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

TL;DR

In South Africa, about 10% of people with drug-resistant tuberculosis had resistance to bedaquiline, with half of these cases likely due to transmission rather than treatment, while linezolid resistance was rare.

Contribution

This study provides insights into the prevalence and transmission dynamics of bedaquiline resistance in rifampicin-resistant tuberculosis patients in South Africa.

Findings

12% of rifampicin-resistant TB patients were fluoroquinolone-resistant, and 12% were bedaquiline-resistant.

Half of the bedaquiline-resistant cases were in first isolates, suggesting transmission rather than treatment-induced resistance.

Linezolid resistance was rare (<1%) and no cases developed resistance during treatment.

Abstract

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.

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.

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.

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.

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