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.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.