Optimal Dose or Optimal Exposure? Consideration for Linezolid in Tuberculosis Treatment

Abstract

Exploring different ways of minimizing linezolid toxicity without compromising efficacy is a major quest in the treatment of drug-resistant tuberculosis (TB). The recently published study by Diacon et al. (1) indicates superior early bactericidal activity (EBA) from an intensive linezolid regimen (1,200 mg daily); however, this dosage has been associated with significant toxicity (2). Given the importance of optimal dose titration, the EBA of linezolid remains to be better characterized in relation to the area under the concentration-time curve (AUC0–24)/MIC ratio, which is the optimal pharmacokinetic/pharmacodynamic (PK/PD) marker of efficacy from hollow fiber system model (2, 3). The authors’ current analysis of EBA refers only to dose category, which is a crude measure of drug exposure. Clinical validation of the current efficacy and resistance suppression target of an AUC0–24/MIC of >100 (2, 3) is also needed from studies like that by Diacon et al. (1). Since in clinical practice, the MIC data are often unavailable during the early phase of the treatment, dose selection could be guided by AUC0–24/MIC thresholds based on the “critical concentration” of linezolid (1 mg/liter) for Mycobacterium tuberculosis (4).