抗感染药物给药方案的设计

PK/PD原理与抗感染方案的设计,中南大学湘雅二医院 刘艺平,抗生素剂量是影响抗感染治疗结果的重要因素,Martinez MN, et al. Dosing regimen matters: the importance of early intervention and rapid attainment of the pharmacokinetic/pharmacodynamic target. Antimicrob Agents Chemother. 2012 Jun;56(6):2795-805.,影响成功抗感染治疗的相互作用因素,药物：宿主：药动学剂量：药量、给药频次、疗程、常量与变量病原菌：敏感性、药效学目标、MPC和MIC,刘老师 对于这两组方案 一般如何界定优化方案的选择 用于什么情况下,yp 15:48:39 考虑两个方面的因素，对于时间依赖性的抗菌药物，Cmax是否在68倍mic；其次tmic 40%.针对具体细菌，mic存在差异，绿脓、鲍曼mic较高，而其它细菌较低，因此，要针对细菌的情况，确定优化方案浮夸 15:52:26 这两组在12h内的蓄积浓度1.5g q6h高于3.0g q8h，时间依赖型：低剂量与高频次vs高剂量与低频次，是依据MIC具体分析吧？是否考虑其他综合因素，这只是理论上计算的数值lyp 15:56:45 当然只是理论上的计算，实际情况更复杂浮夸 15:59:43 那说的PK/PD更多的是理论数据，比如各类抗菌效果的参数要求，有没有具体某一种药物依据PK/PD制定的优化方案。浮夸 16:00:07 这种方案的制定要根据药代动力学数值计算吗,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疗效。,%Time above MIC,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；天然大环内酯类如红霉素，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.,Time above MIC最大化,3“D”原则,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 using 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,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,针对绿脓杆菌，美平的不同给药方案的效果,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.,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 Chemother. 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 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 pharmacodynamic 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 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 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. 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 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