Fecal microbiota transplant for relapsing Clostridium difficile infection using a frozen inoculum from unrelated donors: a randomized, open-label, controlled pilot study

Abstract

Background: Recurrent Clostridium difficile infection (CDI) with poor response to standard antimicrobial therapy is a growing medical concern. We aimed to investigate the outcomes of fecal microbiota transplant (FMT) for relapsing CDI using a frozen suspension from unrelated donors, comparing colonoscopic and nasogastric tube (NGT) administration.

Methods: Healthy volunteer donors were screened and a frozen fecal suspension was generated. Patients with relapsing/refractory CDI were randomized to receive an infusion of donor stools by colonoscopy or NGT. The primary endpoint was clinical resolution of diarrhea without relapse after 8 weeks. The secondary endpoint was self-reported health score using standardized questionnaires.

Results: A total of 20 patients were enrolled, 10 in each treatment arm. Patients had a median of 4 (range, 2-16) relapses prior to study enrollment, with 5 (range, 3-15) antibiotic treatment failures. Resolution of diarrhea was achieved in 14 patients (70%) after a single FMT (8 of 10 in the colonoscopy group and 6 of 10 in the NGT group). Five patients were retreated, with 4 obtaining cure, resulting in an overall cure rate of 90%. Daily number of bowel movements changed from a median of 7 (interquartile range [IQR], 5-10) the day prior to FMT to 2 (IQR, 1-2) after the infusion. Self-ranked health score improved significantly, from a median of 4 (IQR, 2-6) before transplant to 8 (IQR, 5-9) after transplant. No serious or unexpected adverse events occurred.

Conclusions: In our initial feasibility study, FMT using a frozen inoculum from unrelated donors is effective in treating relapsing CDI. NGT administration appears to be as effective as colonoscopic administration.

Clinical trials registration: NCT01704937.

Keywords: Clostridium difficile; fecal microbiota transplant; frozen inoculum; microbiome.

Figure 1.

Enrollment and follow-up.

Figure 2.

Mean number of daily bowel movements (BMs) in both study arms. Baseline represents reported BMs prior to contracting Clostridium difficile as reported by the patients. Six-month follow-up data are missing from 3 patients in the nasogastric tube group and 2 patients in the colonoscopy group. Abbreviation: FMT, fecal microbiota transplant.

Figure 3.

Mean scores of subjective well-being over time as reported using a standardized questionnaire with a scale of 1–10, 1 being the lowest. The colonoscopy group had consistently higher scores, accounted for by a mean higher reported score at day –1. When analyzing the absolute increment in health scores, the groups did not differ (P = .51). Abbreviation: FMT, fecal microbiota transplant.

Figure 4.

Microbiota diversity in fecal samples obtained from fecal microbiota transplant recipients before and after the procedure, as compared with the donors, expressed by the Shannon diversity index. The box-and-whisker plots indicate interquartile ranges (boxes), medians (red horizontal lines), and range (whiskers). Abbreviations: FMT, fecal microbiota transplant; SDI, Shannon diversity index.

Figure 5.

Microbiota diversity in fecal samples obtained from fecal microbiota transplant recipients before and after the procedure, stratified by treatment route and expressed by the Shannon diversity index. The box-and-whisker plots indicate interquartile ranges (boxes), medians (red horizontal lines), and range (whiskers). Abbreviation: SDI, Shannon diversity index.