An easy-to-use predictive score for identifying patients at risk of suboptimal linezolid exposure and candidates for therapeutic drug monitoring

Abstract

Objectives: Due to the high interindividual pharmacokinetic variability, only between 34.5-57.5% patients treated with linezolid fall within its therapeutic range with standard dosing. This study aimed to develop and validate a simple-to-use predictive score to identify patients at risk of sub- or supra-therapeutic linezolid exposure who may benefit from therapeutic drug monitoring (TDM).

Methods: A retrospective observational study was conducted using data from 819 patients treated with linezolid and undergoing TDM (2011-2022). Linezolid trough concentrations were classified as sub-therapeutic, therapeutic and supra-therapeutic (< 2 mg/L, between 2 and 7 mg/L and > 7 mg/L, respectively). A multinomial logistic regression model was used to develop a predictive score, which was externally validated in a separate cohort of 73 patients. Discrimination performance was assessed using ROC curve.

Results: Only 31.5% of patients achieved therapeutic concentrations. Median linezolid trough concentrations were 3.9 mg/L (range: 0.5-63.7 mg/L). Independent predictors of sub-therapeutic concentrations were a younger age, a low linezolid dose/body weight, augmented renal clearance and intensive care unit admission. Predictors of supra-therapeutic concentrations were a higher dose/body weight, renal impairment and liver cirrhosis. The predictive model showed high accuracy for identifying patients at risk of supra-therapeutic exposure (AUC 82% derivation; 90% validation), while performance was moderate for underexposure (AUC 63% derivation; 49% validation). An online calculator was implemented to facilitate score use in clinical practice.

Conclusions: The predictive score provides clinicians with an effective tool to support individualised linezolid therapy and guide TDM implementation, reducing the risk of toxicity or treatment failure.

Keywords: Interindividual variability; Linezolid; Pharmacokinetics; Therapeutic drug monitoring.