β-内酰胺类抗生素在胆汁中的浓度和药动学的实验研究

目的 研究β-内酰胺类抗生素在胆汁中的浓度及其药动学,并对杀菌效力进行评估,为临床上肝胆系统感染选择用药提供参考和依据.方法 家兔行胆总管造瘘术,分别静脉注射哌拉西林/他唑巴坦、头孢曲松和美罗堵南等β-内酰胺类抗生素后于不同时间收集胆汁标本,采用HPLC法测定各抗生素的浓度,并计算出药动学参数.结合最低抑菌浓度(MIC),评估抗生素在胆汁中的杀菌效力.结果 各抗生素在胆汁中的峰浓度和半衰期分别为:哌拉西林(7950.16±3023.00)μg/ml和(1.97±1.23)h,头孢曲松(1107.01±247.61)μg/ml和(3.14±0.57)h,美罗培南(31.97±12.44)μg/ml和(0.36±0.11)h.哌拉西林/他唑巴坦的杀菌指数最大、TMIC最长,对大部分胆道感染常见致病菌均可形成MIC90 100倍以上的浓度,TMIC长达6～8 h;头孢曲松和美罗培南较低.结论 哌拉西林、头孢曲松和美罗培南均可在胆汁中达到有效杀菌浓度,哌拉西林/他唑巴坦杀菌效力最强.

Study on concentrations and pharmacokinetics of beta-lactams antibiotics in rabbit bile

Objective To study the concentrations and pharmacokinetics of beta-lactams antibi-otics in rabbit bile and evaluate their microbicidal potential to present theoretical evidence and reference for choosing effective antibiotics for the prevention and therapy of hepatobiliary infection. Methods After anesthesia, the common bile duct of rabbits was isolated and cannulated with a silicone tube. The rabbits were administered intravenously with the equal-effect dose of beta-lactams antibiotics. Bile (1.5 ml) was collected at the time of 0. 25,0.5,0. 75,1,1.5,2,3,4,6,8 h after administration and as-sayed by HPLC. The bile drug concentration-time data were processed by software to figure out the pharmacokinetic parameters such as maximum concentration (Cmax), peak time (Tmax), half-life time (T1/2), clearance (CL) and apparent volume of distribution (VD). The bile antibiotics concen-tration contrasted to the minimum inhibitory concentration (MIC), and attained the bactericidal index (Cmax/MIC) and the time the drug concentration exceeded the MIC (TMIC) to evaluate microbicidal potential of the antibiotics in bile. Results The Cmax and T1/2 of each antibiotic were as follow: pip-eracillin (7950.16±3023.00)μg/ml and (1.97±1.23) h, ceftriaxone (1107.01±247.61)μg/ml and (3.14±0. 57)h,meropenem (31.97±12.44)μg/ml and (0. 36±0. 11)h. Piperacillin/tazobactam had the largest bactericidal index and the longest TMIC, and it can form 100 times of concentration than the MIC90 of the common pathogens in bile. Also its TMIC maintained 5～8 h. The bactericidal index and TMIC of ceftriaxone and meropenem were smaller as contrasted to the former. Conclusions The bile concentrations of three antibiotics all exceed their effective bactericidal concentrations. Piperacil-lin/tazobactam has the largest bactericidal index and the longest TMIC, so it can be of the first choice for the therapy in hepatobiliary infection.