脓毒症患者在接受持续血液透析滤过时哌拉西林他唑巴坦的药代动力学研究

doi:10.12092/j.issn.1009-2501.2018.08.011

中国临床药理学与治疗学 ›› 2018, Vol. 23 ›› Issue (8): 905-911.doi: 10.12092/j.issn.1009-2501.2018.08.011

脓毒症患者在接受持续血液透析滤过时哌拉西林他唑巴坦的药代动力学研究

蔡云^1,2，徐锦龙³，张茂¹

¹浙江大学医学院附属第二医院急诊科，杭州 310009，浙江；²宁波市鄞州区第二医院重症医学科，宁波 315100，浙江； ³宁波市鄞州区第二医院药剂科，宁波 315100，浙江

收稿日期:2018-03-21 修回日期:2018-04-26 出版日期:2018-08-26 发布日期:2018-08-28
通讯作者: 张茂，男，博士，博士生导师，主任医师，研究方向：严重创伤救治的基础和临床研究。 Tel:13567435186 E-mail:zmhz@hotmail.com
作者简介:蔡云，男，硕士研究生，主治医师，研究方向：脓毒症、急性肾损伤、血流动力学监测。
基金资助:
2014宁波市鄞州区农业与社会发展科技计划项目（2014-4-38）

Pharmacokinetic of piperacillin/tazobactam in patients with sepsis during continuous venovenous hemodiafiltration

CAI Yun ^1,2, XU Jinlong ³, ZHANG Mao¹

¹Department of Emergency, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang, China ; ²Department of Critical Illness, ³Department of Pharmacy, Second Hospital of Yinzhou District, Ningbo 315100, Zhejiang, China

Received:2018-03-21 Revised:2018-04-26 Online:2018-08-26 Published:2018-08-28

摘要/Abstract

摘要：

目的: 分析接受持续静脉-静脉血液透析滤过（CVVHDF）的脓毒症患者哌拉西林/他唑巴坦的药代动力学特点及其影响因素，为临床制定更加合理有效的给药方案提供参考。方法: 选取2014年6月到2016年5月间入住一综合性三级乙等医院重症监护病房接受持续肾脏替代治疗（CRRT）的脓毒症患者作为研究对象。30 min内给予患者首剂4.5 g哌拉西林/他唑巴坦后，采用高效液相色谱法分别对给药结束后0、15、30、45、60、90、120、180、240、360、480 min的静脉血样进行药物浓度测定，采用无房室方法进行药动学分析，DAS 3.2.1软件计算药代学参数，采用线性回归分析患者特征及CRRT参数与药代动力学的关系。以给药后8 h内血药浓度超过最小抑菌浓度（MIC）的时间大于50%（f%T_＞MIC＞50%）作为药效学达标的指标。结果: 总共纳入8名患者。CVVHDF均采用前稀释方式。哌拉西林和他唑巴坦的峰浓度（C _max）分别为116.11（98.03～152.29）和21.60（15.9～29.69） mg/L，分布容积（V _d）分别为1.05（0.70～1.56）和0.69（0.56～0.78）L/kg，清除半衰期（t _1/2）分别为4.79（3.30～8.27）和4.38（3.35～5.52）h，总清除率（CL）分别为7.67（5.66～9.71）和6.11（4.36～10.03）L/h。多因素分析提示哌拉西林的Cmax与置换液流速显著负相关（β：-0.854，95%CI：-0.148～-0.036，P=0.007），CL与废液流速显著正相关（β：0.883，95%CI：0.133～0.433，P=0.004）。假设MIC≤16 mg/L时所有患者均达到药效学目标，当16 mg/L＜MIC＜32 mg/L时，仅有5名患者（62.5%）达标，而当MIC≥64 mg/L，则所有患者均未能达标。结论: 哌拉西林/他唑巴坦在脓毒症患者接受CVVHDF时无论是哌拉西林还是他唑巴坦均表现为C _max明显降低、t _1/2明显延长、CL降低，哌拉西林和他唑巴坦的CL和t _1/2基本一致。对于行CVVHDF的脓毒症患者，当细菌的MIC＞32 mg/L，首剂给予哌拉西林/他唑巴坦4.5 g可能剂量不足。

