Evaluating amikacin dosage regimens in intensive care unit patients: a pharmacokinetic/pharmacodynamic analysis using Monte Carlo simulation

Abstract

The objectives of this study were to conduct a comparative pharmacokinetic/pharmacodynamic (PK/PD) evaluation using Monte Carlo simulation of conventional versus high-dose extended-interval dosage (HDED) regimens of amikacin (AMK) in intensive care unit (ICU) patients for an Acinetobacter baumannii infection model. The simulation was performed in five populations (a control population and four subpopulations of ICU patients). Using a specific AMK PK/PD model and Monte Carlo simulation, the following were generated: simulated AMK steady-state plasma level curves; PK/PD efficacy indexes [time during which the serum drug concentration remains above the minimum inhibitory concentration (MIC) for a dosing period (%T>MIC) and ratio of peak serum concentration to MIC (Cmax/MIC)]; evolution of bacterial growth curves; and adaptive resistance to treatment. A higher probability of bacterial resistance was observed with the HDED regimen compared with the conventional dosage regimen. A statistically significant increase in Cmax/MIC and a statistically significant reduction in %T>MIC with the HDED regimen were obtained. A multiple linear relationship between CFU values at 24h with Cmax/MIC and %T>MIC was obtained. In conclusion, with the infection model tested, the likelihood of resistance to treatment may be higher against pathogens with a high MIC with the HDED regimen, considering that in many ICU patients the %T>MIC may be limited. If a sufficient value of %T>MIC (≥60%) is not reached, even though the Cmax/MIC is high, the therapeutic efficacy of the treatment may not be guaranteed. This study indicates that different AMK dosing strategies could directly influence the efficacy results in ICU patients.