Development of a Model-Informed Dosing Tool to Optimise Initial Antibiotic Dosing - A Translational Example for Intensive Care Units

Abstract

The prevalence and mortality rates of severe infections are high in intensive care units (ICUs). At the same time, the high pharmacokinetic variability observed in ICU patients increases the risk of inadequate antibiotic drug exposure. Therefore, dosing tailored to specific patient characteristics has a high potential to improve outcomes in this vulnerable patient population. This study aimed to develop a tabular dosing decision tool for initial therapy of meropenem integrating hospital-specific, thus far unexploited pathogen susceptibility information. An appropriate meropenem pharmacokinetic model was selected from the literature and evaluated using clinical data. Probability of target attainment (PTA) analysis was conducted for clinically interesting dosing regimens. To inform dosing prior to pathogen identification, the local pathogen-independent mean fraction of response (LPIFR) was calculated based on the observed minimum inhibitory concentrations distribution in the hospital. A simple, tabular, model-informed dosing decision tool was developed for initial meropenem therapy. Dosing recommendations achieving PTA > 90% or LPIFR > 90% for patients with different creatinine clearances were integrated. Based on the experiences during the development process, a generalised workflow for the development of tabular dosing decision tools was derived. The proposed workflow can support the development of model-informed dosing tools for initial therapy of various drugs and hospital-specific conditions.