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

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

3. Clostridium difficile
Brief Overview

4. 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

5. 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:
Has become the most common nosocomial pathogen; 12.1% of all hospital acquired infections
Magill, et al. N Engl J Med. 2014;370(13):

6. PPI
Pathogenesis

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

8. 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 % 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: Khanna et al.Am J Gastroenterol 2012; 107:

10. Severe colitis
Pseudomembranes
Endoscopic appearance

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

12. Treatment: ACG Guidelines
Surawicz et al. Am J Gastroenterol 2013;108:

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

14. Gut Microbiota
species, 1014 bacteria

15. 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 Jan;9(1): Epub 2010 Nov 29
2. Chang JY, Antonopoulos DA, Kalra A, et al. J Infect Dis 2008; 197:435.

16. Fecal Microbiota Transplantation
*** the ultimate probiotic ***

17. 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

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

19. 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.

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

21. 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 doses or
vancomycin followed by rifaximin chaser for 2 weeks).
Refractory moderate to severe
C. difficile diarrhea, failing
vancomycin after >1 week

22. FMT Protocol – The Past

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

24. 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

25. 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.

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

27. Administration via LGIT

28. Preparation and Methods
g of donor stool suspended in 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

29. 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

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

31. 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 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

32. 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

33. Administration via UGIT

34. 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.

35. 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.

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

37. 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): Division of Infectious Diseases, Massachusetts General Hospital.

38. 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

39. 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:

40. 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

41. The Present

42. 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.

43. The Future

44. Live Biotherapeutic Microbiota Preparations

45. 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
NCT

46. 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:
Interim data from phase 2 placebo-controlled ECOSPOR study of 89 patients failed to support a benefit after 8-weeks.
Seres Therapeutics; NCT
Ongoing expanded access study, ECOSPOR 2 is enrolling the patients who had recurrence.
NCT

47. 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 STUDY)

48. 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):
Of note, none of the patients who were colonized at week 6 remained colonized by week 26.

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

50. 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.

51. 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?

52. 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 ???”

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

54. Questions?