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

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 ev...

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Vydáno v:Genome medicine Ročník 12; číslo 1; s. 104
Hlavní autoři: Beckert, Patrick, Sanchez-Padilla, Elisabeth, Merker, Matthias, Dreyer, Viola, Kohl, Thomas A., Utpatel, Christian, Köser, Claudio U., Barilar, Ivan, Ismail, Nazir, Omar, Shaheed Vally, Klopper, Marisa, Warren, Robin M., Hoffmann, Harald, Maphalala, Gugu, Ardizzoni, Elisa, de Jong, Bouke C., Kerschberger, Bernhard, Schramm, Birgit, Andres, Sönke, Kranzer, Katharina, Maurer, Florian P., Bonnet, Maryline, Niemann, Stefan
Médium: Journal Article
Jazyk:angličtina
Vydáno: London BioMed Central 25.11.2020
BioMed Central Ltd
Springer Nature B.V
Témata:
Antitubercular Agents
Archives & records
Bacterial Proteins
Bioinformatics
Biomedical and Life Sciences
Biomedicine
Cancer Research
Clofazimine
Clone Cells
Diarylquinolines
Disease Outbreaks
DNA sequencing
Drug resistance
Drug resistance in microorganisms
Eswatini
Ethics
Genetics
Genomes
Genomics
Human Genetics
Humans
Laboratories
Life Sciences
Medicine/Public Health
Metabolomics
Microbial Sensitivity Tests
Multidrug resistance
Multidrug resistant organisms
Mutation
Mycobacterium tuberculosis
Nucleotide sequencing
Outbreaks
Phylogenetics
RpoB protein
Statistical analysis
Surveys
Systems Biology
The impact of genomics on precision public health
Tuberculosis
Tuberculosis, Multidrug-Resistant
Whole genome sequencing
Belgium
South Africa
Eswatini
Tuberculosis
MDR outbreak strains
Multidrug resistance
Diagnostice escape
Treatment failure
Resistance evolution
Treatment escape
ISSN:1756-994X, 1756-994X
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Shrnutí: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.
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PMCID: PMC7687760
ISSN:1756-994X
1756-994X
DOI:10.1186/s13073-020-00793-8