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

Mohammad Yaseen Abbasi,1 Weerachai Chaijamorn,2 Kamonthip Wiwattanawongsa,1 Taniya Charoensareerat,3 Thitima Doungngern1 1Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Prince Songkla University, Hat Yai, Songkhla, 90110 Thailand; 2Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Pathum Wan, Bangkok, 10330, Thailand; 3Faculty of Pharmacy, Siam University, Bangkok, 10160, ThailandCorrespondence: Thitima Doungngern, Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat Yai, Songkhla, 90110, Thailand, Tel +66-74288877, Fax +66-74428222, Email dthitima@pharmacy.psu.ac.thBackground: 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.Keywords: gentamicin, Cmax/MIC, AUC24h/MIC, nephrotoxicity, critically ill