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

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

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

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

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

Intestinal Microbiota: Environmental Influence and Immune Response

Microbiota and Host Physiology

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

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

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

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

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

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

ACG Rx Guidelines 2013

Fecal Microbiota Transplantation (FMT) 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 Brandt LJ ACG Meeting Oct. 2012

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

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

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

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

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

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;

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

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

Brandt LJ, et al. Am J Gastroenterol 2012 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

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)

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

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

Questions ?