The Current Direction of FMT

Up to 30 percent of patients treated for an initial Clostridium difficile infection (CDI) develop a recurrence within eight weeks of completing a course of anti-CDI therapy and the risk of further recurrence increases with each subsequent episode. Multiply recurrent CDI is a frustrating and debilitating condition that appears to be increasing at a rate four times higher than primary CDI.1 In addition to the physical effects, these patients often feel depressed and hopeless, imagining endless cycles of reinfection, or become isolated from friends and family, fearing that they may be contagious to others. There is usually a significant financial impact, as patients may be unable to work and pay hundreds to thousands of dollars for antibiotics and probiotics.

Within the last few years, fecal microbiota transplantation (FMT) has become more widely utilized to treat CDI. FMT is inarguably the most effective treatment available for recurrent CDI with efficacy rates of over 90 percent demonstrated in multiple prospective clinical trials.2 Various methods have been used to deliver the donor material including nasoenteric tube, enema, lower endoscopy and most recently orally administered capsules; however, endoscopic lower GI routes of delivery appear to be the most effective and permit examination of the colonic mucosa to exclude other processes such as inflammatory bowel disease (IBD) or microscopic colitis. Current treatment guidelines support FMT for patients who have suffered a third recurrence of CDI.3


There is hope that FMT will prove useful in other conditions marked by intestinal dysbiosis, such as IBD.


There is hope that FMT will prove useful in other conditions marked by intestinal dysbiosis, such as IBD. Several recent randomized controlled trials looking at FMT for treatment of ulcerative colitis have shown remission rates as high as 32 percent after serial FMT administration.4 Though these results are exciting, and patients are eager for safer and more “natural” therapies, more data is needed before we can recommend FMT for routine clinical use in IBD. Questions including which disease phenotypes are likely to respond, the optimum composition of donor microbiota, best routes of delivery and dosing schedule will be addressed in future studies. FMT is currently being investigated to treat a number of other conditions, from hepatic encephalopathy to obesity, with a number of ongoing clinical trials.

The U.S. FDA permits physicians to treat patients suffering from CDI with FMT provided there is informed consent, detailing potential risks and stating that the treatment is considered investigational. Stool banks, such as OpenBiome (Sommerville, MA) have greatly facilitated the clinical practice of FMT by centralizing the process of donor identification and screening, providing material that can be stored frozen until needed for clinical use. As a physician, I appreciate the safety and efficiency of this process, which entails comprehensive testing of healthy volunteer donors and saves hours of time previously spent identifying and screening a new donor for each patient treated. Though I still offer directed donor FMT, the majority of my patients prefer banked donor stool, rather than asking a friend or family member to go through the time consuming and expensive screening process. Insurance companies do not generally pay for the banked donor stool, which is not an FDA-approved product. My hospital and others, understanding the value of decreased CDI infection and readmission rates, have wisely decided to absorb the cost of the donor material.


Do you practice FMT?

If so, we encourage you to participate in the AGA FMT National Registry, which will provide the medical community with important real-life data on the short- and long-term patient outcomes associated with this procedure.

Learn more at www.gastro.org/fmtregistry


Industry is working to develop a form of FMT which can be evaluated through the FDA drug-development and approval process, though we are still a few years away from a commercially available “FMT product.” Disappointing results from recent phase 2 clinical trials of several FMT-based therapeutics highlight the difficulties in conducting clinical trials in this population. Nevertheless, a number of companies are forging ahead with phase 3 trials of various forms of FMT. An approved encapsulated product will certainly increase availability; however, I am concerned that the costs of this treatment will become prohibitive for some patients, and hopeful that physicians will be permitted to continue utilizing conventional FMT at their discretion.

FMT appears safe, though reports of infection transmission and complications related to the procedure, such as aspiration pneumonia, are reminders that the procedure is not without risk. Given that alterations in gut bacteria have been associated with a number of conditions — including the metabolic syndrome, autoimmune and neurologic diseases — there is theoretical concern that engraftment of donor microbiota through FMT may affect the recipient’s risk of developing these diseases. The Fecal Microbiota Transplantation National Registry, an NIH-funded study being administered through AGA, is an important step forward in understanding the long-term safety of FMT. This registry, which aims to enroll 4,000 patients from 75 clinical sites who will be followed for up to 10 years post-FMT, will assess safety outcomes; a biobank consisting of before and after fecal specimens from FMT recipients as well as their donors will help us better understand the microbial mechanisms of FMT and investigate any safety findings that emerge.

Dr. Kelly serves as a consultant to Finch Therapeutics and Summit Therapeutics.

References
1. Ma G.K., Brensinger C.M., Wu Q., Lewis J.D. Increasing Incidence of Multiply Recurrent Clostridium difficile Infection in the United States: A Cohort Study. Ann Intern Med. 2017;167(3):152-158.4.
2. Quraishi M.N., Widlak M., Bhala N. et al, Systematic review with meta-analysis: the efficacy of faecal microbiota transplantation for the treatment of recurrent and refractory Clostridium difficile infection. Aliment Pharmacol Ther. 2017;46(5):479-493.
3. Surawicz C.M., Brandt L.J., Binion D.G. et al, Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol. 2013;108(4):478-498; quiz 499.
4. Allegretti J., Eysenbach L.M., El-Nachef N. et al, The Current Landscape and Lessons from Fecal Microbiota Transplantation for Inflammatory Bowel Disease: Past, Present, and Future. Inflammatory bowel diseases. 2017.

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