Fecal Microbiota Transplantation (FMT) For Recurrent Clostridium difficile Infection Nedret Copur-Dahi, MD Associate Clinical Professor of Medicine UCSD, Section of Gastroenterology

Objectives Summarize C.difficile infection Understand when fecal transplantation is an appropriate treatment Discuss the different delivery methods of FMT Identify future treatment options

Clostridium difficile Brief Overview

Clostridium difficile Anaerobic, spore-forming, toxin-producing, gram + rod Transmission: via fecal-oral route Asymptomatic carriers; 5–15% of healthy adults 84.4% in newborns/infants 57% in residents in LTCF

Evolving Magnitude Rising incidence; >450,000 cases in 2011 CDC data Rising CDI-related death rate; 29,000 in 2011 Annual health care costs; up to $5.9 billion/year Lessa FC, et al. N Engl J Med. 2015;372:825-834 Has become the most common nosocomial pathogen; 12.1% of all hospital acquired infections Magill, et al. N Engl J Med. 2014;370(13):1198-1208

PPI Pathogenesis

Antibiotics to Precipitate Sleisenger and Fordtrans Gastrointestinal and liver disease, 9th ed. Saunders: Philadelphia, 2010: 1889-1903.

Recurrence Caused by same or different strain from the 1st infection and due to insufficient immune response and/or persistent dysbiosis Clostridium difficile recurs in 20 - 25 % 1,2 ; 40-60% after 1st recurrence 10% of patients will not respond to standard therapy 1.Kelly et al. N Engl J Med 2008; 359: 1932-1940. 2.Khanna et al.Am J Gastroenterol 2012; 107: 89-95.

Severe colitis Pseudomembranes Endoscopic appearance

Damaged Mucosa Intact Mucosa From J. Guarner MD US Centers for Disease Control and Prevention

Treatment: ACG Guidelines Surawicz et al. Am J Gastroenterol 2013;108:478-498

Surawicz et al. ACG Guidelines. Am J Gastroenterol 2013;108:478-498

Gut Microbiota 1000-1200 species, 1014 bacteria

Gut Microbiota Most important first-line host defense against pathogen colonization resistance to bacterial colonization stimulation of the mucosal immune system Infectious agents and antibiotic use disruption of the normal gut microbiota (dysbiosis) initial or recurrent C. difficile infection = deficient in Bacteroides and Firmicutes 1,2 1. Nat Rev Microbiol. 2011 Jan;9(1):27-38. Epub 2010 Nov 29 2. Chang JY, Antonopoulos DA, Kalra A, et al. J Infect Dis 2008; 197:435.

Fecal Microbiota Transplantation *** the ultimate probiotic ***

FMT History 4th Century: Human fecal suspension for food poisoning or severe diarrhea 16th -17th Century: yellow soup to treat diarrheal illnesses Transfaunation by veterinarians 1958 in Denver: fecal enema for fulminant, life-threatening pseudo-membranous enterocolitis 1983: FMT enema in 65 yo woman with CDI 1991: Via NG tube 200os: Colonoscopy

Is FMT Durable? Infused donor fecal microbiota: stable in composition over a 24-week period prolonged cure rate of 91 -94% immediate and complete resolution of symptoms Yoon SS, Brandt LJ. J Clin Gastroenterol 2010; 44:562

Drekonja D, et al. FMT for CDI: A Systematic Review Drekonja D, et al. FMT for CDI: A Systematic Review. Ann Intern Med May, 2015; 162:630. Minneapolis VAMC.

Drekonja D, et al. FMT for Clostridium difficile Infection: A Systematic Review (1980- Jan,2015). Ann Intern Med 2015; 162:630. Minneapolis VAMC.

Patient Selection Severe and recurrent C. difficile infection Failed multiple (≥3) attempts at conventional antibiotic therapy (vancomycin, metronidazole, fidaxomicin , or 6-8 week vancomycin taper, or vancomycin pulsed regimen of 10-13 doses or vancomycin followed by rifaximin chaser for 2 weeks). Refractory moderate to severe C. difficile diarrhea, failing vancomycin after >1 week

FMT Protocol – The Past

Protocol No standardization in the preparation and administration of the fecal suspension. Every facility prepared their own protocol.

Screening Donor : healthy relative or friend (ideally not sharing living quarters) with normal, daily stools, no recent antibiotics in the last six months, ideally no PMH Check: cbc hepatitis A,B,C, HIV-1,HIV-2, syphilis stool cultures stool ova and parasites stool C. difficile to rule out asymptomatic carriage Recipient: Check: HIV and hepatitis markers to avoid future questions about transmission

Antibiotics and Colon Lavage Oral vancomycin (500 mg twice daily for 7 days) Then single oral lavage with 4 liters of polyethylene glycol with electrolytes Can skip lavage if too ill to tolerate.

Administration Methods Retention enema Colonoscopy Nasogastric/nasoduodenal tube Oral !!!

