Recommendations of Gentamicin Dose Based on Different Pharmacokinetic/Pharmacodynamic Targets for Intensive Care Adult Patients: A Redefining Approach.

Abstract

Background: In addition to the maximum plasma concentration (C_max) to the minimum inhibitory concentration (MIC) ratio, the 24-hour area under the concentration-time curve (AUC_24h) to MIC has recently been suggested as pharmacokinetic/pharmacodynamic (PK/PD) targets for efficacy and safety in once-daily dosing of gentamicin (ODDG) in critically ill patients.

Purpose: This study aimed to predict the optimal effective dose and risk of nephrotoxicity for gentamicin in critically ill patients for two different PK/PD targets within the first 3 days of infection.

Methods: The gathered pharmacokinetic and demographic data in critically ill patients from 21 previously published studies were used to build a one-compartment pharmacokinetic model. The Monte Carlo Simulation (MCS) method was conducted with the use of gentamicin once-daily dosing ranging from 5-10 mg/kg. The percentage target attainment (PTA) for efficacy, C_max/MIC ~8-10 and AUC_24h/MIC ≥110 targets, were studied. The AUC_24h >700 mg⋅h/L and C_min >2 mg/L were used to predict the risk of nephrotoxicity.

Results: Gentamicin 7 mg/kg/day could achieve both efficacy targets for more than 90% when the MIC was <0.5 mg/L. When the MIC increased to 1 mg/L, gentamicin 8 mg/kg/day could reach the PK/PD and safety targets. However, for pathogens with MIC ≥2 mg/L, no studied gentamicin doses were sufficient to reach the efficacy target. The risk of nephrotoxicity using AUC_24h >700 mg⋅h/L was small, but the risk was greater when applying a C_min target >2 mg/L.

Conclusion: Considering both targets of Cmax/MIC ~8-10 and AUC_24h/MIC ≥110, an initial gentamicin dose of 8 mg/kg/day should be recommended in critically ill patients for pathogens with MIC of ≤1 mg/L. Clinical validation of our results is essential.