Exploration of clinical breakpoint of Danofloxacin forGlaesserella parasuisin 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 (CO PD ) and clinical cutoff value (CO CL ), 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 CO PD 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 CO CL 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 MIC 50 and MIC 90 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 (C max ) 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 (T max ) in plasma was 0.23 ± 0.07 h, shorter than that in PELF (1.61 ± 0.15 h). The CO PD in plasma and PELF were 0.125 μg/mL and 0.5 μg/mL, respectively. The CO CL 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 CO CL . The ECV is much higher than the CO PD and CO CL , 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. Importance G. parasuis , a gram-negative respiratory pathogen, can colonize in the upper respiratory tract in swine and cause Glasser’s disease. As the abuse of antibiotics, antimicrobial resistant G. parasuis emerged in different degrees, which brought serious threat to global economy and public health. Danofloxacin in quinolones are one of the best choices for treatment of G. parasuis infection, because of their strong bactericidal activity and good absorption into blood and great distribution in the lung. However, the clinical breakpoint (CBP) for danofloxacin against G. parasuis had not yet been established by clinical laboratory of standard Institute (CLSI) and European Commission of antimicrobial susceptibility testing (EUCAST). 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.