCT of FMT vs Oral Vanco *** Trial stopped early as deemed unethical to continue Van Nood N et. al. NEJM 2013

25. Follow-up Survey • 77 patients > 3 months after FMT • Duration of illness: 11 months • Symptomatic response after FMT • < 3 days in 74% • Primary cure rate: 91% • Secondary cure rate: 98.7% • 97% of patients would have another FMT for recurrent CDI • 58% would chose FMT as their prefered Rx Brandt LJ, et al. Am J Gastroenterol 2012

26. FMT for Recurrent CDI • Drawbacks • Aesthetically unpleasing • No remibursement • Cautions • Potential transmission of pathogens • Pros • Re-establishes diversity of intestinal microbiota • Inexpensive • Efficacy > 90% • Rapidly effective (within hours-days)

27. Indications for FMT for CDI For recurrent, refractory dz – YES For severe dz – arguably yes As first-line therapy – arguably yes For post-C. difficile IBS - possibly

28. Future Direction of FMT • “Universal” donor • Processed and frozen until use • RePOOPulate • Artificial stool synthetic alternative • Indications • Severe, complicated CDI  1st occurrence • Other GI: IBD, IBS, constipation • Non-GI: DM, obesity, Parkinson, MS, ITP, Autism? • Route of administration • LGI transplant better than UGI ? • Safety

29. Questions ?