Exploration of Clinical Breakpoint of Danofloxacin for Glaesserella parasuis in Plasma and in PELF

Zihui Xu; Anxiong Huang; Xun Luo; Peng Zhang; Lingli Huang; Xu Wang; Kun Mi; Shiwei Fang; Xiao Huang; Jun Li; Zonghui Yuan; Haihong Hao

doi:10.3390/antibiotics10070808

Exploration of Clinical Breakpoint of Danofloxacin for Glaesserella parasuis in Plasma and in PELF

Antibiotics (Basel). 2021 Jul 2;10(7):808. doi: 10.3390/antibiotics10070808.

Authors

Zihui Xu^{1

2}, Anxiong Huang^{1

2}, Xun Luo^{1

2}, Peng Zhang¹, Lingli Huang^{1

2}, Xu Wang^{1

2}, Kun Mi^{1

2}, Shiwei Fang^{1

2}, Xiao Huang^{1

2}, Jun Li^{1

2}, Zonghui Yuan^{1

2}, Haihong Hao^{1

2}

Affiliations

¹ National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan 430070, China.
² MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan 430070, China.

Abstract

Background: In order to establish the clinical breakpoint (CBP) of danofloxacin against G. parasuis, three cutoff values, including epidemiological cutoff value (ECV), pharmacokinetic-pharmacodynamic (PK-PD) cutoff value (CO_PD) and clinical cutoff value (CO_CL), were obtained in the present study. Methods: The ECV was calculated using ECOFFinder base on the MIC distribution of danfloxacin against 347 G. parasuis collected from disease pigs. The CO_PD 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_CL 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. 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 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_max) 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_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 largely different from that of PELF. Conclusions: Our study firstly established three cutoff values of danofloxacin against G. parasuis. It suggested that non-wild-type danofloxacin-resistant G. parasuis may lead to ineffective treatment by danofloxacin.

Keywords: Glaesserella parasuis; PK-PD cutoff values; clinical breakpoint; clinical cutoff values; danofloxacin; epidemiological cutoff values.

Abstract

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