抗菌药物的药动学和药效学参数对临床用药的指导作用

目的 探讨抗菌药物的药动学/药效学(PK/PD)参数与临床用药方案的关系.方法 参阅相关文献,依据药效学和药动学理论,结合临床用药实际,确定抗茵药物的用药方案.结果 抗菌药物可分为浓度依赖性抗菌药物和时间依赖性抗菌药物.结论 依据PK/PD综合参数对制定合理给药方案、提高临床疗效有重要意义.     

在抗生素治疗中的药理学指数

使用抗生素治疗已 60年之久 ,而利用药理学参数的方法使抗生素的使用更趋合理的多方面研究工作已达到了最高阶段 ,利用这些指数可以比较不同抗生素的活性 ,并对抗生素的剂量起到正确的指导作用。药动学参数 (如 :AUC、Cmax)和药效学参数 (主要为MIC)用于这一目的。对于浓度 -依赖性抗生素其药理学指数为AUC/MIC和Cmax/MIC ,而时间 -依赖性抗生素的药理学指数为T >MIC。一些作者认为指数AUC/MIC能够作为通用指数 ,但并不是所有的专家都接受这一判断。由于在文献中的各种药理学指数的定义不一致 ,因而抗感染药理学国际学会 (ISAP)公布了药动学和药效学参数和药理学指数的专用名词 ,本文将帮助确保使用一致的专用术语。另外 ,作者指出药理学指数的使用将考虑药动学差异 (患者的特性和感染部位 )和抗生素对不同病原菌 (如 :革兰氏阳性菌和革兰氏阴性菌 )的药效学差异。     

抗菌药物的药动学及药效学相关研究的临床意义

通过对抗菌药物的药动学(PK)、药效学(PD)的相关研究，发现了抗菌药物不同的PK/PD特性；提出了预测抗菌药物疗效的重要PD参数为AUC0-24/MIC，Cmax/MIC，t＞MIC和抗生素后效应(PAE)等；而且对评价药物有效性。指导合理用药，提高药物疗效，避免产生耐药性都有指导性的作用。因此，PK/PD研究是抗菌药合理应用的基础，在研究、设计和制定抗菌药物治疗方案、制定敏感性临界值以及推荐用药指南等方面都具有重要价值。     

基于Excel函数设计抗菌药物间歇静脉滴注给药方案

目的:设计抗菌药物间歇静脉滴注给药方案。方法:以头孢唑啉钠、头孢曲松钠、阿米卡星为例,采用多剂量函数法处理相关药动学数据,将药动学与药效学(PK/PD)参数相结合,应用Excel软件编写计算程序,设计合理给药方案。结果:时间依赖性抗菌药物的杀菌效应主要取决于血药浓度高于细菌最低抑菌浓度(MIC)的时间;对于血浆消除半衰期短的抗菌药物宜采取小剂量均匀分次给药,甚至持续给药;半衰期较长者12～24h给药1次即可。浓度依赖性抗菌药物优化临床抗菌疗效的最佳PK/PD参数为Cmax/MIC,适宜日剂量单次给予。结论:基于PK/PD,应用Excel函数设计抗菌药物间歇静脉滴注给药方案,方法简便、可靠、直观。     

儿童重症患者利奈唑胺药动学/药效学与疗效和安全性分析

目的:研究利奈唑胺在儿童重症患者中的疗效与安全性.方法:以应用利奈唑胺治疗的重症患儿为研究对象,通过测定血药浓度,计算药动学/药效学(PK/PD)参数,评估药物疗效与安全性.结果:纳入63例患儿,利奈唑胺谷浓度和PK/PD在不同年龄、性别患儿中分布无差异;谷浓度≥2 mg·L-1或AUC/MIC≥80时,治疗有效率明显...     

药理学原则在抗微生物药给药方案设计中的应用

从参数的选择与整合,群体药动学与流行病学MIC分布的应用及对细菌的耐药选择等方面对抗微生物药物的药动学/药效学(PK/PD)模型进行了阐述,以期为制定达到最佳细菌学治愈并减少耐药性产生的给药方案提供参考.     

