Fecal Microbiota Transplant for Relapsing Clostridium difficile Infection Using a Frozen Inoculum From Unrelated Donors: A Randomized, Open-Label, Controlled Pilot Study

Recurrent and refractory Clostridium difficile infection (CDI) is a growing medical concern, with a recent dramatic increase in the number of patients globally [1–4]. In the United States, the incidence of CDI has tripled over the last 15 years [3]. Response to standard antimicrobial therapy with oral vancomycin or metronidazole is suboptimal, with CDI recurring in up to 30% of individuals treated for a first episode. After 2 or more episodes of CDI, the estimated risk for subsequent recurrence exceeds 60% with antimicrobial therapy [3, 5–8]. Often, patients with recurrent CDI are treated with prolonged administration of oral vancomycin with tapering of the medication over many months, but this approach is poorly studied. The emergence of a virulent strain of the organism (NAP1/BI/027) has been associated with even higher rates of treatment failure [9, 10]. The consequences of recurrence can be devastating, resulting in life-threatening illness, frequent hospitalizations, and possible surgical interventions. In addition to individual morbidity and mortality, CDI taxes the medical system by requiring patient cohorting, leading to bed closures, delay of discharge, and additional contact precautions. Although the illness is toxin-mediated, overgrowth of the organism in the setting of dysbiosis is thought to be a key inciting event. Failure to reconstitute normal flora was shown to be a factor in severe, recurrent, and prolonged illness [11]. Fecal microbiota transplant (FMT)—reconstitution of normal flora by a stool transplant from a healthy individual—has been a successful therapeutic approach to recurrent/refractory CDI in animal studies [12], numerous case series [13–18], and, more recently, a single randomized clinical trial [19]. Even though an overall CDI resolution rate of about 90% has repeatedly been reported in published reviews and meta-analyses [20–23], practical and aesthetic barriers have hindered the widespread use of FMT to date. Recruitment and screening of donors is a lengthy process associated with significant costs, thus preventing the use of FMT in acute situations. Establishing a repository of prescreened frozen donor stools could make this treatment available for a wider population. Furthermore, many questions remain regarding the optimal protocol donor screening, sample processing, route of administration, and amount of fecal material instilled. In the current study, we aimed to investigate the clinical outcomes of FMT for refractory or relapsing CDI using a frozen suspension from unrelated donors by both upper and lower gastrointestinal routes.