关键词: 脓毒症, 持续静脉-静脉血液透析滤过, 哌拉西林/他唑巴坦, 高效液相分析法, 药代动力学

Abstract:

AIM: To evaluate the pharmacokinetic of piperacillin/tazobactam in patients with sepsis during continuous venovenous hemodiafiltration and to analyse the influencing factors. METHODS: The patients with sepsis requiring CRRT in the intensive care units in a general hospital during June 2014 to May 2016 were enrolled as the subjects. First dose of piperacillin-tazobactam（4.5 g） was administered intravenously over 30 min. Blood samples were taken at 0, 15, 30, 45, 60, 90, 120, 180, 240, 360, 480 min after infusion.The concentrations of piperacillin and tazobactam were determined by high-performance liquid chromatography（HPLC）, PK analysis was conducted using a non-compartmental approach, the DAS 3.2.1 software was used to calculate pharmacokinetic parameters, Linear regression analysis was used to analyze the relationship between patient characteristics/CRRT parameters and pharmacokinetics.Blood concentration maintained above the minimum inhibitory concentration (MIC) for 50%(f%T_＞MIC＞50%) as a pharmacodynamic target. RESULTS: Eight patients with sepsis receiving CVVHDF were included in the investigation. The maximum concentration (C _max) of piperacillin and tazobactam was 116.11（98.03-152.29）and 21.60（15.9-29.69）mg/L,respectively; The volume of distribution (V_d) was 1.05（0.70-1.56）and 0.69（0.56-0.78）L/kg, respectively; The elimination half-time (t_1/2) was 4.79（3.30-8.27）and 4.38（3.35-5.52）h, respectively; The total clearance rate (CL) was 7.67（5.66-9.71）and 6.11（4.36-10.03）L/h, respectively. In the multivariate analysis, the most significant factor associated with Cmax of piperacillin was replacement flow rate (β：-0.854，95%CI：-0.148--0.036，P=0.007), the most significant factor associated with CL of piperacillin was effluent flow rate（β：0.883，95%CI：0.133-0.433，P=0.004）.When MIC≤16 mg/L, all patients reached pharmacodynamic target, when 16 mg/L＜MIC＜32 mg/L, just 5 patients (62.5%) reached the target, while MIC≥64 mg /L, no patient reached the target. CONCLUSION: Both piperacillin and tazobactam for patients with sepsis receiving CVVHDF show significantly lower C _max, significantly longer t_1/2, and decreased CL. CL and t_1/2 remain consistent. When germ's MIC＞32 mg/L, the first dosage of 4.5 g piperacillin/ tazobactam may be not enough.

Key words: sepsis, continuous venovenous hemodiafiltration, piperacillin/tazobactam, high-performance liquid chromatography, pharmacokinetics

中图分类号:

R969.1

蔡云，徐锦龙，张茂. 脓毒症患者在接受持续血液透析滤过时哌拉西林他唑巴坦的药代动力学研究[J]. 中国临床药理学与治疗学, 2018, 23(8): 905-911.

CAI Yun, XU Jinlong, ZHANG Mao. Pharmacokinetic of piperacillin/tazobactam in patients with sepsis during continuous venovenous hemodiafiltration[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2018, 23(8): 905-911.

