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Pharmacodynamic Assessment Based on Mutant Prevention Concentrations of Fluoroquinolones To Prevent the Emergence of Resistant Mutants of Streptococcus pneumoniae

Discovery Research Laboratories, Shionogi and Co., Ltd., Toyonaka, Osaka 561-0825, Japan

Received 2 November 2006/ Returned for modification 11 February 2007/ Accepted 25 July 2007

The objective of this study was to investigate the relationship between pharmacokinetic and pharmacodynamic parameters, on the basis of the mutant prevention concentration (MPC) concept, and the emergence of resistant mutants of Streptococcus pneumoniae to fluoroquinolone antibacterials. Some clinical isolates with various MIC and MPC values of moxifloxacin and levofloxacin were exposed under conditions simulating the time-concentration curves observed when moxifloxacin (400 or 80 mg, once a day) or levofloxacin (200 mg, twice a day) was orally administered by using an in vitro pharmacodynamic model. The decrease in susceptibility was evaluated by altering the population analysis profiles after moxifloxacin or levofloxacin treatment for 72 h. When the area under the concentration-time curve from 0 to 24 h (AUC_0-24)/MPC and peak concentration (C_max)/MPC were above 13.41 and 1.20, respectively, complete eradication occurred and no decrease in susceptibility was observed. On the other hand, when AUC_0-24/MPC and C_max/MPC were below 0.84 and 0.08, respectively, the susceptibility decreased. However, the time inside the mutant selective window and the time above the MPC did not show any correlation with the decrease in susceptibility. These results suggest that AUC_0-24/MPC and C_max/MPC are important parameters for predicting the emergence of resistant mutants and that higher values indicate greater effectiveness.

Published ahead of print on 30 July 2007.