Exploration of Clinical Breakpoint of Danofloxacin for <i>Glaesserella parasuis</i> in Plasma and in PELF

• Main Authors: Zihui Xu (Author), Anxiong Huang (Author), Xun Luo (Author), Peng Zhang (Author), Lingli Huang (Author), Xu Wang (Author), Kun Mi (Author), Shiwei Fang (Author), Xiao Huang (Author), Jun Li (Author), Zonghui Yuan (Author), Haihong Hao (Author)
• Format: Book
• Published: MDPI AG, 2021-07-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

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_PD) and clinical cutoff value (CO_CL), 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_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. <b>Results:</b> The MIC₅₀ and MIC₉₀ 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_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. <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.

Item Description

10.3390/antibiotics10070808
2079-6382