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Antimicrob. Agents Chemother. doi:10.1128/AAC.01372-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Pharmacodynamic Assessment Based on Mutant Prevention Concentration of Fluoroquinolones to Prevent the Emergence of Resistant Mutants of Streptococcus pneumoniae

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

^* To whom correspondence should be addressed. Email: tomoyuki.honma{at}shionogi.co.jp.

	Abstract

The object of this study was to investigate the relationship between pharmacokinetic/pharmacodynamic parameters based on 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 of 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 of 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 MPC did not show any correlation with the decrease of susceptibility. These results suggested that AUC_0-24/MPC and C_max/MPC were important parameters for predicting the emergence of resistant mutants and those higher values indicated more effective.