Empirical Donor Selection, 2-Dose Capsule FMT Regimen Improve C Diff Cure Rates

Findings from a multi-site quality improvement study suggest implementation of empirical donor exclusion and an optimized capsule fecal microbiota transplantation (FMT) dosing regimen may meaningfully improve clinical outcomes for patients with Clostridioides difficile infection (CDI).1

“To our knowledge, this is the first study to apply prospective quality improvement methods to increase FMT cure rates in clinical practice,” Sara Ellegaard Paaske, a researcher in the department of clinical medicine at Aarhus University in Denmark, and colleagues wrote.1

FMT is a known effective treatment for CDI. In 2024, the American Gastroenterological Association released the first comprehensive evidence-based guideline on the use of fecal microbiota-based therapies for gastrointestinal disease, recommending FMT in most cases of recurrent CDI. However, real-world effectiveness data are necessary to refine treatment algorithms.1,2

To provide real-world effectiveness data for refining FMT treatment algorithms, investigators conducted a multi-site Danish quality improvement study of patients with CDI treated with capsule-based FMT from June 2019 to September 2024. For inclusion, patients were required to be ≥18 years of age and treated with encapsulated FMT for CDI, defined as the clinical presence of C. difficile-associated diarrhoea (CDAD), characterized as diarrhea (≥ 3 daily Bristol Stool Form Scale type 6–7 stools) for a ≥ 2 consecutive days, coupled with a positive polymerase chain reaction (PCR) stool test for detection of C. difficile toxins.1

Patients were pretreated with vancomycin, fidaxomicin, metronidazole, or a combination of these drugs before initiating FMT treatment. Before an FMT treatment, patients fasted for 6 hours and received a single 10-mg tablet of metoclopramide. One FMT treatment could be administered as 1 of 3 possible dosing regimens, applying 1, 2, or 3 doses. Multiple-dose FMT included FMT using material from the same donor, administered 1–7 days apart without concurrent antibiotic use between administrations.1

The primary outcome was cure of CDAD 8 weeks after FMT, counted from the final FMT administration and monitored as monthly cure rates over time. The cure of CDAD was defined as either the absence of diarrhea or diarrhea coupled with a negative C. difficile test.1

Investigators identified the exclusion of low-efficacy FMT donors and optimized FMT dosing as two key intervention strategies likely to enhance FMT effectiveness based on the observed variation in cure rates among donors and between 1-dose and 2-dose FMT. Acknowledging this, they identified 3 low-performing donors who were removed from the donor pool and initiated a 2-dose capsule FMT dosing regimen that was later increased to a 3-dose capsule FMT regimen for selected patients at high risk of recurrence with the 2-dose regimen.1

In total, the study included 1176 patients who received 1707 FMT treatments. The included patients had a median age of 71 years, 58% were female, and the majority had severe (54%) CDI.1

The proportion of patients receiving 2-dose capsule FMT rose from 23% to 85% at the primary FMT center and from 19% to 70% at the external FMT sites following the dosing regimen change. Before 2021, the mean cure rate at the primary center was 69% (95% CI, 62%–75%). After upscaling the FMT production, it dropped to 54% (95% CI, 48%–60%). After introducing 2-dose capsule FMT and excluding 3 donors, the mean cure rate at this center increased to 70% (95% CI, 60%–78%). Following the introduction of a differentiated dosing regimen in January 2024, the mean cure rate was 67% (95% CI, 57%–76%).1

At the external FMT sites, before the exclusion of 3 donors, the mean cure rate at the external FMT sites was 50% (95% CI, 45%–56%). After their exclusion, the mean cure rate numerically increased to 59% (95% CI, 55%–63%), though investigators noted the change was not statistically significant. Following the introduction of a 2-dose capsule FMT regimen, the mean cure rate increased to 72% (95% CI, 65%–77%).1

Across all FMT treatments, the mean cure rates were 54% (95% CI, 51%–57%) with 1-dose capsule FMT, 74% (95% CI, 70%–78%) with 2-dose capsule FMT, and 55% (95% CI, 41%–69%) for high-risk vulnerable patients receiving 3-dose capsule FMT. Of note, the greater cure rate with 2-dose capsule FMT persisted across stratifications by CDI episode number, patient age, antibiotic-refractory CDI, severe or fulminant CDI, and patients with inflammatory bowel disease (P <.001).1

“Our study suggests that FMT stool banks should monitor FMT effectiveness continuously to ensure high quality,” investigators concluded.1 “Today, clinical CDI guidelines recommend evaluating donors only for safety but not for effectiveness, and there are no recommendations regarding FMT dosing. Future guidelines could include guidance for optimal treatment strategies, including continuous effectiveness monitoring and FMT dosing.”

References

1. Paaske SE, Baunwall SMD, Rubak T, et al. Improving Clinical Outcomes of Encapsulated Faecal Microbiota Transplantation for Clostridioides difficile Infection Through Empirical Donor Selection and Optimised Dosing: A Quality Improvement Study. Alimentary Pharmacology & Therapeutics. https://doi.org/10.1111/apt.70395

2. Brooks A. AGA Supports Fecal Microbiota-Based Therapies for C Diff in New Guideline. HCPLive. February 21, 2024. Accessed October 17, 2025. https://www.hcplive.com/view/aga-supports-fecal-microbiota-based-therapies-for-c-diff-in-new-guideline