Fecal Microbiota Transplantation Shows Promise for First-Line Primary C Diff Treatment

New phase 3 data suggest fecal microbiota transplantation (FMT) may be a viable first-line treatment for primary Clostridioides difficile infection (CDI), highlighting its noninferiority to standard-of-care vancomycin.1

The randomized, open-label, noninferiority trial was conducted at 20 hospitals in Norway and found clinical cure and no disease recurrence within 60 days without additional treatment was observed in 66.7% of patients with FMT versus 61.2% with vancomycin, demonstrating FMT’s numerical superiority and statistically significant noninferiority to the standard-of-care antibiotic.1

“Fecal microbiota transplantation, the transfer of a healthy person’s stool microbiome to another for medical benefit, is an established treatment for recurrent and refractory Clostridioides difficile infection, but it is still somewhat controversial and is not widely available,” Elizabeth Hohmann, MD, a staff physician in the Infectious Diseases Division at Massachusetts General Hospital, wrote in an accompanying editorial published in Annals of Internal Medicine.2

A 2024 American Gastroenterological Association guideline endorses FMT for recurrent, refractory, or fulminant CDI but cautions that the quality of evidence is low, citing bias, challenges with patient selection, lack of blinding, and lack of randomized, well-controlled, large studies.3 While antibiotic treatment with vancomycin or fidaxomicin is currently recommended for primary CDI, frequent recurrence, adverse effects, and the promotion of antibiotic resistance underscore the need for new treatment options, prompting further research into the potential benefits of CDI in this context.1

To investigate the efficacy and safety of FMT in primary CDI, Frederik Emil Juul, MD, PhD, of Oslo University Hospital, and colleagues conducted an open-label, assessor-blinded, multicenter, noninferiority, phase 3 randomized clinical trial of adult patients with primary CDI, defined as diarrhea (≥3 loose stools per day), a positive stool test result for toxin-producing C difficile according to local procedures, and no diagnosis of CDI within 365 days before enrollment.1

Patients were randomly assigned in a 1:1 ratio to either 1 FMT enema administered within 24 hours of randomization or standard-of-care treatment with 125 mg of oral vancomycin 4 times daily for 10 days. Of 104 randomly assigned patients, 100 received FMT or the first dose of vancomycin and were eligible for analysis.1

The primary endpoint was clinical cure at day 14 after the start of treatment with the assigned treatment alone and no recurrent CDI in the 60 days after the start of treatment. Investigators defined clinical cure as < 3 stools per day or firm stools (Bristol Stool Chart type ≤4) for ≥ 48 hours at day 14. Key secondary endpoints were clinical cure at day 14 with or without additional treatment and no recurrent CDI within 60 days, and adverse events. In patients with clinical cure, recurrence was defined as all of the following: diarrhea for > 48 hours during days 15 to 60 after onset of treatment, a positive stool test result for toxin-producing C difficile, and a clinical indication to start re-treatment as judged by the patient’s physician.1

The trial was terminated in July 2024 based on a recommendation from the Data and Safety Monitoring Board because the interim analysis criterion for noninferiority of the primary end point was met (P = .001).1

Specifically, clinical cure and no disease recurrence within 60 days without additional treatment was observed in 66.7% of patients treated with FMT versus 61.2% treated with vancomycin (difference, 5.4 percentage points; 95.2% CI, −13.5 to 24.4 percentage points; P for noninferiority <.001).1

A total of 11 patients in the FMT group and 4 in the vancomycin group received additional treatment, predominantly oral vancomycin (91% and 75%, respectively).1

The proportion of patients who achieved the secondary end point of clinical cure at day 14 with or without additional treatment and no recurrent CDI before 60 days was 78.4% (95% CI, 64.7% to 88.7%) in the FMT group and 61.2% (95% CI, 46.2% to 74.8%) in the vancomycin group, equating to a difference in treatment success of 17.2 percentage points (95.2% CI, −0.7 to 35.1 percentage points) and a P value <.001 for noninferiority of FMT versus vancomycin.1

Investigators did not observe any significant differences in adverse events between the groups. None of the reported adverse events or deaths (n = 2 for FMT, n = 5 for vancomycin) were deemed to be related to the study treatment.1

“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,” Hohmann wrote.2 “We still have much to learn about how our microbial communities affect human health.”

References

1. Juul FE, Bretthauer M, Johnsen PH, et al. Fecal Microbiota Transplantation Versus Vancomycin for Primary Clostridioides difficile Infection: A Randomized Controlled Trial. Ann Intern Med. doi:10.7326/ANNALS-24-03285

2. Hohmann E. How and When to Use Microbial Restoration Therapies for Clostridioides difficile Infection. Ann Intern Med. doi:10.7326/ANNALS-25-01868

3. Brooks A. AGA Supports Fecal Microbiota-Based Therapies for C Diff in New Guideline. HCPLive. February 21, 2024. Accessed June 18, 2025. https://www.hcplive.com/view/aga-supports-fecal-microbiota-based-therapies-for-c-diff-in-new-guideline