TY - JOUR T1 - Emergence of bedaquiline-resistance in a high-burden country of tuberculosis JF - European Respiratory Journal JO - Eur Respir J DO - 10.1183/13993003.00621-2021 SP - 2100621 AU - Elena Chesov AU - Dumitru Chesov AU - Florian P. Maurer AU - Sönke Andres AU - Christian Utpatel AU - Ivan Barilar AU - Ana Donica AU - Maja Reimann AU - Stefan Niemann AU - Christoph Lange AU - Valeriu Crudu AU - Jan Heyckendorf AU - Matthias Merker Y1 - 2021/01/01 UR - http://erj.ersjournals.com/content/early/2021/08/19/13993003.00621-2021.abstract N2 - 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% (62/203) 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, 4/26 (15.3%) patients harbored strains which acquired bedaquiline resistance under therapy, while 1/26 (3.8%) patients 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 (p=0.012, OR 1.92 per unit increase, 95%CI 1.15–3.21).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.FootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Dr. Chesov has nothing to disclose.Conflict of interest: Dr. Chesov has nothing to disclose.Conflict of interest: Dr. Maurer has nothing to disclose.Conflict of interest: Dr. Andres has nothing to disclose.Conflict of interest: Dr. Utpatel has nothing to disclose.Conflict of interest: Dr. Barilar has nothing to disclose.Conflict of interest: Dr. Donica has nothing to disclose.Conflict of interest: Dr. Reimann has nothing to disclose.Conflict of interest: Dr. Niemann reports grants from EXC 2167 Precision Medicine in Inflammation, grants from Leibniz Science Campus Evolutionary Medicine of the LUNG , grants from German Center for Infection Research, during the conduct of the study.Conflict of interest: Dr. Lange reports personal fees from Chiesi, Gilead, Janssen, Novartis, Oxfordimmunotec and Insmed, outside the submitted work.Conflict of interest: Dr. Crudu has nothing to disclose.Conflict of interest: Dr. Heyckendorf has nothing to disclose.Conflict of interest: Dr. Merker has nothing to disclose. ER -