2. Fecal Microbial Transplant: You’re doing what?

3. Objectives: 1. Review the benefits of Fecal Microbial Transplant for patients. 2. Discuss considerations in developing an FMT program. 3. Review current FDA regulations regarding FMT.

4. “It is now well-appreciated that intestinal microbiota constitute a microbial organ that is integral to overall host physiology, including pivotal roles in metabolism and immune system function.”

5. GI Cholelithiasis Colorectal cancer Hepatic encephalopathy Idiopathic constipation* IBS* IBD* Familial Mediterranean fever Gastric carcinoma and lymphoma Recurrent Clostridium difficile infection* Disorders associated with an altered intestinal microbiome

6. Non-GI Arthritis Asthma Atopy Autism* Autoimmune disorders Chronic fatigue syndrome* Diabetes mellitus and insulin resistance* Eczema Fatty liver Fibromyalgia* Hay fever Hypercholesterolemia Idiopathic thrombocytopenic purpura* Ischemic heart disease Metabolic syndrome* Mood disorders Multiple sclerosis* Myoclonus dystonia* Obesity Oxalic acid kidney stones Parkinson’s disease* Disorders associated with an altered intestinal microbiome

7. Reasons for FMT “So far, recurrent CDI appears to represent the clearest known example of near-complete disruption of the intestinal microbiota resulting in gastrointestinal dysfunction. “

8. C. difficile Statistics The average total cost for a single inpatient C. difficile infection (CDI) is more than $35,000, and the estimated annual cost burden for the healthcare system exceeds $3 billion. C. difficile infection (CDI) is the leading cause of antibiotic-associated diarrhea and a highly problematic healthcare-associated infection. In at least one U.S. region, C. difficile has replaced methicillin-resistant Staphylococcus aureus (MRSA) as the most common cause of HAI.

9. A total of 336,600 CDI-related hospital stays were documented in 2009; representing 0.9 percent of all U.S. hospital stays. In 67 percent of these hospital stays, CDI was listed as a secondary diagnosis. The highest rate of CDI-related hospital stays were in the Northeast, followed by the Midwest, South, and West regions. Persons 65 years of age or older have been most affected, representing over two-thirds of patients with CDI.

10. The incidence of CDI has increased to epidemic proportion over the past 10 to 15 years. In the United States, from 1996 to 2003, CDI increased from 98,000 to 178,000 cases and to 61/100,000 hospital discharges, whereas the unadjusted case-fatality rate rose from 1.2% in 2000 to 2.3% in 2004. It is now estimated that 500,000 to 3 million cases of CDI occur annually in U.S. hospitals and long-term care facilities, with an estimated hospital excess cost of care of approximately $3.2 billion.

11. C. dificile Infection first-line treatment is cessation of the culprit antibiotic, if possible, then treatment with metronidazole, vancomycin, or fidaxomicin, depending on disease severity.

12. Recurrence recurrence rates are 15 %to 35 % Patients who have one recurrence have up to a 45 % chance of a second recurrence. after a second recurrence, up to 65 % of patients will have a third.

13. Quality of life in recurrent C. difficile infection Symptoms Lifestyles changes Worklife affected Financial considerations Hopelessness

14. Recurrence Treatments Recurrences are usually treated with additional courses of metronidazole, oral vancomycin, or prolonged oral vancomycin in various pulsed-tapered regimens, occasionally "chased" by other antibiotics such as rifaximin.

15. What is FMT? Transplanting a donor’s feces into a recipient’s colon via a range of methods.

16. FMT research In all, 92 percent of patients were cured of their recurrent C. difficile, with a range of 81 percent to 100 percent.

17. Long term follow up on FMT 5 medical centers and 77 patients Patients followed for three months Primary cure rate: 91% Secondary cure rate: 98% (defined as cure enabled by use of antibiotics to which the patient has not responded before the FMT or by a second FMT.) Patients had an average of 11 months of symptoms prior to FMT. Resolution of diarrhea within three days: 74%

18. Netherlands study 2012 randomly assigned patients to receive one of three therapies: an initial vancomycin regimen (500 mg orally four times per day for 4 days) followed by a bowel lavage and subsequent infusion of a solution of donor feces through a nasoduodenal tube a standard vancomycin regimen (500 mg orally four times per day for 14 days); a standard vancomycin regimen with bowel lavage. The primary end point was the resolution of diarrhea without relapse after 10 weeks.

19. Research study halted for ethical reasons Success rate necessitated offering the FMT to all participants

20. Results 16 patients received FMT 81% had resolution of diarrhea after first FMT second infusion of FMT from a different donor : 67% resolution of diarrhea 31% of patients receiving vancomycin had resolution of diarrhea 23% of patients receiving vancomycin with bowel lavage had resolution of diarrhea No significant differences in adverse events among the three study groups were observed except for mild diarrhea and abdominal cramping in the FMT group on the infusion day.