β-内酰胺酶抑制剂复方制剂非临床研究技术指南

β-内酰胺酶抑制剂复方制剂在临床上被广泛应用于治疗耐药菌所致感染,由于早期β-内酰胺酶抑制剂的抑酶谱较 窄,抑酶谱更广泛的酶抑制剂在不断研发之中。与一般抗菌药物临床前研究不同,β-内酰胺酶抑制剂复方制剂的临床前研究需 明确β-内酰胺类药物或酶抑制剂本身的抗菌谱与抗菌活性,尤其是明确酶抑制剂是否具有抗菌活性。需要确定合适的β-内酰胺 类药物与酶抑制剂复方制剂,以及适用的不同酶型的目标病原菌。本文主要介绍新型β-内酰胺酶抑制剂复方制剂临床前研究方 法。临床前研究阶段的β-内酰胺酶抑制剂复方制剂研究包括体外研究和体内研究两部分,前者主要为体外药效学研究和体外药 动学/药效学(pharmacokinetic/pharmacodynamic, PK/PD)研究,常用研究方法包括β-内酰胺类药物和β-内酰胺酶抑制剂复方制剂最 低抑菌浓度测定、最低杀菌浓度测定、抗生素后效应测定及时间杀菌曲线。后者主要为动物药动学研究、感染动物药效学研究 和感染动物药动学/药效学研究。在动物药动学/药效学研究中,需考虑β-内酰胺类药物与酶抑制剂的相互影响。这些研究方法的 应用旨在阐明β-内酰胺酶抑制剂复方制剂两组分药效学特点、药动学相似与否、PK/PD指数及其临床前PK/PD靶值,为进入临 床试验阶段目标适应症及剂量选择提供依据。     

肾移植术后泼尼松/泼尼松龙的临床药动学/药效学研究进展

目的:综述近年来肾移植术后糖皮质激素泼尼松/泼尼松龙临床药动学(PK)和药效学(PD)研究现状,为进一步优化其免疫抑制治疗方案提供参考。方法:检索国内外相关文献,总结泼尼松/泼尼松龙在肾移植术后药动学/药效学相关研究情况及未来发展方向。结果:糖皮质激素已应用多年,但其临床给药方案通常凭医生经验制定,缺乏临床药动学/药效学研究指导,因而在进行冲击治疗和长期给药时往往出现多种毒副作用。目前泼尼松/泼尼松龙肾移植术后的临床药动学和药效学研究局限:大部分药动学数据采用非房室分析方法以及两步统计法计算,大多数研究中测定血药浓度为总药物浓度而非实际起效的游离药物浓度,药效学研究多限于药物暴露与毒副作用之间的相关性研究。结论:泼尼松/泼尼松龙肾移植术后的临床药动学、药效学研究具有一定基础但尚不全面,有待考察其系统的定量关系用于指导个体化用药方案的制定。     

抗菌药物双向个体化与老年用药

抗菌药物双向个体化是以感染患者个体的病原菌对抗菌药物的药效学反应浓度(DRC)或最低抑菌浓度(MIC)作药效学基础，同时以患者个体体内药物浓度来推算药动学参数，实现抗菌药物和病原菌之间的体外药效学与抗菌药物和患者的体内药动学的结合，是抗菌药物个体化用药方案设计的理想方法之一。概述抗菌药物双向个体化的概念、特点及在老年严重感染性疾病治疗中的作用，介绍用双向个体化法设计老龄感染患者用药方案及应注意的问题。     

临床用药问题解答

1 抗菌药物根据其药效学特征分为哪几类,其给药方案有 何特点 抗菌药物依照药效学特征可分为浓度依赖型和时间依赖型两大类。不同类型的抗菌药物应从药效学方面的不同来制定不同的给药方案。药效学是衡量药物浓度、药理作用及毒副作用的一门学科。目前,用于指导临床用药的药效学参数包括:①药物浓度高于MIC的时间占给药间期的百分比(T>MIC％),受此参数制约的抗生素主要是β-内酰胺类和大环内酯类。②24小时曲线下面积(AUC)与MIC的比率(24hAUIC),其相关抗菌药物是氨基苷类及喹诺酮类等。③峰浓度(Peak)与MIC的比率,其相关抗菌药物有四环素、氨基苷类及喹诺酮类。     

