Three fluoroquinolones with different epithelial lining fluid penetration in a murine lung infection model: an...

Antimicrobial efficacy in pneumonia is strongly influenced by site-specific drug exposure; however, pharmacokinetic/pharmacodynamic (PK/PD) indices based on plasma concentrations may not adequately reflect drug exposure at the pulmonary infection site. This study evaluated how differences in pulmonary distribution influence the magnitude and interpretation of PK/PD targets by comparing three fluoroquinolones with distinct epithelial lining fluid (ELF) penetration profiles. Using a murine Streptococcus pneumoniae lung infection model, levofloxacin (LVFX), garenoxacin (GRNX), and lascufloxacin (LSFX) were evaluated under identical experimental conditions. Minimum-inhibitory concentrations (MICs) were determined by broth microdilution. Pharmacokinetics were assessed in plasma and ELF, and pharmacodynamics were quantified as changes in pulmonary bacterial burden. PK/PD relationships and exposure targets were estimated based on plasma- and ELF-derived indices. The MICs of LVFX, GRNX, and LSFX were 0.512, 0.032, and 0.032 mg/L, respectively. In plasma-based PK/PD analyses, GRNX and LSFX exhibited bactericidal effects at lower fAUC/MIC values than LVFX. In contrast, ELF-based analyses revealed greater interdrug differences in PK/PD targets attributable to differences in ELF penetration. Notably, LSFX showed substantial divergence between plasma- and ELF-based PK/PD targets, indicating a strong influence of site-specific exposure on antibacterial efficacy. When ELF-based PK/PD targets were translated to predicted human plasma exposure, the resulting values were generally consistent with reported clinical PK/PD benchmarks. Site-specific PK/PD analysis incorporating pulmonary drug distribution is important for interpreting antimicrobial efficacy in pneumonia. For agents with high ELF penetration, ELF-based PK/PD targets may provide a more relevant framework for understanding antibacterial effects and optimizing dosing strategies.