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.
Keywords: AUC/MIC; PK/PD; aminoglycosides; critical illness; pharmacodynamics; pharmacokinetics; therapeutic drug management.
© 2018 Pharmacotherapy Publications, Inc.