21. John Muir Health’s story Once upon a time, Stephanie Haskell RN went to the national SGNA conference in 2012 and heard about the effective and life transforming treatment utilized on a patient with recurrent cdi. She remembered that one of her departments physicians had been advocating for FMT for years and the whole department had responded “over our dead bodies” (or something like that) She became an advocate for FMT

22. Starting an FMT program Who wants it to happen? More than just knowing HOW to do FMT Many hospital departments have an opinion, lots of key players Make it a team effort. Get lots of input from different specialities. Know that it will take longer than you think it should and you may have unexpected speed bumps along the way. Avoid making promises to patients who are waiting for procedures.

23. Key players Identify your core team: MD, RN’s and Tech’s, Department Director. Get administrative buy-in and support. Add in Infection Control (both hospital department staff and Infectious Disease MD’s), Tissue Bank MD, Laboratory leadership, research department MD, Investigational Research Board, Legal/Risk personnel, Medical chair of hospital.

24. Build a structure with policy Purpose Who can perform FMT and where Donor Selection Criteria Donor Exclusion Factors- relative and absolute Donor Screening – time frame, testing

25. Policy (con’t.) Recipient Exclusion Criteria Recipient Screening Procedure Informed Consent Patient/Family Education Patient and donor contact information Documentation Reference literature for your policy rationale.

26. Follow with procedural plan This is where little details get figured out Allow room for individual processes while describing key considerations. ( i.e. containers for mixing donor stool with saline is less important than the goal of mixing stool and saline to achieve a thin slurry. ) New considerations will come up as you do your first cases.

27. Equipment Donor supplies Transplant preparation Recovering isolation patient

28. Current FDA Considerations Is FMT a biologic agent requiring an investigational drug application? FDA requirements as of July 2013 http://www.fda.gov/downloads/BiologicsBloodVaccines/Guid anceComplianceRegulatoryInformation/Guidances/Vaccines/ UCM361393.pdf

29. We, FDA, are informing members of the medical and scientific community, and other interested persons that we intend to exercise enforcement discretion regarding the investigational new drug (IND) requirements for the use of fecal microbiota for transplantation (FMT) to treat Clostridium difficile (C. difficile) infection not responding to standard therapies. FDA intends to exercise this discretion provided that the treating physician obtains adequate informed consent from the patient or his or her legally authorized representative for the use of FMT products. 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. FDA intends to exercise this discretion on an interim basis while the agency develops appropriate policies for the study and use of FMT products under IND.

30. Translation Informed consent with discussion of risks and benefits Patient must be notified that FMT is investigational

32. References: 1.Petrof, E., Gloor, G., Vanner, S., Weese, S., Carter, D., Daigneault, M., Brown, E., Schroeter, K., Allen-Vercoe, E.,: Stool substitute transplant therapy for the eradication of Clostridium difficile infection: ‘RePOOPulating’ the gut. Microbiome 2013 1:3. 2. O’Keefe SJD. Tube feeding, the microbiota, and Clostridium difficile infection. World Journal of Gastroenterology. 2010;16(2):139-42. 3.Bakken, J. S., Borody, T., Brandt, L. J., Brill, J. V., DeMarco, D. C., Franzos, M. A.,... Khorut, A. (2011). Treating Clostridium difficile Infection With Fecal Microbiota Transplantation. CLINICAL GASTROENTEROLOGY AND HEPATOLOGY, 9, 1044-1049. 4. Cohen SH, Gerding DN, Johnson S, Kelly CP, Loo VG, McDonald LC, Pepin J, Wilcox MH: Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA). Infect Control Hosp Epidemiol 2010, 31:431–455. 5.Brandt, L., Aroniadis, O., Mellow, M., Kanatzar, A., Kelly, C., Park, T., Stollman, N., Rohlke, F., Surawicz, C., Long Term Follow-Up of Colonic Fecal Microbiota Transplant for Recurrent Clostridium difficile Infection. The American Journal of Gastroenterology. 2012, 107 6. Kelly, C.P. Fecal Microbiota Transplantation – An Old Therapy Comes of Age. The New England Journal of Medicine :2013, 368:5. 7.Van Nood, E., Vrieze, A., Nieuwdorp, M., Fuentes, S., Zoetendal, E., deVos, W., Visser, C., …Keller, J. Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile. The New England Journal of Medicine. 2013,368:5 8.Brandt, L., Aroniadis, O., An overview of fecal microbiota transplantation: techniques, indications, and outcomes. Gastrointestinal Endoscopy, August 2013, Vol. 78, Issue 2, Pages 240-249