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《乌利希期刊指南》
WHO《西太平洋地区医学索引》来源期刊  
日本科学技术振兴机构数据库(JST)
第七届湖北十大名刊提名奖  
医药导报, 2017, 36(10): 1190-1193
doi: 10.3870/j.issn.1004-0781.2017.10.025
重症监护病房患者美罗培南治疗药物监测队列研究*
Cohort Study of Therapeutic Drug Monitoring on Meropenem in Intensive Care Unit Patients
金路, 罗雪梅, 张海霞, 葛卫红

摘要:

目的 探讨基于治疗药物监测(TDM)的美罗培南个体化给药方案是否有助于提高药动学/药效学(PK/PD)达标率及抗感染疗效。方法 收集南京鼓楼医院2015年1月—12月重症监护病房(ICU)使用美罗培南的患者共36例,分为干预组和对照组进行分析。结果 干预组第4天美罗培南血药浓度为22.5 μg·mL-1,对照组为17.5 μg·mL-1。以最低抑菌浓度(Cmin)>8 μg·mL-1为靶目标,干预组和对照组在第2天达标率均为22.2%,在第4天分别为100.0% 和72.2%(P=0.015)。以Cmin>32 μg·mL-1为靶目标,则干预组和对照组在第2天达标率均为0,在第4天分别为38.9%和5.5%(P=0.015)。干预组和对照组临床治愈率分别为83.3%和72.2%,差异无统计学意义(P=0.437),失败率分别为16.7%,27.8%。干预组细菌清除率为88.9%,对照组为55.5%(P<0.05)。结论 ICU患者基于TDM的美罗培南个体化给药有助于提高PK/PD达标率和抗感染疗效。

关键词: 美罗培南 ; 治疗药物监测 ; 药动学/药效学 ; 最低抑菌浓度

Abstract:

Objective To evaluate whether individualized dosage regimen based on therapeutic drug monitoring (TDM) is beneficial for improving the rate of pharmacokinetics/pharmacodynamics (PK/PD) reaching the standard and anti-infection efficacy. Methods Totally, 36 cases in the intensive care unit (ICU) of Nanjing Drum Tower Hospital using meropenem during January 2015 to December 2015 were collected, and divided into intervention group and control group. Results On the fourth day of administration, meropenem concentration in intervention group was significantly higher than that of the control group (22.5 μg·mL-1 and 17.5 μg·mL-1, respectively, P=0.007).With minimal inhibitory concentration (Cmin) >8 μg·mL-1 serving as target, the rate of reaching the standard was both 22.2% on day 2, 100.0% and 72.2% on day 4 in intervention group and control group, respectively (P=0.015). With minimal inhibitory concentration (Cmin) >32 μg·mL-1 serving as target, the rate of reaching the standard was both 0 on day 2, 38.9% and 5.5% on day 4 in intervention group and control group, respectively (P=0.015). The clinical curative rate of the intervention group and control group was 83.3% and 72.2%, respectively (P=0.437), and the failure rate was 16.7% and 27.8%, respectively.Bacteria clearance rate was 88.9% and 55.5% in the intervention group and control group, respectively(P<0.05). Conclusion Individualized dosage regimen based on TDM in ICU patients is beneficial to improving the rate of PK/PD reaching the standard and anti-infection efficacy.

Key words: Meropenem ; Therapeutic drug monitoring ; Pharmacokinetics/pharmacodynamics ; Minimal inhibitory concentration

近年来,医疗技术与治疗药物有了长足的发展,但重症感染患者临床预后却没有明显改善,发病率和死亡率仍居高不下[1-3]。造成抗感染治疗效果不佳的一个重要原因为抗菌药物的使用没有达到预期效果。大量临床实验证实,目前在重症监护室抗菌药物的给药方案大多数不恰当[4-5]。其原因为重症患者的病理生理状态与一般患者有很大差异,导致抗菌药物在患者体内的药动学(pharmacokinetic,PK)参数发生严重改变。抗菌药物在重症疾病患者体内PK参数(清除率、表观分布容积)的变异引起血药浓度的变化,进而降低抗菌药物获得药动学/药效学(pharmacokinetics/pharmacodynamics,PK/PD)靶目标的机会。而PK/PD靶目标的达标率与临床治愈率和病死率密切相关,是优化抗感染治疗方案的重要依据[6]

