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1、.,抗菌药物在呼吸系统的药代动力学和药效学,南方医院药学部 刘世霆,.,主要内容,抗感染药物治疗的药代/药效要求 药物在肺内转运和穿透屏障的主要机制 药物在肺内转运的影响因素 代表性药物肺内的药代和药效,.,抗感染药物治疗的药代/药效要求,抗菌药物的临床效果除了取决于其抗菌谱、抗菌活性外，还受到它的血浆浓度、到达感染组织的浓度及维持时间的影响。抗菌药物进入体内后必须穿透血-支气管屏障和血-肺屏障才能到达感染部位。,.,抗感染药物治疗的药代/药效要求,.,PK 研究机体对药物的作用 PD 研究药物对机体的作用,剂量对药效的影响,药物对临床疾病的效果 PK/PD 将剂量时间浓度效应的关系联系在一起
2、研究,抗感染药物治疗的药代/药效要求,.,conc,effect,effect,time,time,conc,Pharmacokinetics DoseConc.vs.time,PK/PD DoseEffect.vs.time,Pharmacodynamics Conc. Effect,抗感染药物治疗的药代/药效要求,.,根据PK/PD参数的特点按杀菌活性分类 第一类：时间依赖杀菌剂 -内酰胺类 (青霉素类、头孢菌素、氨曲南、碳烯类)，克林和大环、四环、万古霉素 在 MIC4-5 倍时,杀菌率即处于饱和 杀菌范围主要依赖于接触时间 血药浓度超过MIC时间（TMIC)是与临床疗效相关的主要参数,
3、抗感染药物治疗的药代/药效要求,.,第一类：时间依赖杀菌剂 血药浓度高于 MIC 的时间是最主要参数 给药间期并不需要都超过MIC TMIC30-40% 起效 TMIC 40-50% 保证有效的细菌清除,抗感染药物治疗的药代/药效要求,.,有效的细菌清除： 青霉素： TMIC%40% 头孢菌素：TMIC%50%,肺炎链球菌感染动物的模型,头孢菌素,青霉素,Time above MIC (%),Bacteriologic Cure (%),抗感染药物治疗的药代/药效要求,.,抗感染药物治疗的药代/药效要求,第二类：浓度依赖杀菌药物 有持续的后效应 氨基糖苷类、喹诺酮类、甲硝唑 投药目标达到最大药
4、物接触，药物浓度越高杀菌率及杀菌范围也越大 24小时AUC/MIC(AUIC)、峰浓度(Cmax)/MIC是疗效相关的主要参数,.,Forrest研究发现，64例使用喹诺酮类治疗的肺炎患者中AUC0-24/MIC125时，疗效和细菌清除率为42%和26%,当AUC0-24/MIC125时，两者分别为80和82%，因此认为,AUC0-24/MIC为125时为抗肺炎链球菌的最低有效值,抗感染药物治疗的药代/药效要求,.,喹诺酮类属浓度依赖性抗菌药,评价疗效的主要参数为Cmax/MIC、AUC/MIC,研究表明左氧氟沙星对革兰阴性菌24小时AUC/MIC应在100以上,Cmax/MIC达8-10较合
5、适,抗感染药物治疗的药代/药效要求,.,药物在肺内转运和穿透屏障的主要机制,弥散 肺泡-毛细血管膜是双层的多孔生物膜。 抗菌药物依赖浓度梯度由血管腔经毛细血管孔进入肺间质和肺泡上皮村液（epithelial lining fluid,ELF） 渗透 药物穿透非多孔膜的一种方法，通过毛细血管膜细胞转运，亦属被动过程，但受药物脂溶性的影响，脂溶性高的药物易于渗透。 主动转运 是一种能量依赖的主动转运机制，在达到饱和状态即不再起作用。大环内酯类、克林霉素为巨噬细胞摄取是通过这一过程实现的，而喹诺酮药物摄取可能部分通过 氨基酸运输系统。,.,药物在肺内转运的影响因素,药物因素：脂溶性、蛋白结合率 解剖
6、因素：肺循环和支气管循环提供巨大的血管床表面积 炎症因素：多数抗菌药物在炎症组织的穿透力提高，但喹诺酮、氯霉素、土霉素、多西环素、米诺环素、阿奇霉素则属非炎症依耐性。 其他 ：呼吸道分泌物的H+、Ca2+、Mg2+等可使氨基糖苷类抗生素灭活。,.,代表性药物肺内的药代和药效,阿奇霉素在肺内的药代和药效 喹诺酮类药物在肺内的药代和药效 美罗培南在肺内的药代和药效 利奈唑胺在肺内的药代和药效,.,阿奇霉素在肺内的药代和药效,Azithromycin was widely distributed within the lower respiratory tract and sustained lev
7、els of the drug were detectable at the last sampling time in lung tissue. Doubling the dose of the antibiotic resulted in a proportional increase in lung area under the curve (AUC, 1245.4 versus 2514.2 h x mg/kg) and peak tissue concentration (Cmax, 8.93 2.05 versus 18.6 2.20 mg/kg). The pharmacodyn
8、amic parameter AUC/MIC for susceptible and intermediate strains of Streptococcus pneumoniae (MICs 0.5 and 2 mg/L, respectively) increased after administration of the 1000 mg schedule compared with 500 mg (AUC/MIC0.5 2414 versus 1144 and AUC/MIC2 2112 versus 814.1 h x mg/kg, respectively) in pulmonar