参考文献

［1］Angus DC, Linde-Zwirble WT, Lidicker J,et al.Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care［J］. Crit Care Med,2001, 29 (7): 1303-1310.
［2］Angus DC,van der Poll T. Severe sepsis and septic shock［J］. N Engl J Med,2013,369 (9): 840-851.
［3］Levy MM, Fink MP, Marshall JC,et al.2001 SCCM/ESICM/ACCP/ATS/SIS international sepsis definitions conference［J］.Crit Care Med, 2001, 31(4): 1250-1262.
［4］Kellum J，Lameire N，Aspelin P，et al.Kidney disease: improving global outcomes (kdigo) acute kidney injury work group. KDIGO clinical practice guideline for acute kidney injury［J］. Kidney inter, 2012，2（1）: 1-138 .
［5］Khwaja A. KDIGO clinical practice guidelines for acute kidney injury［J］.Nephron Clin Pract,2012,120(4): c179-184.
［6］Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock［J］.Crit Care Med,2006, 34(6): 1589-1596.
［7］孙仁华,黄东胜.重症血液净化学［M］.杭州:浙江大学出版社,2015:36-39.
［8］Palevsky PM. Intensity of continuous renal replacement therapy in acute kidney injury［J］.Semin Dial,2009,22(2): 151-154.
［9］Varghese JM, Jarrett P, Boots RJ, et al. Pharmacokinetics of piperacillin and tazobactam in plasma and subcutaneous interstitial fluid in critically ill patients receiving continuous venovenous haemodiafiltration［J］.Int J Antimicrob Agents, 2014, 43(4): 343-348.
［10］Bauer SR, Salem C, Connor MJ, et al. Pharmacokinetics and pharmacodynamics of piperacillin-tazobactam in 42 patients treated with concomitant CRRT［J］.Clin J Am Soc Nephrol, 2012, 7(3): 452-457.
［11］Hayashi Y, Roberts JA, Paterson DL, et al. Pharmacokinetic evaluation of piperacillin-tazobactam［J］. Expert Opin Drug Metab Toxicol,2010,6(8): 1017-10131.
［12］Bragadottir G, Redfors B, Ricksten SE.Assessing glomerular filtration rate (GFR) in critically ill patients with acute kidney injury-true GFR versus urinary creatinine clearance and estimating equations［J］.Crit Care,2013, 17(3): R108.
［13］Capellier G, Cornette C, Boillot A, et al.Removal of piperacillin in critically ill patients undergoing continuous venovenous hemofiltration［J］. Crit Care Med，1998，26(1): 88-91.
［14］Mueller SC, Majcher-Peszynska J, Hickstein H, et al. Pharmacokinetics of piperacillin-tazobactam in anuric intensive care patients during continuous venovenous hemodialysis［J］.Antimicrob Agents Chemother，2002，46(5): 1557-1560.
［15］Langsdorf LJ, Zydney AL. Effect of blood contact on the transport properties of hemodialysis membranes: a two-layer membrane model［J］. Blood Purif，1994，12(6): 292-307.
［16］孙亚欣, 朱旭, 邱枫，等. HPLC法同时测定人血浆中哌拉西林/他唑巴坦的浓度及健康人体药动学研究［J］. 广东药学院学报，2012，28(6): 598-602.
［17］范珠. 哌拉西林他唑巴坦钠人体药动学研究［J］. 中国药业，2016，25(9): 5-7,8.
［18］章小敏, 洪冰, 叶军辉，等. PK/PD优化哌拉西林他唑巴坦给药方案治疗下呼吸道感染［J］.中国临床药理学与治疗学， 2015， 20(6): 677-681.
［19］Liu Q, Rand K, Derendorf H.Impact of tazobactam pharmacokinetics on the antimicrobial effect of piperacillin-tazobactam combinations［J］. Int J Antimicrob Agents，2004，23(5): 494-497.

