Reappraisal of Contemporary Pharmacokinetic and Pharmacodynamic Principles for Informing Aminoglycoside Dosing

Abstract

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.

Amikacin Initial Dose in Critically Ill Patients: a Nonparametric Approach To Optimize A Priori Pharmacokinetic/Pharmacodynamic Target Attainments in Individual Patients

“…We did not consider AUC as a predictor of nephrotoxicity. While several studies reported a relationship between aminoglycoside AUC and renal toxicity (5,7,27,28), no clear AUC target has been defined for once-daily amikacin. Further research is necessary about this question.…”

“…Studied efficacy targets were C max /MIC of Ն8 and AUC 0 -24 /MIC of Ն75 (3,4). We considered three putative MIC values for probabilistic therapy: 8 mg/liter (the epidemiological cutoff for susceptible Enterobacteriaceae from EUCAST), 4 mg/liter (the Enterobacteriaceae MIC breakpoint from USCAST), and a lower value of 2 mg/liter (5,49). C max was calculated as the concentration obtained 1 h after the start of the 30-min infusion (3).…”

“…aminoglycoside concentration in plasma to the bacterial MIC (C max /MIC) and the ratio of the area under the concentration-time curve from 0 to 24 h (daily area) to the MIC (AUC 0 -24 /MIC) have been suggested as targets. The conventional targets are C max /MIC of Ն8 to 10 (3) and AUC 0 -24 /MIC of Ն75 (4,5). For amikacin, considering a MIC breakpoint of 8 mg/liter for most susceptible Gram-negative bacteria (8 mg/liter is the EUCAST epidemiological cutoff for several Enterobacteriaceae), a C max of Ն64 mg/ liter and AUC 0 -24 of Ն600 mg/liter•h can be considered reasonable targets for empirical dosing in sepsis.…”

Exploring the Relationship between FEV1 Loss and Recovery and Aminoglycoside Pharmacokinetics in Adult Patients with Cystic Fibrosis: Implications for Clinical Dosing Strategies

“…Increasing aminoglycoside PK/PD exposures has been a recommended approach for severe lifethreatening infections. 5 A target-free AUC 0-24 hr -tominimum inhibitory concentration (MIC) above 110 has been proposed for lung infections. 17 In CF, prolonged aminoglycoside exposure may contribute to higher aminoglycoside MICs and reduced PK/PD attainment.…”

Reappraisal of Contemporary Pharmacokinetic and Pharmacodynamic Principles for Informing Aminoglycoside Dosing

“…In Bland et al . the treatment protocol in section “Support for the Cmax/MIC Ratio as a PK/PD Index” was published with error.…”