Data_Sheet_6_Comparison of PK/PD Targets and Cutoff Values for Danofloxacin Against Pasteurella multocida and Haemophilus parasuis in Piglets.XLSX

Danofloxacin is a synthetic fluoroquinolone with broad-spectrum activity developed for use in veterinary medicine. The aim of this study was to evaluate the pharmacokinetic/pharmacodynamic (PK/PD) targets, PK/PD cutoff values and the optimum doses of danofloxacin against P. multocida and H. parasuis in piglets. Single dose serum pharmacokinetics was determined in piglets after intravenous and intramuscular administration of 2.5 mg/kg. Danofloxacin was well absorbed and fully bioavailable (95.2%) after intramuscular administration of 2.5 mg/kg. The epidemiological cutoff (ECOFF) values of danofloxacin from 931 P. multocida isolates and 263 H. parasuis isolates were 0.03 and 4 mg/L, respectively. Danofloxacin MICs determined in porcine serum were markedly lower than those measured in artificial broth, with a broth/serum ratio of 4.33 for H. parasuis. Compared to P. multocida, danofloxacin exhibited significantly longer post-antibiotic effects (3.18–6.60 h) and post-antibiotic sub-MIC effects (7.02–9.94 h) against H. parasuis. The mean area under the concentration-time curve/MIC (AUC24h/MIC) targets of danofloxacin in serum associated with the static and bactericidal effects were 32 and 49.8, respectively, for P. multocida, whereas they were 14.6 and 37.8, respectively, for H. parasuis. Danofloxacin AUC24h/MIC targets for the same endpoints for P. multocida were higher than those for H. parasuis. At the current dose of 2.5 mg/kg, the PK/PD cutoff (COPD) values of danofloxacin against P. multocida and H. parasuis were calculated to be 0.125 and 0.5 mg/L, respectively, based on Monte Carlo simulations. The predicted optimum doses of danofloxacin for a probability of target attainment (PTA) of > 90% to cover the overall MIC population distributions of P. multocida and H. parasuis in this study were 2.38 and 13.36 mg/kg, respectively. These PK/PD-based results have potential relevance for the clinical dose optimization and evaluation of susceptibility breakpoints for danofloxacin in the treatment of swine respiratory tract infections involving these pathogens.

丹诺氟星系一合成型广谱氟喹诺酮类兽用抗生素，旨在评估其对猪多杀巴氏菌（P. multocida）和猪副嗜血杆菌（H. parasuis）的药代动力学/药效学（PK/PD）目标、PK/PD阈值以及最佳剂量。在猪崽体内进行单剂量血清药代动力学研究，通过静脉和肌肉注射2.5 mg/kg的丹诺氟星。结果显示，在2.5 mg/kg肌肉注射后，丹诺氟星具有良好的吸收率，生物利用度高达95.2%。从931株猪多杀巴氏菌和263株猪副嗜血杆菌分离株中确定的丹诺氟星流行病学阈值（ECOFF）分别为0.03和4 mg/L。在猪血清中测定的丹诺氟星最小抑菌浓度（MIC）明显低于在人工培养基中测定的浓度，猪副嗜血杆菌的培养基/血清比为4.33。与猪多杀巴氏菌相比，丹诺氟星对猪副嗜血杆菌表现出显著更长的抗生素后效应（3.18–6.60小时）和抗生素后亚MIC效应（7.02–9.94小时）。丹诺氟星在血清中与静态和杀菌效应相关的平均浓度-时间曲线下面积/MIC（AUC24h/MIC）目标分别为32和49.8（针对猪多杀巴氏菌），而对于猪副嗜血杆菌，则分别为14.6和37.8。针对猪多杀巴氏菌的同一终点，丹诺氟星的AUC24h/MIC目标高于猪副嗜血杆菌。基于蒙特卡洛模拟，根据当前剂量2.5 mg/kg，丹诺氟星对猪多杀巴氏菌和猪副嗜血杆菌的PK/PD阈值（COPD）值分别计算为0.125和0.5 mg/L。为了覆盖本研究中猪多杀巴氏菌和猪副嗜血杆菌的整体MIC种群分布，以实现目标达成概率（PTA）超过90%，预测的丹诺氟星最佳剂量分别为2.38和13.36 mg/kg。这些基于PK/PD的结果对于临床剂量优化以及评估丹诺氟星在治疗涉及上述病原体的猪呼吸道感染中的敏感性断点具有潜在的相关性。