title: In vivo assessment of SMT19969 in a hamster model of clostridium difficile infection.
abstract: SMT19969 [2,2'-bis(4-pyridyl)3H,3'-H 5,5-bibenzimidazole] is a novel narrow-spectrum nonabsorbable antibiotic currently in development for the treatment of Clostridium difficile infection. The comparative activities of SMT19969 and vancomycin against nonepidemic and epidemic strains of C. difficile were studied in an established hamster model. Against nonepidemic (VA11) strains, the survival rates of SMT19969-treated animals ranged from 80% to 95%. Vancomycin exhibited 100% protection during treatment, with relapse observed starting on day 9 and 50% survival at day 20. At 50 mg/kg of body weight, SMT19969 administered orally once daily for 5 days provided full protection of treated animals on the dosing days and through day 12 against epidemic strains. Vancomycin also protected during the dosing interval, but apparent relapse occurred earlier, starting on day 11. SMT19969 exhibited excellent in vitro activity, with MICs of 0.25 μg/ml for all isolates. The MICs for vancomycin were 2- to 4-fold higher at ≤0.5 to 1 μg/ml. All plasma sample concentrations of SMT19969 were below the limit of quantification (25 ng/ml) at all time points, consistent with the reported lack of bioavailability of the compound. Cecal concentrations were significantly above the MIC (ranging from 96 μg/ml to 172 μg/ml).
authors.affiliation: University of North Texas Health Science Center, Fort Worth, Texas, USA william.weiss@unthsc.edu.
authors.forename: William
authors.initials: W
authors.lastname: Weiss
authors.affiliation: University of North Texas Health Science Center, Fort Worth, Texas, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Pulse
authors.affiliation: Summit plc, Oxfordshire, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Vickers
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D016360:Clostridioides difficile / Q000187:drug effects* / Q000472:pathogenicity*; D003015:Clostridium Infections / Q000188:drug therapy* / Q000382:microbiology; D006224:Cricetinae; D008297:Male; D008647:Mesocricetus; D008795:Metronidazole / Q000627:therapeutic use; D008826:Microbial Sensitivity Tests; D014640:Vancomycin / Q000627:therapeutic use
chemical_list: D000900:Anti-Bacterial Agents; D008795:Metronidazole; D014640:Vancomycin