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. 2011 Nov;55(11):5004-9.
doi: 10.1128/AAC.00068-11. Epub 2011 Aug 15.

Efficacy of human-simulated exposures of tomopenem (formerly CS-023) in a murine model of Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus infection

Kiyoshi Sugihara  1 , Kazuhiro Tateda, Naotoshi Yamamura, Tetsufumi Koga, Chika Sugihara, Keizo Yamaguchi
Affiliations

Efficacy of human-simulated exposures of tomopenem (formerly CS-023) in a murine model of Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus infection

Kiyoshi Sugihara et al. Antimicrob Agents Chemother. 2011 Nov.

Abstract

Tomopenem (formerly CS-023) is a novel carbapenem with improved activity against diverse hospital pathogens, including Pseudomonas aeruginosa and methicillin-resistant Staphylococcus 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 of P. 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 of P. 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 of P. 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 of P. 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 of P. aeruginosa with MICs of ≤ 4 μg/ml (f%T(MIC) ≥ 33). From these results, tomopenem is expected to be effective with an f%T(MIC) of over 40 against P. 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.

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Figures

Fig. 1.
Fig. 1.
Free concentration-time profiles of tomopenem at 750 mg (A), tomopenem at 1,500 mg (B), and meropenem at 1,000 mg (C) in humans versus mice. Each value represents the mean ± standard deviation (n = 3).
Fig. 2.
Fig. 2.
In vivo efficacy of human-simulated exposures of tomopenem at 750 mg TID (A), tomopenem at 1,500 mg TID (B), and meropenem at 1,000 mg TID (C) in a murine model of thigh infection caused by Pseudomonas aeruginosa. Each value represents the mean ± standard error (n = 3).
Fig. 3.
Fig. 3.
In vivo efficacy of human-simulated exposures of tomopenem at 750 mg TID (A) and tomopenem at 1,500 mg TID (B) in a murine model of thigh infection caused by MRSA. Each value represents the mean ± standard error (n = 3).
Fig. 4.
Fig. 4.
Relationship between in vivo efficacy and f%TMIC for tomopenem against Pseudomonas aeruginosa. Each value represents the mean (n = 3).
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