DeRyke C Andrew, Lee Su Young, Kuti Joseph L, Nicolau David P
Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut 06102, USA.
Drugs. 2006;66(1):1-14. doi: 10.2165/00003495-200666010-00001.
Evolving antimicrobial resistance is of global concern. The impact of decreased susceptibility to current antibacterials coupled with the decline in the marketing of new agents with novel mechanisms of action places a tremendous burden on clinicians to appropriately use available agents. Optimising antibacterial dose administration through the use of pharmacodynamic principles can aid clinicians in accomplishing this task more effectively. Methods to achieve this include: continuous or prolonged infusion, or the use of smaller doses administered more frequently for the time-dependent beta-lactam agents; or higher, less frequent dose administration of the concentration-dependent aminoglycosides and fluoroquinolones. Pharmacodynamic breakpoints, which are predictive of clinical and/or microbiological success in the treatment of infection, have been determined for many classes of antibacterials, including the fluoroquinolones, aminoglycosides and beta-lactams. Although surpassing these values may predict efficacy, it may not prevent the development of resistance. Recent studies seek to determine the pharmacodynamic breakpoints that prevent the development of resistance. Numerous studies to this point have determined these values in fluoroquinolones in both Gram-positive and Gram-negative bacteria. However, among the other antibacterial classes, there is a lack of sufficient data. Additionally, a new term, the mutant prevention concentration, has been based on the concentrations above which resistance is unlikely to occur. Future work is needed to fully characterise these target concentrations that prevent resistance.
不断演变的抗菌药物耐药性是全球关注的问题。对当前抗菌药物敏感性降低，再加上具有新作用机制的新型药物上市数量减少，给临床医生合理使用现有药物带来了巨大负担。通过运用药效学原理优化抗菌药物剂量给药，可帮助临床医生更有效地完成这项任务。实现这一目标的方法包括：对于时间依赖性β-内酰胺类药物，采用持续或延长输注，或更频繁地给予较小剂量；对于浓度依赖性氨基糖苷类和氟喹诺酮类药物，则给予更高、给药频率更低的剂量。许多类抗菌药物，包括氟喹诺酮类、氨基糖苷类和β-内酰胺类，都已确定了可预测感染治疗临床和/或微生物学成功的药效学断点。虽然超过这些值可能预示疗效，但可能无法预防耐药性的产生。近期研究试图确定能预防耐药性产生的药效学断点。到目前为止，众多研究已在革兰氏阳性菌和革兰氏阴性菌中确定了氟喹诺酮类药物的这些值。然而，在其他抗菌药物类别中，缺乏足够的数据。此外，一个新术语“突变预防浓度”已基于高于该浓度不太可能产生耐药性的概念提出。需要开展进一步的工作来全面描述这些预防耐药性的目标浓度。
