Benign C difficile Strain May Reduce CDI Recurrence Rates

Janis C. Kelly

May 11, 2015

A new strategy for combatting recurrent Clostridium difficile infection (CDI) by seeding the gastrointestinal (GI) tract with spores of a C difficile strain that does not produce endotoxins appeared safe and successful at reducing CDI recurrence rates in phase 2 trials.

Dale N. Gerding, MD, from the Edward Hines Jr VA Hospital, Hines, Illinois, and Loyola University Chicago, Maywood, Illinois, and colleagues report their findings in an article published in the May 5 issue of JAMA.

"The use of nontoxigenic C diff spores is very interesting," Bruce E. Hirsch, MD, attending physician in infectious diseases at North Shore-LIJ Medical Group, North Shore University Hospital, Manhasset, New York, told Medscape Medical News.

"My major concern," he said, "is that this nontoxigenic C diff spore approach fails to address the central issue with these patients: The normal bacteria in the lower GI tract, so important for health and freedom from CDI, are profoundly disturbed. The nontoxigenic C diff strategy does not correct the dysbiosis which predisposes to C diff recurrence."

In addition, Dr Gerding and colleagues acknowledge that questions remain about whether the nontoxigenic C difficile strain will remain benign. CDI recurrence happens because antimicrobial therapy generally does not eliminate all toxigenic C difficile organisms. Previous laboratory studies demonstrated that toxic C difficile strains can transfer genes required to produce endotoxins to nontoxigenic C difficile, converting them into toxin producers.

The authors write, "These in vitro transfer observations raise concern that transfers could occur in vivo, although this has not been demonstrated. Nonetheless, they reinforce the importance of elimination of toxigenic C difficile with treatment where possible to minimize any chance of in vivo conjugation and pathogenicity locus transfer."

Dr. Hirsch said, "The authors acknowledge the preliminary nature of their findings. Additional clinical experience with nontoxigenic spores will be required to monitor for the potential of horizontal gene transfer and conversion to toxigenic strains. The preliminary findings are encouraging."

Dose-Ranging Trial

The orally administered NTCD-M3 spores were tested in 173 patients (157 of whom completed treatment) in a randomized, double-blind, placebo-controlled, dose-ranging study sponsored by ViroPharma Incorporated/Shire, which is developing C difficile strain M3 (VP20621; NTCD-M3) for commercial use.

All patients had recovered from initial or first recurrent CDI episode after treatment with metronidazole, oral vancomycin, or both at one of 44 study centers in the United States, Canada, and Europe. The nontoxigenic C difficile strain NTCD-M3 was given as an oral liquid formulation. Patients were randomly assigned to one of four treatments:

  • 104 spores/day for 7 days (n = 43),

  • 107 spores/day for 7 days (n = 44),

  • 107 spores/day for 14 days (n = 42), or

  • placebo for 14 days (n = 44).

Overall CDI recurrence rates were 30% with placebo and 5% in patients receiving NTCD-M3 at 107 spores/day for 7 days. However, supplemental data available online show that CDI recurrence rates were not dose dependent. For example, among women, recurrence rates were 31% in the placebo group compared with 15%, 4%, and 18% in the lowest-, medium-, and highest-dose groups, respectively.

The suggested mechanism of action of NTCD-M3 is that it "occupies the same metabolic or adherence niche in the gastrointestinal tract as does toxigenic C difficile and, once established, is able to outcompete resident or newly ingested toxigenic strains."

It is not yet clear how lasting the effect is however. Supplemental data show that both the nontoxic and toxic strains of C difficile declined with time during the 26-week follow-up period in all of the active treatment groups. The toxigenic strain also continued to decline in the placebo group, but less rapidly.

The ability to colonize the patient's gastrointestinal tract was a key factor determining treatment success. Recurrence rates were 2% for patients who became colonized with NTCD-M3 but 31% (similar to placebo) for patients who were treated with NTCD-M3 but did not become colonized (odds ratio, 0.01; 95% confidence interval, 0.00 - 0.05; P < .001).

Safety data were reassuring. One or more treatment-emergent adverse events were reported in 78% of patients receiving NTCD-M3 and in 86% of patients receiving placebo. The most common adverse events were diarrhea (46% of treated patients vs 60% with placebo) and abdominal pain (17% of treated patients vs 33% with placebo). Serious treatment-related adverse effects occurred in 3% of NTCD-M3-treated patients and in 7% of placebo patients. Headache was reported in 10% of NTCD-M3-treated patients and in 2% of placebo patients.

CDI remains the most common healthcare-associated infection in the United States and recurs in nearly one third of patients, despite antibiotic therapy. CDI affects nearly half a million patients per year and kills about 29,000 of them. Fecal microbiota transplant has gained considerable acceptance as a method for reducing recurrence risk. The use of orally administered of spores of nontoxigenic C difficile could add another tactic to that strategy.

Dr. Hirsch said that optimizing dose and duration was beyond the scope of this feasibility study. "A more prolonged dosing strategy would raise the issues of adherence, expense, and convenience, which compares unfavorably with fecal transplant treatments, which have high efficacy after only one or two doses."

The authors conclude, "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."

This study was sponsored by ViroPharma Incorporated, which is now part of the Shire group of companies. Dr Gerding reports holding patents for the prevention of CDI licensed to ViroPharma/Shire; consultancy for ViroPharma/Shire, MedImmune, Sanofi Pasteur, Cubist, Optimer, DaVolterra, and Pfizer; and membership in the advisory boards of Merck, Rebiotix, Summit, and Actelion. Dr Lee reports participation in clinical trials for ViroPharma, Actelion, Cubist, and Merck and membership in the advisory boards for Rebiotix, Cubist, and Merck. Dr Cohen reports membership in the advisory boards of Merck and ViroPharma/Shire and clinical trial participation with ViroPharma/Shire, Cubist, Actelion, and Merck. Dr Poirier reports clinical trial participation with GlaxoSmithKline, Merck, Cubist, Bayer, Actelion, and ViroPharma. Dr Van Schooneveld reports research support from ViroPharma and Cubist and speaker fees from Thermo-Fischer. Dr Pardi reports consultancy for Seres Health and having served on advisory boards for Cubist and Optimer. Dr Barron reports membership in advisory boards for Astellas Pharma US and current clinical trial participation with Astellas Pharma US, ViroPharma/Shire, GlaxoSmithKline, Actelion T2 Biosystems, and Merck. Dr Chen reports Shire stock/options. Dr Chen and Dr Villano were full-time employees of ViroPharma/Shire during the conduct of this study.

JAMA. 2015;313:1719-1727. Abstract

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