Pharmacodynamic profiling of modithromycin: assessment in a pneumococcal murine pneumonia model.
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.
Center for Anti-Infective Research and Development, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102, USA.
Dana
D
Maglio
Center for Anti-Infective Research and Development, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102, USA.
Heather K
HK
Sun
Center for Anti-Infective Research and Development, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102, USA.
Toral
T
Patel
Center for Anti-Infective Research and Development, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102, USA.
Mary Anne
MA
Banevicius
Center for Anti-Infective Research and Development, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102, USA.
Charles H
CH
Nightingale
Enanta Pharmaceuticals, Inc., Watertown, MA, USA.
Anu
A
Arya
Enanta Pharmaceuticals, Inc., Watertown, MA, USA.
Guoqiang
G
Wang
Enanta Pharmaceuticals, Inc., Watertown, MA, USA.
Zhigang
Z
Chen
Enanta Pharmaceuticals, Inc., Watertown, MA, USA.
Ly T
LT
Phan
Center for Anti-Infective Research and Development, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102, USA. Electronic address: david.nicolau@hhchealth.org.
David P
DP
Nicolau
D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D058491:Bacterial Load; D001952:Bridged-Ring Compounds / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D005260:Female; D018942:Macrolides / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D011018:Pneumonia, Pneumococcal / Q000188:drug therapy*; D013296:Streptococcus pneumoniae / Q000187:drug effects*
D000900:Anti-Bacterial Agents; D001952:Bridged-Ring Compounds; C520838:EDP 420; D018942:Macrolides
EDP-420; Modithromycin; Pharmacodynamic; Pneumococci; Streptococcus pneumoniae