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Emergence of bedaquiline resistance in drug-resistant tuberculosis samples from Mozambique

T Fernando(1) C Utpatel(2,3) I Barilar(2,3) C Abujate(1) C Madeira(1) T Niemann(2,3) S Chumane(1) A Manhique(1) I Gundane(1) B José(4) C Mutaquiha(4) N Ismael(1) L D Araujo(2) S Viegas(1) S Niemann(2,3)

1:National Institute of Health (INS) Mozambique; 2:Molecular and Experimental Mycobacteriology, Research Center Borstel, Borstel, 27246, Germany; 3:German Center for Infection Research, Partner Site Hamburg-Lübeck-Borstel-Riems, Borstel, 27246, Germany.; 4:National Tuberculosis Control Program, Directorate of Public Health, Ministry of Health, Maputo City, 1102, Mozambique.; 5:National Reference Center for Mycobacteria, Research Center Borstel, Borstel, 27246, Germany.

Bedaquiline (BDQ) is a key component of the World Health Organization endorsed 6-month BPaLM regimen (BDQ, pretomanid, linezolid and moxifloxacin) for treatment of patients with rifampicin resistant (RR) or multi-drug-resistant (MDR, isoniazid and rifampicin resistance [INHr, RR]) tuberculosis (TB). Recent data from Mozambique indicated an increase of BDQ resistance (BDQr) from 3% to 14% from 2016-2021, suggesting that current RR/MDR-TB treatment regimens are not able to prevent BDQr development at population level. To study current resistance levels, we performed targeted Next-Generation-Sequencing using Deeplex®-Myc-TB from GenoLyse® DNAs extracted from 164 INHr and/or RR (classified by Bruker-Hain GenoTypeMTBDRplus) clinical and cultured samples submitted to the National Tuberculosis Reference Laboratory in Maputo between January/2021 and April/2024. A total of 148 samples were classified RR, 124 at least MDR/RR, 27 fluoroquinolone resistant (16%, FQr), 12 pre-XDR (7%, MDR+FQr), and 10 XDR, (6%, MDR+FQr+BDQr). 33 were BDQr (20%): two INHr+BDQr, two INHr+FQr+BDQr, two RR+FQr+BDQr, 17MDR+BDQr, and 10 XDR. Seven samples had the rpoB I491F mutation as sole RR marker (four MDR+BDQ, two XDR). Alarmingly, these samples were classified rifampicin susceptible by GenoTypeMTBDRplus. Increasing BDQr rates found are alarming and potentially jeopardize DR-TB control in the country. BDQr is observed in a broad spectrum of resistance combinations. “Diagnostic escape” Mycobacterium tuberculosis strains with rpoB I491F RR mutation, not detected by commercial molecular drug resistance assays such as Xpert® MTB/RIF and GenoTypeMTBDRplus, cause an additional challenge for the current DR-TB test algorithms, and underline the urgent need for implementation of rapid comprehensive resistance testing in country.

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