Fecal Microbiota Transplant Success, Challenges, and the FDA Cheryl Griesbach, RN Mayo Clinic in Arizona Fecal Microbiota Transplant Coordinator

Disclosures The Society of Gastroenterology Nurses and Associates, Inc. is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s (ANCC) Commission on Accreditation. Disclosure: Relationships with commercial interest organizations whose products are related to program content include: None No Disclosures to report

Objectives: Explain the impact of C. difficile on the U.S. population. Discuss the benefit of FMT in the patient with refractory, recurrent C. difficile. List obstacles encountered in the development of an FMT program. Describe the guidelines as determined by the FDA for FMT. State the proposed applications of FMT for treatment of various illness and disease.

Fecal Microbiota Transplant What and Why? Origin Application - Currently approved for the treatment of recurrent Clostridium difficile, refractory to therapy Highly toxigenic strain of C. diff BI/NAP1/027 1) Fecal transplant has been performed in animals for over 100 years. For example, veterinarians perform fecal transplantation to treat horses with diarrhea by infusing stool from healthy horses into the rectum of the sick animals, and they administer rumen fluid to cows and alpacas to treat a variety of conditions. The latter application is referred to as transfaunation. 2) FMT for treatment of antibiotic associated colitis in humans was first described by Eisenman et al in 1958 placing feces into liquid medium – saline, water, pasteurized cows milk then homogenized and instilled into humans 3)

This gives us an idea as to why FMT for the treatment of C This gives us an idea as to why FMT for the treatment of C. Diff is so crucial, and the need is so great for program development. Antimicrobial use is widespread in our society and unfortunately leads to some significant distortion of the gut microbiome. In conjunction, a highly epidemic strain of C. difficile which has spread throughout the world, thus impacting our most vulnerable patients and creating the perfect storm. C. Diff infection rates have more than doubled since the turn of the millennium. 14,000 deaths per year attributed to complications from CDI. 15-30% recurrence rate after 1st treatment. Then 40% after that then up to 65%

A quick review of the pathophysiology of C A quick review of the pathophysiology of C. difficile , the impact on the colon, and the benefit of FMT.

The Forest Analogy For those of you who prefer a more visual analogy we can imagine the colon being like a forest. Your gut microbiome is the trees which are thick and lush everything in balance and harmony. Then we introduce a broad spectrum antibiotic which wipes out all of the flora and fauna. Thus allowing the opportunistic growth of weeds– much like dandelions which grow and multiply rapidly so does the C. Diff. creating an imbalance in the flora FMT

Fecal Microbiota Transplant Program Development If you build it they will come I would like to share with you about our program at Mayo Clinic in Arizona. Throughout this process we will explore the successes, hurdles, and the FDA intervention. What the implications of that intervention are and how this impacts the future of FMT.

FMT Program Goals Build a Model FMT Program Infrastructure Workflow processes Safety and outcome monitoring tools Establish a clinical practice Capacity for research Collaborative model Having seen this impact on our patients we felt strongly that we needed to meet this epidemic head on with the best possible treatment option and outcome we could implement.

Current Patient Flow Identified as appropriate FMT recipient Donor Identified and screened Education recipient and donor Procedure – FMT Follow-up – Serial Surveillance Process timeline One of the biggest hurdles for patients with C. Diff is finding a program who is still performing FMT The recent FDA intervention had a profound impact on the availability of this therapy Lets review a patient experience through the FMT process GI or ID Consult Donors -Known Vs. Standard Education Pre and Post Procedure prep, colonoscopy Serial Surveillance 1 wk, 1 mo, 3 mo, 6 mo Treatment in a timely manner

Recipient Eligibility Criteria Refractory Disease – unresponsive to standard therapy Two or more documented episodes of severe CDI Recent positive C. Diff assay consistent with recurrence Presence of diarrhea at least three unformed stools per day Usually three rounds of antimicrobial therapy Flagyl, Vancomycin, Dificid , etc. Hospitalizations, failure to thrive issues At least two positive C. Diff assays

