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Drug resistance patterns in pulmonary tuberculosis patients in Namibia based on targeted Next Generation Sequencing

L Mhuulu(1) O Shavuka(1) H Ekandjo(1) A Diergaardt(1) V Dreyer(2) C Ipinge(3) L de Araujo(2) T Niemann(1,2) N Ruswa(4) G Günther(1,5) M Claassens(1) S Niemann(1,2) E Nepolo(1)

1:Department of Human, Biological & Translational Sciences, School of Medicine, University of Namibia, Namibia; 2:Research Center Borstel - Leibniz Lung Center, Germany; 3:Namibia Institute of Pathology, Namibia; 4:National Tuberculosis and Leprosy Program, Ministry of Health and Social Services, Namibia; 5:Department of Pulmonology and Allergology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

Drug-resistance tuberculosis (TB) is a major global health problem, and an early detection is important for preventing spread and further resistance acquisition. This study aimed to identify mycobacterial genetic patterns causing resistance against both first- and second-line anti-TB drugs, in Namibia, a high TB burden country. A total of 185 clinical M. tuberculosis strains with rifampicin resistance (RR) detected by the Xpert® MTB/RIF were analysed. Targeted Next-Generation Sequencing (tNGS) was performed locally using the Deeplex® Myc-TB kit on an Illumina iSeq100 platform. Data were analysed on the Deeplex Myc-TB web application. Overall, 69% of the RR isolates were further classified as multi-drug resistant (MDR) TB, (3.8%) as extensively drug resistant (XDR) TB and (1.6%) as pre-XDR-TB as per WHO 2021 definitions. Different rates of resistance were observed to isoniazid (83%), pyrazinamide (46%), ethambutol (49%), streptomycin (29%), fluoroquinolone (5%), bedaquiline (3%) and clofazimine (3%). The most prominent mutations conferring resistance to rifampicin were detected in rpoB gene, which are S450L (48%), L430P (11%) and L430P|H445Q (9%). For isoniazid resistance, the mutations katG S315T (64%) and inhA C-15T (31%) predominated. The most frequent resistance mutations to pyrazinamide, ethambutol and streptomycin observed were pncA L35P (17%), embB M306I (27%) and M306V (12%) and rpsL K43R (28%), respectively. This study confirms that most rifampicin resistant strains are also isoniazid resistant. Resistance to fluoroquinolone and emerging resistance to bedaquiline are a major concern with implications for patient outcomes and warranting investment in surveillance for bedaquiline in all RR-TB patients.

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