Administration via LGIT

Preparation and Methods 200-300 g of donor stool suspended in 200-300 mL of normal saline homogenize briefly (2 min) in kitchen blender to a liquid consistency give via enema within 10 minutes or filter then infuse via colonoscopy into TI. retain for at least 6 hours (loperamide pretreatment) and then follow a high fiber diet repeat the process daily for five days (not practical) In less severe cases, a single colonoscopic infusion to the colon is adequate1. 1. Yoon SS, Brandt LJ. J Clin Gastroenterol 2010; 44:562

Via Enema Self-administered home fecal transplantation Stool infusate (~250 mL) was self-administered or administered by a family member . 7 patients : cured of C. difficile infection up to 14 months follow-up Silverman et al. Clin Gastroenterol Hepatol 2010; 8:471

Probiotic Infusion Package for bowel -PIP10  Starter pack for 10 home infusions.

Via Colonoscope Greater area of recolonization greater capacity to inhibit spore formation proximal to the splenic flexure. Deliver the microbiota to the distal small bowel where C. difficile can reside. 26 patients; 92% symptom free average follow-up of 10.7 months 1 Kelly et al. J Clin Gastroenterol..2012 Feb; 46(2):145-9 RCT of 46 patients; received full course vanco then - donor stool (cure rate : 92%) or - autologous stool (63%) or - placebo Kelly et al. Ann Intern Med. 2016;165(9):609. RCT: 3 or more recurrences, completed full course vamco before fmt. Autologous group success likely due to recent abx exposure prior to fmt

Adverse Reactions Transient and mild Post-enema symptoms: Abdominal gurgling, gas, and noise 1 Colonoscopy complications 1. Bowden TA Jr, Mansberger AR Jr, Lykins LE. Am Surg 1981; 47:178

Administration via UGIT

Preparation and Method Patient and stool preparation is similar. PPI (omeprazole 20 mg) evening before and morning of the instillation to decrease gastric acid NG or NJ tube is placed. The positioning is confirmed by x-ray and Gastrografin follow-through. A single instillation of 25 to 30 g of stool diluted in 50 mL of saline.

Via Nasogastric or Nasoduodenal Tube Can deliver the bacteria to the distal small bowel and throughout the colon. 43 patients; vancomycin 500 mg x4/day for 4 days, bowel lavage and duodenal infusion (81% resolution without relapse at 10 weeks) vancomycin 500 mg x4/day for 14 days (31% resolution) vancomycin 500 mg x4/day for 14 days with bowel lavage (23% resolution) van Nood et al. N Engl J Med. 2013;368(5):407.

Adverse Reactions Aspiration of the gastric contents !!!!!

Via Oral A fecal suspension in normal saline using a commercial blender. Concentrated by centrifugation and resuspended in saline at one-tenth the volume. Pipetted into size 0 capsules (650 µL), closed and then sealed in size 00 capsules. Acid resistant capsules were stored frozen at −80°C (−112°F). 1-2 hours prior to administration, they were transferred to −20°C, then transported on dry ice. 30 capsules contained sieved, concentrated material derived from a mean of 48 g of fecal matter. Youngster et al. JAMA. 2014;312(17):1772-1778. Division of Infectious Diseases, Massachusetts General Hospital.

Via Oral 20 patients Total 30 frozen FMT capsules (2 consecutive days). Diarrhea resolved in 14 of 20 patients with single treatment and 4 of 6 nonresponders who were retreated. No serious adverse events within six months follow-up. Larger studies are needed and in process. Youngster et al. JAMA 2014

FMT Appears to Be Safe No complications reported in published series Risks of aspiration with nasogastric tube Colonoscopy procedural risks Potential transmission of infectious agents contained in the stool. Case reports of norovirus GE, E.coli and polymicrobial bacteremia, flare of quiescent UC, herpes zoster after FMT. 77 patient with colonoscopic FMT: 3 mo to >10 years follow-up 4 autoimmune diseases (RA, ITP, Sjogren’s, peripheral neuropathy). No clear relationship. Brandt et al. Am J Gastroenterol 2012;107:1079-87

Post-FMT Recurrence No recurrence in 1 to 3 years in most patients even though a number of patients have subsequently required antibiotics for unrelated infections. Borody TJ, Warren EF, Leis SM, et al. J Clin Gastroenterol 2004; 38:475

The Present

The Present - OpenBiome Non-profit organization established in 2012 in Medford, MA; currently supported largely by charitable donations. Increased the accessibility and ease of FMT Donors: young researchers and scientists within the MIT, Harvard, and Tufts communities, and young professionals from the Tufts University area. Screened and tested every 60 days. Three products: FMP250 : 250mL fecal microbiota preparation for lower delivery (colonoscopy, enema).  FMP30 : 30mL fecal microbiota preparation for upper delivery.  FMT Capsule G3 (30 frozen capsules consumed within 90 min) They perform high-throughput 16S rRNA sequence characterization on stool samples from each of donors. While traditional approaches to FMT donor screening have focused on measuring what is absent, this way they can evaluate what is present in an FMT donor's microbiome.

