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.