Potential Donor Screening and Eligibility Criteria Medical History Screening Social/Lifestyle Screening MEDICAL - gastrointestinal illness ,recurrent or chronic diarrhea, bowel resection surgery, irritable bowel syndrome, inflammatory bowel disease, colon malignancy, antibiotic use within past 3 months, hospitalizations within past 3 months, History of viral illness HAV, HBV, HCV, HIV, etc. , Autoimmune disorder, Personal history of c.diff SOCIAL LIFESTYLE - Recent travel to areas known to be high risk for diarrheal illness, History of illicit drug use, Recent tattoos, Incarceration, High risk sexual practices, MSM - Multiple Sex Partners This assessment is being done at either the clinical visit or via telephone screening. The assumption is that in order to be a donor you must be in good/excellent health. Preference is young participants but we have utilized elderly spouses/partners with equitable success

Serology and Microbiology Donor Screening Serology: Stool Studies: HIV I/II Antibody Bacterial Culture – Enteric Pathogens HTLV I/II Antibody O&P Ova and Parasites RPR or Syphilis EIA Cryptosporidium Antigen Hepatitis A IgM Microsporidia Smear Hepatitis B Surface Antigen C. Difficile Toxin by PCR or EIA Hepatitis B Core Antibody IgG, IgM Hepatitis C Antibody Other programs may require less or even more thorough lab/micro screening Listeria, H pylori

Recipient Education Points Discontinue Antimicrobial and pro-biotic 24 H Prior to FMT Bowel Lavage Colonoscopy / Loperamide 4 mg Post procedure instructions/positioning /diet Serial Surveillance Patient is being given the ultimate Pro-Biotic the FMT. Keep bacterial load low – then don’t want to destroy other good bacteria Importance of Bowel Lavage Loperamide decrease gut transit time Recumbent for 4 hours and lst 24 hrs. implement low residue diet. Day after diet and activity as tolerated Surv. – 1 week, 1 mo., 3 mo., 6 mos. Stress importance

Donor Education Maintain the “Chain of Custody” Dietary – recipient food allergies/low residue Sample Timing - MOM Do not refrigerate Difficulty obtaining sample Maintain the “Chain of Custody” Do not want to take any risk for allergic reaction – have not heard of any thus far Advise donor to avoid foods that are known allergies of recipient for one week prior Implement a low residue diet MOM to ensure a BM have donor take 30 ml night before around 9 pm Goal – produce sample within six hours of scheduled procedure If unable to produce sample in AM Cup of hot coffee tea Take a brisk walk Maintain sample at room temperature Maintain chain of custody of sample Low residue to bulk stool and decrease fiber in sample - this is strained in prep - endo

PRESERVATIVE FREE NORMAL SALINE ~250-350 ML “The Dirty Work” + + PRESERVATIVE FREE NORMAL SALINE ~250-350 ML DONOR SAMPLE HOMOGENIZE TO SLURRY Bless the endoscopy techs for their hard work and hearty nostrils They impregnate gauze with peppermint, vicks or other pleasant oils Optimal sample > 50 GM + = STRAIN FILL SYRINGES INSTILL

The Procedure Colonoscopic route is our preferred method of stool delivery. Our goal is to place the sample into the terminal ileum If multiple diverticula will try to “seed” the pockets

Case Study# 1 71 y.o. male Patient was hospitalized for three weeks following complications from his left femoral bypass – went on to develop MRSA and was treated with multiple antibiotics. Subsequently developed C. difficile and became critically ill - ICU FMT was performed and within three days patient was up walking around feeling so much better. At this point I would like to present a couple of case studies

Case # 2 78 year old female Hospitalized for complications following an exp. Lap for debulking Stage III ovarian cancer Multiple episodes of CDI Leukocytosis WBC-29.2 (day of procedure) Weak, listless, confused, skin was ashen gray FMT into stoma via inserted urinary catheter Less than 1 week later: Patient was coherent, skin color was pink WBC’s dropped to 9.3 four days later Severely immunocompromised Visual appearance remarkable Still suffering from the sequelae of her cancer, but we have improved her quality of life somewhat at this stage in the game. She has been discharged from Rehab in order to build her strength for Chemo

FMT Success MCA ARIZONA: 93 % Success Rates (Oct. 2013) 58 procedures on 53 patients since January 2011 5 repeat pts. Age ranges 21-90 Avg. 62 39 Females 19 Males National Average: 90-100% Ntl avgs. Extrapolated from published data and research

Hurdles and Challenges in FMT

Known versus Unknown Donor Does it make a difference? Ease of scheduling with pre-screened anonymous donor Safety Maintaining anonymity Initial thought was it may be best to use genetic relative or individuals living in same household consuming same foods, water supply, etc. This just has not panned out . Much easy to schedule with a “Standard” donor screening good for 90 days, can donate multiple times

