Epidemiological and PK/PD cutoff values determination and PK/PD-based dose assessment of gamithromycin against Haemophilus parasuis in piglets
Epidemiological and PK/PD cutoff values determination and PK/PD-based dose assessment of gamithromycin against Haemophilus parasuis in piglets
复制标题
加米霉素抗仔猪副猪嗜血杆菌的流行病学和 PK/PD 截止值测定以及基于 PK/PD 的剂量评估
DOI：
10.1186/s12917-020-02300-y
复制
发表时间：
2020-03-05
影响因子：
2.6
通讯作者：
Liao, Xiao-Ping
中科院分区：
文献类型：
--
作者：
Zhou, Yu-Feng;Bu, Ming-Xiao;Liao, Xiao-Ping
背景 加米霉素是一种大环内酯类药物，被批准用于治疗牛和猪呼吸道疾病。我们的研究旨在建立加米霉素对抗仔猪副猪嗜血杆菌的临床断点和最佳剂量方案。结果加米霉素肌肉注射和皮下注射后吸收良好，生物利用度充分（87.2-101%）。加米霉素对 192 株临床副猪嗜血菌分离株的 MIC 范围为 0.008 至 128 mg/L，流行病学临界值 (ECOFF) 计算为 1.0 mg/L。对于副猪嗜血菌，血清对加米霉素的体外敏感性有很大的增强作用，肉汤/血清的 MIC 比为 8.93，MBC 为 4.46。抗生素后效应为 1.5 小时 (1 x MIC) 和 2.4 小时 (4 x MIC)，抗生素后亚 MIC 效应范围为 2.7 至 4.3 小时。加米霉素对副猪嗜血菌具有快速且浓度依赖性的杀灭作用，并且 AUC(24h)/MIC 比值与离体功效密切相关 (R-2 = 0.97)。与抑菌、杀菌和根除活性相关的血清中AUC(24h)/MIC目标分别为15.8、30.3和41.2。基于 PK/PD 的人群剂量预测表明，当前市售剂量 (6 mg/kg) 针对副猪嗜血菌的目标实现概率 (PTA) 为 88.9%。 PTA >= 90% 的加米霉素计算剂量为 6.55 mg/kg。根据蒙特卡罗模拟，PK/PD 截止值 (COPD) 确定为 0.25 mg/L。结论 确定的临界值和基于 PK/PD 的剂量预测对于加米霉素耐药性监测非常重要，并且是建立最佳剂量方案和临床断点的重要步骤。
Background Gamithromycin is a macrolide approved for the treatment of bovine and swine respiratory diseases. Our study aims to establish the clinical breakpoint and optimum dose regimen for gamithromycin against Haemophilus parasuis in piglets. Results Gamithromycin was well absorbed and fully bioavailable (87.2-101%) after intramuscular and subcutaneous administrations. The MICs of gamithromycin for 192 clinical H. parasuis isolates ranged from 0.008 to 128 mg/L and the epidemiological cutoff (ECOFF) was calculated as 1.0 mg/L. A large potentiation effect of serum on in vitro susceptibility of gamithromycin was observed for H. parasuis, with broth/serum ratios of 8.93 for MICs and 4.46 for MBCs, respectively. The postantibiotic effects were 1.5 h (1 x MIC) and 2.4 h (4 x MIC), and the postantibiotic sub-MIC effects ranged from 2.7 to 4.3 h. Gamithromycin had rapid and concentration-dependent killing against H. parasuis, and the AUC(24h)/MIC ratio correlated well with ex vivo efficacy (R-2 = 0.97). The AUC(24h)/MIC targets in serum associated with bacteriostatic, bactericidal and eradication activities were 15.8, 30.3 and 41.2, respectively. The PK/PD-based population dose prediction indicated a probability of target attainment (PTA) for the current marketed dose (6 mg/kg) of 88.9% against H. parasuis. The calculated gamithromycin dose for a PTA >= 90% was 6.55 mg/kg. Based on Monte Carlo simulations, the PK/PD cutoff (COPD) was determined to be 0.25 mg/L. Conclusion The determined cutoffs and PK/PD-based dose prediction will be of great importance in gamithromycin resistance surveillance and serve as an important step in the establishment of optimum dose regimen and clinical breakpoints.