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Pharmacodynamic profiling of modithromycin: assessment in a pneumococcal murine pneumonia model.

Abstract：

: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 μg/mL to 0.125 μg/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 Emax 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 (Cmax/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.

journal_name

Int J Antimicrob Agents

journal_title

International journal of antimicrobial agents

authors

Maglio D,Sun HK,Patel T,Banevicius MA,Nightingale CH,Arya A,Wang G,Chen Z,Phan LT,Nicolau DP

doi

10.1016/j.ijantimicag.2014.01.029

subject

Has Abstract

pub_date

2014-06-01 00:00:00

pages

540-6

issue

6

eissn

0924-8579

issn

1872-7913

pii

S0924-8579(14)00058-2

journal_volume

43

pub_type

杂志文章

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