Li Xiao-Dong, Chi Sheng-Qing, Wu Li-Yun, Liu Can, Sun Tong, Hong Juan, Chen Xun, Chen Xiao-Gang, Wang Guan-Song, Yu Dao-Jin
Fujian Key Laboratory of Traditional Chinese Veterinary Medicine and Animal Health, Fujian Agriculture and Forestry University, Fuzhou, China.
BMC Vet Res. 2019 Aug 1;15(1):272. doi: 10.1186/s12917-019-2008-4.
Ceftiofur Sodium is widely used in China. Our aim was to determine Ceftiofur Sodium activity and optimize dosing regimens against the pathogen Haemophilus parasuis using an in vitro and ex vivo pharmacokinetics/pharmacodynamics modeling approach. By adopting these strategies, we wanted to extend the effective life of Ceftiofur Sodium in reduce drug-resistance in pigs.
We established an H. parasuis infection model in pigs, and assessed the pharmacokinetics of Ceftiofur Sodium in both healthy and infected animals. After Ceftiofur Sodium (10 mg/kg, i.m.) administration to healthy and H. parasuis-infected pigs, plasma based desfuroylceftiofur (a metabolite of Ceftiofur Sodium) was measured by High Performance Liquid Chromatography. The pharmacokinetics of Ceftiofur Sodium (desfuroylceftiofur) was consistent with a two-compartment open model, with first-order absorption. We observed no significant differences (P > 0.05) in pharmacokinetic parameters between healthy and infected pigs. Pharmacodynamics data showed that Ceftiofur Sodium was highly inhibitory against H. parasuis, with MIC, MBC, and MPC values of 0.003125, 0.0125 and 0.032 μg/mL, respectively. Desfuroylceftiofur in plasma also had strong bactericidal activity. Almost all H. parasuis cultured in plasma medium of Ceftiofur Sodium-inoculated healthy pigs, at each time point, were killed within 24 h. A weaker antibacterial activity was measured in infected-pig plasma medium at 18, 24, 36, and 48 h, after Ceftiofur Sodium inoculation. Pharmacokinetic parameters were combined with ex vivo pharmacodynamic parameters, and the bacteriostatic effect (36.006 h), bactericidal effect (71.637 h) and clearance (90.619 h) within 24 h, were determined using the Hill equation. Dose-calculation equations revealed the optimal dose of Ceftiofur Sodium to be 0.599-1.507 mg/kg.
There were no significant differences in Ceftiofur Sodium pharmacokinetic parameters between healthy and infected pigs, although pharmacokinetics/pharmacodynamics fitting curves showed obviously differences. The optimal dose of Ceftiofur Sodium was lower than recommended (3 mg/kg), which may provide improved treatments for Glässers disease, with lower drug-resistance possibility.
头孢噻呋钠在中国广泛使用。我们的目的是使用体外和离体药代动力学/药效学建模方法，确定头孢噻呋钠对副猪嗜血杆菌病原体的活性，并优化给药方案。通过采用这些策略，我们希望延长头孢噻呋钠的有效使用期，降低猪的耐药性。
我们在猪身上建立了副猪嗜血杆菌感染模型，并评估了头孢噻呋钠在健康和感染动物体内的药代动力学。对健康和副猪嗜血杆菌感染的猪肌肉注射头孢噻呋钠（10mg/kg）后，采用高效液相色谱法测定血浆中的去呋喃甲酰头孢噻呋（头孢噻呋钠的一种代谢物）。头孢噻呋钠（去呋喃甲酰头孢噻呋）的药代动力学符合二室开放模型，具有一级吸收。我们观察到健康猪和感染猪之间的药代动力学参数没有显著差异（P>0.05）。药效学数据表明，头孢噻呋钠对副猪嗜血杆菌具有高度抑制作用，MIC、MBC和MPC值分别为0.003125、0.0125和0.032μg/mL。血浆中的去呋喃甲酰头孢噻呋也具有很强的杀菌活性。在每个时间点，接种头孢噻呋钠的健康猪血浆培养基中培养的几乎所有副猪嗜血杆菌在24小时内被杀死。接种头孢噻呋钠后18、24、36和48小时，在感染猪血浆培养基中测得的抗菌活性较弱。将药代动力学参数与离体药效学参数相结合，使用希尔方程确定了24小时内的抑菌效果（36.006小时）、杀菌效果（71.637小时）和清除率（90.619小时）。剂量计算方程显示头孢噻呋钠的最佳剂量为0.599-1.507mg/kg。
健康猪和感染猪之间头孢噻呋钠的药代动力学参数没有显著差异，尽管药代动力学/药效学拟合曲线显示出明显差异。头孢噻呋钠的最佳剂量低于推荐剂量（3mg/kg），这可能为猪传染性胸膜肺炎提供更好的治疗方法，且耐药可能性较低。
