抗感染藥物給藥方案的設(shè)計(jì)

PK/PD原理與抗感染方案的設(shè)計(jì),中南大學(xué)湘雅二醫(yī)院 劉藝平,抗生素劑量是影響抗感染治療結(jié)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.,影響成功抗感染治療的相互作用因素,藥物：宿主：藥動學(xué)劑量：藥量、給藥頻次、療程、常量與變量病原菌：敏感性、藥效學(xué)目標(biāo)、MPC和MIC,劉老師 對于這兩組方案 一般如何界定優(yōu)化方案的選擇 用于什么情況下,yp 15:48:39 考慮兩個(gè)方面的因素，對于時(shí)間依賴性的抗菌藥物，Cmax是否在68倍mic；其次tmic 40%.針對具體細(xì)菌，mic存在差異，綠膿、鮑曼mic較高，而其它細(xì)菌較低，因此，要針對細(xì)菌的情況，確定優(yōu)化方案浮夸 15:52:26 這兩組在12h內(nèi)的蓄積濃度1.5g q6h高于3.0g q8h，時(shí)間依賴型：低劑量與高頻次vs高劑量與低頻次，是依據(jù)MIC具體分析吧？是否考慮其他綜合因素，這只是理論上計(jì)算的數(shù)值lyp 15:56:45 當(dāng)然只是理論上的計(jì)算，實(shí)際情況更復(fù)雜浮夸 15:59:43 那說的PK/PD更多的是理論數(shù)據(jù)，比如各類抗菌效果的參數(shù)要求，有沒有具體某一種藥物依據(jù)PK/PD制定的優(yōu)化方案。浮夸 16:00:07 這種方案的制定要根據(jù)藥代動力學(xué)數(shù)值計(jì)算嗎,根據(jù)抗菌藥物PK，PD特點(diǎn)，抗菌藥物大致可分為兩大類,濃度依賴性抗菌藥物 concentration dependent antimicrobial agents時(shí)間依賴性抗菌藥物 time dependent antimicrobial agents,引言,時(shí)間依賴性抗生素,當(dāng)血藥濃度致病菌4-5 MIC時(shí)，其殺菌效果便達(dá)到飽和程度，繼續(xù)增加血藥濃度，殺菌效應(yīng)也不再增加?？咕饔门c藥物在體內(nèi)大于對病原菌最低抑菌濃度（MIC）的時(shí)間相關(guān)，與血藥峰濃度關(guān)系并不密切。對該類藥物應(yīng)提高TMIC（tcmic40%）這一指標(biāo)來增加臨床療效。,%Time above MIC,hour,-內(nèi)酰胺類抗生素包括青霉素類，頭孢菌素類，碳青霉烯類等；天然大環(huán)內(nèi)酯類如紅霉素，糖肽類抗生素如萬古霉素，及林可霉素類,時(shí)間依賴性抗菌藥物,-內(nèi)酰胺類: 優(yōu)化藥物暴露時(shí)間,不同的-內(nèi)酰胺類其最優(yōu)化的藥物暴露時(shí)間不同療效最大化所需要的 %TMIC : 60%70% for 頭孢菌素類 50% for 青霉素類 40% for 碳青霉烯類,Drusano GL. Clin Infect Dis. 2003;36(suppl 1):S42-S50.,Time above MIC最大化,3“D”原則,給藥方案的設(shè)計(jì),延長輸注法（prolonged infusion therapy ，PIT）優(yōu)化兩步滴定法（ optimized two-step infusion therapy，OTIT）,文獻(xiàn)綜述、文獻(xiàn)分析與論證,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歲，體重60kg，血肌酐值為72mol/L,現(xiàn)發(fā)熱，體溫升高39.5，診斷為敗血癥，血培養(yǎng)為非耐藥的鮑曼不動桿菌，如果選擇美羅培南作為抗感染藥物，如何選擇給藥方案。,作者：李昕、李煥德待發(fā)表,注：CL為中央室清除率；Q為室間清除率；V1為中央室表觀分布容積；V2為外周室表觀分布容積；Ccr為內(nèi)生肌酐清除率；Age：年齡；WT：體重；：個(gè)體間變異；APACHE：急性生理學(xué)及慢性健康狀況評分；OEDEMA：水腫，0或1表示,注：Age為年齡；WT為體重；Scr為血肌酐值；HT為身高；一般情況下應(yīng)使用Cockcroft公式；當(dāng)為危重患者時(shí)，使用Durate公式計(jì)算,注：Css為重復(fù)給藥達(dá)穩(wěn)態(tài)時(shí)上升段的血藥濃度值；Css為重復(fù)給藥達(dá)穩(wěn)態(tài)時(shí)下降段的血藥濃度值；k0為藥物靜脈滴注的速度，k0=X0/T；T為靜滴的時(shí)間；為兩次給藥的間隔時(shí)間,k求算：,結(jié)果：2.0g ivgtt 3h1.0givgtt 3h2.0g ivgtt 30min1.0g ivgtt 30min0.5g ivgtt 3h0.5g ivgtt 30min,針對綠膿桿菌，美平的不同給藥方案的效果,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.,結(jié)果,基于模擬的結(jié)果：對于綠膿桿菌和鮑曼不動桿菌，美平0.5g q8h無法達(dá)到滿意的療效，推薦美平1g q8h 點(diǎn)滴3小時(shí)將會有更優(yōu)異的療效,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.,優(yōu)化兩步輸注法,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.,結(jié)論與啟示,1. 延長輸注與優(yōu)化兩步輸注法可以改變時(shí)間依耐性性藥物Tmic的時(shí)間，體外實(shí)驗(yàn)證實(shí)直接影響細(xì)菌的清除效果。2.臨床中可通過輔助設(shè)計(jì)提高抗感染藥物的療效。3.體內(nèi)療效有待于進(jìn)一步研究。,參考文獻(xiàn),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.,參考文獻(xiàn),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