Bedaquiline and linezolid resistance in people with rifampicin-resistant tuberculosis in the Western Cape Province of South Africa

Introduction: South Africa was an early implementer of bedaquiline and linezolid for drug-resistant tuberculosis (TB), however, programmatic capacity for drug susceptibility testing (DST) was not initially available. Methods : We analysed people with rifampicin-resistant (RR)-TB (n=3138) programmatically tested with Xpert MTB/XDR and bedaquiline and linezolid phenotypic (p)DST in the same episode for diagnosis or treatment monitoring. Data from respiratory specimens collected 01/01/2023-31/12/2024 across six districts in Western Cape, South Africa, were included. Findings: 89% (2799/3138) of people were successfully tested with Xpert MTB/XDR, with 12% (332/2799) fluoroquinolone-resistant. 77% (2423/3138) successfully underwent bedaquiline pDST, with 12% (278/2423) resistant. 84% (232/278) of bedaquiline resistance was in the diagnostic (first) isolate. Of these, 51% (118/232) had no prior DR-TB (45 prior drug-susceptible TB, 73 no prior TB). We did not identify associations with bedaquiline-resistance, other than residence in Cape Town (OR 1.61, 1.19–2.20) and resistance to other drugs (fluoroquinolone resistance the strongest; OR 4.38, 3.20–5.96). In people initially bedaquiline-susceptible with a later isolate tested, 22% (45/201) gained resistance. Bedaquiline-resistance was most frequent in the Overberg region [14% (8, 23) of RR/MDR-TB]. 86% (2411/2799) of people had a successful linezolid pDST, with <1% (2/2411) resistant. All 128 people with repeat linezolid pDST remained susceptible. Conclusion: About one in ten people with RR/MDR-TB had bedaquiline-resistance, with half due to primary transmission. One in five people with RR/MDR-TB did not have bedaquiline DST done, highlighting care cascade gaps. Despite long treatment and sustained culture positivity, minimal linezolid resistance occurred.