Jacobs M R
Department of Pathology, Case Western Reserve University, University Hospitals of Cleveland, 11100 Euclid Ave, Cleveland, OH 44106, USA.
Clin Microbiol Infect. 2001 Nov;7(11):589-96. doi: 10.1046/j.1198-743x.2001.00295.x.
To understand the relationship between drug dose and efficacy, pharmacokinetic (PK) and pharmacodynamic (PD) characteristics need to be integrated. Patterns of antimicrobial activity fall into one of two major patterns: time-dependent killing and concentration-dependent killing. Time-dependent killing is characteristic of many antibiotic classes, such as beta-lactams and macrolides, and seeks to optimise the duration of exposure of a pathogen to an antimicrobial. The major PK/PD parameter correlating with efficacy of time-dependent antimicrobials is the serum concentration present for 40-50% of the dosing interval, and this concentration is the susceptibility limit or breakpoint for the dosing regimen used. The second pattern, concentration-dependent killing, seeks to maximise antimicrobial concentration and is seen with aminoglycosides, quinolones and azalides. The major PK/PD parameter correlating with efficacy of these agents is the 24-h area under the curve to MIC ratio, which should be > or =25 for less severe infections or in immunocompetent hosts, and > or =100 in more severe infections or in immunocompromised hosts. PK/PD breakpoints for concentration-dependent agents can therefore be calculated from the formula AUC divided by 25. This enables development of PK/PD breakpoints based on the above parameters for time- and concentration-dependent agents for defined dosing regimens. For an antimicrobial to be useful empirically, the MIC90s of the agent against the common pathogens responsible for the disease being treated should be below the PK/PD breakpoint. This is particularly important for oral dosing regimens for treating emerging resistant respiratory tract pathogens, where efficacy against the predominant pathogens, Streptococcus pneumoniae and Haemophilus influenzae, is required.
为了解药物剂量与疗效之间的关系，需要整合药代动力学（PK）和药效动力学（PD）特征。抗菌活性模式分为两种主要模式之一：时间依赖性杀菌和浓度依赖性杀菌。时间依赖性杀菌是许多抗生素类别的特征，如β-内酰胺类和大环内酯类，旨在优化病原体对抗菌药物的暴露持续时间。与时间依赖性抗菌药物疗效相关的主要PK/PD参数是给药间隔40%-50%时间内的血清浓度，该浓度是所用给药方案的敏感性极限或折点。第二种模式，浓度依赖性杀菌，旨在使抗菌浓度最大化，见于氨基糖苷类、喹诺酮类和氮杂内酯类。与这些药物疗效相关的主要PK/PD参数是曲线下24小时面积与最低抑菌浓度（MIC）之比，对于不太严重的感染或免疫功能正常的宿主，该比值应≥25，对于更严重的感染或免疫功能低下的宿主，该比值应≥100。因此，浓度依赖性药物的PK/PD折点可以根据AUC除以25的公式计算。这使得能够根据上述时间依赖性和浓度依赖性药物的参数，为确定的给药方案制定PK/PD折点。对于凭经验使用的抗菌药物，该药物对导致所治疗疾病的常见病原体的MIC90应低于PK/PD折点。这对于治疗新出现的耐药呼吸道病原体的口服给药方案尤为重要，在这种情况下，需要对主要病原体肺炎链球菌和流感嗜血杆菌有效。
