Emergence of bedaquiline resistance in a high tuberculosis burden country.

Abstract

RATIONALE:

Bedaquiline has been classified as a group A drug for the treatment of multidrug-resistant tuberculosis (MDR-TB) by the World Health Organization; however, globally emerging resistance threatens the effectivity of novel MDR-TB treatment regimens.

OBJECTIVES:

We analysed pre-existing and emerging bedaquiline resistance in bedaquiline-based MDR-TB therapies, and risk factors associated with treatment failure and death.

METHODS:

In a cross-sectional cohort study, we employed patient data, whole-genome sequencing (WGS) and phenotyping of Mycobacterium tuberculosis complex (MTBC) isolates. We could retrieve baseline isolates from 30.5% (62 out of 203) of all MDR-TB patients who received bedaquiline between 2016 and 2018 in the Republic of Moldova. This includes 26 patients for whom we could also retrieve a follow-up isolate.

MEASUREMENTS AND MAIN RESULTS:

At baseline, all MTBC isolates were susceptible to bedaquiline. Among 26 patients with available baseline and follow-up isolates, four (15.3%) patients harboured strains which acquired bedaquiline resistance under therapy, while one (3.8%) patient was re-infected with a second bedaquiline-resistant strain. Treatment failure and death were associated with cavitary disease (p=0.011), and any additional drug prescribed in the bedaquiline-containing regimen with WGS-predicted resistance at baseline (OR 1.92 per unit increase, 95% CI 1.15-3.21; p=0.012).

CONCLUSIONS:

MDR-TB treatments based on bedaquiline require a functional background regimen to achieve high cure rates and to prevent the evolution of bedaquiline resistance. Novel MDR-TB therapies with bedaquiline require timely and comprehensive drug resistance monitoring.

• Authors: Elena Chesov, Dumitru Chesov, Florian P Maurer, Sönke Andres, Christian Utpatel, Ivan Barilar, Ana Donica, Maja Reimann, Stefan Niemann, Christoph Lange, Valeriu Crudu, Jan Heyckendorf, Matthias Merker
• Journal: The European respiratory journal (Eur Respir J) Vol. 59 Issue 3 (03 2022) ISSN: 1399-3003 [Electronic] England
• PMID: 34503982 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright ©The authors 2022.

Chemical References

• Antitubercular Agents
• Diarylquinolines
• bedaquiline

Topics

• Antitubercular Agents (therapeutic use)
• Cross-Sectional Studies
• Diarylquinolines (therapeutic use)
• Humans
• Mycobacterium tuberculosis (genetics)
• Tuberculosis (drug therapy)
• Tuberculosis, Multidrug-Resistant (drug therapy, microbiology)