比较美罗培南传统延长和优化延长输注在脓毒症大鼠不同组织中的药代动力学/药效动力学

中国临床药理学与治疗学 ›› 2017, Vol. 22 ›› Issue (7): 767-774.

比较美罗培南传统延长和优化延长输注在脓毒症大鼠不同组织中的药代动力学/药效动力学

吴永磊¹，王丹²，张睢扬³，王英³，孙芹⁴

¹嘉兴市第一医院呼吸内科，嘉兴 314001，浙江； ²中国人民解放军火箭军总医院呼吸及重症医学科，³药剂科，⁴口腔科，北京 100088

收稿日期:2016-12-08 修回日期:2017-06-07 出版日期:2017-07-26 发布日期:2017-07-19
通讯作者: 张睢扬，男，博士，主任医师，博士生导师，研究方向：呼吸及危重症医学。 Tel:18910883377 E-mail：suiyangzhang@hotmail.com
作者简介:吴永磊，男，硕士研究生，住院医师，研究方向：脓毒症。 Tel:18757360513 E-mail：wqrespiratory@163.com
基金资助:
国家自然科学基金青年项目（81301662）；北京市科技新星计划（Z161100004916165）

Pharmacokinetics and pharmacodynamics of meropene administered by traditional prolonged infusion or optimized prolonged infusion in different tissues of septic rats

WU Yonglei¹, WANG Dan², ZHANG Suiyang³, WANG Ying ³, SUN Qin ⁴

¹Department of Respiratory Medicine, the First Hospital of Jiaxing, Jiaxing 314000, Zhejiang, China^{; 2} Department of Respiratory and Critical Care Medicine,³ Department of Pharmacy,⁴ Department of Stomatology, the PLA Rocket Force General Hospital, Beijing 100088, China

Received:2016-12-08 Revised:2017-06-07 Online:2017-07-26 Published:2017-07-19

摘要/Abstract

摘要：

目的: 利用微透析技术研究美罗培南不同输注方式在脓毒症大鼠不同组织药代动力学状况；用蒙特卡洛模拟美罗培南在脓毒症大鼠体内两种输注方式下的药效动力学，比较两者差异。方法: 12只雄性SD大鼠随机分为传统延长及优化延长2组（n=6）用于药代动力学实验。微透析探针植入大鼠颈静脉、股二头肌、皮下脂肪及肺。基于非房室模型计算药代动力学参数。通过蒙特卡洛模拟比较两种输注方式药效动力学差异。结果: 两种输注方式下AUC组织（0-6 h）/AUC血浆(0-6 h)均小于1；传统延长和优化延长输注组间比较显示，Tmax在血液、肺组织、骨骼肌及皮下脂肪组织中差异具有统计学意义；在不同最小抑菌浓度（MIC）值时，优化延长输注方式游离美罗培南的在不同组织中的40%fT>MIC的目标获得概率（PTA）优于传统延长输注方式。结论: 根据血浆药物浓度可能会高估了抗生素的活性导致高估了其临床疗效，以组织液的药代动力学特点指导美罗培南用药较根据血浆中的药代动力学更为合理。实验PK/PD结果提示，美罗培南的优化延长输注的给药方案较传统延长输注的给药方案可能更为合理。

关键词: 脓毒症, 药代动力学, 药效动力学, 美罗培南, 蒙特卡洛模拟

Abstract:

AIM: To study the pharmacokinetics of meropenem infused through different methods in varied parts of septic rats by microdialysis and to evaluate the pharmacodynamics of the two different infusion methods using of Monte Carlo simulation. METHODS: Twelve male Sprague Dawley rats were randomly divided into two groups (traditional prolonged infusion vs. the optimized prolonged infusion, n=6) for the pharmacokinetics study. Microdialysis probes were inserted into the jugular vein, hind leg muscle, subcutaneous adipose tissue and lung. Pharmacokinetic parameters were calculated by non-compartmental analysis. Monte Carlo simulations(10 000 rats) were performed to calculate 40％fT>MIC and the probability of target attainment (PTA) at different MICs，then to compare the effect of two infusion models. RESULTS: The tissue distribution factors (AUCtissue(0 to 6 h)/AUCplasma(0 to 6 h) ratio) of the two groups were both less than 1 for lung, muscle and subcutaneous adipose tissue relative to plasma; the Tmaxs in plasma, lung, muscle and subcutaneous adipose tissue had statistically difference between the optimized prolonged infusion group and the traditional prolonged infusion method group; at different MICs, using the optimized prolonged infusion method, the PTA values of the 40%fT>MIC for the free meropenem in different tissues were higher than using the traditional prolonged infusion method. CONCLUSION: Using total plasma concentrations can overestimate the antibacterial activity of the drug and therefore its clinical efficacy. According to the pharmacokinetic of meropenem in the target infected tissues is more reasonable than plasma to guide the meropenem dosing regimen. Optimized prolonged infusion method is likely more reasonable than traditional prolonged infusion method.

