Rybak Michael J
Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan 48201, USA.
Am J Med. 2006 Jun;119(6 Suppl 1):S37-44; discussion S62-70. doi: 10.1016/j.amjmed.2006.04.001.
Antibiotic pharmacodynamics (PD) describes the impact of an antimicrobial agent on a target pathogen and is based on the drug's pharmacokinetics (PK) and microbiologic activity toward that pathogen, together with the pathogen's susceptibility to the drug. Patient or host factors play an important role in antibiotic PD by affecting drug PK and patient susceptibility to infection. The 3 PD parameters commonly used to predict antibiotic efficacy are (1) the ratio of maximum serum concentration to the minimum inhibitory concentration (MIC) (C(max)/MIC); (2) the ratio of the area under the plasma concentration versus time curve (AUC) versus MIC (AUC/MIC) and (3) the duration of the dosing interval that plasma concentrations exceed the MIC (T>MIC). The C(max)/MIC ratio has been shown to predict aminoglycoside efficacy, AUC/MIC best describes fluoroquinolone, glycopeptide, and ketolide efficacy, and T>MIC best describes the efficacy of beta-lactams and macrolides. Traditionally, PK and PD (PK/PD) parameters have been used to predict antibiotic efficacy, but there is now increasing interest in trying to use PK/PD parameters to minimize development of resistance. With respect to fluoroquinolone resistance, the "mutant selection window" hypothesis has been developed to describe how drug exposures below the mutant prevention concentration may create conditions for the selection of resistant bacterial strains. The AUC/MIC ratio has also been used to describe fluoroquinolone drug exposures associated with either increased or decreased risk of resistance emergence. The accessory gene regulator (agr) locus in Staphylococcus aureus--and particularly agr group II--has been associated with reduced susceptibility or resistance of S aureus to vancomycin. Recent experiments suggest that the AUC/MIC ratio may be used to identify vancomycin exposures associated with emergence of resistance in S aureus. More generally, AUC/MIC ratios may be additive, and combination therapies may represent 1 approach to lowering the emergence rate of bacterial resistance associated with antibiotic therapy. But, further work needs to be done before this conclusion can be verified.
抗生素药效学（PD）描述了抗菌药物对目标病原体的影响，它基于药物的药代动力学（PK）、对该病原体的微生物活性以及病原体对药物的敏感性。患者或宿主因素通过影响药物PK和患者对感染的易感性，在抗生素PD中发挥重要作用。常用于预测抗生素疗效的3个PD参数为：（1）血清最大浓度与最低抑菌浓度（MIC）之比（C(max)/MIC）；（2）血药浓度-时间曲线下面积（AUC）与MIC之比（AUC/MIC）；（3）血浆浓度超过MIC的给药间隔持续时间（T>MIC）。C(max)/MIC比值已被证明可预测氨基糖苷类药物的疗效，AUC/MIC最能描述氟喹诺酮类、糖肽类和酮内酯类药物的疗效，而T>MIC最能描述β-内酰胺类和大环内酯类药物的疗效。传统上，PK和PD（PK/PD）参数一直用于预测抗生素疗效，但现在人们越来越有兴趣尝试使用PK/PD参数来尽量减少耐药性的产生。关于氟喹诺酮类耐药性，已提出“突变选择窗”假说，以描述低于突变预防浓度的药物暴露如何为耐药菌株的选择创造条件。AUC/MIC比值也已用于描述与耐药性出现风险增加或降低相关的氟喹诺酮类药物暴露情况。金黄色葡萄球菌中的辅助基因调节因子（agr）位点——尤其是agr II组——与金黄色葡萄球菌对万古霉素的敏感性降低或耐药性有关。最近的实验表明，AUC/MIC比值可用于识别与金黄色葡萄球菌耐药性出现相关的万古霉素暴露情况。更一般地说，AUC/MIC比值可能具有累加性，联合治疗可能是降低与抗生素治疗相关的细菌耐药性出现率的一种方法。但是，在验证这一结论之前，还需要做进一步的工作。
