Experts’ Perspectives: AGA Recommends FMT for C Diff

Fecal microbiota transplant (FMT) is a safe and effective treatment option for most cases of recurrent Clostridioides difficile infection (CDI), according to recommendations from the American Gastroenterological Association (AGA)’s new evidence-based guideline on the use of fecal microbiota-based therapies for gastrointestinal disease.¹

Although the guideline recommends FMT-based therapy in patients with recurrent CDI at high risk of recurrence following standard-of-care antibiotics and in hospitalized patients with severe CDI after standard-of-care antibiotics if there is no improvement, it suggests against the use of FMT therapies for inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS).¹

The guideline was developed by a panel of members from the AGA guideline committee, a senior methodologist, a junior methodologist, and experts in fecal microbiota-based therapies using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework. Of note, a patient representative also participated in the development of the recommendations.²

Together, the guideline panel identified 7 clinically relevant questions using the PICO format, selecting desirable and undesirable patient-important outcomes and summarizing the evidence for each of the questions. Randomized controlled trials were used to address PICO questions, but investigators supplemented with observational comparative studies and single-arm observational studies as needed when other evidence was not available.²

The intervention of interest was the administration of fecal microbiota-based therapies. Accordingly, investigators considered studies with conventional FMT using unrelated and minimally manipulated donor stool, FDA-approved fecal microbiota, live-jslm , FDA-approved fecal microbiota spores, live-brpk, and the investigational product CP101. In total, 66 studies were included in the review to inform the clinical guidance.²

In immunocompetent adults with recurrent CDI, the guideline suggests select use of fecal microbiota-based therapies after completing standard-of-care antibiotics to prevent recurrence. Additionally, the AGA recommends select use of conventional FMT in mildly or moderately immunocompromised adults with recurrent CDI as well as in adults hospitalized with severe or fulminant CDI not responding to standard-of-care antibiotics.²

In severely immunocompromised adults, the AGA does not recommend the use of any fecal microbiota-based therapies to prevent recurrent CDI. The guideline also suggests against the use of conventional FMT as treatment for IBD or IBS, except in the context of clinical trials.²

For further insight into the recommendations made in the AGA guideline, how they will inform clinicians’ approach to treating different gastrointestinal diseases, and potential areas fecal microbiota-based therapies may be recommended in the future, the editorial team of HCPLive Gastroenterology reached out to several members of the guideline panel. These included Colleen Kelly, MD, gastroenterologist at Brigham and Women’s Hospital and Harvard Medical School, Byron Vaughn, MD, MS, associate professor of medicine in the division of gastroenterology, hepatology, and nutrition at the University of Minnesota, and Osama Altayar, MD, assistant professor of medicine in the department of gastroenterology at Washington University School of Medicine.

HCPLive Gastroenterology: Can you describe the uncertainties/hesitations regarding the use of fecal microbiota-based therapies prior to this evidence-based guideline?

Colleen Kelly: I think a significant number of people were very comfortable with FMT with the growing body of evidence supporting safety over the past few years. That being said, a few high-profile infection transmissions made some people skittish. I think GI physicians have more readily and wholly embraced FMT, while infectious disease doctors have more concern about the infectious risk. It is nice to see this looked at in a systematic way, which will hopefully relieve some worries about short-term risk.

Byron Vaughn: A lot of providers have limited experience with how to perform and administer FMT. We covered this in the guideline’s very detailed implementation remarks. However, implementation may be the most important pre-guideline hesitation. I think a lot of referring providers recognized that a patient ‘might need FMT’ but didn’t know what to do after that.

Osama Altayar: Prior to this guideline there was a lack of clear guidance regarding the use of FMT in immunocompromised patients and patients with severe/fulminant CDI.

HCPLive Gastroenterology: Can you give an overview of the recommendations made in this guideline and what they tell clinicians about instances FMT should and should not be used?

Osama Altayar: Prevention with fecal microbiota-based therapies is suggested in patients after the second recurrence (third episode) of C. difficile infection (CDI) or in select patients at high risk for either recurrent CDI or a morbid CDI recurrence. Adults hospitalized with severe or fulminant CDI not responding to antimicrobial therapy require a multidisciplinary approach and select use of conventional FMT as adjuvant treatment is suggested. Conventional fecal microbiota transplant as treatment for IBD or IBS should only be considered in the context of clinical trials.

HCPLive Gastroenterology: Looking specifically at patients with recurrent C diff, how does this guideline impact clinicians’ approach to treatment of these individuals?

Osama Altayar and Colleen Kelly: We gave clear guidance on how to position fecal microbiota-based therapies in the treatment of recurrent CDI, and how to use it for frontline clinicians. We also supported the use of the newly approved therapies which we hope will have an impact for policy makers. We gave guidance regarding expanding the use in patients other than patients with more than 2 recurrences, e.g. patients with prior severe episodes, patients with mild to moderate immunocompromise, and patients hospitalized with severe and fulminant CDI not responding to antibiotics. The team included experts with a lot of FMT experience and besides just being a systematic review of the literature, we were able to share more practical recommendations (e.g. addressed diagnosis, what to do with anti-C diff therapies when administering FMT by capsule vs colon, and suggested treatment protocols in severe/fulminant CDI).”

HCPLive Gastroenterology: Are there any other areas you could foresee FMT being recommended in the future, beyond what is encompassed in this guideline?

Osama Altayar: There is potential use for FMT in IBD, specifically ulcerative colitis, but where to position the treatment is unclear. There is also potential for use in IBS but which population may benefit from it is still unclear. We gave future directions in our guideline on what we need to advance the field to implement those treatments.

Colleen Kelly: I think we will have a microbiota-based therapy in UC that will be used as adjuvant therapy to help patients in flare achieve remission. I don't think it will pan out at all in IBS (just my gut instinct). I think we MAY see it being used in decolonization multi-drug resistant organisms (MDROs), checkpoint inhibitor colitis, graft vs host disease, autism spectrum (pretty compelling animal data).

References:

1. ^{American Gastroenterological Association. AGA now recommends fecal microbiota transplant for the majority of recurrent C. diff patients. EurekAlert! February 21, 2024. Accessed February 21, 2024. https://www.eurekalert.org/news-releases/1034424}
2. ^{Peery AF, Kelly CR, Kao D, et al. American Gastroenterological Association Clinical Practice Guideline on Fecal Microbiota-Based Therapies for Select Gastrointestinal Diseases. Gastroenterology. https://www.gastrojournal.org/article/S0016-5085(24)00041-6/fulltext}