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
Bacteroidetes reduced 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)
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

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): ;

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. 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

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 ?