Class-dependent relevance of tissue distribution in the interpretation of anti-infective pharmacokinetic/pharmacodynamic indices

The pharmacokinetic/pharmacodynamic (PK/PD) indices useful for predicting antimicrobial clinical efficacy are well established. The most common indices include the time free drug concentration in plasma is above the minimum inhibitory concentration (MIC) (fT_>MIC) expressed as a percent of the dosing interval, the ratio of maximum concentration to MIC (C_max/MIC), and the ratio of the area under the 24-h concentration–time curve to MIC (AUC_0–24/MIC). A single PK/PD index may correlate well with an entire antimicrobial class. For example, the β-lactams correlate well with the fT_>MIC. However, other classes may be more complex and a single index cannot be generalised to the class, e.g. the macrolides. The rationale behind which PK/PD index best correlates with efficacy depends on several factors, including the mechanism of action, the microbial kill kinetics, the degree of protein binding and the degree of tissue distribution. Studies have traditionally emphasised the first two factors, whilst the significance of protein binding and tissue distribution is increasingly appreciated. In fact, the latter two factors may partially elucidate why the magnitude of reported target indices are not always as expected. For example, tigecycline and telithromycin are clinically efficacious with average serum concentrations below their MICs over a 24-h period. Therefore, to understand more fully the PK/PD relationship of antibiotics and to better predict the clinical efficacy of antibiotic dosing regimens, assessment of free drug concentrations at the site of action is warranted.     

Rational dosing of antibiotics: the use of plasma concentrations versus tissue concentrations

At the moment, the most common pharmacokinetic/pharmacodynamic (PK/PD) approaches for anti-infective agents, such as time above MIC, C(max)/MIC and AUC(24)/MIC, rely on plasma concentration as the PK input value and minimum inhibitory concentration (MIC) as the PD input value. However, only the free tissue concentrations of antibiotics at the target site are responsible for the therapeutic effect. Using plasma concentrations frequently overestimates the target site concentrations and therefore clinical efficacy. Microdialysis is a new technique that allows direct measurement of unbound tissue concentrations. Furthermore, a better PD approach, bacterial time-kill curves, can offer more detailed information about the antibacterial activity as a function of time and antibiotic concentration than MICs.     

药物动力学和药效动力学在抗菌药物新药开发和临床治疗上的应用

制定合理的给药方案是抗菌药物开发中临床试验成败的关键。近十年来群体药物动力学和药效动力学的发展和在抗菌药新药开发上的应用，对抗菌药物合理给药方案的制定有了突破性进展，已基本上形成了抗菌药物新药开发的一个模式。这一模式以药动药效学理论指导下的体外动力学模型、动物体内感染模型和Ⅰ期临床药动学试验为基础，以随机化统计模型和蒙地卡罗模拟为手段对Ⅲ期临床试验的给药方案进行统计比较以确定最佳的给药剂量和频率。本文系统性地描述如何从临床前和临床试验中获得准确可靠的数据进而建立药动药效学数学模型，着重于阐述抗菌药物药效学的基本概念、试验方法学的基本原理并简单介绍药动药效学的计算方法.     

