抗菌药物在胆汁中药物代谢动力学特点的实验研究及杀菌效力评价

Experimental study on concentrations and pharmacokinetics of antibiotics in bile and evaluation of their microbicidal potential

目的 探讨6种抗菌药物在胆汁中的药物代谢动力学特点,并评估其杀菌效力.方法 实验用健康家兔36只,随机分为6组,每组6只.行胆总管造瘘术后,分别静脉注射头孢曲松、头孢哌酮/舒巴坦钠、哌拉西林/他唑巴坦、美罗培南、左氧氟沙星、甲硝唑,于注射后不同时间收集家兔胆汁标本,采用高效液相色谱法测定各抗菌药物的浓度,并计算出药物代谢动力学参数.结合最低抑菌浓度（MIC）评估各抗菌药物在胆汁中的杀菌效力.结果 各抗菌药物在胆汁中的峰浓度和半衰期分别为：哌拉西林（7 950 ±3 023） mg/L和（1.97±1.23）h,头孢曲松（1 104±248） mg/L和（3.14±0.57）h,头孢哌酮（5 215 ±2 225） mg/L和（0.89 ±0.13）h,美罗培南（31.97 ±12.44） mg/L和（0.36±0.11）h,左氧氟沙星（66.3±36.9） mg/L和（3.32±2.57）h,甲硝唑（28.2±10.2） mg/L和（0.81 ±0.33）h.哌拉西林/他唑巴坦和头孢哌酮/舒巴坦的杀菌指数最大,分别为（62.1±23.6） ～（993.8±377.9）和（164.8 ±69.0） ～ （659.3 ±275.9）,其药物浓度持续在MIC以上的时间（T＞MIC）最长,两药的T＞MIC分别为（6.00±2.53）～（8.00±0.00）h和（6.33±1.97） ～ （8.00±0.00）h;左氧氟沙星的杀菌指数[（2.1±1.2）～（8.3±4.6）]和T＞MIC[（0.54±0.25）～（2.67±1.03）h]最小,头孢曲松和美罗培南居中,其杀菌指数和T＞MIC分别为（4.3±1.0） ～ （69.2±15.5）、（1.42±0.65）～（8.00±0.00）h和（2.0±0.8）～（1 031.3 ±401.4）、（0.29 ±0.10） ～ （1.83 ±0.26）h.甲硝唑对厌氧菌的杀菌指数和T＞MIC分别为7.4 ～294.9和1.88 ～5.00 h.结论 6种抗菌药物均可在胆汁中达到有效杀菌浓度,哌拉西林、头孢哌酮、美罗培南、甲硝唑在家兔胆汁中呈一房室模型,头孢曲松、左氧氟沙星为二房室模型分布.哌拉西林/他唑巴坦和头孢哌酮/舒巴坦杀菌效力最强,甲硝唑对厌氧菌有较强的杀菌力,肝胆系统感染应结合临床选用杀菌效力强的抗菌药物.

Objective To study the concentrations and pharmacokinetics of 6 different kinds of antibiotics in rabbit bile,and evaluate their microbicidal potential.Methods Thirty-six health rabbits were randomly divided into 6 groups,and each group was 6 rabbits.After anaesthesia,the common bile duct of rabbit was isolated and cumulated with a silicone tube.The rabbits were administered intravenously with the equal-effect dose of antibiotics.Bile（1.5 ml） was collected at different time points after administration,and the concentration of antibiotics of bile was assayed by high performance liquid chromatography.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 concentration contrasted to the minimum inhibitorv concentration （MIC）,and attained the bactericidal index（Cmax/MIC） and the time when the drug concentration exceeded the MIC（T〉MIC）.Results The C and T1/2 of each antibiotic were as the followings：piperacillin（7 950 ± 3 023） mg/L and （1.97 ± 1.23） h,ceftriaxone （1 104 ± 248） mg/L and （3.14 ± 0.57） h,cefoperazone （5 215 ±2 225） mg/Land （0.89±0.13） h,meropenem（31.97 ±12.44） mg/L and （0.36±0.11） h,levofloxacin （66.3 ± 36.9） mg/L and （3.32 ± 2.57） h,metronidazole（28.2 ± 10.2） mg/L and （0.81 ± 0.33） h,respectively.Piperacillin/tazobactam and cefoperazone/sulbactam had the largest bactericidal index and the longest T〉MIC,and their bactericidal indexes were （62.1 ±23.6）-（993.8 ±377.9） and（164.8 ± 69.0）-（659.3 ±275.9）,their T〉MIC were（6.00±2.53）-（8.00±0.00） b and（6.33 ± 1.97）-（8.00 ±0.00） h.The bactericidal index and T〉MIC of levofloxacin were the smallest,which were （2.1 ± 1.2）-（8.3 ± 4.6） and （0.54 ± 0.25）-（2.67 ± 1.03） h.Ceftriaxone and meropenem were as the medium,and their bactericidal indexes and T 〉 MIC were （4.3 ± 1.0）-（69.2 ± 15.5）,（1.42 ± 0.65）-（8.00±0.00） h and （2.0 ±0.8）-（1 031.3 ±401.4）,（0.29 ± 0.10）-（1.83 ±0.26） h.The bactericidal index of metronidazole to anaerobic ranged from 7.4 to 294.9,and the T 〉 MIC ranged from 1.88 to 5.00 h.Conclusions The bile concentrations of six antibiotics all exceed their effective bactericidal concentrations.The concentration-time curves of piperacillin,cefoperazone,meropenem and metronidazole conformed to one-compartment model,and ceftriaxone and levofloxacin are conformed to two-compartment model.Piperacillin/tazobactam and cefoperazone/sulbactam have the largest bactericidal index and the longest T〉MIC,so they can be chosen as the first choice for the therapy of hepatobiliary infection.For the anaerobic,the microbicidal potential of metronidazole is high.