Fourteen-Day Bactericidal Activity, Safety, and Pharmacokinetics of Linezolid in Adults with Drug-Sensitive Pulmonary Tuberculosis
Date
2020-01
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
Background: Linezolid is increasingly used for the treatment of tuberculosis resistant to first-line agents, but the most effective dosing strategy is yet unknown. Methods: Between November 2014 and November 2016, we randomised 114 drug-sensitive treatment-naïve pulmonary tuberculosis patients from Cape Town, South Africa, to one of six 14-day treatment arms containing linezolid 300 mg once daily (qd), 300 mg twice daily (bd), 600 mg qd, 600 mg bd, 1200 mg qd, 1200 mg three times per week (tiw) or a combination of isoniazid, rifampicin, pyrazinamide and ethambutol. Sixteen-hour sputum samples were collected overnight, and bactericidal activity characterized by the daily percentage change in time to positivity (TTP) and colony forming units (CFU). We also assessed the safety and pharmacokinetics of the study treatments. Results: Bactericidal activity increased with increasing doses of linezolid. Based on the daily percentage change in TTP, activity was highest for 1200 mg qd (4.5; 95% Bayesian confidence interval [BCI]: 3.3-5.6), followed by 600 mg bd (4.1; BCI: 2.5-5.7), 600 mg qd (4.1; BCI: 2.9-5.3), 300 mg bd (3.3; BCI: 1.9-4.7), 300 mg qd (2.3; BCI: 1.1-3.5) and 1200 mg tiw (2.2; BCI: 1.1-3.3). 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 minimum inhibitory concentration. There were no unexpected adverse events. Conclusion: 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 1200 mg given three times weekly, showed the least activity.
Description
CITATION: Diacon AH, De Jager VR, Dawson R,
Narunsky K, Vanker N, Burger DA, Everitt D,
Pappas F, Nedelman J, Mendel CM. 2020.
Fourteen-day bactericidal activity, safety, and
pharmacokinetics of linezolid in adults with
drug-sensitive pulmonary tuberculosis.
Antimicrob Agents Chemother 64:e02012-19.
https://doi.org/10.1128/AAC.02012-19.
Keywords
Bactericidal Activity, Safety, Pharmacokinetics, Pulmonary Tuberculosis
Citation
doi.org/10.1128/AAC.02012-19.