Update: What is the role for commercially available fecal microbiota transplantation products in managing recurrent Clostridioides difficile infection?

Introduction
Clostridioides difficile infections are associated with significant morbidity and mortality, and recurrent C. difficile infection is common.1 Over 35% of patients treated for a first C. difficile episode will experience recurrent C. difficile infection, and approximately 65% of patients with an initial C. difficile recurrence will go on to experience subsequent recurrences. Risk of C. difficile recurrence is increased in certain subpopulations, including patients with inflammatory bowel disease and patients who are immunocompromised.2

Fecal microbiota transplantation (FMT) has emerged as an important approach to preventing recurrent C. difficile infection in patients who have experienced multiple recurrences.1 Traditional FMT typically involves the administration of diluted donor fecal samples via rectal enema or nasogastric/nasoduodenal tube.3 More recently, 2 commercially available FMT products were approved for use in the United States: Rebyota (fecal microbiota, live-jslm) in 2022 and Vowst (fecal microbiota spores, live-brpk) in 2023.4,5 Rebyota is administered as a single-dose rectal enema, while Vowst is administered over 3 consecutive days in the form of oral capsules.

A frequently asked question (FAQ) published in October 2023 summarized data on the commercially available FMT products for prevention of recurrent C. difficile infection. The FAQ is available here. The purpose of this FAQ is to update the 2023 review with new guidelines and additional data on these products.

Additional Data for Commercially Available Products
The recently published PUNCH CD3-OLS study provides additional data for Rebyota.6 PUNCH CD3-OLS was a prospective, phase 3, open-label study that included data from 697 adults with documented recurrent C. difficile infection. This study differed from previous trials in those patients with comorbid conditions (e.g., irritable bowel syndrome, inflammatory bowel disease, mild to moderate immunocompromising conditions) could be enrolled. All participants received a single 150-mL dose of Rebyota 24 to 72 hours after completion of antibiotics for C. difficile. Patients could receive an additional dose of Rebyota within 21 days if they met criteria for treatment failure. The primary endpoint was the incidence of Rebyota- or administration-related treatment-emergent adverse events (TEAEs); secondary endpoints included treatment success (defined as the absence of C. difficile diarrhea through 8 weeks after Rebyota administration) and sustained clinical response (defined as treatment success and no new C. difficile episodes within 6 months of Rebyota administration).

Among the enrolled patients, 20.2% were immunocompromised due to an underlying condition or medication; ulcerative colitis, Crohn disease, and irritable bowel syndrome were documented in 6.5%, 3.6%, and 13.9% of patients, respectively.6 Rebyota was administered after the first C. difficile recurrence in 26.7% of patients, the second recurrence in 38.5% of patients, and the third or later recurrence in 34.3% of patients. Rates of TEAEs were greatest within the first 8 weeks following Rebyota administration, with 47.3% of patients reporting a TEAE during this period. Most TEAEs were mild to moderate in severity. The most common TEAEs were gastrointestinal disorders (diarrhea, abdominal pain and distension, nausea). Serious TEAEs were reported in 3.9% of patients within 8 weeks of Rebyota administration, but only 1 serious TEAE (ulcerative colitis flare) was deemed potentially related to Rebyota. Although serious infections occurred during the study, all were assessed as being unrelated to Rebyota or its administration. In terms of efficacy, 73.8% of patients achieved treatment success at 8 weeks; among these initial responders, 91% remained recurrence-free through 6 months. Overall, this study provides preliminary evidence to support the safety and efficacy of Rebyota in a broader population of patients with recurrent C. difficile infection; however, the trial is limited by its single-arm, open-label design. The inclusion of patients who received Rebyota after their first C. difficile recurrence also limits external applicability, as FMT is typically reserved for patients who have experienced multiple recurrences in clinical practice.6-11

New Guidelines for FMT
Previous guidelines on C. difficile infection from the Infectious Diseases Society of America (IDSA), the American College of Gastroenterology (ACG), and the American Society of Colon and Rectal Surgeons (ASCRS) discuss the place in therapy for FMT, but do not address the specific role for the commercially available FMT products.7-10 In February 2024, the American Gastroenterological Association (AGA) published a new guideline on the use of fecal microbiota-based therapies for gastrointestinal diseases, including C. difficile infection.11 This guideline provides more specific recommendations on the appropriate use of Rebyota and Vowst.