治疗药物监测(therapeutic drug monitoring,TDM)常用来针对那些治疗指数窄的药物,从而减少毒副作用的发生或增强疗效。同时,用来优化给药方案以应对患者间个体差异较大导致的药物PK参数变化。多年来,临床上已对万古霉素、抗癫痫药、抗精神病药等常规进行血药浓度监测。因此,笔者在本研究设计了临床队列研究,考察基于TDM的个体化给药方案是否有利于增加重症患者美罗培南的PK/PD靶目标达标率,以及是否有助于提高抗感染治疗的效果。

1 材料与方法
1.1 病例选择

本院应用美罗培南(商品名:美平,日本住友株式会社)治疗的住院患者共36例纳入研究,收集患者人口学信息,临床和实验室检查以及血药浓度数据。

暴露队列为2015年7月—12月前瞻性收集本院住院应用美罗培南并根据TDM结果调整剂量的患者18例设为干预组。比较队列为2015年1月—6月本院住院应用美罗培南并进行TDM,但未根据TDM结果调整剂量的患者中简单随机抽样18例设为对照组。该研究经南京鼓楼医院伦理委员会批准,所有参与者均签署知情同意书。入选标准:①年龄≥18岁;②需要美罗培南治疗;③美罗培南疗程>4 d并进行血药浓度监测。排除标准:①妊娠或哺乳期患者;②缺乏临床及实验室抗感染评价指标者。③治疗期间使用丙戊酸钠者。两组间体质量指数、APACHEⅡ评分、肌酐清除率等各项指标均差异无统计学意义。感染特征上肺炎占大多数,两组分别为67.0%和72.0%。而医院获得性感染在两组都是主要来源,分别为83.0%和88.0%,见表1。

表1 两组患者一般资料比较
Tab.1 Baseline data between two groups of patients
组别 例数 年龄/岁 体质量/kg 体质量指数/
[kg·(m2)-1]
APACHE Ⅱ评分 肌酐清除率/(mL·min-1)
范围 平均 范围 平均 范围 平均 第2天 第4天
范围 平均 范围 平均 范围 平均
对照组 18 48~64 56 65~89 75 22~27 24 13~24 18 94~170 117 91~166 149
干预组 18 42~76 55 69~88 76 22~28 25 12~25 19 100~166 129 83~180 156
组别 不良反应
发生率/%
疾病类型
肺炎 支气管炎 腹膜炎 血流感染 发热性中性
粒细胞减少
社区获得
性感染
医院获得
性感染
对照组 0.0 13 3 1 0 1 2 16
干预组 0.0 12 3 1 1 1 3 15

表1 两组患者一般资料比较

Tab.1 Baseline data between two groups of patients

1.2 药物定量分析

采用高效液相色谱(HPLC) 法测定美罗培南血药浓度。分别在给药第2天和第4天给药前测定谷浓度。

1.3 给药方案调整

干预组根据基于第2天血药谷浓度结果按事先制定好的给药方案调整规则(图1)进行干预。对照组仅根据医生经验进行给药方案调整。两组美罗培南静脉滴注时间为30 min。将100%T>4MIC(两次给药间隔时间内血药浓度始终大于4倍的MIC值)即Cmin/MIC>4作为靶目标,得出敏感和中介MIC值时PK/PD的达标情况。根据欧洲微生物协会制定标准,美罗培南药敏试验标准:MIC≤2.0 μg·mL-1为敏感,8.0 μg·mL-1为中介,≥16 μg·mL-1为耐药。故将Cmin>8 μg·mL-1Cmin>32 μg·mL-1作为PK/PD靶目标。

图1 干预组基于血药浓度结果调整给药方案策略

Fig.1 Therapeutic drug monitoring(TDM)-based dose adaptation strategy in intervention group