The integration of pharmacokinetics and pathogen susceptibility data in the design of rational dosing regimens

The integration of pharmacokinetic and pathogen susceptibility data has had an increasing impact on the design of dosage regimens. Pathogen susceptibility is often described by the minimum inhibitory concentration (MIC). While the MIC is an indicator of drug potency, it does not predict pharmacologic response in vivo when drug concentrations are fluctuating. To this end, three pharmacokinetic/pharmacodynamic (PK/PD) parameters that result from indexing pharmacokinetics to MIC have proven quite useful. A number of experimental models of infection have determined the magnitude of each parameter, AUC/MIC, Cmax/MIC and %T>MIC, required for the optimal treatment of specific pathogens. These measurements have proven to be predictive of clinical outcomes as well. As a result, PK/PD breakpoints have been determined based on the likelihood that the pharmacokinetic profile of a given dose will achieve a target PK/PD parameter value. These breakpoints correlate well with treatment success or failure, particularly evident in infections conducive to microbiologic sampling such as otitis media. Therefore, PK/PD assessments have fostered a much more targeted approach to the treatment of patients with infectious diseases, and have proven useful in the selection of antimicrobial therapy and the development of novel dosing strategies.     

Integration of pharmacokinetic/pharmacodynamic modeling and simulation in the development of new anti-infective agents – minimum inhibitory concentration versus time-kill curves

The selection of appropriate doses and dosing regimens is extremely important in antimicrobial therapy in order to increase the chances of clinical success and decrease the likelihood of toxic side effects and the development of resistance. Therefore, empirical treatment of bacterial infections is not reliable enough and more rational approaches are needed. Pharmacokinetic/pharmacodynamic (PK/PD) modeling provides a powerful tool to systematically link PK and PD properties in order to predict antimicrobial efficacy. However, commonly used minimum inhibitory concentration (MIC) based PK/PD indices, although easy to obtain, have a number of limitations. Thus, more reliable PK/PD indices need to be developed. The following article provides an overview of the present PK/PD approaches used in anti-infective therapy and discusses their role in improving drug therapy.     

泰比培南对小鼠肺炎克雷伯菌大腿感染模型的PK/PD研究

目的：通过泰比培南对小鼠大腿克雷伯菌感染模型PK/PD研究,预测最佳PK/PD参数。方法：选用临床肺炎克雷伯菌1株,采用琼脂二倍稀释法检测药物的最低抑菌浓度（MIC）;构建小鼠的肺炎克雷伯菌大腿感染模型,分三种剂量（50、15、3 mg·kg-1）给予受试药物,观察给药24 h后大腿组织感染量变化,并采用HPLC法检测血药浓度。结果：体外测得MIC为0.03μg· mL-1;在小鼠的肺炎克雷伯菌大腿感染模型中,50、15、3 mg·kg-1三种剂量均对感染有治疗作用, PK/PD参数AUC/MIC、Cmax/MIC、T〉MIC的相关系数r2分别为0.8、0.75、0.54。结论：体内PK/PD研究表明,AUC/MIC、Cmax/MIC参数是反映泰比培南对小鼠的肺炎克雷伯菌大腿感染治疗效果主要的PK/PD参数。     

抗菌药的PK/PD理论及其在新抗菌药的药效研究中应用

大约在20年前发现,美国临床和实验室标准化学会发布的关于口服抗菌药的细菌药物敏感性折点,常与临床、微生物学和药代动力学结果不符。因此科学家提出了一个基于药代动力学一药效动力学(PK/PD)模型和临床结果的新方法,并以此推测细菌学转归及细菌学结果与药物敏感性的关系,并将抗菌药分为3种活性类型:①浓度依赖性杀菌和较长的持续效应,其药效依赖于给药量(AUC)或峰浓度与MIC的比值;②时间依赖杀菌却仅有低到中度的持续效应,其疗效更多地依赖于给药次数(血药浓度超过MIC的时间);③时间依赖杀菌而有较长的持续效应,其药效依赖于给药量(AUC)与MIC的比值。对此本文作了介绍。     

