New Fecal Microbiota Options for Prevention of Recurrent Clostridioides difficile

Recurrent Clostridioides difficile infection (CDI) is defined as an additional onset of symptoms with positive assay results typically within 2-8 weeks of an index infection. This is more likely to occur in patients over age 65, immunocompromised patients, or in patients who present initially with severe CDI.¹

Recurrent CDI can impact not only medical costs, but also add to missed time at work or further complications from the inflammatory processes initiated by the infection.2 Recently, two fecal microbiota products have been introduced to prevent recurrent CDI, live-jslm (Rebyota, RYA) and live-brpk (Vowst, VST). These are not yet described in either the American College of Gastroenterology (ACG) or Infectious Disease Society of America (IDSA) guidelines but may play a role in prevention of recurrent CDI in our high-risk populations.^1,3

Fecal microbiota transplantation (FMT) was recommended as a viable, safe, and effective treatment for recurrent or refractory CDI as early as the 2010s. The theory behind this treatment is that FMT would replace the protective microbiome of the natural gut flora after disruption.⁴ This theory still comprises the background theory in the development of RYA and VST, but these new products have developed consistency in their preparation, manufacture, and clinical data in order to achieve FDA approval.

RYA is administered rectally by a trained medical professional in a one-time dose that should be retained in the gut for up to 15 minutes after administration. This should be administered within 24-72 hours after completion of antibiotics for CDI, and patients should be instructed to not take antibiotics for another 8 weeks unless directed by a medical provider.⁵ RYA was approved after the PUNCH CD3 trial, which was a randomized, double-blind, placebo-controlled phase 3 trial of patients with at least 1 recurrence of CDI or 2 episodes of severe CDI resulting in hospitalization in the prior year. After enrollment difficulties, the investigators pooled data from the PUNCH CD2 phase IIb trial to perform a Bayesian analysis. This resulted in an estimated 70.6% of patients treated with RYA that did not have recurrent CDI diarrhea within 8 weeks of treatment versus 57.5% of placebo patients.⁶ Over 87% of participants in this trial were treated initially with oral vancomycin, so results from this study cannot directly be extrapolated to the use of other antibiotics.

The most recent fecal microbiota product, VST, is delivered as oral capsules that should be administered on an empty stomach 2-4 days after completion of CDI antibiotic therapy. Prior to initiation of VST, patients need to complete a bowel regimen with magnesium citrate. In clinical studies, polyethylene glycol electrolyte solution (GoLytelyTM) was used in patients with impaired renal function, although this is not an approved indication for this product at this time.⁷ ECOSPOR III was a double-blind, placebo-controlled trial of patients experiencing at least a third episode of CDI. There was a reduction in recurrence of CDI from 40% to 12% (p < 0.001) versus placebo, and the benefits of VST remained consistent when stratified by age or antibiotic (vancomycin or fidaxomicin) used to treat the CDI.⁸ Almost half of the patients in this trial were under 65 years old, but the inclusion of them after 3 episodes of CDI increased their potential risk for recurrent CDI.

When comparing these 2 products, reported side effects in clinical trials are very similar: abdominal distension, diarrhea, and other gastrointestinal complaints were common. Safety concerns mirror concerns of fecal microbiota transplantation. For both products, there are theoretical possibilities of infectious disease transmission or anaphylaxis due to allergens that may be contained in the donor fecal product. Neither of these potential effects were observed in the trials leading to FDA approval of RYA or VST, however.^5,7

Recurrent CDI can be disastrous for patients repeatedly affected with infections. However, these recent new additions to the arsenal of preventative options against recurrent CDI have the potential to reduce recurrence in some of our most at-risk patient populations. It would be prudent to recognize these new options as additional tools targeting the reduction of recurrent CDI.

References

1. 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 the Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2017;66(7):e1-e48. doi: 10.1093/cid/cix1085
2. Gupta A & Anathakrishnan AN. Economic burden and cost-effectiveness of therapies for Clostridioides difficile infection: a narrative review. Ther Adv Gastroenterol. 2021;14:1-13. doi: 10.1177/17562848211018654
3. Kelly CR, Fischer M, Allegretti JR, et al. ACG Clinical Guidelines: Prevention, Diagnosis, and Treatment of Clostridioides difficile infections. Am J Gastroenterol. 2021;116:1124-1147. doi: 10.14309/ajg.0000000000001278
4. Rohlke F & Stollman N. Fecal microbiota transplantation in relapsing Clostridium difficile infection. Therap. Adv. Gastroenterol. 2012;5(6):403-420. doi: 10.1177/1756283X12453637
5. Rebyota [Product Insert]. Parsippany, NJ: Ferring Pharmaceuticals, Inc.;2022.
6. Khanna S, Assi M, Lee C, et al. Efficacy and Safety of RBX2660 in PUNCH CD3, a Phase III, Randomized, Double-Blind, Placebo-Controlled Trial with a Bayesian Primary Analysis for the Prevention of Recurrent Clostridioides difficile infection. 2022;82:1527-1538. doi: 10.1007/s40265-022-01797-x
7. Vowst [Product Insert]. Cambridge, MA: Seres Therapeutics, Inc.; 2023.
8. Feuerstadt P, Louie TJ, Lashner B, et al. SER-109, an Oral Microbiome Therapy for Recurrent Clostridioides difficile Infection. N Engl J Med. 2022;386:220-229. doi: 10.1056/NEJMoa2106516