Transcript Fecal Microbiota Transplant 9.14.2013
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
10 14 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 2 nd recurrence: 40%; 3 rd 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
4 th
Century: Oral human fecal suspension (
“
yellow soup
”
) for severe diarrheal illnesses
17 th
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 1 st 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: 1 st RCT of FMT vs Oral Vanco
Van Nood N et. al. NEJM 2013
FMT in Recurrent CDI: 1 st RCT of FMT vs Oral Vanco *** Trial stopped early as deemed unethical to continue
Van Nood N et. al. NEJM 2013
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
1 st occurrence Other GI: IBD, IBS, constipation Non-GI: DM, obesity, Parkinson, MS, ITP, Autism?
Route of administration
LGI transplant better than UGI ?
Safety