Pharmacodynamic profiling of modithromycin: Assessment in a pneumococcal murine pneumonia model

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• 作者：Dana Maglio^a ; Heather K. Sun^a ; Toral Patel^a ; Mary Anne Banevicius^a ; Charles H. Nightingale^a ; Anu Arya^b ; Guoqiang Wang^b ; Zhigang Chen^b ; Ly T. Phan^b ; David P. Nicolau^a ; ^{david.nicolau@hhchealth.org" class="auth_mail}
• 关键词：Modithromycin ; EDP-420 ; Pharmacodynamic ; Streptococcus pneumoniae ; Pneumococci
• 刊名：International Journal of Antimicrobial Agents
• 出版年：June 2014
• 年：2014
• 卷：43
• 期：6
• 页码：540-546
• 全文大小：477 K

文摘

The pharmacodynamic profile of modithromycin (EDP-420, EP-013420, S-013420), a novel bicyclolide, was evaluated in a neutropenic pneumococcal murine pneumonia model. Streptococcus pneumoniae median minimum inhibitory concentrations (MICs) for five genotypically diverse isolates ranged from 0.016 渭g/mL to 0.125 渭g/mL and were unaffected by macrolide or penicillin resistance determinants. The modithromycin dosing regimens (total daily doses of 3.125–1000 mg/kg/day) were derived from the pharmacokinetic profile of the compound in infected mice and were selected to produce a wide range of exposures. Dose–response relationships characterised using the E_max model demonstrated high correlations both with the ratio of the area under the concentration–time curve to MIC (AUC/MIC) and the ratio of the maximum drug concentration to MIC (C_max/MIC). However, dose fractionation studies suggest that the AUC/MIC is the predominant driver of in vivo efficacy. The free drug AUC/MIC (fAUC/MIC) required for stasis and for 80% of maximum activity ranged from 4 to 53 and 25–99, respectively. The fAUC/MIC needed to achieve a 1 log reduction in bacterial density, which is a conventional measure of the required exposure in man to reliably predict efficacy, ranged from 9 to 69. These data demonstrate the in vitro and in vivo potency of modithromycin against S. pneumoniae irrespective of its phenotypic profile to the macrolides or penicillin.