For immunocompetent adults with recurrent C. difficile infection, AGA conditionally recommends the use of fecal microbiota-based therapies upon completion of standard of care antibiotics.11 In this group of patients, fecal microbiota-based therapies may include conventional FMT, Rebyota, or Vowst. Prevention of recurrence with fecal microbiota-based therapies can be considered after the second recurrence (third episode) of C. difficile infection, or in select patients with a high risk of either recurrent C. difficile infection or morbid C. difficile recurrence. This may include patients who have recovered from severe, fulminant, or treatment-refractory C. difficile infection, as well as patients with significant comorbidities. Patients who require frequent antibiotics or long-term antibiotic prophylaxis may not be appropriate for fecal microbiota-based therapies, as ongoing antibiotic treatment can diminish efficacy. A shared decision-making process should be used when deciding whether to administer fecal microbiota-based therapies, with consideration for the individual patient’s risks, values, and preferences. Appropriate alternatives to fecal microbiota-based therapies for the prevention of recurrent C. difficile infection may include a vancomycin taper, tapered-pulsed fidaxomicin, or bezlotoxumab.

For adults with recurrent C. difficile infection who are mildly or moderately immunocompromised, AGA conditionally recommends conventional FMT upon completion of standard of care antibiotics.11 Evidence is insufficient to recommend Rebyota or Vowst in this patient population. Authors of the AGA guideline note that the stool donor process for Rebyota and Vowst may be cause for concern in immunocompromised patients. Because the stool donors for these products are paid donors (rather than volunteers), they may be more likely to inaccurately report their health or risk behaviors, which could lead to unintentional contamination of the product. This concern is based on literature in the field of blood donation, which has shown that paid and professional blood donors are more likely to have an infectious disease than voluntary donors. No form of FMT is suggested for patients with recurrent C. difficile infection who are severely immunocompromised (e.g., patients receiving active cytotoxic cancer therapy; patients who have received chimeric antigen receptor [CAR] T-cell therapy or hematopoietic cell transplantation [if neutropenic]; patients with neutropenia, severe primary immunodeficiency, or advanced/untreated HIV infection), due to a lack of adequate data in this patient population.

Conclusion
The approval of 2 commercially available FMT products offers new options for prevention of recurrent C. difficile infection. Although more data are emerging to support the efficacy and safety of these products in vulnerable subpopulations, additional data are needed before they can be recommended over traditional FMT in patients who are immunocompromised. A new guideline from the AGA recommends Rebyota, Vowst, and traditional FMT as options to prevent recurrent C. difficile infection in immunocompetent adults. A shared decision-making process should be employed when selecting therapy for prevention of recurrent C. difficile infection.

References

  1. Stallhofer J, Steube A, Katzer K, Stallmach A. Microbiota-based therapeutics as new standard-of-care treatment for recurrent Clostridioides difficile infection. Visc Med. 2024;40(2):82-91. doi: 10.1159/000535851
  2. Feuerstadt P, Theriault N, Tillotson G. The burden of CDI in the United States: a multifactorial challenge. BMC Infect Dis. 2023;23(1):132. doi: 10.1186/s12879-023-08096-0
  3. Wang Y, Hunt A, Danziger L, Drwiega EN. A comparison of currently available and investigational fecal microbiota transplant products for recurrent Clostridioides difficile infection. Antibiotics (Basel). 2024;13(5):436. doi: 10.3390/antibiotics13050436
  4. Rebyota. Package insert. Ferring Pharmaceuticals; 2022.
  5. Vowst. Package insert. Aimmune Therapeutics; 2024.
  6. Feuerstadt P, Chopra T, Knapple W, et al. PUNCH CD3-OLS: a phase 3 prospective observational cohort study to evaluate the safety and efficacy of fecal microbiota, live-jslm (REBYOTA) in adults with recurrent Clostridioides difficile infection. Clin Infect Dis. Published online August 24, 2024. doi: 10.1093/cid/ciae437
  7. McDonald LC, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018;66(7):e1-e48. doi:10.1093/cid/cix1085
  8. Johnson S, Lavergne V, Skinner AM, et al. Clinical practice guideline by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA): 2021 focused update guidelines on management of Clostridioides difficile infection in adults. Clin Infect Dis. 2021;73(5):e1029-e1044. doi:10.1093/cid/ciab549
  9. Kelly CR, Fischer M, Allegretti JR, et al. ACG clinical guidelines: prevention, diagnosis, and treatment of Clostridioides difficile infections. Am J Gastroenterol. 2021;116(6):1124-1147. doi:10.14309/ajg.0000000000001278
  10. Poylin V, Hawkins AT, Bhama AR, et al. The American Society of Colon and Rectal Surgeons clinical practice guidelines for the management of Clostridioides difficile infection. Dis Colon Rectum. 2021;64(6):650-668. doi: 10.1097/DCR.0000000000002047
  11. Peery AF, Kelly CR, Kao D, et al. AGA clinical practice guideline on fecal microbiota-based therapies for select gastrointestinal diseases. Gastroenterology. 2024;166(3):409-434. doi: 10.1053/j.gastro.2024.01.008

Prepared by:
Laura Koppen, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

October 2024

The information presented is current as of September 20, 2024. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.