Bedaquiline, Delamanid, Linezolid and Clofazimine for Treatment of Pre-extensively Drug-Resistant Tuberculosis

Abstract

Background: Treatment success rates for multidrug-resistant tuberculosis (MDR-TB) remain low globally. Availability of newer drugs has given scope to develop regimens that can be patient-friendly, less toxic, with improved outcomes. We proposed to determine the effectiveness of an entirely oral, short-course regimen with Bedaquiline and Delamanid in treating MDR-TB with additional resistance to fluoroquinolones (MDR-TBFQ+) or second-line injectable (MDR-TBSLI+).

Methods: We prospectively determined the effectiveness and safety of combining two new drugs with two repurposed drugs - Bedaquiline, Delamanid, Linezolid, and Clofazimine for 24-36 weeks in adults with pulmonary MDR-TBFQ+ or/and MDR-TBSLI+. The primary outcome was a favorable response at end of treatment, defined as two consecutive negative cultures taken four weeks apart. The unfavorable outcomes included bacteriologic or clinical failure during treatment period.

Results: Of the 165 participants enrolled, 158 had MDR-TBFQ+. At the end of treatment, after excluding 12 patients due to baseline drug susceptibility and culture negatives, 139 of 153 patients (91%) had a favorable outcome. Fourteen patients (9%) had unfavorable outcomes: four deaths, seven treatment changes, two bacteriological failures, and one withdrawal. During treatment, 85 patients (52%) developed myelosuppression, 69 (42%) reported peripheral neuropathy, and none had QTc(F) prolongation >500msec. At 48 weeks of follow-up, 131 patients showed sustained treatment success with the resolution of adverse events in the majority.

Conclusion: After 24-36 weeks of treatment, this regimen resulted in a satisfactory favorable outcome in pulmonary MDR-TB patients with additional drug resistance. Cardiotoxicity was minimal, and myelosuppression, while common, was detected early and treated successfully.

Keywords: Delamanid; Drug-resistant Tuberculosis; Effectiveness; Linezolid; Short-course.

Figure 1.

CONSORT checklist of participants in BEAT-India study. Abbreviations: CONSORT, Consolidated Standards of Reporting Trials; DST, drug susceptibility test; MGIT, mycobacterial growth indicator tube.

Figure 2.

Kaplan-Meier plot showing the time to sputum culture conversion among the participants on the study regimen. Abbreviation: MGIT, mycobacterial growth indicator tube.

Figure 3.

A, Median QTc(f) on ECG among BEAT-India study participants during the treatment phase. B, Median QTc(f) on ECG in BEAT-India study participants during the post-treatment follow-up period. Abbreviation: ECG, electrocardiography.