Alarming Findings from a Prospective Study on Bedaquiline Resistance

A groundbreaking prospective study conducted in the Western Cape province of South Africa has revealed significant levels of bedaquiline resistance among patients diagnosed with rifampicin-resistant tuberculosis (RR-TB). Published in The Lancet Microbe on February 19, 2026, the research analyzed consecutive Mycobacterium tuberculosis isolates from patients tested positive for RR-TB using the Xpert MTB/RIF Ultra diagnostic tool. Researchers found that 12% of baseline isolates (45 out of 364) and a striking 41% of longitudinal isolates (15 out of 37) exhibited bedaquiline resistance, highlighting a pressing challenge in tuberculosis (TB) treatment.

This discovery underscores the rapid evolution of drug resistance in high-burden settings like South Africa, where bedaquiline—a critical drug for drug-resistant TB (DR-TB)—has been widely deployed since 2019. The study's implications extend beyond clinical care, signaling the need for enhanced surveillance and innovative research led by South African universities.

The Burden of Rifampicin-Resistant TB in South Africa

Tuberculosis, caused by the bacterium Mycobacterium tuberculosis, remains one of South Africa's most formidable public health threats. Rifampicin-resistant TB (RR-TB) refers to strains that do not respond to rifampicin, a cornerstone first-line antibiotic, often overlapping with multidrug-resistant TB (MDR-TB), which resists both rifampicin and isoniazid. In 2024, South Africa accounted for a substantial portion of global DR-TB cases, with treatment success rates hovering around 62% for DR-TB.

The Western Cape, home to leading academic institutions, faces particularly high rates. National data indicate RR-TB comprises about 61.7% of DR-TB notifications, straining healthcare resources that allocate over 33% of TB funding to just 3% of cases. Factors like HIV co-infection, poverty, and migration exacerbate transmission, making robust research from local universities vital for tailored interventions.

What is Bedaquiline and Its Role in TB Treatment?

Bedaquiline (BDQ), branded as Sirturo, is a diarylquinoline-class drug approved by the World Health Organization (WHO) in 2012 for MDR-TB and RR-TB. It uniquely inhibits mycobacterial ATP synthase, depleting energy production in the bacteria. South Africa pioneered its programmatic use, incorporating it into shorter all-oral regimens to replace toxic injectables.

Since 2019, bedaquiline has transformed outcomes, reducing mortality by up to 55% in observational studies. The recent national rollout of the 6-month BPaL regimen—bedaquiline, pretomanid, and linezolid (BPaL), sometimes with moxifloxacin (BPaLM)—in September 2023 promises even better results, with success rates exceeding 90% in trials. However, widespread use without adequate resistance monitoring risks undermining these gains.

Methodology of the Western Cape Prospective Study

Led by researchers from Stellenbosch University (SU)'s SAMRC Centre for Tuberculosis Research and the University of Cape Town (UCT), the study prospectively collected 701 sputum sediments from March 2023 to January 2024 across 53 hospitals in the Western Cape. Samples underwent culture, phenotypic drug susceptibility testing (pDST) via MGIT960, and genotypic analysis using the innovative Deeplex Myc-TB next-generation sequencing (NGS) assay.

The Deeplex assay achieved 93% sensitivity and 99% specificity for bedaquiline resistance detection, processing results in under 5 days—far faster than traditional pDST (median 56 days). This collaboration between SU, UCT, National Health Laboratory Service (NHLS), and international partners like UCSF exemplifies higher education's pivotal role in advancing TB diagnostics.

Key Results: Prevalence and Risk Factors

Of 570 successful cultures, 19% were culture-negative, often from smear-scanty samples. Among sequenced baseline isolates, bedaquiline resistance stood at 12% (95% CI 9-16%), rising to 41% in follow-up samples from patients with recent prior treatment (median 5.4 months post-diagnosis).

