TY - JOUR
T1 - In vivo assessment of smt 19969 in a hamster model of clostridium difficile infection
AU - Weiss, William
AU - Pulse, Mark
AU - Vickers, Richard
N1 - Publisher Copyright:
© 2014 Weiss et al. This is an open access article distributed under the terms of the Creative Commons Attribtion 30 Unported license.
PY - 2014/10/1
Y1 - 2014/10/1
N2 - 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).
AB - 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).
UR - http://www.scopus.com/inward/record.url?scp=84907276010&partnerID=8YFLogxK
U2 - 10.1128/AAC.02903-14
DO - 10.1128/AAC.02903-14
M3 - Article
C2 - 25022586
AN - SCOPUS:84907276010
SN - 0066-4804
VL - 58
SP - 5714
EP - 5718
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
IS - 10
ER -