The Comparative Efficacy of Different Forms of Fecal Matter Transplantation (FMT) for Recurrent Clostridium difficile colitisMONISHA BHATIAINFECTIOUS DISEASE ACESEPTEMBER 23, 2016

Case Presentation

89 year old Caucasian female

HPI: Since January admitted 4x for c. difficile colitis◦ 2/20-3/7/16 for diarrhea, positive c.diff., PNA, started on Flagyl, d/c on

vancomycin PO regimen◦ 3/28-3/31 diarrhea worsened, positive c.diff, discharged on 6 week vanc taper◦ 5/11-5/15 diarrhea, positive c.diff, discharged on 10 week vanc taper◦ 8/31 Readmitted with worsening diarrhea, positive c.diff, some 3-4 bowel

movements per day on oral vancomycinHad received workup for fecal transplant with GI outpatient (intended granddaughter as donor) but fell through due to readmission and decompensation)

PMH: Hereditary Factor IX deficiency, DM 2, Hyperchol, MVR, aortic stenosis, breast cancer s/p mastectomy 1980, torticollis s/p botox injections

FHX: Mother – colon cancer treated with colectomy, father – CAD and stroke

SHX: Retired, widowed, lives with daughter on a sheep farm with grandchildren and greatgrandchildren

PDX: Wt 44.75 Pulse 80 RR 18 BP 115/71 Tc 36.9◦ GI: bowel sounds faint, diffusely tender to palpation, mild voluntary guarding,

no Murphy's sign, no hepatomegaly, no splenomegaly

For adult patients with recurrent clostridium difficile colitis,

what is the best method of fecal transplant, and how does this treatment option compare in terms of complications and symptom resolution

with extended-taper, broad-spectrum antibiotics?

QUESTION:

C. Difficile PathogenesisTcdA and TcdB are protein toxins that cause the symptoms associated with c. difficileResistant to heat, acid, and antibiotics

Risk FactorsWeakening of the fecal microbiota by antibioticsAdvanced ageAntineoplastic chemotherapySevere underlying diseaseImmunosuppressionIBD

Toxins inactivate Rho GTPases colonocyte death loss of barrier function neutrophilic colitis

Leffler DA, Lamont JT. N Engl J Med 2015;372:1539-1548.

History of C. Difficile Infections as a Public Health Problem

Early 2000s◦ hospitals report increases in

severe c. difficile infection

2016◦ The incidence of c.diff

infections has tripled in the last 15 years

Leffler DA, Lamont JT. N Engl J Med 2015;372:1539-1548.

Standard of Care for Recurrent C. Difficile

NEJM (2015) IDSA Guidelines (2010, new guidelines in progress)

First Recurrence

oral vancomycin 125 mg 4 mg per day for 14 days OR oral fidaxomicin (200 mg BID for 10 days

Mild- moderate: Metronidazole 500 mg orally 3 times per day for 10–14 daysSevere: Vancomycin 125 mg orally 4 times per day for 10–14 daysSevere/complicated: vancomycin 500 mg PO 4 /day and 500 mg in 100 mL normal saline as enema every 6 hours, metronidazole every 8 hours 500 mg IV

Second Recurrence

Second or further recurrence vancomycin tapered/pulsed regimen 125 mg 4 times a day for 1 week 125 mg 3 times a day for 1 week 125 mg 2 times a day for 1 week 124 mg once a day for 1 week 125 mg once every other day for 1 week 125 mg every 3 days for 1 week Fidaxomicin 200 mg bid for 10 days

As above; or treatment of the second or later recurrence of CDI with vancomycin therapy using a tapered and/or pulse regimen is the preferred next strategy

Is FMT better than the standard of care?Randomly assigned patients to get

Vanc regimen (500 mg orally 4x/day) bowel lavage and infusion of donor feces through NGT

Standard vanc regimen 500 mg PO 4/day for 14 days Standard vanc regimen with bowel lavage

Study stopped with interim analysis 81% had resolution of C. diff diarrhea after the first infusion; 3 remaining had second infusion with different donor (resolution 2/3) Resolution with vanc regimen was 31% with vanc alone and 23% in vanc

with bowel lavage Adverse events: Cramping, belching for 3 hours or so

Fecal matter donation was much more effective than the current standard of care.

