Empirical linezolid target attainment in critically ill patients: integrating local susceptibility data and dosing strategies

Linezolid is important for treating infections caused by Gram-positive bacteria resistant to first-line agents. Severe infections often require empirical therapy before pathogen identification and susceptibility testing. This evaluation aims to compare different empirical linezolid dosing strategies in intensive care unit (ICU) patients to improve pharmacokinetic/pharmacodynamic target attainment while minimising toxicities. Three dosing strategies were compared: (i) standard dosing, (ii) therapeutic drug monitoring (TDM)-guided dosing, and (iii) a theoretical model-informed precision dosing (MIPD) strategy based on Bayesian forecasting with a population pharmacokinetic model. Each scenario was combined with an ICU-specific minimal inhibitory concentration (MIC) distribution comprising more than 19,000 isolates collected over 10 years. Data from 117 critically ill patients with 2184 TDM samples were available. Linezolid resistance was highest in ICU isolates (9.6%) compared with isolates from the intermediate care unit (4.3%), general wards (3.6%), and emergency room (1.6%). Among ICU isolates, resistance increased significantly over the 10-year study period, from 6.3% in 2015 to 11.4% in 2024. Empirical target attainment was 36.6% with standard dosing and 48.5% with TDM-guided dose adaptation, in two different ICU cohorts that showed 35.9% and 59.4% baseline target attainment, respectively. Theoretical MIPD projected target attainment in 71.4-81.6% of patients. After excluding resistant isolates, the corresponding values were 40.5%, 53.7%, and 79.0-90.3%, respectively. Integrating a large contemporary ICU-specific MIC distribution with patient-level pharmacokinetic data, our results suggest MIPD may represent a promising strategy improving target attainment, in contrast to standard regimens and TDM-guided dosing which failed to achieve adequate target exposure in ICU patients.