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.

丹诺沙星（danofloxacin）是一种合成氟喹诺酮类药物，具备广谱抗菌活性，专为兽医学应用研发。本研究旨在评估丹诺沙星针对仔猪源多杀性巴氏杆菌（Pasteurella multocida, P. multocida）和副猪嗜血杆菌（Haemophilus parasuis, H. parasuis）的药代动力学/药效学（pharmacokinetic/pharmacodynamic, PK/PD）靶标、PK/PD临界值以及最优给药剂量。
以2.5 mg/kg的剂量对仔猪分别进行静脉注射与肌内注射后，测定其单次给药后的血清药代动力学特征。
肌内注射2.5 mg/kg剂量后，丹诺沙星吸收良好，生物利用度高达95.2%。
从931株多杀性巴氏杆菌分离株与263株副猪嗜血杆菌分离株中得到的丹诺沙星流行病学临界值（epidemiological cutoff, ECOFF）分别为0.03 mg/L和4 mg/L。
在猪血清中测定的丹诺沙星最低抑菌浓度（minimum inhibitory concentration, MIC）显著低于人工培养基中的测定值，副猪嗜血杆菌的培养基/血清比值为4.33。
与多杀性巴氏杆菌相比，丹诺沙星对副猪嗜血杆菌的抗生素后效应（post-antibiotic effect, PAE）和抗生素后亚抑菌浓度效应（post-antibiotic sub-MIC effect, PA-SME）更长，分别为3.18~6.60 h和7.02~9.94 h。
针对多杀性巴氏杆菌，与静态抑菌和杀菌效应相关的血清中丹诺沙星的浓度-时间曲线下面积/MIC（area under the concentration-time curve/MIC, AUC24h/MIC）靶标分别为32和49.8；而针对副猪嗜血杆菌，该靶标分别为14.6和37.8。针对相同效应终点，丹诺沙星对多杀性巴氏杆菌的AUC24h/MIC靶标高于副猪嗜血杆菌。
基于蒙特卡洛（Monte Carlo）模拟，以当前2.5 mg/kg的给药剂量计算，丹诺沙星针对多杀性巴氏杆菌和副猪嗜血杆菌的PK/PD临界值（PK/PD cutoff, COPD）分别为0.125 mg/L和0.5 mg/L。
为达到靶标达成概率（probability of target attainment, PTA）>90%，以覆盖本研究中多杀性巴氏杆菌和副猪嗜血杆菌的整体MIC群体分布，丹诺沙星的预测最优给药剂量分别为2.38 mg/kg和13.36 mg/kg。
这些基于PK/PD的研究结果，可为丹诺沙星治疗由上述病原菌引发的猪呼吸道感染的临床剂量优化以及药敏折点评估提供潜在参考价值。