ArticleFrontiers in pharmacology2026
Optimization of linezolid infusion duration in critically ill patients: a population pharmacokinetic analysis of the trade-off between efficacy and toxicity.
Article in Frontiers in pharmacology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Background: Linezolid is a cornerstone therapy for multidrug-resistant Gram-positive infections. While prolonged intermittent infusion (PII) or continuous infusion (CI) can optimize the efficacy of time-dependent antibiotics, their application to linezolid remains controversial. Specifically, it is debated whether the theoretical efficacy gains of CI are negated by the elimination of the concentration nadir, which may trigger accumulation-related toxicity. Quantitative evidence dissecting this delicate trade-off is currently absent. Objectives: This study aimed to quantify the interplay between infusion duration, efficacy, and toxicity. By developing a population pharmacokinetic (PopPK) model and employing a "composite efficacy-safety target", we sought to identify precision dosing strategies for critically ill patients. Methods: Plasma concentration-time data obtained from 20 critically ill patients were used to develop a PopPK model using nonlinear mixed-effects modeling (NONMEM v7.5). Based on final model parameters, Monte Carlo simulations were performed for 1,000 virtual patients. A composite target was established comprising a pharmacodynamic efficacy threshold (AUC Results: The pharmacokinetics were best described by a one-compartment model, with body weight (WT) and creatinine clearance (CLcr) identified as critical determinants of distribution volume (V) and clearance (CL), respectively. Simulations revealed a non-linear relationship between infusion duration and composite PTA. While prolonged intermittent infusion enhanced efficacy by improving % T > MIC, indiscriminate extension to CI, particularly at moderate-to-high doses, resulted in a systematic breach of the safety threshold (C Conclusion: In critically ill patients, the optimal infusion duration for linezolid exhibits a non-linear dependency on dose and MIC. For high-MIC pathogens requiring intensified dosing (e.g., 900 mg q12 h), a prolonged infusion of 2-5 h optimizes the therapeutic index, synergizing maximal efficacy with a necessary elimination phase to mitigate toxicity.
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