ena-STUDY-FZB-04-05-2020-15:09:42:989-435
GeneXpert-evading MDR M. tuberculosis outbreak clone in Eswatini has elevated bedaquiline and clofazimine resistance levels dated to the pre-treatment era
Multidrug resistant (MDR) Mycobacterium tuberculosis complex (Mtbc) strains not detected by commercial molecular drug susceptibility testing (mDST) assays due to a particular resistance mutation (RpoB I491F) are threatening the control of MDR tuberculosis (MDR TB) in Eswatini. Here, we investigate the evolution and spread of MDR-Mtbc strains in Eswatini with a focus on bedaquiline (BDQ) and clofazimine (CFZ) resistance using whole genome sequencing in two collections (1: drug resistance survey 2009-2010, 2: MDR strains 2014-2017). We found that MDR-strains in collection 1 had an extraordinarily 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 carried the RpoB I491F mutation missed by commercial mDST. In addition, 24 (60%) gCL10 isolates had mutation in the BDQ and CFZ resistance gene Rv0678 and had increased BDQ/CFZ mMinimal inhibitory concentrations (MIC) compared to wild type isolates. These strains could be detected also in the later cohort .  The high clustering rate suggests that transmission is driving the MDR-TB epidemic in Eswatini over decades. The high and further increasing prevalence of gCL10 I491F isolates threatens the use of commercial mDST assays (e.g. Xpert MTB/RIF), and of new drugs such as BDQ and CFZ. Measures containing the spread of these outbreak isolates need to be urgently implemented.
Multidrug resistant (MDR) Mycobacterium tuberculosis complex (Mtbc) strains not detected by commercial molecular drug susceptibility testing (mDST) assays due to a particular resistance mutation (RpoB I491F) are threatening the control of MDR tuberculosis (MDR TB) in Eswatini. Here, we investigate the evolution and spread of MDR-Mtbc strains in Eswatini with a focus on bedaquiline (BDQ) and clofazimine (CFZ) resistance using whole genome sequencing in two collections (1: drug resistance survey 2009-2010, 2: MDR strains 2014-2017). We found that MDR-strains in collection 1 had an extraordinarily 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 carried the RpoB I491F mutation missed by commercial mDST. In addition, 24 (60%) gCL10 isolates had mutation in the BDQ and CFZ resistance gene Rv0678 and had increased BDQ/CFZ mMinimal inhibitory concentrations (MIC) compared to wild type isolates. These strains could be detected also in the later cohort .  The high clustering rate suggests that transmission is driving the MDR-TB epidemic in Eswatini over decades. The high and further increasing prevalence of gCL10 I491F isolates threatens the use of commercial mDST assays (e.g. Xpert MTB/RIF), and of new drugs such as BDQ and CFZ. Measures containing the spread of these outbreak isolates need to be urgently implemented.