Fecal Microbiota Transplant vs Oral Vancomycin Taper: Important Undiscussed Limitations Free

To the Editor—I read with interest the report by Hota et al [1] who found that a course of tapered oral vancomycin was as effective as a single fecal microbiota transplantation (FMT) delivered by enema for recurrent Clostridium difficile infection. After review of the article, unaddressed limitations impair the ability to interpret the results and conclusions as presented.

First, the trial used FMT delivered by enema, which is one of the least effective administration methods described in the available literature [2]. While use of FMT delivered by enema is not optimal, the key limitation is the assumption of a 92% success rate for power and futility calculations when using this delivery method. The trial by Lee et al [3], which included 219 patients and is referenced by the authors, found that success rates of a single FMT delivered by enema was 50.5% and 52.8% for fresh and frozen FMT preparations, respectively. This is also supported by the PUNCH-CD trial, which found a success rate of 51.6% after a single administration of FMT by enema [4]. As such, the assumed success rate of 92% used in the statistical calculations of the published trial is not supported by current literature and inflates the results in favor of vancomycin taper.

Second, Table 1 in the article presents P values between randomized and nonrandomized patients [1]. The clinical use of this analysis is highly questionable, as the primary outcome was to describe differences in recurrence rates between patients who were randomized to FMT and those randomized to vancomycin taper [1]. When the randomized population is compared, it becomes important to note that patients who were assigned to the FMT group were older (75.7 years vs 69.6 years), had used other antibiotics within 3 months of enrollment (100% vs 83.3%), and were on proton pump inhibitors (46.7% vs 41.7%) [1]. These are known risk factors for C. difficile infection [5, 6] and would favor recurrence in the FMT arm.

Other factors that must be taken into consideration include the fact that 37.5% of patients in the FMT group received less than 40 g of stool in the FMT preparation [1]. While 50 g of stool has been targeted in some recent literature [4, 7], most randomized trials target 100–150 g of stool for FMT administration [3, 8, 9]. Additionally, enema retention time, which could potentially have some correlation with success [4], was not disclosed in this analysis. Finally, day 0 in the vancomycin taper arm was defined as day 14 of vancomycin therapy; this allowed for patients in the vancomycin group to receive therapy active against C. difficile for 28 days into the follow-up period.

While the prospective, randomized trial design to evaluate a previously unanswered question brought initial appeal, the unaddressed limitations lead to misleading interpretation and conclusions. Due to the above, the need for a larger analysis using accurate treatment assumptions and full disclosure of limitations is necessary before the true effect of FMT compared to vancomycin taper can be appreciated for clinical practice.

Notes

Potential conflicts of interest. The author certifies no potential conflicts of interest. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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Author notes