Fecal Microbiota Transplant Found Noninferior to Antibiotic as Initial Treatment for C. Diff

Fecal microbiota transplantation (FMT) proved noninferior to vancomycin for treating primary Clostridioides difficile infection in a randomized controlled trial, with 66.7% of FMT patients achieving clinical cure without recurrence compared to 61.2% receiving standard vancomycin therapy. The findings suggest FMT could serve as first-line therapy for initial C. difficile episodes, potentially reducing antibiotic use and associated resistance concerns, the authors wrote in the Annals of Internal Medicine.

Frederik Emil Juul, MD, PhD

Courtesy of University of Oslo

The study addresses a critical gap in treatment guidance, the authors stressed, as current recommendations are to initiate therapy with antibiotics like vancomycin or fidaxomicin for primary infection, despite known limitations including recurrence rates of 10% to 20% and contribution to antimicrobial resistance.

"Fecal microbiota transplant even showed a 5.4% numerical superiority to vancomycin, which, although not statistically significant, indicates that fecal microbiota transplant has the potential to change the current practice of antibiotic therapy and may establish fecal microbiota transplant as a first-line treatment for primary C. difficile infection," the authors wrote.

The Norwegian research group, led by Frederik Emil Juul, MD, PhD, of the University of Oslo in Norway, conducted this multicenter, open-label noninferiority trial across 20 hospitals and primary care facilities from June 2019 to March 2024. Juul and team enrolled 104 adults with primary CDI, defined as at least 3 loose stools daily, positive stool toxin tests, and no CDI diagnosis within the previous 365 days. The study excluded patients with other enteric pathogens, ongoing antibiotic therapy, inflammatory bowel disease, immunodeficiency, or severe conditions requiring intensive care.

The final study population reflected real-world clinical practice, with median ages of 70-71 years, high antibiotic exposure rates (85-90% within 3 months), and substantial comorbidity burdens. One-third of patients had severe CDI, and over 40% had Charlson Comorbidity Index scores of 4 or higher. Of the 100 patients who received treatment, 51 were assigned to FMT and 49 to vancomycin.

FMT consisted of a single enema containing 50 g of donor feces suspended in saline and glycerol, administered without antibiotic pretreatment. The vancomycin group received 125 mg capsules 4 times daily for 10 days.

Clinical Cure and Recurrence

The trial's primary endpoint measured clinical cure at day 14, defined as fewer than 3 stools daily or firm stools for 48 hours, with assigned treatment alone and no recurrence within 60 days. Clinical cure at day 14 occurred in 70.6% of participants treated with FMT vs 77.6% of those treated with vancomycin. However, recurrence rates differed significantly: only 5.6% of those initially cured in the FMT group experienced recurrence compared to 21.1% in the vancomycin group.

The primary endpoint success rate of 66.7% for FMT versus 61.2% for vancomycin yielded a difference of 5.4 percentage points (95.2% CI, −13.5 to 24.4 percentage points), with P <.001 for noninferiority. The predetermined noninferiority margin of 25 percentage points reflected the clinical advantages of avoiding antibiotics, including reduced resistance pressure and simplified administration, Juul and colleagues wrote.

Eleven FMT-treated participants required additional treatment compared to 4 vancomycin-treated participants, with follow-up treatment choice determined by treating physicians. When accounting for additional treatments, 78.4% of FMT patients achieved the secondary endpoint of clinical cure without recurrence versus 61.2% of vancomycin patients (difference 17.2 percentage points, 95.2% CI, −0.7 to 35.1).

"Fecal microbiota transplant even showed a 5.4% numerical superiority to vancomycin, which, although not statistically significant, indicates that fecal microbiota transplant has the potential to change the current practice of antibiotic therapy and may establish fecal microbiota transplant as a first-line treatment for primary C. difficile infection."

Safety profiles appeared similar between groups. Twenty-three FMT patients (45.1%) experienced adverse events compared to 17 vancomycin patients (34.7%), with no significant difference in serious adverse events. The Data and Safety Monitoring Board recommended early trial termination after interim analysis of 104 patients confirmed noninferiority, deeming continued enrollment unethical given the established benefit.

Study limitations include the open-label design, reliance on clinical rather than microbiological endpoints, and comparison with vancomycin rather than fidaxomicin.

"There is little to criticize about Juul and colleagues' study in terms of design and execution, except for the fact that it is not a double-blinded study," wrote Elizabeth Hohmann, MD, of Massachusetts General Hospital in Boston, in an accompanying editorial.2

Juul and colleagues concluded with optimism: "Our results indicate that it is reasonable to treat patients with primary CDI with FMT and provide antibiotics only to patients with ongoing symptoms or recurrence after FMT. Additional FMT doses may also be considered, as this has been shown to increase the treatment success rate in recurrent CDI."1

Editorialist Hohmann, on the other hand, was less enthusiastic. "We need a fast and inexpensive test for gut dysbiosis...that could help direct us, independent of [C. diff] episode number," she wrote. "I do not believe that we in the United States will see FMT as a primary treatment of C. difficile infection anytime soon, but FMT should remain available, with appropriate sources of carefully screened inocula for care and for further research into the many illnesses and therapies that are influenced by the health of the gut microbiome."2

References
1. Juul FE, Bretthauer M, Johnsen PH, et al. Fecal microbiota transplantation versus vancomycin for primary Clostridioides difficile infection. Ann Intern Med. Published online June 17, 2025. doi: DOI: 10.7326/ANNALS-24-03285.
2. Hohman E. How and when to use microbial restoration therapies for Clostridioides difficile infection. Ann Intern Med. Published online June 17, 2025. doi: 10.7326/ANNALS-25-01868.