Duodenal infusion of donor feces for recurrent Clostridium difficile.0. van Nood E, Vrieze A, Nieuwdorp M, et al. The New England journal of medicine 2013; 368:407-15.

Ponte A, Pinho R, Mota M, Silva J, Vieira N, Oliveira R, Pinto-Pais T, Fernandes C, Ribeiro I, Rodrigues J, Lopes P, Teixeira T, Carvalho J. Initial experience with fecal microbiota transplantation in Clostridium difficile infection - transplant protocol and preliminary results. Rev Esp Enferm Dig. 2015 Jul;107(7):402-7. PubMed PMID: 26140631.

Donor Selection Unrelated volunteersExclusion High risk sexual behaviors, ilicit drug use, tattoo or body piercings <6 m, travel to areas with endemic

diarrheal illness, history of GI malignancy/polyposis, antibiotics in the preceeding 3 months, immunosuppression, obesity, major GI surgery, autoimmunity syndrome

Testing Syphilis, HIV, hep A, B, C C. Diff toxinBacterial culture for enteric pathogens, ova, parasites, Giardia antigen, and cryptosporidium antigen

Preparation Lactulose the night beforeStool Prep 1) Suspended in saline 2) manually mixed to homogenize suspension 3) 50 g of feces into dilutent 4) 25-

50 mL and 250-500 mL for administration through endoscopy OR colonoscopy respectively 5) filtration through gauze pads 6) 50 cc opaque syringes 6) within 24 hours of FMT, refrigerated until that time

Recipient prep Stayed on abx recommended until prep with 4L of polyethylene glycol the night before the procedure40 mg IV pantoprazole before upper endoscopy OR 2 mg PO loperamide if given via colonoscopy

Instillation Endoscopy without sedation: instilled into duodenum, 25 ml water flush, minimal insufflationColonoscopy with deep sedation: terminal ileum infusion and 50 cc syringe with 50 mL of liquid stool along the entire bowel, sparing the rectum

RESULTS NGT: 7/8 via endoscopy, 1/8 via colonoscopy 5/6 (83.3% cure rate) for endoscopy, Colonoscopy: 1/1 for colonoscopy. Time to resolution ranged from 1-2 days; no adverse events during the follow up time

Youngster I, Russell GH, Pindar C, et al. Oral, capsulized, frozen fecal microbiota transplantation for relapsing Clostridium difficile infection. JAMA 2014 ;312:1772-8. DOI: 10.1001/jama.2014.13875

Donor Selection

Unrelated volunteers

Exclusion No medications, normal BMI, no significant past medical history except traumatic injury, antibiotics in past 6 months, AABB questionnaire,

Testing general lab screening tests; enteric pathogens in feces, blood screened for hep A, B, C, HIV, Treponema pallidum within 2 weeks of donation interim questionnaire for symptoms; stored for 4 weeks; paid small stipend.

Preparation refrain from eating common allergens within 5 days of stool donationStool Prep 1) Fecal suspension in normal saline, commercial blender 2) sieve 3) centrifugation and concentration 4) 1/10

volume of initial sample + 10% glycerol for bacterial cryoprotection 5) pipetted into 650 µL capsules, closed in another capsule 6) storage at -80 C 7) Acid resistant hypromellose capsules used

Recipient prep

Discontinue antibiotics for CDI 48 hours before FMT and asked to fast for 4 hours before and 1 hour after capsule intake. 15 capsules handed individually by an investigator on 2 consecutive days. No improvement at 72 hours retreatment with same donors innoculum

Instillation Endoscopy without sedation: instilled into duodenum, 25 ml water flush, minimal insuflationColonoscopy with deep sedation: terminal ileum infusion and 50 cc syringe with 50 mL of liquid stool along the entire bowel, sparing the rectum

RESULTS No serious adverse events 70% had resolution after first administration, and remained symptom free at 8 weeks. Non-responders re-treated at 7 days, 5/6 with resolution after second.

