Fecal Microbiota Therapy (FMT) in the Management of

C. difficile Infection (CDI)

Lawrence J. Brandt, MDEmeritus Chief, Gastroenterology

Montefiore Medical CenterProfessor of Medicine and SurgeryAlbert Einstein College of Medicine

Freston Symposium

Conflicts of Interest

Cipac: Advisory Board

Incidence and Impact of C. difficile

~ 500,000 cases~ $5 billion in excess costs~ 30,000 deaths annually

Campbell et al. Infect Control Hosp Epidemiol. 2009:30:523-33 Dubberke et al. Emerg Infect Dis. 2008;14:1031-8

Dubberke et al. Clin Infect Dis. 2008;46:497-504 Elixhauser et al. HCUP Statistical Brief #50. 2008

ACG Rx Guidelines for CDI, 2013Mild-moderate MZ (500 mg po tid) x 10 days

♦ Strong recommend, high qual evid

Severe Vanco (125 mg po qid) x 10 days ♦ Cond recommend, mod qual evid

if NR Vanco (500 mg po qid) plus MZ (500 mg IV tid)

♦ Strong recommend, mod qual evid

Complicated Vanco po (125-500 mg qid) and pr (500 mg in 500 mL qid) plus MZ (500 mg IV tid) if ileus, toxic colitis, distention

♦ Strong recommend, low qual evidconsider surgRx if: BP (pressors); sepsis, MOF; MS change; WBC≥50 K, lactate ≥5; no improvement (5d) ♦ Strong recommend, mod qual evid

Am J Gastroenterol, 2013

Fidaxomicin vs Vanco

Louie TJ et al. N Engl J Med 2011; 364:422-431

200mg BID x 10 d

125mg QID x 10 d

@28d

Fidaxomicin is superior to Vanco for 1st CDI recurrence

Cornely, OA et al. CID 2012:55 (Suppl 2); 154-61

20% (13/66) recurrence

36% (22/62) recurrence

Standard therapy x 10-14 days (MZ , 82%; Vanco,18%) followed by:

Placebo or Rifaximin (400 mg tid x 20 days)

Rifaximin “chaser” for Recurrent CDI

Garey et al. J Antimicrob Chemother 2011

Outcome Rifaximin(n=33)

Placebo(n=35)

 

Recurrent diarrhea 21% 49% P = 0.018Recurrent CDI 15% 31% P = 0.11

Rifaxamin

Placebo

Antibody and Vaccine Rx

Antibodies RDBPC study of fully human monoclonal antibodies against C. difficile toxins A and B

♦ administered as a single infusion (10mg/kg) ♦ 200 patients, receiving abx for active CDI

♦ primary outcome: recurrence w/in 84 days -- antibodies: 7%, placebo: 25% antibodies: 7%, placebo: 25% -- pts with BI/NAP1/027: 8% vs 32% pts with BI/NAP1/027: 8% vs 32%

- - pts with prior recurrence: 7% vs 38%pts with prior recurrence: 7% vs 38%Vaccines

Sanofi announced (Aug 2013) starting late-stage trials (15,000 people) testing C. difficile vaccine

Lowy I et al. N Engl J Med 2010; 362:197-205

Non-toxigenic C. difficile (NTCD) Strain VP 20261*

Phase II trial (ViroPharma, Inc)CDI patients on oral vancomycinPlacebo (n=43)or NTCD (n=125)

- 104 x 7 days (n=41)

- 107 x 7 days (n=43)

- 107 x 14 days (n=41)

2% CDI recurrence rate in colonized pts

0%

69%

30%

11%

0%

20%

40%

60%

80%

100%

Colonizedby NTCD

Recurrenceof CDI

Placebo NTCD

P<0.0001

P<0.01

Recurrent C.difficile Infection

15-20% of patients relapse re-infection post-C. difficile IBS

2nd recurrence: 30-45%; 3rd recurrence: 45-60%

Rx failure before 2003 <10%; after 2003 ~20%

Relapses can continue for years

No universal Rx algorithm

Rx recommendations are not evidence-based

Recurrent C.difficile Infection Why Do We Get It?

Impaired host-response

Altered intestinal microbiome

Spor A, Koren O, Ley R. Nature Reviews Microbiology, 2011

Bacteroidetes~16%

Firmicutes~76%

Decreased Diversity of the Fecal Microbiome in Recurrent C.difficile

Chang JY, et al. J Infect Dis 2008:197;435-8

Bacteroidetes and Firmicutes are reduced in patients with recurrent C.difficile not in patients with just one episode of C.difficile infection

Patients with recurrent C.difficile have decreased phylogenetic richness

Mouse Model for C. difficile-Mediated Dysbiosis... and Successful FMT

Modified from: Lawley TD et al.. PLoS Pathog (2012); 8: e1002995.

or FMT

Antibiotic perturbation (clinda x 7d)

C. difficile (027/B1)

Simplified microbiota

↑ pro-inflammatory genes

↓ butyrate, acetate ↑succinate

Homeostasis

Transient dysbiosis

Disrupted dysbiosis

↓ shedding C. difficile

Persistent dysbiosis

Vanco

BacterioRx (6 spp) or FMT

Expansion of microbiota

ACG Rx Guidelines for CDI, 2013Recurrent CDI 1st: Can use same Rx as for initial episode;

if severe, use Vanco 2nd: Pulsed vanco regimen ♦ Cond recommend, low qual evid

3rd: Pulsed-tapered Vanco; (no comparative data) - 125 mg daily pulsed Q3D for 10 doses - qid tid bid qd regimen

- qid interval dosing (q2d, q3d, q4d) Consider FMT.

