抗感染藥物給藥方案的設計

PK/PD原理與抗感染方案的設計,中南大學湘雅二醫(yī)院 劉藝平,抗生素劑量是影響抗感染治療結果的重要因素,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：藥動學劑量：藥量、給藥頻次、療程、常量與變量病原菌：敏感性、藥效學目標、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 考慮兩個方面的因素，對于時間依賴性的抗菌藥物，Cmax是否在68倍mic；其次tmic 40%.針對具體細菌，mic存在差異，綠膿、鮑曼mic較高，而其它細菌較低，因此，要針對細菌的情況，確定優(yōu)化方案浮夸 15:52:26 這兩組在12h內的蓄積濃度1.5g q6h高于3.0g q8h，時間依賴型：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，這只是理論上計算的數(shù)值lyp 15:56:45 當然只是理論上的計算，實際情況更復雜浮夸 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)藥代動力學數(shù)值計算嗎,根據(jù)抗菌藥物PK，PD特點，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時間依賴性抗菌藥物 time dependent antimicrobial agents,引言,時間依賴性抗生素,當血藥濃度致病菌4-5 MIC時，其殺菌效果便達到飽和程度，繼續(xù)增加血藥濃度，殺菌效應也不再增加。抗菌作用與藥物在體內大于對病原菌最低抑菌濃度（MIC）的時間相關，與血藥峰濃度關系并不密切。對該類藥物應提高TMIC（tcmic40%）這一指標來增加臨床療效。,%Time above MIC,hour,-內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)內酯類如紅霉素，糖肽類抗生素如萬古霉素，及林可霉素類,時間依賴性抗菌藥物,-內酰胺類: 優(yōu)化藥物暴露時間,不同的-內酰胺類其最優(yōu)化的藥物暴露時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,給藥方案的設計,延長輸注法（prolonged infusion therapy ，PIT）優(yōu)化兩步滴定法（ optimized two-step infusion therapy，OTIT）,文獻綜述、文獻分析與論證,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為內生肌酐清除率；Age：年齡；WT：體重；：個體間變異；APACHE：急性生理學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；一般情況下應使用Cockcroft公式；當為危重患者時，使用Durate公式計算,注：Css為重復給藥達穩(wěn)態(tài)時上升段的血藥濃度值；Css為重復給藥達穩(wěn)態(tài)時下降段的血藥濃度值；k0為藥物靜脈滴注的速度，k0=X0/T；T為靜滴的時間；為兩次給藥的間隔時間,k求算：,結果：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.,結果,基于模擬的結果：對于綠膿桿菌和鮑曼不動桿菌，美平0.5g q8h無法達到滿意的療效，推薦美平1g q8h 點滴3小時將會有更優(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.,結論與啟示,1. 延長輸注與優(yōu)化兩步輸注法可以改變時間依耐性性藥物Tmic的時間，體外實驗證實直接影響細菌的清除效果。2.臨床中可通過輔助設計提高抗感染藥物的療效。3.體內療效有待于進一步研究。,參考文獻,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,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