MDR M. tuberculosis outbreak clone in Eswatini missed by Xpert has elevated bedaquiline resistance dated to the pre-trea
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RESEARCH
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MDR M. tuberculosis outbreak clone in Eswatini missed by Xpert has elevated bedaquiline resistance dated to the pre-treatment era Patrick Beckert1,2†, Elisabeth Sanchez-Padilla3†, Matthias Merker1†, Viola Dreyer1, Thomas A. Kohl1, Christian Utpatel1, Claudio U. Köser4, Ivan Barilar1, Nazir Ismail5,6,7, Shaheed Vally Omar5, Marisa Klopper8,9, Robin M. Warren8,9, Harald Hoffmann10, Gugu Maphalala11, Elisa Ardizzoni12, Bouke C. de Jong12, Bernhard Kerschberger13, Birgit Schramm3, Sönke Andres14, Katharina Kranzer14,15, Florian P. Maurer14,16, Maryline Bonnet3,17 and Stefan Niemann1,2,14,18*
Abstract Background: Multidrug-resistant (MDR) Mycobacterium tuberculosis complex strains not detected by commercial molecular drug susceptibility testing (mDST) assays due to the RpoB I491F resistance mutation are threatening the control of MDR tuberculosis (MDR-TB) in Eswatini. Methods: We investigate the evolution and spread of MDR strains in Eswatini with a focus on bedaquiline (BDQ) and clofazimine (CFZ) resistance using whole-genome sequencing in two collections ((1) national drug resistance survey, 2009–2010; (2) MDR strains from the Nhlangano region, 2014–2017). Results: MDR strains in collection 1 had a high cluster rate (95%, 117/123 MDR strains) with 55% grouped into the two largest clusters (gCL3, n = 28; gCL10, n = 40). All gCL10 isolates, which likely emerged around 1993 (95% highest posterior density 1987–1998), carried the mutation RpoB I491F that is missed by commercial mDST assays. In addition, 21 (53%) gCL10 isolates shared a Rv0678 M146T mutation that correlated with elevated minimum inhibitory concentrations (MICs) to BDQ and CFZ compared to wild type isolates. gCL10 isolates with the Rv0678 M146T mutation were also detected in collection 2. Conclusion: The high clustering rate suggests that transmission has been driving the MDR-TB epidemic in Eswatini for three decades. The presence of MDR strains in Eswatini that are not detected by commercial mDST assays and have elevated MICs to BDQ and CFZ potentially jeopardizes the successful implementation of new MDR-TB treatment guidelines. Measures to limit the spread of these outbreak isolates need to be implemented urgently. Keywords: Tuberculosis, Multidrug resistance, Resistance evolution, MDR outbreak strains, Diagnostice escape, Treatment escape, Treatment failure
* Correspondence: [email protected] † Patrick Beckert, Elisabeth Sanchez-Padilla and Matthias Merker contributed equally to this work. 1 Molecular and Experimental Mycobacteriology, Research Center Borstel, Parkallee 1, 23845 Borstel, Germany 2 German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Borstel, Germany Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to
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