♦ Cond recommend, low qual evid

Intravenous immune globulin (IVIG) may be helpful in hypo-gammaglobulinemic pts

♦ Strong recommend, low qual evidAm J Gastroenterol, 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 by re-introduction of donor feces

Rationale for FMT in Recurrent CDI

Avoid prolonged, repeated courses of antibiotics

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

4th century: Ge Hong described use of human fecal suspension by mouth for food poisoning or severe diarrhea “Zghou Hou Bei Ji Fang” (Handy Therapy for Emergencies)

Early History of FMT

16th century: Li Shizhen detailed prescriptions of fermented fecal solution, fresh fecal suspension, dry feces or infant feces for abdominal diseases with diarrhea, abdominal pain, fever, vomiting and constipation; “yellow dragon soup” “Ben Cao Gang Mu ” (Compendium of Materia Medica )

17th century: veterinary medicine: transfaunation (transfer of cecal contents or fresh feces) from healthy horses to treat horses with chronic diarrhea

rumen transfaunation is used to refaunate cows that have been off-feed because of mastitis or other illness

Later History of FMT

1958: Eismann et al. 4 pts with pseudomembranous colitis (Micrococcus pyogenes) Rxd with FMT enema

1983: Schwann, et al. CDI Rxd with FMT enema

Other methods of FMT 1991: NG tube (Aas, Gessert, Bakken) 1998: gastroscopy and colonoscopy (Lund-TØnnesen) 2000: colonoscopy (Persky, Brandt) 2010: self-administered enemas (Silverman, Davis, Pillai)

Protocol for FMT in Recurrent CDIChoose donor

any healthy person universal donor

Donor exclusions antibiotic use within 3 months diarrhea, constipation, IBS, IBD, colorectal CA, immunocompromise, anti-neoplastic drugs,

high-risk behaviors: MSMP, recent body piercing or tattoo other: diabetes, obesity, atopy, ASCVD... ? psychologic or mood disorder, neurologic disease...

Donor testing stool: culture (incl Listeria, Vibrios), O & P, C. difficile, H. pylori Ag, Giardia Ag, cryptosporidium, isospora, norovirus blood: hepatitis A, B, C, syphilis, HIV 1, 2

POOP

Protocol for FMT in Recurrent CDI

Recipient D/C antibiotics 2-3 days before procedure? Large-volume colonoscopy prep the evening before procedure Loperamide before procedure?

Donor Gentle laxative (e.g., MOM) the night before the procedure? Freshly passed stool is used within 6 hours Stool need not be refrigerated

Protocol for Colonoscopic FMT in Recurrent CDI

Stool Transplant Donor stool → suspension with non-bacteriostatic saline mix by hand mix by blender Filtered through gauze into canister Use of a hood (stool is a level 2 biohazard) 60 cc catheter-tip syringe connected to “suction” tubing Volume of ~300cc instilled into ascending colon

Kassam et al . AM J Gastroenterol, 2013

Meta-analysis of Clinical Resolution Rates (11of 2709 reports, 273 patients)

Resolution 90% overall lower: 91% upper: 82% No AEs

Site of FMT

Dose of FMT(mean g/mls)

Success Rate (%)

# of Pts

Stomach 109 25/68 81

Duod/Jejunum 97 63/252 86

Cecum/Asc Colon 214 93/281 93

Distal Colon 116 58/272 84

Cammarota G, Ianiro G, Gasbarrini, A. J Clin Gastroenterol, 2014

FMT for Treatment of CDI: A Systematic Review

Nasoduodenal FMT for Recurrent CDI: a RCT

van Nood E , Vrieze A , Nieuwdorp M et al. N Engl J Med 2013;368:407–15

Study terminated by DSMB AEs: transient cramping, belchingSAEs: none

Follow-up Survey 77 patients > 3 months after FMT

Mean duration of illness: 11 months

Symptomatic response after FMT mean of 6 days < 3 days in 74%

Primary cure rate: 91 % Secondary cure rate: 98.7% 97% of patients would have another FMT for recurrent CDI

and 58.3 % would choose FMT as their preferred Rx

All late recurrences occurred in setting of subsequent unrelated antibiotics

Brandt LJ, et al. Am J Gastroenterol, 2012

Cure Rates and AEsin 146 Patients > 65 years of Age

CDI (n) Primary cure rate

Secondary cure rate

Transient AEs

Serious AEs

R-CDI (89)

82% 94.4% 11.2% 2.2%

S-CDI (45)

88.8% 97.7% 4.4% 4.4%

C-CDI (12)

67% 100% 0% 16.6%

Total(146)

82.8% 95.8% 7.5% 4.1%

Agrawal M, Aroniadis O, Brandt L, et al, DDW, 2014

How Do Patients Feel About FMT?

