FMT Tops Standard of Care for First or Second C. Diff Infections

Early use of fecal microbiota transplantation (FMT) following a course of antibiotics offered a superior treatment option for patients experiencing a first or second Clostridioides difficile infection, according to a randomized trial.

In the single-center trial of 42 patients, all of whom received a 10-day course of vancomycin, those subsequently treated with FMT had significantly higher rates of C. diff-associated diarrhea resolution at 8 weeks versus those assigned placebo (90% vs 33%, P=0.0003), reported Simon Mark Dahl Baunwall, MD, of the Aarhus University Hospital in Denmark, and colleagues.

In addition, more FMT patients achieved negative C. diff test results on PCR at this time point (85% vs 19%, P=0.00003), they stated in Lancet Gastroenterology and Hepatology.

“Our new study shows that we can effectively cure the infection through the early use of [FMT] after completing the standard treatment,” Baunwall said in a press release.

The so-called EarlyFMT trial initially planned to enroll twice as many patients but was halted early due to the overwhelmingly lower cure rate among the placebo group.

“In rare cases, it can happen that you discover that the treatment you are investigating is so effective that it is ethically indefensible to continue,” said Baunwall. “Our study is one example, in that the new FMT treatment is so much better than the standard treatment with antibiotics that it would be unethical to continue.”

FMT showed superiority for C. diff-associated diarrhea resolution at week 8 when stratified both by first (93% vs 36% with placebo) or second (86% vs 30%) infection.

In an accompanying comment, Jessica Allegretti, MD, MPH, of Harvard Medical School in Boston, said the trial showed the “potential promise” of early FMT treatment “to reduce recurrences and prevent subsequent morbidity and mortality associated with recurrent C. difficile infection.”

She pointed out, however, that the primary antibiotic treatment used in the trial (vancomycin) now falls behind fidaxomicin in the Infectious Diseases Society of America’s 2018 guidelines for C. diff infection.

C. diff presents an ongoing threat to healthcare systems, and only a few treatment options are available to target it. While no FMT product currently has FDA approval, that may soon change. The agency currently allows FMT treatments using live biotherapeutics for recurrent C. Diff via the policy of “enforcement discretion,” Allegretti noted, with informed patient consent that it remains an investigational therapy.

“It is unlikely that fecal microbiota transplantation will be implemented earlier in the treatment framework in the USA since it seems likely that once an FDA-approved live biotherapeutic is available, the policy of enforcement discretion is likely to be rescinded,” Allegretti stated. “The bigger question for the field will be regarding how these novel live biotherapeutics will be positioned within the C. difficile treatment armamentarium.”

From June 2021 to April 2022, a total of 42 patients in the double-blind EarlyFMT trial were randomized 1:1 to receive two doses of encapsulated FMT or placebo, following a 10-day course of vancomycin. Patients fasted for a minimum of 6 hours before administration of FMT or placebo, and received oral metoclopramide 10 minutes prior.

Median patient age was 59 years, about three-fourths were women, and a greater proportion were experiencing a first (52-67%) rather than second (33-48%) C. diff infection. Most had severe infections, and over half had been hospitalized.

Baunwall’s group noted that the study’s broad inclusion criteria — which differed from previous FMT trials — could explain the placebo group’s “lower-than-expected” cure rate, but that it was made in an effort to reflect a real-world patient population.

“We included frail patients in nursing homes, patients with multimorbidities, immunocompromised patients, and patients with inflammatory bowel disease,” they explained. “Although this difference might explain the low efficacy of vancomycin alone, fecal microbiota transplantation maintained its anticipated high efficacy.”

Adverse event (AE) rates were similar between the investigational and placebo groups, respectively, with 95% and 100% experiencing at least one. AEs more common in the FMT group included diarrhea (23 vs 14), abdominal pain (14 vs 11), and nausea (12 vs 5). Three serious AEs occurred that were potentially related to the intervention (one in the FMT group; two in the placebo group), but no deaths or colectomies were reported.

Study limitations included safety concerns surrounding the use of donor feces in FMT, which may not be safe for all C. diff patients, although the authors explained that crude feces came from “five thoroughly screened healthy blood donors,” per international guidelines.