Fourteen-Day Bactericidal Activity, Safety, and Pharmacokinetics of Linezolid in Adults with Drug-Sensitive Pulmonary Tuberculosis

Abstract

Linezolid is increasingly used for the treatment of tuberculosis resistant to first-line agents, but the most effective dosing strategy is yet unknown. From November 2014 to November 2016, we randomized 114 drug-sensitive treatment-naive pulmonary tuberculosis patients from Cape Town, South Africa, to one of six 14-day treatment arms containing linezolid at 300 mg once daily (QD), 300 mg twice daily (BD), 600 mg QD, 600 mg BD, 1,200 mg QD, 1,200 mg three times per week (TIW), or a combination of isoniazid, rifampin, pyrazinamide, and ethambutol. Sixteen-hour sputum samples were collected overnight, and bactericidal activity was characterized by the daily percentage change in time to positivity (TTP) and the daily rate of change in log10(CFU). We also assessed the safety and pharmacokinetics of the study treatments. We found that bactericidal activity increased with increasing doses of linezolid. Based on the daily percentage change in TTP, activity was highest for 1,200 mg QD (4.5%; 95% Bayesian confidence interval [BCI], 3.3 to 5.6), followed by 600 mg BD (4.1%; BCI, 2.5 to 5.7), 600 mg QD (4.1%; BCI, 2.9 to 5.3), 300 mg BD (3.3%; BCI, 1.9 to 4.7), 300 mg QD (2.3%; BCI, 1.1 to 3.5), and 1,200 mg TIW (2.2%; BCI, 1.1 to 3.3). Similar results were seen with bactericidal activity characterized by the daily rate of change in CFU count. Antimycobacterial activity correlated positively with plasma drug exposure and percentage time over MIC. There were no unexpected adverse events. All linezolid doses showed bactericidal activity. For the same total daily dose, once-daily dosing proved to be at least as effective as a divided twice-daily dose. An intermittent dosing regimen, with 1,200 mg given three times weekly, showed the least activity. (This study has been registered at ClinicalTrials.gov under identifier NCT02279875.)

Pretomanid with bedaquiline and linezolid for drug-resistant TB: a comparison of prospective cohorts

“… 12 The starting LZD dose of 1200 mg may have added to the efficacy of the regimen, as the EBA-associated mycobactericidal effect of LZD was shown to be dose-dependent in drug-susceptible TB. 18 A 1200 mg daily LZD dose may be associated with better outcomes, and this dose is also likely to have the best effect in terms of preventing resistance amplification based on pharmacokinetic studies (given the higher bactericidal activity). 12 , 19 Nevertheless, drug efficacy is likely to be related to a number of factors, including population-level heterogeneity in AUC/MIC (area under the curve/minimum inhibitory concentration) targets, host-related factors (absorption, metabolism, genetics, etc.)…”

Chemical Classes Presenting Novel Antituberculosis Agents Currently in Different Phases of Drug Development: A 2010–2020 Review

“…In a study on adults with drug-sensitive pulmonary TB, LZD (300, 900, and 1200 mg) exhibited dose-dependent bactericidal activity in all dose ranges across the populations studied. The best activity was observed with the highest once-daily dose of 1200 mg with a Cmax of 20.01 µg/mL, Tmax of 2 h, AUC 0–24 of 228.4 µg·h/mL, a half-life of 5.4 h, and a MIC of 0.125–1.0 µg/mL [ 128 ].…”

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

“…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 (AUC 0 -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 AUC 0 -24 /MIC of Ͼ100 (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 AUC 0 -24 / MIC thresholds based on the "critical concentration" of linezolid (1 mg/liter) for Mycobacterium tuberculosis (4).…”