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Bedaquiline Resistance: Why a Tiered Diagnostic Strategy Is the Way Forward
Bedaquiline has revolutionized the treatment of rifampicin-resistant tuberculosis (RR-TB), becoming the backbone of modern, all-oral treatment regimens. However, the emergence of bedaquiline resistance now threatens these advances.
A recent retrospective study conducted in South Africa by Mdlenyani et al. published in The Lancet Infectious Diseases highlights the clinical impact of this growing challenge. Patients with bedaquiline-resistant tuberculosis experienced a median time to sputum culture conversion of 175 days, compared with 32 days in bedaquiline-susceptible cases. Two-thirds had unfavourable treatment outcomes, and almost one-quarter died within 18 months.
175 days vs. 32 days — the median time to sputum culture conversion in bedaquiline-resistant vs. bedaquiline-susceptible TB.
These findings underscore a critical reality: identifying bedaquiline resistance early is essential to preserving treatment effectiveness.
The Challenge
Current phenotypic drug susceptibility testing (DST) can take several months to report results. In the Lancet study, laboratory confirmation of bedaquiline resistance was delayed by a median of 4.5 months, during which patients often remained on ineffective regimens, increasing the risk of treatment failure, ongoing transmission, and accumulation of additional drug resistance.
Yet developing a rapid molecular test for bedaquiline resistance is not straightforward.
Unlike rifampicin resistance, where most mutations occur within a single genomic hotspot, bedaquiline resistance is associated with diverse mutations spread across multiple genes, including Rv0678, atpE, and pepQ. This makes it unlikely that any single molecular assay will detect every resistance-conferring mutation.
A Practical Solution
Rather than striving for a perfect molecular test, a tiered diagnostic strategy offers a more practical approach.
A rapid molecular assay can serve as the first-line screening tool, detecting the majority of clinically significant resistance mutations within hours. Samples that test negative, but where clinical suspicion remains high due to previous bedaquiline exposure, treatment failure, or persistent culture positivity, can then be referred for phenotypic DST or targeted next-generation sequencing (NGS).
This approach combines the speed of molecular diagnostics with the comprehensive coverage of phenotypic and sequencing-based methods. It enables earlier treatment decisions while ensuring that uncommon or emerging resistance mechanisms are not missed.
Looking Ahead
As treatment regimens for drug-resistant tuberculosis continue to evolve, diagnostic strategies must evolve alongside them.
The future of TB diagnostics will not be defined solely by rapid detection of Mycobacterium tuberculosis, but by the ability to provide timely, actionable resistance information that guides individualized therapy.
A tiered approach to bedaquiline resistance testing, and linezolid for that matter, represents a practical and sustainable strategy for high-burden settings, balancing speed, affordability, and diagnostic accuracy. Most importantly, it offers an opportunity to preserve the effectiveness of one of the most important drugs in modern tuberculosis treatment and strengthen the global fight against drug-resistant TB.