Abstract
BackgroundMultidrug-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.MethodsWe 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).ResultsMDR 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.ConclusionThe 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.
Highlights
Multidrug-resistant (MDR) Mycobacterium tuberculosis complex strains not detected by commercial molecular drug susceptibility testing assays due to the RpoB I491F resistance mutation are threatening the control of MDR tuberculosis (MDR-TB) in Eswatini
Population structure, clustering rates, and evolution of Mycobacterium tuberculosis complex strains from national drug resistance survey from 2009 to 2010 Based on classical genotyping, the 412 Mtbc strains investigated were classified into nine previously defined phylogenetic lineages and sublineages, which showed no difference in distribution across the four study regions of HhoHho, Lubombo, Manzini, and Shiselweni (Table 1, Additional file 3: Fig. S1 and S2)
All World Health Organization (WHO)-endorsed molecular drug susceptibility testing (mDST) assays do not interrogate the RpoB I491F that is common to all gCL10 strains, we found that these strains all shared the KatG S315T mutation that is covered by all WHO-endorsed line probe assays for first-line drugs
Summary
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. Delayed diagnosis and inappropriate treatment of DR-TB, together with suboptimal implementation of infection control measures, contribute to the emergence and transmission of multidrug-resistant and extensively drug-resistant (MDR, resistant to isoniazid [INH] and rifampicin [RMP]; XDR, MDR strains with additional resistance to a fluoroquinolone [FQ] and one second-line injectable drug [SLID]) Mycobacterium tuberculosis complex (Mtbc) strains [2, 3]. To address the expanding MDR-TB epidemic, Eswatini has rolled-out the Xpert MTB/RIF, a rapid molecular TB diagnostic with the additional benefit of diagnosing RMP resistance; has expanded access to universal first- and second-line drug susceptibility testing (DST); and has decentralized DR-TB care [6]
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call