MDR M. tuberculosis outbreak clone in Eswatini missed by Xpert has elevated bedaquiline resistance dated to the pre-treatment era

Patrick Beckert, Elisabeth Sanchez-Padilla, Matthias Merker, Viola Dreyer, Thomas A. Kohl, Christian Utpatel, Claudio U. Koeser, Ivan Barilar, Nazir Ismail, Shaheed Vally Omar, Marisa Klopper, Robin M. Warren, Harald Hoffmann, Gugu Maphalala, Elisa Ardizzoni, Bouke C. de Jong, Bernhard Kerschberger, Birgit Schramm, Soenke Andres, Katharina KranzerFlorian P. Maurer, Maryline Bonnet, Stefan Niemann

Research output: Contribution to journalA1: Web of Science-article

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.

Original languageEnglish
Article number104
JournalGenome Medicine
Volume12
Issue number1
Number of pages11
ISSN1756-994X
DOIs
Publication statusPublished - 2020

Keywords

  • Tuberculosis
  • Multidrug resistance
  • Resistance evolution
  • MDR outbreak strains
  • Diagnostice escape
  • Treatment escape
  • Treatment failure
  • HIGH PREVALENCE
  • SWAZILAND
  • SUSCEPTIBILITY
  • MTB/RIF
  • COMPLEX

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