Pharmacokinetic/pharmacodynamic evaluation of tobramycin dosing in critically ill patients: the Hartford nomogram does not fit.

Abstract

Extended-interval dosing of tobramycin is widely applied in patients with the Hartford nomogram as a representative, while this dosing approach has not been extensively evaluated in critically ill patients. The goal of this study was to characterize the pharmacokinetics of tobramycin and to evaluate the appropriateness of the Hartford nomogram in critically ill patients. A retrospective analysis was performed based on a medical critical care database. The extracted concentration data of tobramycin were used for the construction of the population pharmacokinetic model using a non-linear mixed-effects modelling approach. Real-world data-based simulations were conducted to evaluate the pharmacodynamic target attainment (Cmax/MIC ≥10) and safety (concentration <0.5 mg/L for at least 4 h) of the Hartford nomogram. A population pharmacokinetic model was built based on 307 measurements in 140 unique patients and externally validated by an independent study dataset. A two-compartment model was optimal for the structure model and creatinine clearance remained as the only covariate in the final model correlating to the clearance of tobramycin. Simulations indicated that the Hartford nomogram is effective for infections due to pathogens with an MIC of ≤1 mg/L, but not with an MIC of 2 mg/L. The percentage of patients who reached the non-toxicity target was quite low under the Hartford nomogram and a further extension of the dosing interval was necessary to minimize the toxicity. The Hartford nomogram was not suitable for critically ill patients with pathogen MICs of 2 mg/L and drug monitoring is required to manage efficacy and toxicity.