Déjà Vu: Unanswered Questions About Fecal Microbiota Transplantation for Recurrent <i>Clostridioides difficile</i> Infection

(See the Major Article by Drekonja et al. on pages 52–60.) To date, more than a dozen clinical trials have examined the effectiveness of fecal microbiota transplantation (FMT) in reducing recurrences of Clostridioides difficile infection (CDI) in patients with multiple previous recurrences. Overall, the data suggest that FMT is effective [1], and most clinical practice guidelines now recommend FMT for multiply-recurrent CDI [2–4]. However, questions remain around the wide variability in effectiveness reported in published trials, ranging from less than 50% to more than 90%. In this issue of Clinical Infectious Diseases, Shaukat et al describe a randomized, double-blinded, placebo-controlled trial evaluating the effectiveness and safety of oral, encapsulated FMT for preventing recurrent CDI. The trial was stopped for futility, after enrollment of 153 participants, with 32.9% in the FMT arm and 29.9% in the placebo arm experiencing the primary endpoint of possible or definite recurrence or death within 56 days. On initial glance, this may seem disappointing. However, the study makes several notable contributions to the field. First, it is a randomized, double-blinded, placebo-controlled trial with a large sample size compared with prior trials evaluating FMT for recurrent CDI. The majority of earlier randomized studies were small, open-label, and not placebo-controlled. One blinded study involving 46 participants compared FMT from donor stools with autologous FMT via colonoscopy. While autologous FMT may be a valid comparator for a study evaluating the effectiveness of FMT, it is not equivalent to placebo, given that the instillation of stool into the dysbiotic colon may itself impact microbiota. Second, the current study involved Veterans Health Administration (VA) sites across 40 states, encompassing urban and rural sites. This may represent the greatest geographic diversity of enrollment of any randomized FMT trial in the CDI literature to date (not including commercial microbial therapeutics). The study also used a previously validated oral, encapsulated FMT as the study intervention, providing details on the manufacturing and stability of the FMT product. Finally, the study is pragmatic in many ways. For example, prescribing physicians were allowed discretion in choosing standard antibiotic treatment regimens; both polymerase chain reaction (PCR) and toxin testing were accepted for enrollment of participants with compatible symptoms of CDI; possible and confirmed recurrences of CDI were included in the primary endpoint, and proton pump inhibitor and probiotic use were permitted. Pragmatism is important when evaluating the effectiveness of FMT for recurrent CDI, since standard-of-care antibiotic therapy is typically initiated by a different provider than the clinician administering FMT, and CDI testing methodologies differ across jurisdictions. The negative outcome of the study is important to acknowledge and should not be dismissed as an aberrancy. In 2017, we published a randomized controlled trial that was terminated at an interim analysis due to lack of effectiveness of FMT compared with standard-of-care antibiotics (vancomycin taper-pulse) [5]. The weight of evidence today still appears to favor FMT for the prevention of recurrent CDI. Indeed, a recent Cochrane meta-analysis that included our trial concluded with moderate certainty that “FMT likely results in a large increase in resolution of symptoms in patients with recurrent CDI” [1]. However, now with 2 negative published studies of conventional FMT in recurrent CDI, it behooves us to understand why FMT does not work in all trials. Perhaps the most significant factor to consider in the study by Shaukat et al is the population enrolled in the study. Seventy-eight percent of the participants had only 1 recurrence of CDI prior to randomization. Most trials evaluating FMT for recurrent CDI have targeted individuals with a history of 2 or more recurrences. After a single recurrence, the risk of further recurrence is expected to be lower compared with subsequence recurrences [6], potentially because the colon is in a less dysbiotic state. The effect of FMT on recurrence risk for patients who have experienced a single recurrence of CDI is less studied. To date, 1 randomized, double-blinded, placebo-controlled study has evaluated conventional FMT in patients with a first or second episode of CDI. This study was stopped early after randomizing 42 participants when 90% in the FMT and 33% in the placebo arm demonstrated resolution of symptoms at week 8 [7]. The high rate of recurrence in the placebo arm of this trial is unusual and may be related to the severity of the participants’ disease, as 76% were classified as severe CDI and 52% were admitted to hospital on randomization. This is in contrast to the study by Shaukat et al, which was designed to recruit a geographically diverse outpatient population, which is presumably a less severely-affected group. The study by Shaukat et al was not designed or powered to evaluate the effect of FMT on recurrence risk in patients with a single recurrence of CDI. Notably, in subgroup analysis, in participants with more than 1 recurrence of CDI prior to randomization, there was a trend towards effectiveness of FMT (proportion meeting primary endpoint: 37.5% for FMT and 50% for placebo). In addition, the timing of FMT delivery relative to the acute episode of CDI and the number of FMT administrations are relevant [8]. The authors state that study personnel prioritized enrollment as early as possible in the enrollment window. The median time lag between the last date of antimicrobial agent and randomization was 5 days, with a range of 2 through 19 days. Patients had to report resolution or symptom improvement for 48 hours during treatment of their most recent CDI episode. Introducing FMT so early after a bout of acute CDI and potentially at a time prior to symptom resolution may incur challenges in uptake of donor microbiota due to persistent intestinal inflammation or possible residual vancomycin [9]. Further to this, only a single administration of the FMT was used, which may not have been sufficient to allow microbiota uptake. Our data [10] suggest increased uptake of donor stool microbiota with repeated FMT administrations. The authors did not describe recipients’ microbiota profile post-FMT, making it unclear how much inadequate uptake of donor microbiota may have played a role in their negative outcome. Finally, the microbiota profile and diversity of the donor stool used to manufacture the FMT product used in their trial were not described. Our data suggest that FMT from donors with higher diversity in their stool microbiota has higher success rates for resolution of recurrent CDI compared with those with lower diversity [11]. While FMT has been placed in multiple international guidelines as standard of care for patients with 2 or more recurrences of CDI, this study, which primarily assessed effectiveness after a single CDI recurrence, reminds us of unanswered questions about optimal timing, dosage, donor profile, and patient population for FMT. Ongoing research into answering these questions should continue in order to optimize the manufacturing and delivery of FMT to produce the best patient outcomes.

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