https://orcid.org/0000-0002-2083-8084
Abstract
Background
In addition to the maximum plasma concentration (Cmax) to the minimum inhibitory concentration (MIC) ratio, the 24-hour area under the concentration-time curve (AUC24h) 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, Cmax/MIC ~8–10 and AUC24h/MIC ≥110 targets, were studied. The AUC24h >700 mg⋅h/L and Cmin >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 AUC24h >700 mg⋅h/L was small, but the risk was greater when applying a Cmin target >2 mg/L.
Conclusion
Considering both targets of Cmax/MIC ~8–10 and AUC24h/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.
Abbreviations
AUC24h, 24-hour area under the concentration-time curve; Cmax, maximum gentamicin plasma concentration; Cmin, minimum gentamicin plasma concentration; CL, clearance; Ke, elimination rate constant; IIV, inter- or intra-patient variability; ODDG, once-daily dosing of gentamicin; MCS, Monte Carlo simulation; MIC, minimum inhibitory concentration; PD, pharmacodynamic; PK, pharmacokinetic; PTA, probability of target attainment; USCAST, The United States Committee on Antimicrobial Susceptibility Testing; Vd, volume of distribution.
Data Sharing Statement
The datasets utilized and analyzed in this research are accessible from the corresponding authors upon request in the future without any specific rationale.
Acknowledgments
We would like to thank Assistant Professor Dr. Sutthiporn Pattharachayakul, and Associate Professor Dr. Wibul Wongpoowarak and for their valuable notes for this manuscript.
Disclosure
The authors declare that they have no conflicts of interest in this work.