抗感染药物给药方案的设计-刘艺平

1、抗感染药物给药方案的设计2013-11-5卫生部临床药师师资培训 文献阅读报告根据抗菌药物PK，PD特点，抗菌药物大致可分为两大类浓度依赖性抗菌药物 concentration dependent antimicrobial agents时间依赖性抗菌药物 time dependent antimicrobial agents引言时间依赖性抗生素当血药浓度致病菌4-5 MIC时，其杀菌效果便达到饱和程度，继续增加血药浓度，杀菌效应也不再增加。抗菌作用与药物在体内大于对病原菌最低抑菌浓度（MIC）的时间相关，与血药峰浓度关系并不密切。对该类药物应提高TMIC（tcmic40%）这一指标来增加临床

2、疗效。（g/mL）MICTime above MICTime above MICTMIC（tcmic40%）hour-内酰胺类抗生素包括青霉素类，头孢菌素类，碳青霉烯类等；糖肽类抗生素如万古霉素，及林可霉素类时间依赖性抗菌药物-内酰胺类: 优化药物暴露时间不同的-内酰胺类其最优化的药物暴露时间不同疗效最大化所需要的 %TMIC : 60%70% for 头孢菌素类 50% for 青霉素类 40% for 碳青霉烯类Drusano GL. Clin Infect Dis. 2003;36(suppl 1):S42-S50.提高TMIC的方法（3“D”原则）Drug1、PD 优异的抗菌活性 (M

3、IC90値低的药物)2、PK 具有充分的用药量 (安全性高的药物)Dose3、增加每天的用药次数4、增加每次的使用剂量Duration5、延长每次用药的持续时间给药方案的设计延长输注法（prolonged infusion therapy ，PIT）优化两步滴定法（ optimized two-step infusion therapy，OTIT）文献综述、文献分析与论证Eguchi K, etal. Experimental verification of the efficacy of optimized two-step infusion therapy with meropenem u

4、sing an in vitro pharmacodynamic model and Monte Carlo simulation. J Infect Chemother. 2010. 16(1): 1-9.案例男45岁，体重60kg，血肌酐值为72mol/L,现发热，体温升高39.5，诊断为败血症，血培养为非耐药的鲍曼不动杆菌，如果选择美罗培南作为抗感染药物，如何选择给药方案。作者：李昕、李焕德待发表Mic注：CL为中央室清除率；Q为室间清除率；V1为中央室表观分布容积；V2为外周室表观分布容积；Ccr为内生肌酐清除率；Age：年龄；WT：体重；：个体间变异；APACHE：急性生理学及慢性健

5、康状况评分；OEDEMA：水肿，0或1表示注：Age为年龄；WT为体重；Scr为血肌酐值；HT为身高；一般情况下应使用Cockcroft公式；当为危重患者时，使用Durate公式计算注：Css为重复给药达稳态时上升段的血药浓度值；Css为重复给药达稳态时下降段的血药浓度值；k0为药物静脉滴注的速度，k0=X0/T；T为静滴的时间；为两次给药的间隔时间k求算： 结果：2.0g ivgtt 3h1.0givgtt 3h2.0g ivgtt 30min1.0g ivgtt 30min0.5g ivgtt 3h0.5g ivgtt 30min当Mic16g/mL 会怎样呢？美罗培南的不同给药方案的效果

6、Lomaestro BM, etal . Pharmacodynamic evaluation of extending the administration time of meropenem using a Monte Carlo simulation. Antimicrob Agents Chemother. 2005. 49(1): 461-3.MIC通过以下方法相应MIC达成标概率1g q8h（3h）1g q8h （1h）500mg q8h （1h）0.00810010099.950.01610010099.80.12510099.9999.450.2510099.9798.650.

7、510099.8295.4110099.2889.65210096.2165.45499.181.0831.9879.623.124.41614.20032000结果基于模拟的结果：对于绿脓杆菌和鲍曼不动杆菌，美平0.5g q8h无法达到满意的疗效，推荐美平1g q8h 点滴3小时将会有更优异的疗效Lomaestro BM, etal . Pharmacodynamic evaluation of extending the administration time of meropenem using a Monte Carlo simulation. Antimicrob Agents Ch

8、emother. 2005. 49(1): 461-3.优化两步输注法Eguchi K, etal. Experimental verification of the efficacy of optimized two-step infusion therapy with meropenem using an in vitro pharmacodynamic model and Monte Carlo simulation. J Infect Chemother. 2010. 16(1): 1-9.Eguchi K, etal. Experimental verification of the

9、 efficacy of optimized two-step infusion therapy with meropenem using an in vitro pharmacodynamic model and Monte Carlo simulation. J Infect Chemother. 2010. 16(1): 1-9.Eguchi K, etal. Experimental verification of the efficacy of optimized two-step infusion therapy with meropenem using an in vitro p

10、harmacodynamic model and Monte Carlo simulation. J Infect Chemother. 2010. 16(1): 1-9. Table 1 Pharmacokinetic-pharmacodynamic parameters of meropenem simulated by an in vitro pharmacodyanmic model Eguchi K, etal. Experimental verification of the efficacy of optimized two-step infusion therapy with

11、meropenem using an in vitro pharmacodynamic model and Monte Carlo simulation. J Infect Chemother. 2010. 16(1): 1-9.Fig.2 Bactericidal activity of meropenem against P.aeruginosa Eguchi K, etal. Experimental verification of the efficacy of optimized two-step infusion therapy with meropenem using an in

12、 vitro pharmacodynamic model and Monte Carlo simulation. J Infect Chemother. 2010. 16(1): 1-9.Eguchi K, etal. Experimental verification of the efficacy of optimized two-step infusion therapy with meropenem using an in vitro pharmacodynamic model and Monte Carlo simulation. J Infect Chemother. 2010.

13、16(1): 1-9.Eguchi K, etal. Experimental verification of the efficacy of optimized two-step infusion therapy with meropenem using an in vitro pharmacodynamic model and Monte Carlo simulation. J Infect Chemother. 2010. 16(1): 1-9.结论与启示1. 延长输注与优化两步输注法可以改变时间依耐性性药物Tmic的时间，体外实验证实直接影响细菌的清除效果。2.临床中可通过辅助设计提高

14、抗感染药物的疗效。3.体内疗效有待于进一步研究。参考文献 1 Li C, Kuti J L, Nightingale C H, et al. Population pharmacokinetic analysis and dosing regimen optimization of meropenem in adult patientsJ. J Clin Pharmacol,2006,46(10):1171-1178. 2 Zhou Q T, He B, Zhang C, et al. Pharmacokinetics and pharmacodynamics of meropenem in

15、elderly chinese with lower respiratory tract infections: population pharmacokinetics analysis using nonlinear mixed-effects modelling and clinical pharmacodynamics studyJ. Drugs Aging,2011,28(11):903-912.3 Du X, Li C, Kuti J L, et al. Population pharmacokinetics and pharmacodynamics of meropenem in pediatric patientsJ. J Clin Pharmacol,2006,46(1):69-75.参考文献4Lomaestro BM, Drusano GL. Pharmacodynamic evaluation of extending the administration time of meropenem using a Monte Carlo simulation. Antimicrob Agents Chemother. 2005. 49(1): 461-3.5Eguchi K, Kana