Enteric microbiome profiles during a randomized Phase 2 clinical trial of surotomycin versus vancomycin for the treatment of Clostridium difficile infection.

Objectives: The effects of surotomycin (CB-183,315, MK-4261), a bactericidal cyclic lipopeptide, and vancomycin, the current standard-of-care for Clostridium difficile infection (CDI), on intestinal pathogens and microbiota were evaluated parallel to a Phase 2 randomized, double-blind clinical trial. Methods: The single-centre cohort included 26 patients receiving surotomycin [125 or 250mg twice daily (n=9 each)] or oral vancomycin [125mg four times daily (n=8)] for 10 days. Faecal samples were collected at days 0-42 to quantify both C. difficile by conventional culture and the major components of the microbiome by quantitative PCR. Results: Surotomycin 250mg twice daily or vancomycin 125mg four times daily reduced faecal C. difficile counts from similar to 10(5)-10(7) log(10) cfu/g at baseline to <= 10(2) cfu/g by days 4-10 of treatment. Day 10 counts of C. difficile in 3/9 patients receiving surotomycin 125mg twice daily remained detectable, including one patient who failed to achieve clinical cure. Bacteroidetes and Prevotella mean counts increased 0.7 log(10) or remained unchanged with surotomycin 125 and 250mg twice daily, respectively, whereas vancomycin reduced counts by 2.5-3.2 log(10) (P < 0.02). Vancomycin reduced Firmicutes counts by 2.5-2.8 log(10); surotomycin moderately suppressed these microbes in a dose-dependent manner. Conclusions: In this Phase 2 trial substudy, compared with vancomycin 125mg four times daily, surotomycin 250mg twice daily is as active in vivo against C. difficile, but was more sparing of microbiota. Surotomycin is no longer in development due to failed Phase 3 efficacy results.