Lessening the ‘ick’ in fecal microbiota-based therapies
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Fecal microbiota-based therapies are becoming more prevalent in the management of Clostridioides difficile infection.
The practice of transferring donor stool to a recipient for a therapeutic purpose goes back to 4th century China, where “yellow soup” (ie, human fecal slurry) was used to treat patients with severe diarrhea and food poisoning. The first “modern” fecal microbiota-based therapy (FMT) dates to 1958, when fecal enemas were used to cure four patients with pseudomembranous colitis, likely caused by C. difficile.
The threat of C. difficile infection (CDI) and its burden on health care systems became more evident in the 2000s, coinciding with increasing rates of recurrent disease. This shed more light on the utility of FMT, and the first randomized controlled trial of the therapy in 2013 by van Nood and colleagues showed that infusion of donor stool in patients with recurrent CDI had a 94% cure rate compared with those who received vancomycin alone (31%).
Today, antibiotic exposure remains one of the most prominent risk factors for the development of CDI. Antibiotics lead to the disruption of the gut microbiome, or dysbiosis, by causing critical losses in microbiota that contain bile salt-metabolizing enzymes needed to inhibit C. difficile growth. Fidaxomicin and oral vancomycin are the mainstays of CDI treatment. However, FMT has proven to be a safe and effective alternative for patients with two or more CDI recurrences, with cure rates ranging from 70% to 90%.
The American Gastroenterological Association (AGA) published the first comprehensive guideline on the use of FMTs for gastrointestinal disease earlier this year. This article describes when to employ FMT and for whom, what conventional and commercial FMTs are available and the possible future directions of the therapy.
When to consider FMT
The AGA guidelines make seven recommendations in total, all of which are conditional recommendations with low to very low certainty of evidence. The first suggests use of FMT in immunocompetent adults with recurrent CDI after the second recurrence (ie, third CDI episode) following standard-of-care antibiotic therapy with either fidaxomicin or vancomycin. Patients who may benefit from earlier preventive efforts with FMT include those recovered from severe or fulminant CDI, or CDI that is more refractory to standard treatment. Patients on chronic suppressive antibiotic therapy and/or who require frequent antibiotic courses warrant careful consideration before moving forward with FMT because antibiotic exposure may diminish FMT efficacy.
Second, conventional FMT may be used in mildly to moderately immunosuppressed patients with recurrent CDI. The recommendation is based on evidence from 25 observational studies that included patients with malignancy (n = 84), inflammatory bowel disease (n = 461), solid organ transplant (n = 115) and a heterogeneous population with various types of immunocompromise (n = 500) in whom conventional FMT was administered. Notably, severely immunosuppressed patients were often excluded, leading the AGA to recommend against the use of FMT in these patients. Severe immunosuppression includes patients receiving cytotoxic therapy for solid or hematological malignancies, bone marrow transplant (during neutropenia), any neutropenia and patients with severe primary immunodeficiency.
Several CDI-focused guidelines — including in the United States and Europe — align in recommending conventional FMT in immunocompetent patients with a history of two or more CDI recurrences. The AGA also suggests select use of conventional FMT as an adjuvant treatment for adults hospitalized with severe or fulminant CDI who do not respond to standard therapy.
However, conventional FMT remains a regulatory challenge. In the U.S. and Canada, conventional FMT is considered a biologic drug. In the United Kingdom, it is considered a medicinal product, whereas other European Union countries regulate conventional FMT as tissue. China, Finland and India are countries where FMT is unregulated. There continues to be several hurdles for using conventional FMT in clinical and research settings.
