Data_Sheet_1_Comparison of PK/PD Targets and Cutoff Values for Danofloxacin Against Pasteurella multocida and Haemophilus parasuis in Piglets.PDF

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.

丹诺氟辛是一种广谱氟喹诺酮类合成抗生素，专为兽医用途而开发。本研究旨在评估丹诺氟辛针对多杀巴氏杆菌和猪链球菌在猪仔体内的药代动力学/药效学（PK/PD）靶点、PK/PD阈值以及最佳剂量。通过静脉和肌肉注射2.5 mg/kg剂量给药后，在猪仔体内进行了单剂量血清药代动力学分析。丹诺氟辛在2.5 mg/kg肌肉注射后具有良好的吸收率，生物利用度达到95.2%。从931株多杀巴氏杆菌和263株猪链球菌分离株中测定的丹诺氟辛流行病学阈值（ECOFF）分别为0.03 mg/L和4 mg/L。在猪血清中测定的丹诺氟辛最小抑菌浓度（MIC）明显低于在人工肉汤中测定的值，猪链球菌的肉汤/血清比为4.33。与多杀巴氏杆菌相比，丹诺氟辛对猪链球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）。与静态和杀菌效应相关的丹诺氟辛在血清中的平均浓度-时间曲线下面积/最小抑菌浓度（AUC24h/MIC）靶点分别为32和49.8，对于猪链球菌；而对于猪链球菌，它们分别为14.6和37.8。丹诺氟辛针对相同终点的AUC24h/MIC靶点对于猪链球菌高于猪链球菌。基于蒙特卡洛模拟，根据当前2.5 mg/kg的剂量，丹诺氟辛针对多杀巴氏杆菌和猪链球菌的PK/PD阈值（COPD）值分别为0.125 mg/L和0.5 mg/L。为了覆盖本研究中多杀巴氏杆菌和猪链球菌的整体MIC人群分布，预测的丹诺氟辛最佳剂量以实现大于90%的目标达成概率（PTA）分别为2.38 mg/kg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辛在治疗涉及这些病原体的猪呼吸道感染中的敏感性断点具有重要意义。