New Therapies Offer Hope Amid Rising Recurrent Clostridioides difficile infection as Traditional FMT Access Declines

Key Highlights:

• Recurrent Clostridioides difficile infection (rCDI) affects 1 in 6 patients within 2 to 8 weeks of an initial episode.
• Fecal microbiota transplantation is effective for rCDI but no longer widely available due to regulatory and logistical barriers.
• FDA-approved live biotherapeutics (rectal and oral) show strong efficacy in preventing recurrence.
• Antibiotic stewardship and early follow-up are key components of comprehensive rCDI management.

A presentation by Jessica R. Allegretti MD, MPH, FACG, and Joel J. Heidelbaugh MD, FAAFP, FACG, at Practical Updates in Primary Care examined best practices in recurrent Clostridioides difficile infection (rCDI), which remains a major challenge in both inpatient and outpatient care. The infection recurs in approximately 16% of patients within 2 to 8 weeks after initial resolution, with recurrence risk increasing with each subsequent episode.

Recently approved microbiota-based therapies offer new avenues for effective prevention of rCDI and may help clinicians overcome the barriers of access and safety concerns associated with traditional fecal microbiota transplantation (FMT).

C difficile is a spore-forming, anaerobic bacterium that is a common gut commensal in healthy individuals but can cause severe colitis when the intestinal microbiota is disrupted, particularly following antibiotic use. Over the past decade, incidence has risen dramatically both in healthcare settings and the community, leading to ~ 500,000 cases annually in the United States. and nearly 30,000 deaths. Notably, more than 80% of C difficile-related deaths occur in patients older than 65 years of age. The disease burden highlights the need for effective prevention strategies and a shift in focus toward long-term management of recurrence risk.

Diagnosis of rCDI is based on clinical symptoms (new-onset watery diarrhea in patients with risk factors) and confirmed using a multistep testing algorithm involving polymerase chain reaction and toxin assays. Treatment of initial infection typically involves oral vancomycin or fidaxomicin for 10 days. However, recurrence is common due to persistent spores or reinfection with new strains. Contributing factors include impaired host immune response, disrupted bile acid metabolism, and reduced microbial diversity—particularly loss of Firmicutes and Bacteroidetes. Treatment strategies for recurrence emphasize altering the gut microbiota. Vancomycin tapering, fidaxomicin, and repeat FMT have been employed, though the availability of FMT is now severely limited due to changes in FDA regulations and discontinuation of OpenBiome shipments.

Two FDA-approved live biotherapeutics—fecal microbiota, live-jslm (rectal) and fecal microbiota spores, live-brpk (oral)—have emerged as effective alternatives. In the PUNCH CD3 trial, live-jslm achieved a 71.6% recurrence-free rate at 8 weeks compared to 57.5% with placebo. Similarly, ECOSPOR III demonstrated 88.9% efficacy at 8 weeks for live-brpk capsules versus 58.7% for placebo, with no serious treatment-related adverse events. These agents offer practical and scalable options, although insurance coverage, speed of product acquisition, and patient eligibility may affect adoption.

The presenters noted challenges with product access due to cost and insurance, discontinuation of adjunctive agents like bezlotoxumab, and limited data in patients with IBD, immunocompromised status, or other comorbidities who have been excluded from trials. Additionally, regulatory complexity around FMT continues to create barriers in clinical practice.

Reference:
Allegretti JR, Heidelbaugh JJ. Combating recurrent C. difficile infection: from diagnosis to cure. Presented at: Practical Updates in Primary Care; September 17-19, 2025. https://www.hmpglobalevents.com/pupc