Commercial FMT products
In 2022, the first commercial FMT product, Rebyota (fecal microbiota, live-jslm), was approved by the FDA for rectal administration. Like conventional FMT stool suspensions, the mixture of microbes from donor stool is undefined. The product does ensure a minimum concentration of Bacteroides species, a known organism of the normal microbiota. In a phase 3 trial, it significantly reduced CDI recurrence (70.6% vs. 57.5%) compared with placebo among immunocompetent patients. An ad hoc analysis of the PUNCH CD3-OLS trial evaluated the safety and efficacy of Rebyota in immunosuppressed patients and found that 79.5% and 73.5% of patients with (n = 91) and without (n =392) mild to moderate immunocompromising conditions, respectively, did not have a recurrent CDI episode through 8 weeks after treatment. Results for sustained clinical success were similar (with: 80%; without: 85%).
Vowst (fecal microbiota spores, live-brpk) was approved by the FDA in 2023 as the first commercial oral FMT product for recurrent CDI. Vowst contains only donor-derived spores of Firmicutes, a predominant type of bacteria in the microbiota. In patients who had three or more CDI episodes within a year, Vowst led to a lower recurrence rate after 8 weeks compared with placebo (12.4% vs. 39.8%). Some immunocompromised patients (29%) were included in the phase 3 trial. However, more studies are needed to fully understand the impact in this population, which is at a higher risk for recurrent CDI. Given the limited evidence supporting Rebyota and Vowst in immunocompromised patients, the AGA guideline supports use in immunocompetent patients presently.
The future of FMTs
FMT, once a last-resort therapy option, is now a recommended standard treatment for recurrent CDI and patients who have recovered from severe or fulminant disease. The exact mechanism of FMT remains somewhat unclear. What specific microbes are needed to repopulate the gut flora to resist C. difficile, or are they even needed? The efficacy of Vowst suggests the spore-forming component of the microbiota is all that is required. It is speculated that the commercial FMT products will be safer than conventional FMT because of standardized manufacturing, and, in some cases, narrower spectrum products containing only the organisms necessary for therapeutic effects.
Most recently, the randomized controlled MATCH study compared the efficacy and safety of capsule-delivered FMT with placebo, administered after successful initial antibiotic treatment of recurrent CDI, for the prevention of subsequent diarrhea and CDI recurrence among veterans in the U.S. There was no difference in the rates of recurrent CDI or death between patients who received FMT (n = 76) and placebo (n = 77). No studies to date have compared conventional FMT with commercial products, which is needed to better understand the potential advantages and disadvantages of the available FMT products.
The mystery of the gut microbiota endures. Concerns persist about slippage of pathogens, including more antibiotic-resistant ones, through screening, and how to approach unknown pathogen transmission threats via stool. Additionally, there are vague associations between the gut microbiota and other conditions, such as diabetes and cancer, that may pose a risk for future development after receipt of FMT. The threat of CDI still looms large.
AGA’s FMT guideline gives more clear direction on when FMT is a viable therapy to prevent recurrence in select patient populations, lessening the “ick” often associated with the treatment.
References:
- Barron M. Fecal microbiota transplants (FMT): Past, present and future. American Society of Microbiology. Feb. 9, 2024. Accessed Sept. 25, 2024. https://asm.org/Articles/2024/February/Fecal-Microbiota-Transplants-Past-Present-Future.
- Drekonja DM, et al. Clin Infect Dis. 2024;doi:10.1093/cid/ciae467.
- Four analyses of data for Rebyota (fecal microbiota, live-jslm), the first FDA-approved microbiome-based treatment for the prevention of recurrent C. difficile infection, presented at DDW 2023. https://ferringusa.com/?press=four-analyses-of-data-for-rebyota-fecal-microbiota-live-jslm-the-first-fda-approved-microbiome-based-treatment-for-the-prevention-of-recurrent-c-difficile-infection-presented. Published May 8, 2023. Accessed Sept. 25, 2024.
- Peery AF, et al. Gastroenterology. 2024;doi:10.1053/j.gastro.2024.01.008.
- Yadegar A, et al. Clin Microbiol Rev. 2024;doi:10.1128/cmr.00060-22.
For more information:
Jennifer Ross, PharmD, BCIDP, is an infectious diseases clinical pharmacist at M Health Fairview – University of Minnesota Medical Center. Ross can be reached at jross13@fairview.org.
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