Hypothetical case scenarios given to clinic attendees (n=192) efficacy data alone (Floral Reconstitution) (85%) awareness of fecal nature of FR (81%) FMT chosen if by pill (90%) or if MD recommended (94%)

FMT issues found most unappealing need to handle stool (65%) receiving FMT by NGT (75%) women: all aspects of FMT unappealing, “gross” (odor,

handling stool) men: concerned with safety issues no signif diff in age or education level older patients: FMT less unappealing

Zipursky, et al. Clin Infect Dis, 2013

How Do Physicians Feel About FMT?

2010 (Kelly et al): 73 physicians 10% had performed FMT or knew a colleague who had

48% willing to try FMT 34% unwilling to try FMT 2013 (Sofi et al): 118 physicians (85 GE, 32 ID)

86% willing to do FMT 9% unwilling to do FMT need for published Guidelines concerns for safety

Kelly, ACG meeting 2010; Sofi, Am J Gastroenterol 2013

FDA RegulationsEarly 2013. Fecal microbiota falls within the definition of a

biologic product and a drug. Since FMT has not yet been approved by the FDA for any specific clinical indication, it constitutes an investigational agent and requires an Investigational New Drug application (IND) from Center for Biologics Evaluation and Research (CBER) . 

May, 2013. Public workshop on FMT

July, 2013. FDA intends to exercise “enforcement discretion” regarding IND requirements for the use of FMT to treat C. difficile infection not responding to standard therapies…provided that the treating physician obtains [appropriate] adequate informed consent . Informed consent should include, at a minimum, a statement that the use of FMT products to treat C. difficile is investigational and a discussion of its potential risks.

FMT…the next steps

Donor Material N Success* RecurrencePt-identified donor 10 7/10 (70%) 3/10 (30%)

Std donor, fresh 12 11/12 (92%)

Std donor, frozen 21 19/21 (90%)

Total 43 37/43 (86%) 6/43 (14%)

3/33 (9%)

4 of 6 patients with RCDI had a 2nd FMT (std donor) all cleared their infection final success rate of 41/43 (95%)

*Hamilton, et al. Am J Gastroenterol 2012;

A. Frozen fecal material from a universal donor*

B. Synthetic stool (33 bacterial strains) from healthy donor(Repoopulate) # 2 patients cured of RCDI

# Petrov ,, et al. Microbiome 2013; Graham, ACG. 2013

C. 3 strains of Bacteroides (ovatus, fragilis, thetaiotaomicron) 1 patient cured of RCDI

D. Poop pills%: 27 patients took 24-34 pills all cured of RCDI

%Thomas Louie, Univ of Calgary; ID week, 2013

Therapeutic unit of full-spectrum microbiota

Petrof EO, Khoruts A. Gastroenterology 2014

Anatomy of a Robogut

Petrof EO, Khoruts A. Gastroenterology 2014

LactateProducers

SCFAProducers

Methanogens

MucinDegraders

Fecal Microbial Transplant Consortium Single strain BioactiveMolecule

Specificity

Ecosystem Effects

Modfied from Olle, B. Nature Biotechnology, 2013

Safety and Ethical Concerns Acute infections bacterial, viral, parasitic colonic, systemic

Acute allergic reactions

Long-term concerns is it possible that we are predisposing the recipient to

(some, all) of the diseases /conditions that the donor will develop in his/her lifetime?

have we created a microbiomic clone of the donor? for how long will the donor microbiota populate the

recipient’s colon?

Future Areas of Investigation

Indications CDI: severe, complicated disease? 1st occurrence? other GI diseases: IBD, IBS, constipation non-GI diseases: diabetes, obesity, Parkinson’s, MS, autism?

Route and means of administration Safety and ethical concerns:

short-term: infections, allergies long-term: diseases of the donor, altered microbiota

Product development processed stool → spec strains ± bioactive molecules

Solutions

Use the safest product possible stool is most problematic stool-derived product from volunteer population

is probably safer bioengineered (commercial) product is safest

Monitor results carefully national registry for all FMT

Take Home Points

Current guidelines are rational and initial routine care should be concordant with these

recommendations Fidaxomicin is effective FMT has reached a “critical mass” and is likely

the most appropriate salvage therapy currently available for multiply recurrent CDI.

More robust (RCTs) data are needed. Concern for long-term sequelae

FMT will be replaced by bioengineered product(s)