Expanded Evidence for Frozen Fecal Microbiota Transplantation for Clostridium difficile Infection

In this issue of JAMA, Lee and colleagues⁹ present the results of a randomized noninferiority trial conducted at 6 academic medical centers in Canada comparing frozen and thawed FMT with fresh FMT to treat patients with multiply recurrent CDI or refractory CDI. Recurrent CDI was defined as “recurrence of CDI symptoms for 48 hours or longer within 8 weeks following the completion of at least 10-day CDI treatment.” Refractory CDI was defined as “persistent or worsening of diarrhea characteristic of CDI and 1 of the following: ongoing abdominal pain, fever (temperature >38.0 C), or peripheral white blood cell (WBC) counts greater than 15.0 × 10⁹/L despite treatment with oral vancomycin at a dose of 500 mg 4 times daily for at least 5 days.” Study participants were randomly assigned to receive frozen or fresh FMT via rectal enema. Primary outcome measures included clinical resolution of diarrhea without relapse at 13 weeks and adverse events. The noninferiority margin was set at 15%.

A total of 219 patients (n = 108 in the frozen FMT group, n = 111 in the fresh FMT group) were included in the modified intention-to-treat population. Of these patients, 178 (n = 91 in the frozen FMT group, n = 87 in the fresh FMT group) were included in the per-protocol population. In the per-protocol population, the proportions of patients achieving clinical resolution of diarrhea were 83.5% in the frozen FMT group and 85.1% in the fresh FMT group (difference, −1.6% [95% CI, −10.5% to ∞). In the modified intention-to-treat population, clinical resolution was observed in 75.0% of the frozen FMT group and 70.3% of the fresh FMT group (difference, 4.7% [95% CI, −5.2% to ∞). Noninferiority thresholds were met, and there were no observed differences in adverse events between the treatment groups.

The results presented by Lee et al offer the best evidence to date supporting the use of frozen stool, with their finding that use of frozen stool for FMT resulted in a rate of clinical resolution of diarrhea that was no worse than that obtained with fresh stool for FMT and will likely expand the availability of FMT for patients with recurrent CDI. The ability to use frozen stool eliminates many of the logistical burdens inherent to FMT, because stool collection and processing need not be tied to the procedure date and time. This study also provides greater support for the practice of using centralized stool banks, which could further remove barriers to FMT by making available to clinicians safe, screened stool that can be shipped and stored frozen and thawed for use as needed. In theory, procedure costs may also be decreased, since comprehensive donor screening is expensive.

Although the current results add to an increasing number of reports in the literature and help guide clinical practice, several questions remain. In particular, there is growing interest in using FMT in other settings (eg, severe, complicated, and refractory CDI), not just recurrent CDI. Of note, the study population in the investigation by Lee et al included patients with refractory CDI, but the numbers are too small to make meaningful conclusions. Additional high-quality clinical studies are needed to answer these questions, and frozen stool may help facilitate such investigation. The current collective understanding of the microbiome remains incomplete, but given demonstrated associations between the gut microbiota and conditions such as obesity, inflammatory bowel disease, diabetes, and colon cancer, there is also increased interest in expanding the therapeutic scope of FMT.¹⁰