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Outbreak of multidrug-resistant tuberculosis in South Africa undetected by WHO-endorsed commercial tests: an observational study

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Show simple item record Makhado, N. A. en_US Matabane, E. en_US Faccin, M. en_US Pincon, C. en_US Jouet, A. en_US Boutachkourt, F. en_US Goeminne, L. en_US Gaudin, C. en_US Maphalala, G. en_US Beckert, P. en_US Niemann, S. en_US Delvenne, J. C. en_US Delmee, M. en_US Razwiedani, L. en_US Nchabeleng, M. en_US Supply, P. en_US de Jong, B. C. en_US Andre, E. en_US 2019-06-04T12:21:49Z 2019-06-04T12:21:49Z 2018 en_US
dc.identifier.issn 1473-3099 en_US
dc.identifier.doi en_US
dc.identifier.other en_US
dc.identifier.other 30 en_US
dc.identifier.other ITG-B17A; DBM; U-MYCOB; JIF; DOI; PDF; PMC; Abstract; ITMPUB; DSPACE65 en_US
dc.description.abstract BACKGROUND: Global roll-out of rapid molecular assays is revolutionising the diagnosis of rifampicin resistance, predictive of multidrug-resistance, in tuberculosis. However, 30% of the multidrug-resistant (MDR) strains in an eSwatini study harboured the Ile491Phe mutation in the rpoB gene, which is associated with poor rifampicin-based treatment outcomes but is missed by commercial molecular assays or scored as susceptible by phenotypic drug-susceptibility testing deployed in South Africa. We evaluated the presence of Ile491Phe among South African tuberculosis isolates reported as isoniazid-monoresistant according to current national testing algorithms. METHODS: We screened records of 37 644 Mycobacterium tuberculosis positive cultures from four South African provinces, diagnosed at the National Health Laboratory Service-Dr George Mukhari Tertiary Laboratory, to identify isolates with rifampicin sensitivity and isoniazid resistance according to Xpert MTB/RIF, GenoType MTBDRplus, and BACTEC MGIT 960. Of 1823 isolates that met these criteria, 277 were randomly selected and screened for Ile491Phe with multiplex allele-specific PCR and Sanger sequencing of rpoB. Ile491Phe-positive strains (as well as 17 Ile491Phe-bearing isolates from the eSwatini study) were then tested by Deeplex-MycTB deep sequencing and whole-genome sequencing to evaluate their patterns of extensive resistance, transmission, and evolution. FINDINGS: Ile491Phe was identified in 37 (15%) of 249 samples with valid multiplex allele-specific PCR and sequencing results, thus reclassifying them as MDR. All 37 isolates were additionally identified as genotypically resistant to all first-line drugs by Deeplex-MycTB. Six of the South African isolates harboured four distinct mutations potentially associated with decreased bedaquiline sensitivity. Consistent with Deeplex-MycTB genotypic profiles, whole-genome sequencing revealed concurrent silent spread in South Africa of a MDR tuberculosis strain lineage extending from the eSwatini outbreak and at least another independently emerged Ile491Phe-bearing lineage. Whole-genome sequencing further suggested acquisition of mechanisms compensating for the Ile491Phe fitness cost, and of additional bedaquiline resistance following the introduction of this drug in South Africa. INTERPRETATION: A substantial number of MDR tuberculosis cases harbouring the Ile491Phe mutation in the rpoB gene in South Africa are missed by current diagnostic strategies, resulting in ineffective first-line treatment, continued amplification of drug resistance, and concurrent silent spread in the community. FUNDING: VLIR-UOS, National Research Foundation (South Africa), and INNOVIRIS. en_US
dc.language English en_US
dc.relation.uri en_US
dc.subject Tuberculosis-multidrug-resistant en_US
dc.subject Bacterial diseases en_US
dc.subject Outbreaks en_US
dc.subject Surveillance en_US
dc.subject Diagnostic tests en_US
dc.subject South Africa en_US
dc.subject Africa-Southern en_US
dc.title Outbreak of multidrug-resistant tuberculosis in South Africa undetected by WHO-endorsed commercial tests: an observational study en_US
dc.type Article en_US
dc.citation.issue 12 en_US
dc.citation.jtitle Lancet Infectious Diseases en_US
dc.citation.volume 18 en_US
dc.citation.pages 1350-1359 en_US
dc.citation.abbreviation Lancet Infect Dis en_US

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