[1]	何雪茹, 李颖, 马银玲, 付裕豪, 荀雪姣, 董占军. 索拉非尼和达格列净在大鼠体中药代动力学相互作用研究[J]. 中国临床药理学与治疗学, 2023, 28(5): 498-507.
[2]	李梦雪, 何杰, 余霞霞, 胡琳璘, 邵华. 利妥昔单抗群体药代动力学研究进展[J]. 中国临床药理学与治疗学, 2023, 28(4): 468-474.
[3]	周佳婷, 张玄, 谢子兰, 李智. 肠道菌群与左旋甲状腺素：相互影响与临床意义[J]. 中国临床药理学与治疗学, 2023, 28(11): 1307-1314.
[4]	吴莉莉, 梁至, 黄思咏, 王妍. 肾功能亢进对感染性心内膜炎患者万古霉素药动学的影响及有效性与安全性研究[J]. 中国临床药理学与治疗学, 2023, 28(10): 1139-1145.
[5]	徐涛, 朱素燕, 邱相君, 徐萍. 肾功能不全患者人群中替考拉宁群体药代动力学模型的建立与验证[J]. 中国临床药理学与治疗学, 2022, 27(9): 977-983.
[6]	马申, 刘玉硕, 唐辉, 陈文斌, 高聆. 改善非酒精性脂肪性肝病药物的药代动力学及其临床意义[J]. 中国临床药理学与治疗学, 2022, 27(8): 908-918.
[7]	戴静怡, 王晶晶, 张菁, 郁继诚, 李南洋, 黄志伟. 吸入性甲氧氟烷的临床应用及研究进展[J]. 中国临床药理学与治疗学, 2022, 27(7): 808-813.
[8]	潘淑, 吴义金, 张洒洒, 王启海, 罗婷婷, 殷勤. 基于OAT3介导的MTX治疗佐剂诱导性关节炎大鼠的药动学研究[J]. 中国临床药理学与治疗学, 2022, 27(5): 516-525.
[9]	邢博民, 郭娜, 宁海慧, 丁新耘, 马玉清. Rho激酶抑制剂对脓毒症肝损伤的影响[J]. 中国临床药理学与治疗学, 2022, 27(5): 544-550.
[10]	吴娟, 王志强, 周仁鹏, 杨晶晶, 秦慧玲, 张茜, 鲁超, 胡伟. 甲苯磺酸索拉非尼片在中国健康受试者的生物等效性研究[J]. 中国临床药理学与治疗学, 2022, 27(3): 281-286.
[11]	史革鑫, 崇锐, 贺坤, 吴海棠, 周宇, 顿中军, 温清, 张继国, 张荣. 吗替麦考酚酯胶囊在中国健康男性受试者空腹及餐后状态下的完全重复交叉设计的生物等效性研究[J]. 中国临床药理学与治疗学, 2022, 27(11): 1255-1263.
[12]	郭璐, 钟振东, 韩奕岑, 石毅, 杨勇, 边原, 刘晓姝, 张静, 郎琴, 钟甜. 不同给药方式在大鼠内对利巴韦林的药代动力学和组织分布的影响[J]. 中国临床药理学与治疗学, 2022, 27(1): 25-32.
[13]	林良沫, 符祥俊, 钟莉莉, 王和芳, 吴琼诗, 肖坚. 中性粒细胞缺乏患者万古霉素群体药代动力学模型的建立[J]. 中国临床药理学与治疗学, 2021, 26(9): 1014-1022.
[14]	付淑军, 黄芳华, 顾景凯, 吴伟, 孙涛, 王庆利. 纳米药物非临床药代动力学的研究策略及关注要点[J]. 中国临床药理学与治疗学, 2021, 26(8): 842-850.
[15]	徐慧, 杨新宇, 赵哲辉, 王琰. 多糖药物体内代谢及PK/PD关键技术研究的进展与思考[J]. 中国临床药理学与治疗学, 2021, 26(8): 851-862.

脓毒症患者在接受持续血液透析滤过时哌拉西林他唑巴坦的药代动力学研究

Pharmacokinetic of piperacillin/tazobactam in patients with sepsis during continuous venovenous hemodiafiltration

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 15

编辑推荐

Metrics

本文评价