1.4 疗效评价

在研究第7天分别评价患者临床疗效和细菌学疗效。临床治愈为患者与感染相关的症状、体征、实验室检查结果(不包括细菌学检查)恢复至正常。临床失败为治疗后症状、体征或实验室检查结果无好转或恶化。细菌学疗效评价分为有效和无效。其中细菌学有效为细菌清除和假定清除,细菌学无效为细菌未清除和假定未清除[4]

1.5 统计学方法

采用GrapmPad Prism 6软件进行统计分析。对连续变量采用中位数加四分卫距(IQR)方式表示,并使用t检验。对分类变量采用数值和百分比方式表达,并使用Wilcoxon秩和检验。以P<0.05为差异有统计学意义。

2 结果
2.1 美罗培南TDM结果

本研究共获得美罗培南TDM谷浓度数据72次。其中对照组、干预组在治疗第2天和第4天分别测定美罗培南谷浓度1次。见图2。在调整前(第2天)对照组和干预组美罗培南谷浓度分别为5 μg·mL-1(IQR 3~7.25)和4.5 μg·mL-1(IQR 3~6.75),差异无统计学意义(P=0.927)。根据方案调整后,对照组经验性给药后浓度为17.5 μg·mL-1(IQR 7.0~21.25),干预组美罗培南浓度为22.5 μg·mL-1(IQR 18.75~37.25),两组间差异有统计学意义(P=0.007)。

在PK/PD达标率方面,若以Cmin>8 μg·mL-1为靶目标,对照组和干预组在第2天达标率均为22.2%,在第4天分别为72.2% 和100.0%(P=0.015)。若以Cmin>32 μg·mL-1为靶目标,对照组和干预组在第2天达标率均为0%,在第4天分别为5.5%和38.9%(P=0.015)。

图2 美罗培南治疗第2天、第4天谷浓度

Fig.2 Trough concentration of meropenem on day 2 and day 4 of treatment

2.2 疗效分析

对照组和干预组临床治愈率分别为72.2%和83.3%,差异无统计学意义(P=0.437),失败率分别为27.8%,16.7%。对照组细菌清除率为55.5%,干预组仅为88.9%,差异有统计学意义(P=0.025)。

3 讨论

已有大量临床研究证实抗感染药物PK/PD达标率与疗效密切相关,如何提高抗感染药物的PK/PD达标率是近年来抗感染药物合理应用的一个研究重点。研究者尝试通过持续性输注、延长滴注时间、运用群体药动学模型设计给药方案等方式获得更好的PK/PD达标率。本研究中,笔者发现基于TDM结果的给药方案调整策略相比经验性给药有助于提高PK/PD达标率,以及获得更好的疗效。

本研究中TDM结果显示,干预组不但谷浓度明显提高,而且细菌清除率显著优于对照组。但两组间临床疗效差异无统计学意义,这可能是由于两组在总体抗感染治疗中有其他临床治疗因素的影响,也可能本研究样本量偏少导致。

值得注意的是,当以中介值MIC=8 μg·mL-1设立PK/PD靶目标Cmin>32 μg·mL-1时,对照组仅5.5%患者达标,干预组也仅有38.9%达标。提示目前针对病原菌对美罗培南MIC值为中介以上的ICU患者时,美罗培南给药剂量可能仍然不足。

虽然TDM在提高美罗培南PK/PD达标率上有着潜在优势,但在安全性上仍缺乏足够研究。美罗培南的谷浓度与不良反应发生率关系仍不明确,使得目前无法运用TDM减少其不良反应的发生。

基于TDM调整美罗培南的文献报道有限[7],故目前在临床治疗中运用TDM仍存争议。需要更多大样本量临床实验去证实。已有部分临床病例报道[8-10]显示在针对不同病原菌和不同感染部位的抗感染治疗中,TDM已发挥出重要的作用。

综上所述,基于TDM的美罗培南个体化给药方案有助于获得更好的PK/PD达标率,应在临床抗感染治疗中加以运用,尤其是针对ICU患者。

The authors have declared that no competing interests exist.

