Data_Sheet_4_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.

多诺氟昔酸是一种广谱合成氟喹诺酮类药物，专为兽医医学使用而开发。本研究旨在评估多诺氟昔酸针对多杀性巴氏杆菌和猪链球菌在仔猪体内的药代动力学/药效学（PK/PD）靶点、PK/PD截止值以及最佳剂量。在仔猪体内经静脉和肌肉注射2.5 mg/kg后，进行了单剂量血清药代动力学测定。在2.5 mg/kg肌肉注射后，多诺氟昔酸被良好吸收，生物利用度达到100%（95.2%）。从931株多杀性巴氏杆菌和263株猪链球菌分离株中测得的多诺氟昔酸的流行病学截止值（ECOFF）分别为0.03和4 mg/L。在猪血清中确定的多诺氟昔酸最小抑菌浓度（MIC）明显低于在人工肉汤中测得的值，猪链球菌的肉汤/血清比为4.33。与多杀性巴氏杆菌相比，多诺氟昔酸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）。与静态和杀菌作用相关的血清中多诺氟昔酸的均值浓度-时间曲线下面积/MIC（AUC24h/MIC）靶点分别为32和49.8，而对于猪链球菌，它们分别为14.6和37.8。对于多杀性巴氏杆菌，多诺氟昔酸在相同终点上的AUC24h/MIC靶点高于猪链球菌。基于蒙特卡洛模拟，在当前2.5 mg/kg剂量下，多诺氟昔酸针对多杀性巴氏杆菌和猪链球菌的药代动力学/药效学截止值（PK/PD cutoff，COPD）分别为0.125和0.5 mg/L。为了达到90%以上的目标实现概率（PTA），以覆盖本研究中多杀性巴氏杆菌和猪链球菌的整体MIC种群分布，预测的多诺氟昔酸最佳剂量分别为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多诺氟昔酸在治疗涉及这些病原体的猪呼吸道感染中的抗药性阈值具有潜在的相关性。