title: Impact of Surotomycin on the Gut Microbiota of Healthy Volunteers in a Phase 1 Clinical Trial.
abstract: Clostridium difficile-associated diarrhea has been associated with disruption of the normal intestinal microbiota, particularly theBacteroides fragilisgroup andPrevotellaspecies. Surotomycin is a bactericidal cyclic lipopeptide in development for treatment ofClostridium difficile-associated diarrhea that has selective and potent activity againstC. difficileand other Gram-positive bacteria and a minimal impact on intestinal Gram-negative organisms. The impacts of ascending doses of surotomycin on major organism groups in the gut microbiota of healthy volunteers were evaluated during a randomized, double-blind, placebo-controlled, multiple-dose phase 1 study. Thirty volunteers were randomized into 3 cohorts, using a 4:1 ratio, to receive 250 mg, 500 mg, or 1,000 mg of surotomycin, or placebo, twice daily for 14 days. Stool samples collected at baseline (days 0 and 1) and at the end of treatment (days 13 to 15) were cultured quantitatively. TheB. fragilisgroup, theBacteroides/Prevotellagroup, andEnterobacteriaceaewere also quantified by quantitative real-time PCR. Baseline and end-of-treatment stool samples showed 1- to 2-log10CFU/g reductions in total bacterial counts for most volunteers. Various decreases in clostridial,Lactobacillus-Bifidobacteriumgroup, and enterococcus-streptococcus group counts occurred while patients were receiving surotomycin, whereas the enterobacteria and theB. fragilisgroup persisted at the end of treatment. There was no change in enterococcus MICs of surotomycin, nor was vancomycin-resistantEnterococcusdetected after exposure. Surotomycin at doses of up to 1,000 mg twice daily had only modest disruptive effects on the gut microbiota. The potential sparing of the gut microbiota by surotomycin may decrease the risk of disease recurrence.
authors.affiliation: R. M. Alden Research Laboratory, Culver City, California, USA d.m.citron@att.net.
authors.forename: Diane M
authors.initials: DM
authors.lastname: Citron
authors.affiliation: R. M. Alden Research Laboratory, Culver City, California, USA.
authors.forename: Kerin L
authors.initials: KL
authors.lastname: Tyrrell
authors.affiliation: ACM Global Central Laboratory, Rochester, New York, USA.
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Dale
authors.affiliation: Merck and Co., Inc., Kenilworth, New Jersey, USA.
authors.forename: Laurent
authors.initials: L
authors.lastname: Chesnel
authors.affiliation: R. M. Alden Research Laboratory, Culver City, California, USA.
authors.forename: Ellie J C
authors.initials: EJ
authors.lastname: Goldstein
mesh_terms: D000328:Adult; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001441:Bacteroides fragilis / Q000187:drug effects / Q000502:physiology; D004311:Double-Blind Method; D004755:Enterobacteriaceae / Q000187:drug effects / Q000502:physiology; D016983:Enterococcus / Q000187:drug effects / Q000502:physiology; D005243:Feces / Q000382:microbiology; D005260:Female; D000069196:Gastrointestinal Microbiome / Q000187:drug effects* / Q000502:physiology; D064368:Healthy Volunteers; D006801:Humans; D055666:Lipopeptides / Q000494:pharmacology*; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000494:pharmacology*; D018720:Prevotella / Q000187:drug effects / Q000502:physiology
chemical_list: D000900:Anti-Bacterial Agents; C574454:CB-183,315; D055666:Lipopeptides; D010456:Peptides, Cyclic