| Summary: | <b>Background:</b> In order to establish the clinical breakpoint (CBP) of danofloxacin against <i>G. parasuis</i>, three cutoff values, including epidemiological cutoff value (ECV), pharmacokinetic-pharmacodynamic (PK-PD) cutoff value (CO<sub>PD</sub>) and clinical cutoff value (CO<sub>CL</sub>), were obtained in the present study. <b>Methods:</b> The ECV was calculated using ECOFFinder base on the MIC distribution of danfloxacin against 347 <i>G. parasuis</i> collected from disease pigs. The CO<sub>PD</sub> was established based on in vivo and ex vivo PK-PD modeling of danofloxacin both in plasma and pulmonary epithelial lining fluid (PELF) using Hill formula and Monte Carlo analysis. The CO<sub>CL</sub> was established based on the relationship between the possibility of cure (POC) and MIC in the clinical trials using the “WindoW” approach, nonlinear regression and CART analysis. <b>Results:</b> The MIC<sub>50</sub> and MIC<sub>90</sub> of danofloxacin against 347 <i>G. parasuis</i> were 2 μg/mL and 8 μg/mL, respectively. The ECV value was set to 8 μg/mL using ECOFFinder. Concentration-time curves of danofloxacin were fitted with a two-compartment PK model. The PK parameters of the maximum concentration (C<sub>max</sub>) and area under concentration-time curves (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 ± 0.01 μg/mL and 4.47 ± 0.51 h·μg/mL). The peak time (T<sub>max</sub>) in plasma was 0.23 ± 0.07 h, shorter than that in PELF (1.61 ± 0.15 h). The CO<sub>PD</sub> in plasma and PELF were 0.125 μg/mL and 0.5 μg/mL, respectively. The CO<sub>CL</sub> 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<sub>CL</sub>. The ECV is much higher than the CO<sub>PD</sub> and CO<sub>CL</sub>, and the clinical breakpoint based on data in plasma was largely different from that of PELF. <b>Conclusions:</b> Our study firstly established three cutoff values of danofloxacin against <i>G. parasuis.</i> It suggested that non-wild-type danofloxacin-resistant <i>G. parasuis</i> may lead to ineffective treatment by danofloxacin.
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