Fecal Microbiota Transplantation (FMT)

Fecal Microbiota Transplantation (FMT)

Spencer A. Wilson, MD

Northside Gastroenterology

September 14, 2013

Spencer A. Wilson, MD

Northside Gastroenterology

September 14, 2013

OverviewOverview

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 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 MicrobiotaIntestinal 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

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

Intestinal Microbiota:Role in Health and Disease

De Vos, WM. SelfCare 2012;3(S1):1-68

Intestinal Microbiota:Alterations During Human Life Cycle

Intestinal Microbiota:Alterations During Human Life Cycle

Ottman, N. Front Cell Infect Microbiol. 2012;2:104

Intestinal Microbiota:Environmental Influence and Immune Response

Intestinal Microbiota:Environmental Influence and Immune Response

Microbiota and Host PhysiologyMicrobiota and Host Physiology

C. difficile Infection (CDI)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

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 ManifestationsC. 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

Carrier state C. difficile - associated

diarrhea (CDAD) C. difficile colitis Pseudomembranous colitis Fulminant Colitis / Toxic

megacolon Atypical (e.g., sepsis,

ascites) Recurrent disease

Recurrent CDIRecurrent 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

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 ?Why Do We Get Recurrent CDI ?

Impaired host-response

Altered intestinal microbiome “Dysbiosis” = decreased microbiota

diversity

Impaired host-response

Altered intestinal microbiome “Dysbiosis” = decreased microbiota

diversity

Host Immune Response to C. difficile Infection

Host Immune Response to C. difficile Infection

IgG anti-toxin A protects against diarrhea and colitis IgG anti-toxin A protects against diarrhea and colitis

Decreased Diversity of Fecal Microbiome in Recurrent CDIDecreased 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

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 ACG Rx Guidelines 2013

Fecal Microbiota Transplantation (FMT)

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

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 FMTRecurrent CDI:

Rationale for FMT

Avoid prolonged, repeated courses of antibiotics

Re-establish normal diversity of the intestinal microbiome, thus restoring “colonization resistance”

Avoid prolonged, repeated courses of antibiotics

Re-establish normal diversity of the intestinal microbiome, thus restoring “colonization resistance”

Early History of FMTEarly 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

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 CDIProtocol 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

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 CDIProtocol 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

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 CDIProtocol 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

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

Current History of FMT in Recurrent C. difficile infection

Kleger, A; Schnell, J; Essig, A; Wagner, M; Bommer, M; Seufferlein, T; Härter, GFecal Transplant in Refractory Clostridium difficile ColitisDtsch Arztebl Int 2013; 110(7): 108-15;

FMT in Recurrent CDI: 1st RCT of FMT vs Oral Vanco

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

FMT in Recurrent CDI: 1st RCT of FMT vs Oral Vanco

Van Nood N et. al. NEJM 2013 *** Trial stopped early as deemed unethical to continue

Follow-up Survey 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

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 CDIFMT 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)

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 CDIIndications 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

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 FMTFuture 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

“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 ?Questions ?