Clinical and Administrative Pharmacy, University of Georgia College of Pharmacy, Savannah, Georgia.
Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan.
Pharmacotherapy. 2018 Dec;38(12):1229-1238. doi: 10.1002/phar.2193.
Therapeutic drug management is regularly performed for aminoglycosides in an effort to maximize their effectiveness and safety. The ratio of maximum plasma drug concentration to minimum inhibitory concentration (Cmax/MIC) has long been regarded as the primary pharmacokinetic/pharmacodynamic (PK/PD) index of clinical efficacy for aminoglycosides due to their concentration-dependent killing. In this review, however, we discuss why the area under the plasma concentration-time curve (AUC)/MIC ratio may be a more reliable indicator of bacterial killing and clinical efficacy for these agents. The definitive AUC/MIC efficacy targets for aminoglycosides are less clear, unlike those that exist for fluoroquinolones. Evaluation of available literature suggests that an AUC/MIC ratio of 30-50 for aminoglycoside therapy may provide optimal outcomes when targeting non-critically ill immunocompetent patients with low-bacterial burden gram-negative infections such as urinary tract infections or in patients receiving additional gram-negative therapy with good source control. However, an AUC/MIC target of 80-100 may be more prudent when treating patients with aminoglycoside monotherapy or in critically ill patients with high-bacterial burden infections, such as nosocomial pneumonia. Reappraisal of current antimicrobial susceptibility breakpoints for aminoglycosides against gram-negative bacteria may also be necessary to achieve these AUC/MIC targets and ensure that current empiric doses are not grossly suboptimal in critically ill patients. Although it has been historically difficult to calculate AUCs in clinical practice, equation-based and Bayesian approaches now can be used to estimate the AUC in clinical practice, with limited PK sampling. Additional research is needed to better define optimal AUC/MIC targets for efficacy, especially when drugs are used in combination, as well as PK/PD targets associated with suppression of resistance. It is also important to determine if AUC can predict nephrotoxicity of these agents or whether trough concentrations should be used instead.
治疗药物管理通常用于氨基糖苷类药物，以最大限度地提高其疗效和安全性。由于氨基糖苷类药物具有浓度依赖性杀菌作用，最大血浆药物浓度与最小抑菌浓度（Cmax/MIC）的比值长期以来一直被视为临床疗效的主要药代动力学/药效学（PK/PD）指标。然而，在这篇综述中，我们讨论了为什么氨基糖苷类药物的血浆浓度-时间曲线下面积（AUC）/MIC 比值可能是这些药物杀菌和临床疗效的更可靠指标。与氟喹诺酮类药物不同，氨基糖苷类药物的明确 AUC/MIC 疗效目标不太明确。评估现有文献表明，氨基糖苷类药物治疗的 AUC/MIC 比值为 30-50 时，对于目标为非重症免疫功能正常患者的低细菌负荷革兰阴性感染（如尿路感染）或接受良好源控制的额外革兰阴性治疗的患者，可能会获得最佳结果。然而，对于接受氨基糖苷类药物单药治疗或患有高细菌负荷感染（如医院获得性肺炎）的患者，AUC/MIC 目标为 80-100 可能更为谨慎。重新评估当前针对革兰阴性菌的氨基糖苷类药物的抗菌药物敏感性折点，以达到这些 AUC/MIC 目标并确保当前经验性剂量在重症患者中不会明显不足，这也是必要的。尽管在临床实践中计算 AUC 一直具有挑战性，但现在可以使用基于方程和贝叶斯的方法来估计 AUC，而无需进行大量 PK 采样。需要进一步研究以更好地定义疗效的最佳 AUC/MIC 目标，特别是当药物联合使用时，以及与抑制耐药性相关的 PK/PD 目标。确定 AUC 是否可以预测这些药物的肾毒性，或者是否应该使用谷浓度代替，也很重要。
