By Jake Scott, MD
Synopsis: In a randomized controlled trial conducted in Norway, fecal microbiota transplantation (FMT) was noninferior to vancomycin for the treatment of primary Clostridioides difficile infection, with 66.7% of patients in the FMT group achieving clinical cure without recurrence compared to 61.2% in the vancomycin group over 60 days of follow-up.
Source: 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. 2025; Jun 17. doi: 10.7326/ANNALS-24-03285. [Online ahead of print].
The authors conducted a randomized, open-label, noninferiority trial comparing fecal microbiota transplantation (FMT) to vancomycin for the treatment of primary Clostridioides difficile infection (CDI).1 The study was conducted at 20 hospitals in Norway between June 2019 and March 2024. Participants were eligible if they were 18 years of age or older with primary CDI, defined as diarrhea (≥ 3 loose stools per day), a positive stool test for toxin-producing C. difficile, and no diagnosis of CDI within 365 days before enrollment. Key exclusion criteria included severe immunocompromise, ongoing antibiotic treatment that could not be stopped, inflammatory bowel disease, life expectancy of three months or less, need for intensive care at enrollment, and more than one dose of C. difficile-directed treatment already administered.
Patients were randomly assigned 1:1 to receive either one FMT enema administered within 24 hours of randomization or standard-of-care treatment with 125 mg of oral vancomycin four times daily for 10 days. The FMT was delivered by the Norwegian stool donor bank and consisted of 50 g of donor feces suspended in saline and glycerol, administered as an enema without antibiotic pretreatment. The primary endpoint was clinical cure at day 14 (defined as fewer than three stools per day or firm stools for at least 48 hours) with the assigned treatment alone and no recurrent CDI within 60 days.
A total of 104 patients were randomly assigned, with 100 patients receiving treatment and eligible for analysis (51 in the FMT group and 49 in the vancomycin group). The median age was 70-71 years in both groups, and most patients (85% to 90%) had used antibiotics within the previous three months. Approximately one-third of patients had severe CDI, defined as leukocyte count > 15 × 109 per liter, creatinine level > 1.5 mg/dL, or temperature > 38.5° Celsius.
Clinical cure at day 14 and no recurrence within 60 days with the assigned treatment alone was observed in 34 of 51 patients (66.7%) in the FMT group vs. 30 of 49 patients (61.2%) in the vancomycin group (difference, 5.4 percentage points; 95.2% confidence interval [CI], -13.5 to 24.4 percentage points; P < 0.001 for noninferiority). The study met its prespecified noninferiority margin of 25 percentage points. Eleven patients in the FMT group and four in the vancomycin group required additional treatment, predominantly with oral vancomycin.1
When including patients who received additional treatment, clinical cure at day 14 and no recurrence within 60 days was achieved in 40 of 51 patients (78.4%) in the FMT group compared to 30 of 49 patients (61.2%) in the vancomycin group. Recurrence rates among those who achieved initial clinical cure were notably lower in the FMT group (5.6%) compared to the vancomycin group (21.1%). Adverse events were similar between groups, with no significant differences in serious adverse events. Seven patients died during the 60-day follow-up period, with one death in each group attributed to CDI recurrence.
Commentary
This study represents the first adequately powered randomized controlled trial to demonstrate noninferiority of FMT compared to standard antibiotic therapy for primary CDI. However, the findings must be interpreted within the current treatment landscape where fidaxomicin, not vancomycin, is now the preferred first-line therapy according to Infectious Diseases Society of America (IDSA) guidelines.2,3
The study’s comparison with vancomycin rather than fidaxomicin represents a significant limitation when interpreting these results for current practice. Fidaxomicin has superior sustained response rates compared to vancomycin, with recurrence rates of approximately 15% vs. 25%, respectively. The observed 5.6% recurrence rate with FMT is notably lower than expected rates with either antibiotic, suggesting FMT may offer superior prevention of recurrence, but direct comparison with fidaxomicin is needed.
The treatment landscape has become increasingly complex with the availability of Food and Drug Administration (FDA)-approved fecal microbiota products — Rebyota (rectal suspension) and Vowst (oral capsules) — for preventing recurrence in patients with prior CDI episodes.4 These standardized products offer advantages including consistent quality and reduced logistical complexity compared to traditional FMT, although they remain expensive and not widely accessible. As noted in an accompanying editorial, immediate adoption of FMT as primary therapy in the United States is unlikely, but these products support the principle of microbiome restoration.5
The study’s strengths include its randomized, multicenter design and real-world setting. The investigators justified their 25 percentage-point noninferiority margin based on FMT being a minimally invasive, one-time procedure that avoids antibiotic exposure and promotes antimicrobial stewardship. The early termination for efficacy after meeting prespecified criteria strengthens the findings.
Several limitations warrant consideration beyond the comparator choice. The open-label design may have introduced bias, although this likely would underestimate FMT effectiveness since clinicians might more readily provide rescue treatment for FMT failures. The study relied on clinical endpoints without microbiologic confirmation of C. difficile clearance or assessment of microbiome restoration.
From a practical standpoint, FMT administration via enema requires minimal training, and the Norwegian stool bank model provides a framework for quality-assured preparation. However, establishing such infrastructure requires significant investment, making commercial products potentially more feasible for widespread implementation.
Key questions remain for future research and clinical practice: How does FMT compare directly to fidaxomicin for primary CDI? What is the optimal sequencing of fidaxomicin, traditional FMT, and commercial microbiota products? Should treatment algorithms be individualized based on patient risk factors? When should microbiome-based therapies be preferred over antibiotics?
In summary, this landmark trial provides compelling evidence that FMT may be considered for primary CDI treatment, representing a potential paradigm shift toward microbiome restoration over antimicrobial therapy. However, the comparison with vancomycin rather than current preferred therapy limits immediate clinical applicability. Future studies comparing FMT directly with fidaxomicin and evaluating commercial microbiota products as first-line therapy are needed to guide evidence-based treatment algorithms in our evolving therapeutic landscape.
Jake Scott, MD, is Clinical Associate Professor, Infectious Diseases and Geographic Medicine, Stanford University School of Medicine; Antimicrobial Stewardship Program Medical Director, Stanford Health Care Tri-Valley.
References
- 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. 2025; Jun 17. doi: 10.7326/ANNALS-24-03285. [Online ahead of print].
- 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.
- 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.
- 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(3):220-229.
- Hohmann E. How and when to use microbial restoration therapies for Clostridioides difficile infection. Ann Intern Med. 2025; Jun 17. doi: 10.7326/ANNALS-25-01868. [Online ahead of print].
In a randomized controlled trial conducted in Norway, fecal microbiota transplantation (FMT) was noninferior to vancomycin for the treatment of primary Clostridioides difficile infection, with 66.7% of patients in the FMT group achieving clinical cure without recurrence compared to 61.2% in the vancomycin group over 60 days of follow-up.
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