Treatment of Highly Drug-Resistant Pulmonary Tuberculosis.

Abstract

BACKGROUND:

Patients with highly drug-resistant forms of tuberculosis have limited treatment options and historically have had poor outcomes.

METHODS:

In an open-label, single-group study in which follow-up is ongoing at three South African sites, we investigated treatment with three oral drugs - bedaquiline, pretomanid, and linezolid - that have bactericidal activity against tuberculosis and to which there is little preexisting resistance. We evaluated the safety and efficacy of the drug combination for 26 weeks in patients with extensively drug-resistant tuberculosis and patients with multidrug-resistant tuberculosis that was not responsive to treatment or for which a second-line regimen had been discontinued because of side effects. The primary end point was the incidence of an unfavorable outcome, defined as treatment failure (bacteriologic or clinical) or relapse during follow-up, which continued until 6 months after the end of treatment. Patients were classified as having a favorable outcome at 6 months if they had resolution of clinical disease, a negative culture status, and had not already been classified as having had an unfavorable outcome. Other efficacy end points and safety were also evaluated.

RESULTS:

A total of 109 patients were enrolled in the study and were included in the evaluation of efficacy and safety end points. At 6 months after the end of treatment in the intention-to-treat analysis, 11 patients (10%) had an unfavorable outcome and 98 patients (90%; 95% confidence interval, 83 to 95) had a favorable outcome. The 11 unfavorable outcomes were 7 deaths (6 during treatment and 1 from an unknown cause during follow-up), 1 withdrawal of consent during treatment, 2 relapses during follow-up, and 1 loss to follow-up. The expected linezolid toxic effects of peripheral neuropathy (occurring in 81% of patients) and myelosuppression (48%), although common, were manageable, often leading to dose reductions or interruptions in treatment with linezolid.

CONCLUSIONS:

The combination of bedaquiline, pretomanid, and linezolid led to a favorable outcome at 6 months after the end of therapy in a high percentage of patients with highly drug-resistant forms of tuberculosis; some associated toxic effects were observed. (Funded by the TB Alliance and others; ClinicalTrials.gov number, NCT02333799.).

• Authors: Francesca Conradie, Andreas H Diacon, Nosipho Ngubane, Pauline Howell, Daniel Everitt, Angela M Crook, Carl M Mendel, Erica Egizi, Joanna Moreira, Juliano Timm, Timothy D McHugh, Genevieve H Wills, Anna Bateson, Robert Hunt, Christo Van Niekerk, Mengchun Li, Morounfolu Olugbosi, Melvin Spigelman, Nix-TB Trial Team
• Journal: The New England journal of medicine (N Engl J Med) Vol. 382 Issue 10 Pg. 893-902 (03 05 2020) ISSN: 1533-4406 [Electronic] United States
• PMID: 32130813 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Massachusetts Medical Society.

Chemical References

• Antitubercular Agents
• Diarylquinolines
• Nitroimidazoles
• pretomanid
• bedaquiline
• Linezolid

Topics

• Administration, Oral
• Adolescent
• Adult
• Antitubercular Agents (administration & dosage, adverse effects)
• Bacterial Load
• Diarylquinolines (administration & dosage, adverse effects)
• Drug Therapy, Combination
• Extensively Drug-Resistant Tuberculosis (drug therapy, mortality)
• Female
• Humans
• Intention to Treat Analysis
• Linezolid (administration & dosage, adverse effects)
• Male
• Middle Aged
• Mycobacterium tuberculosis (isolation & purification)
• Nitroimidazoles (administration & dosage, adverse effects)
• Treatment Outcome
• Tuberculosis, Multidrug-Resistant (drug therapy)
• Tuberculosis, Pulmonary (drug therapy)
• Young Adult