Therapeutic Drug Monitoring of Gentamicin Peak Concentrations in Critically Ill Patients

Background: Adequate gentamicin peak concentrations (C-max) are important for optimal clinical efficacy. Within a critically ill patient, substantial variability in C-max can occur over time, hampering the usefulness of therapeutic drug monitoring (TDM). The aim of this study was to evaluate the effect of gentamicin dosing based on C-max after the first dose on gentamicin target attainment in critically ill patients. Methods: From gentamicin-treated critically ill patients, dosing information, clinical parameters, and serum concentrations were collected prospectively. A population pharmacokinetic model was developed using nonlinear mixed-effects modeling to estimate C-max after each dose. To evaluate the usefulness of routine TDM, percentages of Cmax within (% Cther, 15-20 mg/L), above (>20 mg/L), and below (% C-subther, <15 mg/L) the therapeutic range after the first and second doses were compared. In addition, simulations were performed to evaluate the impact of TDM. Results: Four hundred sixteen measurements from 59 patients receiving 130 gentamicin doses were included. In the 30 patients who received >1 dose, TDM increased % C-ther from 40% after a first median dose of 5.0 mg/kg to 50% after the second dose, and decreased % C-subther from 47% to 30%. Simulations using a 5 mg/kg starting dose revealed % C-ther after the second dose of 28.4% without and 36.8% with TDM and % C-subther of 56.9% and 29.3%, respectively. Increasing the simulated starting dose to 6 mg/kg increased % C-ther after the first dose from 27.7% to 33.5% and decreased % C-subther from 58.6% to 35.6%. TDM after a first dose of 6 mg/kg had no substantial effect on % C-ther or % C-subther after the second dose. Conclusions: Gentamicin dosing based on C-max after the first dose increased % C-ther and decreased % C-subther, but did not result in therapeutic C-max in half of the patients. When simulating a higher starting dose, % C-subther after the first dose decreased, and TDM showed no additional influence. These data suggest that a starting dose of 6 mg/kg should be considered and that repeated C-max measurements are not of added value