Key words: sepsis, pharmacokinetics, pharmacodynamics, meropenem, Monte Carlo simulation

中图分类号:

R965.2

吴永磊，王丹，张睢扬，王英，孙芹. 比较美罗培南传统延长和优化延长输注在脓毒症大鼠不同组织中的药代动力学/药效动力学[J]. 中国临床药理学与治疗学, 2017, 22(7): 767-774.

WU Yonglei, WANG Dan, ZHANG Suiyang, WANG Ying, SUN Qin. Pharmacokinetics and pharmacodynamics of meropene administered by traditional prolonged infusion or optimized prolonged infusion in different tissues of septic rats[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2017, 22(7): 767-774.

参考文献

［1］Singer M, Deutschman CS, Seymour CW, et al.The third international consensus definitions for sepsis and septic shock (sepsis-3)［J］. JAMA, 2016,315(8):801-810.
［2］Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock, 2012［J］. Intensive Care Med, 2013,39(2):165-228.
［3］Roberts JA, Paul SK, Akova M, et al. DALI: defining antibiotic levels in intensive care unit patients: are current beta-lactam antibiotic doses sufficient for critically ill patients?［J］Clin Infect Dis,2014,58(8):1072-1083.
［4］Blot SI, Pea F, Lipman J. The effect of pathophysiology on pharmacokinetics in the critically ill patient--concepts appraised by the example of antimicrobial agents［J］. Adv Drug Deliv Rev, 2014,77:3-11.
［5］McKenzie C.Antibiotic dosing in critical illness［J］. J Antimicrob Chemother， 2011,66 Suppl 2:ii25-31.
［6］Kiang TK, Hafeli UO, Ensom MH. A comprehensive review on the pharmacokinetics of antibiotics in interstitial fluid spaces in humans: implications on dosing and clinical pharmacokinetic monitoring［J］. Clin Pharmacokinet, 2014,53(8):695-730.
［7］Isla A, Canut A, Arribas J, et al.Meropenem dosing requirements against Enterobacteriaceae in critically ill patients: influence of renal function, geographical area and presence of extended-spectrum beta-lactamases［J］. Eur J Clin Microbiol Infect Dis，2016,35(3):511-519.
［8］Abdul-Aziz MH, Sulaiman H, Mat-Nor MB, et al. Beta-Lactam Infusion in Severe Sepsis (BLISS): a prospective, two-centre, open-labelled randomised controlled trial of continuous versus intermittent beta-lactam infusion in critically ill patients with severe sepsis［J］. Intensive Care Med，2016， 42(10):1535-1545.
［9］Petrosillo N, Drapeau CM, Agrafiotis M, et al. Some current issues in the pharmacokinetics/pharmacodynamics of antimicrobials in intensive care［J］. Minerva Anestesiol，2010,76(7):509-524.
［10］郭松喜, 王丹, 刘春生, 等. 脓毒症实验动物模型的研究进展［J］. 中华肺部疾病杂志 (电子版), 2015,5:027.
［11］Rittirsch D, Huber-Lang MS, Flierl MA, et al.Immunodesign of experimental sepsis by cecal ligation and puncture［J］. Nat Protoc，2009,4(1):31-36.
［12］Marchand S, Dahyot C, Lamarche I, et al. Microdialysis study of imipenem distribution in skeletal muscle and lung extracellular fluids of noninfected rats［J］. Antimicrob Agents Chemother, 2005,49(6):2356-2361.
［13］Marchand S, Dahyot C, Lamarche I, et al. Lack of effect of experimental hypovolemia on imipenem muscle distribution in rats assessed by microdialysis［J］. Antimicrob Agents Chemother, 2005,49(12):4974-4979.
［14］de Araujo BV, Laureano JV, Grunspan LD, et al. Validation of an efficient LC-microdialysis method for gemifloxacin quantitation in lung, kidney and liver of rats［J］. J Chromatogr B Analyt Technol Biomed Life Sci, 2013,919-920:62-66.
［15］Joukhadar C, Thallinger C, Poppl W, et al. Concentrations of voriconazole in healthy and inflamed lung in rats［J］. Antimicrob Agents Chemother, 2009,53(6):2684-2686.
［16］Tasso L, Bettoni CC, Oliveira LK, et al. Evaluation of gatifloxacin penetration into skeletal muscle and lung by microdialysis in rats［J］. Int J Pharm, 2008,358(1/2):96-101.
［17］Liu P, Fuhrherr R, Webb AI, et al. Tissue penetration of cefpodoxime into the skeletal muscle and lung in rats［J］. Eur J Pharm Sci, 2005,25(4/5):439-44.
［18］Dahyot C, Marchand S, Pessini GL, et al. Microdialysis study of imipenem distribution in skeletal muscle and lung extracellular fluids of Acinetobacter baumannii-infected rats［J］. Antimicrob Agents Chemother, 2006,50(6):2265-2267.
