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.).

Keywords: Mycobacterium tuberculosis; bactericidal activity; linezolid.

Copyright © 2020 Diacon et al.

Figures

FIG 1

Participant disposition. One participant (receiving linezolid at 1,200 mg TIW) died from massive hemoptysis (not related to study treatment). Four participants (one each receiving 300 mg QD, 600 mg QD, 600 mg BD, and 1200 mg TIW) were withdrawn for elevations in liver enzymes (alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST]) that reached grade 4 in two cases and grade 3 in another two cases. Two participants withdrew consent from further study participation (1,200 mg QD and 600 mg QD) for personal reasons not related to an adverse event. LIN, linezolid; QD, once daily; BID, twice daily; TIW, three times weekly; AE, adverse event. HRZE is a fixed-dose combination of isoniazid, rifampin, pyrazinamide, and ethambutol.

FIG 2

Posterior estimates of mean log10(TTP) over 14 treatment days. Abbreviations are as described for Fig. 1.

FIG 3

Posterior estimates of mean log10(CFU) count over 14 treatment days. Abbreviations are as described for Fig. 1.