Fresh or Frozen? Fecal Transplant Samples in Recurrent CDI

Frozen vs Fresh Fecal Microbiota Transplantation and Clinical Resolution of Diarrhea in Patients With Recurrent Clostridium difficile Infection: A Randomized Clinical Trial

Lee CH, Steiner T, Petrof EO, et al
JAMA. 2016;315:142-149

Testing Fresh vs Frozen Donor Stool

Fecal microbiota transplantation (FMT) has been a hot topic in the medical literature and general media as of late. It sounds simple (the substrate is readily available), and a quick search on the Internet indicates that the efficacy is > 90% to stop recurrent Clostridium difficile infection (CDI).

However, there are actually a lot of moving parts and unknowns when it comes to FMT. Where will the donor stool come from? What pathogens should the donor be screened for? How will donor pathogen screening be paid for? What kind of diluent, and how much of it, should be used for stool processing? How much FMT should be administered? How and where will FMT be administered?

Another question is whether the FMT product has to be made fresh, or whether frozen stool would suffice. This is important, because not all donors are able to "deliver" on the momentous day. This study by Lee and colleagues provides the best evidence to date that the efficacy of frozen FMT product is equal to that of fresh FMT product.

People aged ≥ 18 years were eligible for the study if they had recurrent CDI (defined as recurrence of CDI symptoms within 8 weeks of completing therapy for a previous episode of CDI) or refractory CDI (defined as persistence or worsening of CDI symptoms despite at least 5 days of oral vancomycin). Donors were prospectively screened and rescreened every 6 months, and most stools were obtained from three donors. Relatives of study participants were also permitted to donate stool for the study.

Study participants were randomly assigned to receive fresh or frozen FMT. FMT preparation involved mixing approximately 100 g of stool in 300 mL of bottled water, and 50 mL was drawn up in a 60-mL syringe. Frozen suspensions were maintained at -20°C for up to 30 days and thawed overnight at 25°C before use. A single 50-mL dose was administered by enema for each FMT. All patients received a single dose of FMT, but could receive additional doses 5-8 days after the previous dose for persistent symptoms of CDI.

The primary outcome was no recurrence of CDI at 13 weeks after receiving up to two doses of FMT, without the need for antibiotics for recurrent CDI. The per-protocol (PP) population comprised patients who received up to two same-modality (eg, fresh or frozen) FMTs, did not require antibiotics for CDI between the two FMT doses, and did not receive systemic antibiotics for other infections during the study period. The modified intention-to-treat (mITT) population included all participants who received at least one dose of FMT according to study treatment assignment.

The study participants and investigators were blinded to the treatment assignment. This study was powered as a noninferiority trial, and it was determined that at least 78 patients were needed in each group, assuming an 85% efficacy for fresh FMT.

The frozen FMT group comprised 108 patients (mITT population), of whom 91 met criteria for the PP population. The fresh FMT group had 111 patients (mITT population), of whom 87 met criteria for the PP population.

In the PP population, treatment success after two doses at most was achieved in 83.5% of those who received frozen FMT, compared with 85.1% of those who received fresh mITT. In the mITT population, success after two doses at most was 75.0% and 70.3%, respectively. Of note, treatment success after a single dose was achieved in only 62.7% (frozen FMT) and 62.1% (fresh FMT) of the PP population, and 52.8% and 50.5% (respectively) of the mITT population.

Only 7% of study participants had refractory CDI, so this study does not answer the question of whether FMT is efficacious for refractory CDI.

Viewpoint

This study has helped clarify the question of whether fresh or frozen FMT product has greater efficacy in preventing recurrent CDI. However, one important take-home message is that contrary to popular belief, the efficacy of FMT is not > 90%.

In the PP population, success after a single dose was 62.7% to 62.1%. In the mITT population, which more closely resembles real-world management of patients with recurrent CDI, the success rate was only 52.8% to 50.5%. It took two doses to increase the efficacy to 85% in the PP population and 75% in the mITT population. This is consistent with the numerous recent prospective trials^[1,2,3,4,5] of FMT for recurrent CDI, in which the efficacy after a single dose has been found to be 59%-81% after a single dose and 88%-94% after multiple doses, with no obvious difference in efficacy according to route of administration (pills, duodenal tube, colonoscopy, enema).

Confidence in the use of frozen FMT product greatly simplifies the FMT process. However, it is equally important when discussing treatment options for recurrent CDI that patients are aware that they may require more than one dose.

In summary, this study demonstrates that frozen stool specimens for FMT are as effective as fresh-stool FMT for recurrent CDI, and provides additional evidence that multiple doses of FMT are needed to achieve an efficacy of > 90%.

Abstract

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