Administration of Spores of NontoxigenicClostridium difficileStrain M3 for Prevention of RecurrentC difficileInfection

Abstract

IMPORTANCE Clostridium difficile is the most common cause of health care-associated infection in US hospitals. Recurrence occurs in 25% to 30% of patients. OBJECTIVE To determine the safety, fecal colonization, recurrence rate, and optimal dosing schedule of nontoxigenic C difficile strain M3 (VP20621; NTCD-M3) for prevention of recurrent C difficile infection (CDI). DESIGN, SETTING, AND PARTICIPANTS Phase 2, randomized, double-blind, placebo-controlled, dose-ranging study conducted from June 2011 to June 2013 among 173 patients aged 18 years or older who were diagnosed as having CDI (first episode or first recurrence) and had successfully completed treatment with metronidazole, oral vancomycin, or both at 44 study centers in the United States, Canada, and Europe. INTERVENTIONS Patients were randomly assigned to receive 1 of 4 treatments: oral liquid formulation of NTCD-M3, 10 4 spores/d for 7 days (n = 43), 10 7 spores/d for 7 days (n = 44), or 10 7 spores/d for 14 days (n = 42), or placebo for 14 days (n = 44). MAIN OUTCOMES AND MEASURES The primary outcome was safety and tolerability of NTCD-M3 within 7 days of treatment. Exploratory secondary outcomes included fecal colonization with NTCD-M3 from end of study drug through week 6 and CDI recurrence from day 1 through week 6. RESULTS Among 168 patients who started treatment, 157 completed treatment. One or more treatment-emergent adverse events were reported in 78% of patients receiving NTCD-M3 and 86% of patients receiving placebo. Diarrhea and abdominal pain were reported in 46% and 17% of patients receiving NTCD-M3 and 60% and 33% of placebo patients, respectively. Serious treatment-emergent adverse events were reported in 7% of patients receiving placebo and 3% of all patients who received NTCD-M3. Headache was reported in 10% of patients receiving NTCD-M3 and 2% of placebo patients. Fecal colonization occurred in 69% of NTCD-M3 patients: 71% with 10 7 spores/d and 63% with 10 4 spores/d. Recurrence of CDI occurred in 13 (30%) of 43 placebo patients and 14 (11%) of 125 NTCD-M3 patients (odds ratio [OR], 0.28; 95% CI, 0.11-0.69; P = .006); the lowest recurrence was in 2 (5%) of 43 patients receiving 10 7 spores/d for 7 days (OR, 0.1; 95% CI, 0.0-0.6; P = .01 vs placebo]). Recurrence occurred in 2 (2%) of 86 patients who were colonized vs 12 (31%) of 39 patients who received NTCD-M3 and were not colonized (OR, 0.01; 95% CI, 0.00-0.05; P < .001). CONCLUSIONS AND RELEVANCE Among patients with CDI who clinically recovered following treatment with metronidazole or vancomycin, oral administration of spores of NTCD-M3 was well tolerated and appeared to be safe. Nontoxigenic C difficile strain M3 colonized the gastrointestinal tract and significantly reduced CDI recurrence.

New and emerging therapies for Clostridium difficile infection

“…63 About two thirds (69%) of NTCD recipients were colonized, with only a 2% CDI recurrence rate in these patients.…”

Challenges in fecal donor selection and screening for fecal microbiota transplantation: A review

“…Recent randomized controlled studies have also shown that rates of these minor adverse effects were similar in treatment and control groups, suggesting that they are not necessarily intrinsic to the FMT material. 3,26 Currently, clinical trials that are approved by the FDA under an Investigational New Drug (IND) application are chiefly submitted as Phase I clinical trials and as their results are published, understanding of safety and attributable adverse effects of FMT will improve. Further, a national registry for FMT outcomes data was recently announced, which will also enhance short-and long-term safety end point data collection and feedback into appropriate donor selection and screening.…”

“…26 Validated commercial assays testing alternative PCR targets that identify donors colonized with non-pathogenic strains of C. difficile, while ruling out asymptomatic carriage of other viral, bacterial and protozoal pathogens would be a helpful inclusion criterion for ideal stool donors. Understanding how to effectively screen donors will help to streamline logistical processes, while protecting the health of FMT recipients.…”

Clostridium difficile Infection

“…By contrast, patients asymptomatically colonized by non-toxigenic strains do not seem to have an increased risk or are even protected from progressing to CDI. This concept was recently tested in humans; patients who could be colonized by a non-toxigenic C. difficile strain after receiving standard of care treatment for CDI had significantly reduced CDI recurrence rates 187 . However, further explorations of this approach should consider that nontoxinogenic strains can become toxinogenic by horizontal gene transfer 188 , although it is unknown whether this process also occurs in a human host.…”