9、y tissue.,.,Pharmacokinetic parameters of azithromycin in plasma of 48 patients,Each value is the mean S.D. of 24 patients. aP 0.05 compared with azithromycin 500 mg once daily for 3 days.,.,Pharmacokinetic and pharmacodynamic parameters of azithromycin in lung and bronchial washing of 48 patients,C
10、maxand Tmax are the mean S.D. of four patients. aP 0.05 compared with azithromycin 500 mg once daily for 3 days. bPharmacodynamic parameters are calculated on the basis of the MIC for azithromycin-susceptible (0.5 mg/L) or -intermediate (2 mg/L) S. pneumoniae.,.,喹诺酮类药物在肺内的药动和药效,Oral administration o
11、f moxifloxacin （ MXF）, 400 mg, levofloxacin （ LEVO）, 500 mg daily for five doses, BAL and venipuncture were completed at 4, 8, 12, or 24 h following the dministration of the last dose.,.,Steady-State MXF and LEVO Concentrations in the Plasma, pulmonary e pithelial lining fluid (ELF), and alveolar ma
12、crophage (AM)*,* Values given as mean SD, unless otherwise indicated. Three subjects. One subject was excluded due to insufficient data on the cell differential.,.,Pharmacodynamic Profile (AUC/MIC) of S pneumoniae for MFX and LEVO in Plasma and ELF*,* MIC90 values of S pneumoniae for each agent were
13、 obtained from US surveillance studies: MXF, 0.25 g/mL; LEVO, 1 g/mL.,.,喹诺酮类药物在肺内的药动和药效,The intrapulmonary concentrations of MXF, LEV were superior to those obtained in the plasma. The AM concentrations of all agents studied were more than adequate relative to the minimum concentration required to i
14、nhibit 90% of the organism population (MIC90) of the common intracellular pathogens ( 1 g/mL). based on the agents current minimum inhibitory concentration profile, whereas the mean concentrations of MXF and LEVO in the ELF exceed the MIC90 of the S pneumoniae population. Moreover, MXF concentration
15、s exceeded the S pneumoniae susceptibility breakpoint (1.0 g/mL) at all time points, while 2 of 15 concentrations (13%) failed to maintain LEVO concentrations above the breakpoint (2.0 g/mL) throughout the dosing interval.,.,美洛培南在肺内的药代和药效,Patients received 1 g of meropenem intravenously (i.v.) as a
16、20-min infusion every 8 h. In each patient, two microdialysis probes were placed percutaneously under direct vision 2 cm apart well into pneumonic tissue at the end of the operation, directly before the planned fifth dose of meropenem. By use of a microinfusion pump the in situ probes were constantly perfused with Ringers solution at a flow rate of 1.5 l/min. Microdialysis was started approximately 30 min after probe insertion, and the patients were monitored on the inte