• Higher prevalence in previously treated patients: 5.0% vs. 1.6% in new cases.
• Resistance profiles: 24% RR/isoniazid-susceptible (9% BDQ-resistant), 67% MDR-TB, 5% XDR-TB.
• Heteroresistance: 33% of resistant isolates showed mixed populations, higher than for other drugs (p<0.0001).

These figures surpass earlier estimates (2-10% nationally), signaling an upward trend amid scale-up.

Genetic Mechanisms Driving Bedaquiline Resistance

Resistance primarily stemmed from mutations in the mmpR5 gene (96% of cases), a transcriptional repressor of an efflux pump that expels the drug. Notably, 28% involved uncharacterized variants, yet 94% correlated with phenotypic resistance. Two isolates showed IS6110 insertions disrupting mmpR5.

Heteroresistance—low-level mixtures (<=20% resistant subpopulation)—was prevalent (33%), potentially enabling undetected transmission. Unlike atpE mutations (rare globally), mmpR5 dominates in SA, with low fitness costs allowing persistence.Read the full Lancet study.

Implications for TB Treatment Programs in South Africa

Bedaquiline resistance threatens the BPaL rollout, as no effective alternatives exist for resistant strains, leading to prolonged regimens with poor outcomes (success <50%). Experts warn of transmission risks, especially in isoniazid-susceptible RR-TB cases without prior exposure.

South Africa's National TB Recovery Plan 4.0 emphasizes surveillance, yet pDST coverage lags (<80%). Rapid tools like Deeplex, validated here, could guide individualized therapy. For higher ed, this bolsters calls for more research funding and research positions in TB genomics.

Challenges in Diagnosis and Surveillance

Culture negativity (19%) and smear-scantiness (48%) complicate detection, particularly in advanced HIV settings prevalent in SA. Traditional pDST delays (56 days) risk inappropriate treatment. The study pilots NGS integration, but scale-up requires infrastructure investment.

• Need for routine BDQ susceptibility testing in all RR-TB cases.
• Addressing heteroresistance, unmonitored by WHO breakpoints.
• Enhancing linkage to care (current 95% target unmet).

Universities like SU and UCT are at the forefront, training the next generation of researchers. Aspiring academics can explore opportunities via higher-ed-jobs.

South African Universities Leading the Fight Against TB Resistance

Stellenbosch University's DSI-NRF Centre of Excellence for Biomedical TB Research anchors the study, with UCT's Division of Medical Microbiology providing critical lab support. These institutions have pioneered BDQ resistance tracking since 2015, contributing to global knowledge on transmission clusters.

SU's work on efflux pump induction and UCT's targeted NGS trials exemplify how higher education drives policy—e.g., informing NHLS workflows. For students and faculty, this field offers impactful careers; check university-jobs for openings in public health and microbiology.

Global Context and Comparative Trends

While SA's 5-12% BDQ resistance exceeds global averages (3-5%), similar rises occur post-introduction (e.g., Mozambique 14%). WHO urges second-line drug surveillance, with SA's data informing African strategies.

Cross-border spread via migration amplifies risks. Lessons from SA could guide high-burden nations, emphasizing university-led genomic surveillance.

Future Outlook: Solutions and Innovations

Optimism lies in rapid diagnostics, new regimens (e.g., pretomanid combinations), and vaccines. SA's TB Recovery Plan prioritizes BPaL while mandating resistance testing. Universities are innovating: SU on novel antibiotics, UCT on AI-driven diagnostics.

Actionable insights include prioritizing NGS rollout and training via higher-ed-career-advice. International funding (e.g., Unitaid) supports these efforts.

Photo by Alexandra Fuller on Unsplash

Call to Action for Researchers and Policymakers

This study spotlights the urgency for sustained investment in TB research. South African universities continue to lead, but need more talent. Explore rate-my-professor for insights on TB experts, apply to higher-ed-jobs and university-jobs, or seek higher-ed-career-advice. Together, we can curb resistance and save lives.