The Future

Live Biotherapeutic Microbiota Preparations

Refined FMT: Synthetic Preparations Human synthetic stool mixture: 33 different bacteria two elderly patients symptom free for 6 months Petrof et al. Microbiome. 2013;1(1):3. Ongoing proof-of-concept study, estimated enrolment of 30 and completion in mid-2017, results pending NCT01372943

Refined FMT: Fecal Spore Preparations Encapsulated spore fractions containing 50 species from the Firmicutes bacteria phylum were prepared from donor stool for oral delivery as SER-109. 30 patients treated with 2 doses of encapsulated spores Absence of recurrence in 8 weeks follow-up was 87% Khanna S,et al. Aliment Pharmacol Ther.2016;44:715-727. Interim data from phase 2 placebo-controlled ECOSPOR study of 89 patients failed to support a benefit after 8-weeks. Seres Therapeutics; NCT02437487 Ongoing expanded access study, ECOSPOR 2 is enrolling the patients who had recurrence. NCT02437500

Refined FMT: Fecal Spore Preparations The SER-262: first synthetically-derived and designed microbiome therapeutic ever to reach clinical-stage development Phase 1b study 24-week randomized, placebo-controlled, dose escalation study expected to enroll approximately 60 patients who have experienced a first episode of CDI. The primary endpoint of the study will compare the CDI recurrence rate between the SER-262 and placebo groups at up to 8 weeks after dosing. SER-262 (SER-262-001 STUDY)

Nontoxigenic C.difficile Spores Multi-center phase 2 RCT of nontoxicogenic C.difficile (NTCD) M3 spores in an oral liquid. 173 patients with primary CDI or first recurrence. Treated with metronidazole, vanco or both, then randomized into 4 groups (3 M3 dosing regimens and placebo). 5% recurrence of 43 patients receiving 107 spores/d for 7 days vs 30% of 43 placebo patients. 31% recurrence when not colonized (similar to placebo). Gerding et al. JAMA. 2015;313(17):1719-1727 Of note, none of the patients who were colonized at week 6 remained colonized by week 26.

Ideal C. difficile vaccines should include targets that reduce primary colonization and toxin neutralization.

Summary Important to restore the normal fecal microbiota to resolve refractory C.difficile infection. Fecal microbiota transplantation durably restores the normal microbiota. FMT should be considered in patients with 3rd recurrence after a pulsed vancomycin regimen. FMT appears to be safe. Risk of transmission of infectious agents may be reduced by obtaining stool from healthy donors and by testing stool and blood for common viral, bacterial pathogens and parasites.

Future Research FMT treatment of IBD and IBS; promising results from case series. (randomized controlled trials are needed to validate clinical observations) Is FMT a valid treatment for a variety of non-GI diseases like Parkinson’s, autism, Multiple Sclerosis, chronic fatigue, and obesity among others?

Future Research “A poop capsule a day keeps the doctor away ???” OpenBiome Active Studies ENROLLING • Longitudinal Safety Study of FMT (STOOL Study) • CDI in Liver Transplant Recipients • recurrent CDI • Adult Active Moderate Ulcerative Colitis • Diarrheal-Predominant Irritable Bowel Syndrome 1 • Diarrheal-Predominant Irritable Bowel Syndrome 2 • HIV-Associated Diarrhea • Obesity • Pediatric Ulcerative Colitis • Post-Operative Crohn’s Disease • Pouchitis • Primary Sclerosing Cholangitis COMPLETED ENROLLMENT • Adult Ulcerative Colitis • Hepatic Encephalopathy • Inflammatory Bowel Disease (Ulcerative Colitis and Crohn's Disease) Planning and Design CDI • Geriatric CDI Prophylaxis • Primary CDI • Severe-Complicated CDI Non-CDI • Allergies • Autoimmune Disease • Antibiotic Resistant Bacteria • Antibiotic Dependent Pouchitis • Gut-Brain Conditions • Infectious Disease • Metabolic Disease • Pediatric Crohn's Disease • Pouchitis Diagnostics and Biomarkers CDI • CDI Detection Non-CDI • Autism • IBD Biomarkers • Nutrition • Parkinson’s Disease • Rotavirus Assay Development • Sleep Deprivation FMT treatment of IBD and IBS; promising results from case series. (randomized controlled trials are needed to validate clinical observations) Is FMT a valid treatment for a variety of non-GI diseases like Parkinson’s, autism, DM, Multiple Sclerosis, chronic fatigue, and obesity among others? “A poop capsule a day keeps the doctor away ???”

Every part of our body interacts with every other part. Our colony of micro-organisms is no exception.

Questions?