［19］Mauric O, Thallinger C, Kugler SA, et al.The ability of fluconazole to penetrate into ventilated, healthy and inflamed lung tissue in a model of severe sepsis in rats［J］.Pharmacology, 2011,87(3/4):130-134.
［20］梁艳冰, 唐皓, 翟诚顺, 等. 脓毒症大鼠心肌细胞凋亡与 p53 和 Bcl-2 基因表达的关系［J］. 中华急诊医学杂志, 2008,17(2):128-131.
［21］徐叔云, 卞如濂, 陈修. 药理实验方法学［M］.人民卫生出版社,1991;2002.
［22］Lindenmann J, Kugler SA, Matzi V, et al.High extracellular levels of cefpirome in unaffected and infected lung tissue of patients［J］. J Antimicrob Chemother, 2011,66(1):160-164.
［23］Hutschala D, Kinstner C, Skhirtladze K, et al. The impact of perioperative atelectasis on antibiotic penetration into lung tissue: an in vivo microdialysis study［J］. Intensive Care Med, 2008,34(10):1827-1834.
［24］李奕, 华翔, 肖和平, 等.微透析法研究左氧氟沙星静脉注射在肺炎链球菌肺炎大鼠肺部的药动学［J］. 中国感染与化疗杂志, 2013,13(2):109-114.
［25］Kuti JL, Dandekar PK, Nightingale CH, et al. Use of Monte Carlo simulation to design an optimized pharmacodynamic dosing strategy for meropenem［J］. J Clin Pharmacol，2003,43(10):1116-1123.
［26］Shea KM, Cheatham SC, Smith DW, et al.Comparative pharmacodynamics of intermittent and prolonged infusions of piperacillin/tazobactam using Monte Carlo simulations and steady-state pharmacokinetic data from hospitalized patients［J］. Ann Pharmacother, 2009,43(11):1747-1754.
［27］Wang H, Zhang B, Ni Y, et al. Pharmacodynamic target attainment of seven antimicrobials against Gram-negative bacteria collected from China in 2003 and 2004［J］. Int J Antimicrob Agents, 2007,30(5):452-457.
［28］Cheatham SC, Kays MB, Smith DW, et al. Steady-state pharmacokinetics and pharmacodynamics of meropenem in hospitalized patients［J］. Pharmacotherapy, 2008,28(6):691-698.
［29］Eguchi K, Kanazawa K, Shimizudani T, et al. Experimental verification of the efficacy of optimized two-step infusion therapy with meropenem using an in vitro pharmacodynamic model and Monte Carlo simulation［J］. J Infect Chemother，2010,16(1):1-9.
［30］Roberts JA, Kirkpatrick CM, Roberts MS, et al. Meropenem dosing in critically ill patients with sepsis and without renal dysfunction: intermittent bolus versus continuous administration? Monte Carlo dosing simulations and subcutaneous tissue distribution［J］. J Antimicrob Chemother，2009,64(1):142-150.
［31］Abdul-Aziz MH, Lipman J, Mouton JW, et al.Applying pharmacokinetic/pharmacodynamic principles in critically ill patients: optimizing efficacy and reducing resistance development［J］. Semin Respir Crit Care Med，2015， 36(1):136-153.
［32］Dhanani J, Roberts JA, Chew M, et al. Antimicrobial chemotherapy and lung microdialysis: a review［J］. Int J Antimicrob Agents, 2010,36(6):491-500.
［33］Thalhammer F, Horl WH. Pharmacokinetics of meropenem in patients with renal failure and patients receiving renal replacement therapy［J］. Clin Pharmacokinet, 2000,39(4):271-279.
［34］Martinez MN, Papich MG, Drusano GL. Dosing regimen matters: the importance of early intervention and rapid attainment of the pharmacokinetic/pharmacodynamic target［J］. Antimicrob Agents Chemother, 2012,56(6):2795-2805.
［35］Drusano GL, Lodise TP, Melnick D, et al. Meropenem penetration into epithelial lining fluid in mice and humans and delineation of exposure targets［J］. Antimicrob Agents Chemother，2011,55(7):3406-3412.
［36］Louie A, Liu W, Fikes S, et al. Impact of meropenem in combination with tobramycin in a murine model of pseudomonas aeruginosa pneumonia［J］. Antimicrob Agents Chemother，2013,57(6):2788-2792.
［37］Lodise TP, Sorgel F, Melnick D, et al.Penetration of meropenem into epithelial lining fluid of patients with ventilator-associated pneumonia［J］. Antimicrob Agents Chemother，2011,55(4):1606-1610.
［38］Duszynska W. Pharmacokinetic-pharmacodynamic modelling of antibiotic therapy in severe sepsis［J］. Anaesthesiol Intensive Ther，2012,44(3):158-164.

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