New Advances for Drug-Resistant TB
29 August 2025
There are approximately 500 000 new cases of rifampicin-resistant or multidrug-resistant (RR/MDR) tuberculosis every year. In 2022, WHO recommended the all-oral bedaquiline, pretomanid, linezolid (BPaL), and moxifloxacin (BPaLM) regimen for 6 months in patients with RR/MDR tuberculosis aged 14 years or older without previous exposure to BPaL. Then, in 2024, WHO recommended four more oral short-course regimens, which all contain bedaquiline, for the treatment of RR/MDR tuberculosis. Access issues, emerging bedaquiline resistance, and linezolid toxicity are hampering the use of these regimens. In clinical trials, 20% of individuals receiving the standard dose of linezolid (an oxalidizinone) had a grade 3 or higher adverse event. Despite this concerning safety profile, linezolid is a backbone drug in the majority of WHO-recommended, oral short-course regimens. New evidence for urgently required safer alternatives for linezolid and personalised treatment has revitalised drug-resistant tuberculosis efforts.
Two phase 2b trials recently published in this journal, PanACEA-SUDOCU-01 and PanACEA-DECODE-01, have identified sutezolid and delpazolid, respectively, as alternative oxazolidinones with strong antimicrobial activity that could be candidates to potentially replace linezolid in BPaL regimens. Maximum efficacy of delpazolid was associated with a 1200-mg dose, whereas no maximum active dose was established for sutezolid. In these trials, the investigational drugs were not tested as monotherapy and instead they were administered as part of a background combination regimen, allowing treatment exposure to be studied for a longer time (12 weeks vs 14 days in monotherapy trials) and informing the design of future dose-finding trials for new tuberculosis drugs. For both sutezolid and depazolid, fully optimised phase 3 trials with larger sample sizes, more generalisable populations, and longer exposure to study drugs are required next.
There has been considerable interest in the use of personalised medicine treatment approaches based on bacillary burden, resistant patterns, and/or lung damage for the management of drug-resistant tuberculosis. The end-TB Q trial, recently published in The Lancet Respiratory Medicine, has provided evidence of the feasibility of a personalised treatment approach in pre-extensively drug-resistant tuberculosis. endTB-Q, which assessed the efficacy and safety of the bedaquiline, delaminid, linezolid, and clofazimine (BDLC) regimen against the WHO-recommended 18-month regimen for extensively drug-resistant tuberculosis, applied treatment stratification according to disease extent. A favourable outcome was reached by 141 (87%) of 163 participants in the experimental BDLC group, although the non-inferiority margin for the primary efficacy endpoint was not met. The proportion of favourable outcomes was higher in participants in the BDLC group with limited disease than in those with extensive disease (risk difference 5·6% vs –7·5%). The findings of endTB-Q highlight that shorter oral regimens are not a one-size-fits-all solution and that individualised and rapid resistance testing by targeted next-generation sequencing can be used, along with sputum testing and imaging, to establish whether shorter-course oral regimens are suitable for patients with more severe drug-resistant tuberculosis.
Despite these advances, the threat of bedaquiline resistance represents a growing concern. A recent matched cohort study published in this journal, and conducted in South Africa, showed that 54 (67%) of 81 participants with bedaquiline-resistant tuberculosis had unsuccessful end-of-treatment outcomes. At 18 months, 23% of the participants with bedaquiline-resistant tuberculosis had died. Drug susceptibility testing (DST) results for bedaquiline were obtained a median of 4·5 months (IQR 3·4–6·7) after sputum collection. This study highlights the urgent need for rapid DST for bedaquiline to initiate timely treatment and disrupt community transmission of bedaquiline resistance, and that clinical outcomes in case of bedaquiline resistance are poor.
To better control drug-resistant tuberculosis, future efforts should focus on improving current regimens, identifying drug alternatives with lower toxicity, personalising treatment, providing comprehensive tuberculosis care services, and ensuring accessible rapid DST. These goals will only be achieved if there is solidarity in the global tuberculosis community. Non-governmental organisations and large multidisciplinary consortia will need to continue to play a key role in conducting trials for drug-resistant tuberculosis, especially given the reduced and uncertain funding for tuberculosis.
Source: The Lancet Infectious Diseases, Editorial
