Optimization of dose and dose regimen of biapenem based on pharmacokinetic and pharmacodynamic analysis

Abstract

Pharmacokinetic and pharmacodynamic (PK/PD) parameters, which are important indices of the therapeutic efficacy of antimicrobials, and the minimum inhibitory concentration (MIC) predictive of clinical efficacy at common clinical doses, were examined for biapenem (BIPM; 300 mg b.i.d.), imipenem/cilastatin (IPM/CS; 500 mg/500 mg b.i.d.), meropenem (MEPM; 500 mg b.i.d.), and ceftazidime (CAZ; 1000 mg b.i.d.), using a mouse model of thigh infection caused by Pseudomonas aeruginosa. The PK/PD parameter that most closely correlated with the therapeutic efficacy of all these antimicrobials was time above MIC (T ≫ MIC). The values of T ≫ MIC predictive of clinical efficacy against P. aeruginosa infection varied among antimicrobials and were ≧17%, ≧17%, ≧23%, and ≧33% for BIPM, IPM/CS, MEPM, and CAZ, respectively. From these values and the known plasma concentrations of the antimicrobials in humans after administration at the common clinical doses, the MIC for bacterial strains at which clinical efficacy can be expected was estimated to be ≦4.4 µg/ml for BIPM, ≦6.1 µg/ml for IPM/CS, ≦2.2 µg/ml for MEPM, and ≦13.6 µg/ml for CAZ. These MICs nearly coincided with the MIC₈₀ of the antimicrobials for 104 clinical isolates of P. aeruginosa strains. These results indicate that, even at a low dose, of 300 mg b.i.d., the clinical efficacy of BIPM against P. aeruginosa infection can be expected to be comparable to that of IPM/CS, MEPM, and CAZ.