Exploration of clinical breakpoint of Danofloxacin for Glaesserella parasuis in plasma and in PELF
Background: To establish the clinical breakpoint (CBP) of danofloxacin to G. parasuis, three cutoff values, including epidemiological cutoff value (ECV), pharmacodynamic cutoff value (COPD) and clinical cutoff value (COCL), was obtained in the present study. Methods: The ECV was calculated using ECOFFinder base on MIC distribution of 347 G. parasuis collected from disease pigs. The COPD was established base on in vivo and ex vivo pharmacokinetic (PK)-pharmacodynamic (PD) modeling of danofloxacin both in plasma and pulmonary epithelial lining fluid (PELF) using Hill formula and Monte Carlo analysis. The COCL was established based on the relationship between possibility of cure (POC) and MIC in the clinical trials using 'WindoW' approach, nonlinear regression and CART analysis. Results: The MIC50 and MIC90 of danofloxacin against 347 G. parasuis were 2 μg/mL and 8 μg/mL, respectively. The ECV value was set up as 8 μg/mL using ECOFFinder. Concentration-time curve of danofloxacin indicated a two-compartment model for PK analysis. The PK parameters of the maximum concentration (Cmax) and area under concentration-time curve (AUC) in PELF were 3.67 ± 0.25 μg/mL and 24.28 ± 2.70 h·μg/mL, higher than those in plasma (0.67 ± 0.01μg/mL and 4.47 ± 0.51 h·μg/mL). The peak time (Tmax) in plasma was 0.23 ± 0.07 h, shorter than that in PELF (1.61 ± 0.15 h). The COPD in plasma and PELF were 0.125 μg/mL and 0.5 μg/mL, respectively. The COCL calculated by WindoW approach, nonlinear regression and CART analysis were 0.125~4 μg/mL, 0.428 μg/mL and 0.56 μg/mL, respectively. The 0.5 μg/mL was selected as eligible COCL. The ECV is much higher than the COPD and COCL, and the clinical breakpoint based on data in plasma was large different with that of in PELF. Conclusions: Our study firstly established three cutoff values of danofloxacin against G. parasuis. It suggested that epidemiological danofloxacin-resistant G. parasuis may lead to the ineffective treatment by danofloxacin.