Rising resistance to linezolid among critically ill patients calls for model-informed precision dosing in empirical setting

ObjectivesLinezolid is highly valuable for treating infections caused by Gram-positive bacteria that are resistant to first-line agents. Severe infections require empirical therapy, where treatment is initiated before the pathogen and its susceptibility are identified. This evaluation aims to compare different dosing strategies for empirical dosing of linezolid in an intensive care unit (ICU) setting, with the goal of optimising pathogen eradication while minimising toxicities. MethodsThree dosing strategies were compared, all based on two previously published datasets of prospective clinical studies: (i) standard dosing, (ii) therapeutic drug monitoring (TDM) guided dosing, and (iii) a theoretical model-informed precision dosing (MIPD) guided by a population pharmacokinetic model using a Bayesian approach. Each scenario was combined with an ICU-specific minimal inhibitory concentration (MIC) distribution sampled over ten years and containing over 19,000 pathogens. The pharmacokinetic-pharmacodynamic target for pathogen eradication was defined as the minimum concentration above the MIC, and the toxicity limit was set at minimum concentrations exceeding 8 mg/L. ResultsData from 117 critically ill patients with 2184 TDM samples were available. Within the past 10 years, the rate of resistance to linezolid has increased significantly among intensive care patients, rising from 6.3% in 2015 to 11.4-15% between 2021 and 2024. Using standard dosing, only 35.7% of patients were within the target range. This number increased slightly to 46.3% when dose adaptations with TDM were possible. In contrast, MIPD projected target attainment in 70.9-81.3% of patients. ConclusionsIn the era of increasing antimicrobial resistance, particularly against linezolid, novel dosing strategies such as MIPD become urgently necessary. Our results suggest that empirical linezolid dosing based on standard regimens as well as dose adaptation based on TDM failed to achieve sufficient target concentrations in ICU patients. Dosing guided by MIPD should therefore be further explored and implemented in future clinical practice.