Pulmonary pharmacokinetics, epithelial lining fluid exposure and PK/PD characterization of the novel pleuromutilin derivative APTM against methicillin-resistant Staphylococcus aureus and Streptococcus pneumoniae in mice.

Authors

Weicong Yang, Luoju Wang, Lei Yan, Haibo Wang, Xiaona Ma, Taiming Lv, Huanzhong Ding

Published in

The Journal of antimicrobial chemotherapy. Volume 81. Issue 9. Aug 04, 2026.

Abstract

To characterize pulmonary pharmacokinetics (PK), epithelial lining fluid (ELF) exposure, antibacterial activity and preliminary PK/pharmacodynamic (PK/PD) relationships of the pleuromutilin derivative APTM in neutropenic murine lung infection models.
Plasma PK and ELF exposure were assessed after a single oral dose in healthy mice. Minimum inhibitory concentrations (MICs) and in vitro time-kill activity were determined against methicillin-resistant Staphylococcus aureus USA300 and Streptococcus pneumoniae ATCC 49619. In vivo efficacy was assessed in neutropenic murine lung infection models. The ratio of the 24 h area under the plasma concentration-time curve to MIC (AUC0-24h/MIC) and the ratio of maximum plasma concentration to MIC (Cmax/MIC) were evaluated as candidate indices using Sigmoid Imax models.
Plasma exposure increased approximately linearly over 10-150 mg/kg. Mean total ELF/plasma ratios were 1.21 for Cmax and 2.05 for the area under the concentration-time curve from time zero to infinity (AUC0-∞). MICs were 0.25 mg/L for USA300 and 0.5 mg/L for ATCC 49619. Relative to the 2 h baseline, maximal mean reductions in pulmonary bacterial burden at 150 mg/kg were 3.39 log10 cfu/mL for USA300 and 1.63 log10 cfu/mL for ATCC 49619. Under the single every-12-h (q12h) regimen, AUC0-24h/MIC showed a stronger association with antibacterial efficacy than Cmax/MIC.
APTM achieved measurable pulmonary exposure and antibacterial activity in murine lung infection models. AUC0-24h/MIC was the best-performing exposure metric among those evaluated under the present conditions; it should not be interpreted as a definitive PK/PD driver. These exploratory, isolate-specific findings support further PK/PD studies of APTM for respiratory infections.

PMID:
42669629
Bibliographic data and abstract were imported from PubMed on 31 Aug 2026.

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