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).
Highlights
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
Hamsters were infected with an inoculum of 5.44 to 6.09 log10 CFU C. difficile VA11, of which there were 4.59 log10 spores contained in the inoculum
The hamster model of clindamycin-induced Clostridium difficile infection (CDI) is the current standard in vivo model used to assess the potential efficacies of agents, including antibiotics, toxin antibodies, and vaccines [10, 11]
Summary
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. Clostridium difficile infection (CDI) has emerged as a significant infectious disease and, with the emergence of hypervirulent strains, an increasing threat in terms of morbidity and mortality [1,2,3]. When recurrent cases of CDI are included, the incidence in long-term care facilities may exceed that reported in the hospital setting [6]. With a narrow spectrum of activity and typically Ͼ1,000fold selectivity for C. difficile over Gram-positive and Gram-negative anaerobic and facultative fecal flora [10], SMT19969 has therapeutic potential for the treatment of CDI. We report the results from studies in an established hamster model [11] of CDI comparing vancomycin with SMT19969
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