Establishing a Fecal Microbiota Transplant service for the treatment of clostridium difficile infection SP Costello, EC Tucker, J La Brooy, MN Schoeman, JM Andrews Clin Infect Dis. (Oct 2016) doi: 10.1093/cid/civ994

Screening: No evidence that certain enterotypes have better outcomes; only 31% of 44 respondents were eligible for donation Psychiatric, malignancy, neurologic disease, autoimmune disease,

atopic disease, metabolic syndrome

Sample Prep: Frozen stool samples produced with 10% glycerol, 65% saline for 1 minute in 200 mL aliquots Manual and mechanical mixing are both acceptable Variation in yield from each donor Blender should be autoclaved between uses

Delivery : 1) Stop vancomycin, 2) bowel lavage if colonoscopy elected, 3) loperamide or PPI prep depending on the delivery method 4) thaw sample 5) perform procedure 6) review at 1 week

Regulation and Payment Issues Two stool banks as of March 2016 – Open Biome in Medford, MA and AdvancingBio in Mather CA (with 500 and 15 hospital customers so far)

IND sub-investigator approval via IRB might be an undue burden, not currently clear what hospitals have to do to have access to the stool samples

Master File as a way of understanding the quality controls of stool samples

Initially FDA had placed a moratorium on FMT but now has used enforcement discretion to avoid suppressing efforts to implement FMT

While FMT has proven benefit, not currently reimbursed by most third party payers

ConclusionsCONCLUSIONS

FMT is a highly effective treatment for recurrent c. difficile colitis

NGT is equally safe as colonoscopy in several trials, but both pose risks due to the delivery method itself

PO method may be limited by high pill burden, less effective than other methods

Colonoscopy may be marginally better but imposes greater risks due to anesthesia than endoscopy or PO option

Variation in exclusion criteria has not had a discernible impact on treatment failure or complications

REMAINING QUESTIONS

Benefit of multidonor pooled FMT?

Necessity of each of the steps in current protocols?

Something we could offer inpatient if fecal samples are already available?

Which specialty to deliver the care? More like donation than transplantTechnically within GI’s wheelhouse as it currently

is executedPO options? Other microbiome Reconstitution procedures?

References1. David Salisbury, These Days, Fecal Transplantation is No Joke, Vanderbilt University Research News (Jul 12,

2016) (available at: https://news.vanderbilt.edu/2016/07/12/these-days-fecal-transplantation-is-no-joke/)

2. Leffler DA, Lamont JT. N Engl J Med 2015;372:1539-1548 (http://www.nejm.org.proxy.library.vanderbilt.edu/doi/full/10.1056/NEJMra1403772)

3. Youngster I, Russell GH, Pindar C, et al. Oral, capsulized, frozen fecal microbiota transplantation for relapsing Clostridium difficile infection. JAMA 2014 ;312:1772-8. DOI: 10.1001/jama.2014.13875

4. Drekonja D, Reich J, Gezahegn S, Greer N, Shaukat A, MacDonald R, et al. Fecal Microbiota Transplantation for Clostridium difficile Infection: A Systematic Review. Ann Intern Med. 2015;162:630-638. doi:10.7326/M14-2693

5. Ponte et al, Initial Experience With Fecal Microbiota Transplantation in Clostridium Difficile Infection – Transplant Protocol and Preliminary Results, Rev Esp Enferm Dig (Madrid)

6. Duodenal infusion of donor feces for recurrent Clostridium difficile.0. van Nood E, Vrieze A, Nieuwdorp M, et al. The New England journal of medicine 2013; 368:407-15.