Recruitment of Anonymous Donors We Need You! No compensation, time commitment Burnout Cost and cost distribution need to rescreen every three months Most advantageous to the patient Can treat critically ill patients within 24 hours

Delivery Method Colonoscope NG Tube/Nasal Duodenoscopy Enema Misc. other methods TI reservoir of bacteria for populating large intestine Initial concerns over perhaps inducing small bowel bacterial overgrowth this also has not proven out. Enema – does it go high enough in the colon / premature expulsion / bowel prep prior advantages No prep, cost effective, no sedation

Fresh vs. Frozen Stool Considerations: Product efficacy Storage Equipment –process Lab preparation time technician cost Anything lost through freezing? Potency

Over RX of Antimicrobials Re-education and continued education is the key Providers – Mindful prescribing Patients – Educate your patients about viral vs. bacterial infections. UTI’s - make sure a culture and sensitivity is done Nursing plays a big and profound role in educating provider and patients. Avoid Clindamycin, fluroquinalones, and other broad spectrum antibiotics unless absolutely necessary UTI Culture before tx.

Post FMT Stool Testing ? If it ain’t broke don’t fix it…….. Certain individuals can be colonized May be helpful in IBD patients Patients are so fearful of not completely getting rid of C. diff. Focus on Symptoms if their stool is solid, abd. Pain is gone, etc. IBD, IBS patients may be beneficial. They think the diarrhea related to their IBD IBS

Unanswered Questions……. Is Metronidazole the optimal first line therapy? Should FMT be the first line therapy for C. diff infection? How do we contain costs and provide this treatment for all patients in need? How will the new health care changes impact moving forward from here?

FMT AND THE FDA

FMT and the FDA May 3 2013 Fecal Microbiota When used to cure, treat, mitigate or prevent a disease fecal microbiota for transplantation meets the legal definition of a drug and/or biological product If the fecal microbiota are being used to cure, treat, mitigate or prevent a disease or condition it is considered an unapproved new drug for which an Investigational New Drug application (IND) is required. Primary objective of IND is to assure the safety and rights of subjects Safety – also chain of custody of sample

Potential Long-term Effects of Alterations in the Gut Microbiome Immune status Nutritional status Body weight Diabetes risk Cardiovascular risk Autoimmune status Cognition/mood Cancer risk Other? We just don’t have enough data This is of prime concern.

IND Requirement - Yes then No Overwhelming feedback from physicians, scientists, Institutions, CDC and patients. This prompted a recant of the IND requirement with suggested guidelines Feedback was overwhelming prompting a recant by the FDA for the IND requirement

Modified Statement from the FDA On June 17th 2013 a statement was issued: “The agency acknowledges these concerns and intends to exercise enforcement discretion regarding the IND requirements for the use of FMT to treat C. difficile infection not responding to standard therapies provided 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. At consult this is clearly presented to patient and documented in the patient’s medical record. This is on our endoscopy consent as well. We also have all donors known or standard sign a consent that they are willing to donate their stool. This consent also includes a statement about the unknown risks.

FMT What does the future hold?

Gastroenterology Neurology IBD –Ulcerative colitis, Crohns IBS – Chronic constipation, diarrhea (not c.diff rel.) Motility Nutrition and Absorption Obesity Neurology Parkinson's Disease Chronic Fatigue Syndrome, Autism, Autoimmune disorders….. The list goes on IBD and IBS require IND Questions – how many treatments, over what period of time and via what route is beneficial? Could repopulation of correct microbiota improve motility? Relates to Nutrition and absorption as well as obesity. Preliminary studies in rat models – instilling FMT of slender mice into obese mice shows a shift towards weight loss

In Summary Rates of CDI continue to rise and the strains of the bacteria are more resistant and virulent FMT is a safe and effective treatment for CDI - Success Rates 90-100% FDA is exercising enforcement discretion regarding the IND requirements for the use of FMT to treat CDI Patient Safety : Informed consent-Investigational treatment Chain of custody of stool sample Thorough screening of donor health/diagnostics It is imperative that we as clinicians continue to forge ahead with research into the possible application of FMT for treatment of other diseases and conditions. Thank you for your time.