Efficacy of Human-Simulated Exposures of Tomopenem (Formerly CS-023) in a Murine Model of Pseudomonas aeruginosa and Methicillin-Resistant Staphylococcus aureus Infection

Tomopenem (formerly CS-023) is a novel carbapenem with improved activity against diverse hospital pathogens, includingPseudomonas aeruginosa and methicillin-resistantStaphylococcus aureus (MRSA), and has a half-life about twice longer than the half-lives of other carbapenems such as imipenem and meropenem. Our objective in this study was to estimate the efficacy of tomopenem in humans by human-simulated exposures in a neutropenic murine thigh infection model against 9 clinical isolates ofP. aeruginosa with MICs of 4 to 32 μg/ml and 9 clinical isolates of MRSA with MICs of 4 to 16 μg/ml. Human-simulated dosing regimens in neutropenic mice were designed to approximate the cumulative percentage of a 24-h period that the free drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (f %T MIC ) observed with tomopenem at 750 and 1,500 mg given as a 0.5-h infusion three times a day (TID) in humans. As reported previously, there was no difference between the target values ofP. aeruginosa and MRSA required for efficacy (K. Sugihara et al., Antimicrob. Agents Chemother.54: 5298-5302, 2010). Tomopenem at 750 mg showed bactericidal or bacteriostatic effects against 10 of 11 strains ofP. aeruginosa and MRSA with MICs of ≤8 μg/ml (f %T MIC ≥ 41), and tomopenem at 1,500 mg showed bactericidal effects against 16 of 17 strains ofP. aeruginosa and MRSA with MICs of ≤16 μg/ml (f %T MIC ≥ 43). Meropenem at 1,000 mg TID was tested for comparison purposes and showed bactericidal or bacteriostatic effects against 3 of 4 strains ofP. aeruginosa with MICs of ≤4 μg/ml (f %T MIC ≥ 33). From these results, tomopenem is expected to be effective with anf %T MIC of over 40 againstP. aeruginosa and MRSA strains with MICs of ≤8 μg/ml at doses of 750 mg TID and strains with MICs of ≤16 μg/ml at doses of 1,500 mg TID.