依据抗菌药物PK／PD理论对我院门诊药房抗菌药物不合理处方的点评及案例解析

目的：依据抗菌药物PK/PD理论,对我院门诊药房抗菌药物不合理处方进行点评与分析,以期优化临床给药方案。方法：基于4例出现频数较高的不合理抗菌药物处方,结合抗菌药物PK/PD理论,明确药师在抗菌药物应用的适应证、用法用量、给药频次等问题的处方点评策略。结果：β-内酰胺类抗菌药物为时间依赖性抗菌药物,为取得较好临床疗效,β-内酰胺类抗菌药物的T 〉 MIC需要超过给药间歇的40%;阿奇霉素片为大环内酯类抗菌药物,属于时间依赖性且PAE较长的抗菌药物,推荐给药频次为qd;氟喹诺酮类药物属于浓度依赖性抗菌药物,其有较高的组织浓度,AUC0-24 h/MIC ≥100和/或Cmax/MIC〉8时可发挥良好的疗效。结论：在处方点评过程中,药师应评估患者的综合情况,以抗菌药物PK/PD理论为指导,开展有效地处方点评工作,对不合理处方积极干预,以促进临床合理用药。     

Pharmacokinetic-pharmacodynamic modeling and simulation for in vivo bactericidal effect in murine infection model

A pharmacokinetic (PK)/pharmacodynamic (PD) modeling strategy to simulate in vivo bactericidal effects for three carbapenem antibiotics, doripenem (DRPM), meropenem (MEPM)/cilastatin (CS), and imipenem (IPM)/CS, against a Pseudomonas aeruginosa (P. aeruginosa) strain is proposed. The PD model we have already developed to explain in vitro time-kill profiles was modified to incorporate the growth rate, bactericidal activities, and PK profiles in murine lung infection models. Plasma concentration data and bacterial time-kill data for each antibiotic consist of six and eight time points, respectively, at one dose regimen (four or five mouse/point). In vivo time-kill curves could be well simulated for each antibiotic by the PK/PD model. Simulated bacterial counts at 24 h and PK/PD indices derived from total drug concentrations (time above the minimum inhibitory concentration (MIC) (T > MIC), C(max)/MIC, and AUC/MIC) for various dose regimens were examined for MEPM/CS and IPM/CS. Simulated bacterial counts correlated only with T > MIC (correlation coefficient: 0.951 for MEPM/CS, 0.982 for IPM/CS) and T > MIC values to achieve a bacteriostatic effect and a 2-log killing effect for both antibiotics were estimated to be approximately 15 and 20%, respectively, which are similar to previously reported results. These findings suggested that the proposed PK/PD model is a good tool for predicting in vivo bactericidal effects.     

Continuous infusion of ticarcillin-clavulanate for home treatment of serious infections: clinical efficacy, safety, pharmacokinetics and pharmacodynamics

Continuous infusion (CI) ticarcillin–clavulanate is a potential therapeutic improvement over conventional intermittent dosing because the major pharmacodynamic (PD) predictor of efficacy of β-lactams is the time that free drug levels exceed the MIC. This study incorporated a 6-year retrospective arm evaluating efficacy and safety of CI ticarcillin–clavulanate in the home treatment of serious infections and a prospective arm additionally evaluating pharmacokinetics (PK) and PD. In the prospective arm, steady-state serum ticarcillin and clavulanate levels and MIC testing of significant pathogens were performed. One hundred and twelve patients (median age, 56 years) were treated with a CI dose of 9.3–12.4 g/day and mean CI duration of 18.0 days. Infections treated included osteomyelitis (50 patients), septic arthritis (6), cellulitis (17), pulmonary infections (12), febrile neutropenia (7), vascular infections (7), intra-abdominal infections (2), and Gram-negative endocarditis (2); 91/112 (81%) of patients were cured, 14 (13%) had partial response and 7 (6%) failed therapy. Nine patients had PICC line complications and five patients had drug adverse events. Eighteen patients had prospective PK/PD assessment although only four patients had sufficient data for a full PK/PD evaluation (both serum steady-state drug levels and ticarcillin and clavulanate MICs from a bacteriological isolate), as this was difficult to obtain in home-based patients, particularly as serum clavulanate levels were found to deteriorate rapidly on storage. Three of four patients with matched PK/PD assessment had free drug levels exceeding the MIC of the pathogen. Home CI of ticarcillin–clavulanate is a safe, effective, convenient and practical therapy and is a therapeutic advance over traditional intermittent dosing when used in the home setting.