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.

• Authors: Dana Maglio, Heather K Sun, Toral Patel, Mary Anne Banevicius, Charles H Nightingale, Anu Arya, Guoqiang Wang, Zhigang Chen, Ly T Phan, David P Nicolau
• Journal: International journal of antimicrobial agents (Int J Antimicrob Agents) Vol. 43 Issue 6 Pg. 540-6 (Jun 2014) ISSN: 1872-7913 [Electronic] Netherlands
• PMID: 24703590 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Chemical References

• Anti-Bacterial Agents
• Bridged-Ring Compounds
• EDP 420
• Macrolides

Topics

• Animals
• Anti-Bacterial Agents (pharmacokinetics, pharmacology, therapeutic use)
• Bacterial Load
• Bridged-Ring Compounds (pharmacokinetics, pharmacology, therapeutic use)
• Disease Models, Animal
• Female
• Macrolides (pharmacokinetics, pharmacology, therapeutic use)
• Mice, Inbred ICR
• Microbial Sensitivity Tests
• Pneumonia, Pneumococcal (drug therapy)
• Streptococcus pneumoniae (drug effects)