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[8] HAYASHI Y,LIPMAN J,UDY A A,et al.Beta-lactam thera-peutic drug monitoring in the critically ill:optimising drug exposure in patients with fluctuating renal function and hypoalbuminaemia[J].Int J Antimicrob Agents,2013,41(2):162-166.
β-Lactams are routinely prescribed in the treatment of serious infections. Empirical dosing schedules are typically derived from studies in healthy volunteers and largely fail to consider the significant changes in antibacterial pharmacokinetics often encountered in the critically ill. These changes are primarily driven by the underlying pathophysiology and the interventions provided, leading to altered protein binding, poor tissue penetration, and fluctuations in the volume of distribution and drug clearance. Each separately, and in combination, is likely to complicate successful β-lactam administration in this setting. Although antibacterial therapeutic drug monitoring (TDM) has traditionally been employed to minimise drug toxicity, the challenges to achieving 'optimal' drug concentrations in the critically ill suggest β-lactam TDM as an attractive means to optimise drug exposure. Whilst there is currently little evidence to support routine widespread application of such a service, β-lactam TDM may still have a role in select patients where difficulty in establishing therapeutic concentrations can be illustrated. This series utilises three representative cases from a β-lactam TDM service that highlight the utility of this intervention in optimising antibacterial dosing. These preliminary data support an expanding role for β-lactam TDM in select critically ill patients and provide insight into the subpopulations most at risk of suboptimal drug exposure. Future studies investigating the clinical outcome benefits of β-lactam TDM in these patient groups are now warranted.
DOI:10.1016/j.ijantimicag.2012.10.002      PMID:23153962      URL    
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[9] UDY A A,PUTT M T,SHANMUGATHASAN S,et al.Augmented renal clearance in the intensive care unit:an illustrative case series[J].Int J Antimicrob Agents,2010,35(6):606-608.
The substantial underlying disease burden, in combination with the therapeutic interventions provided, can result in significantly altered end-organ function in the critically ill. These changes can in turn affect key pharmacokinetic (PK) indices for many antibiotics, including drug clearance, promoting potentially subtherapeutic concentrations for lengthy periods of the dosing interval, therapeutic failure or the selection of resistant organisms. This paper presents three instructional cases from our tertiary-level Intensive Care Unit, where established antibiotic dosing regimens failed to achieve predefined PK targets for optimal bacterial killing. Using therapeutic drug monitoring (TDM), significant dose modification was subsequently undertaken. We propose augmented renal clearance as a possible mechanism underlying this phenomenon, particularly in young post-operative, burns or head-injured patients with normal serum creatinine concentrations. TDM, or at least a measured creatinine clearance, should be considered early in this setting to allow the optimisation of antibiotic exposure.
DOI:10.1016/j.ijantimicag.2010.02.013      PMID:20307958      URL    
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[10] TACCONE F S,COTTON F,ROISIN S,et al.Optimal mero-penem concentrations to treat multidrug-resistant Pseudomonas aeruginosa septic shock[J].Antimicrob Agents Chemother,2012,56(4):2129-2131.
A patient with septic shock due to extensively drug resistant (XDR) Pseudomonas aeruginosa was cured by optimizing the meropenem (MEM) regimen to obtain at least 40% of the time between two administrations in which drug levels were four times higher than the MIC of the pathogen. As the standard drug dose did not achieve these optimal concentrations, the MEM regimen was progressively increased up to 12 g/day (3 g every 6 h in a 3-h extended infusion), which eventually resulted in sepsis resolution. High MEM dosage may represent a valuable therapeutic option for infection due to multidrug-resistant (MDR) strains, and drug monitoring would allow rapid regimen adjustment in clinical practice.
DOI:10.1128/AAC.06389-11      PMID:3318384      URL    
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关键词(key words)
美罗培南
治疗药物监测
药动学/药效学
最低抑菌浓度

Meropenem
Therapeutic drug monitori...
Pharmacokinetics/pharmaco...
Minimal inhibitory concen...

作者
金路
罗雪梅
张海霞
葛卫红

JIN Lu
LUO Xuemei
ZHANG Haixia
GE Weihong