393: Hidden Resistance: tNGS Reveals Rifampicin and Bedaquiline Resistance in Eswatini

Vambe D et al., Nature Communications - This study reports the programmatic introduction of targeted next-generation sequencing (tNGS) in Eswatini and shows that tNGS detected large amounts of rifampicin and bedaquiline resistance missed by routine diagnostics. Among 234 patient samples, tNGS reclassified many infections, revealed frequent co-occurrence of rpoB I491F and Rv0678 mutations, and guided treatment changes with high treatment success in a clinical subset. Key terms: tNGS, rifampicin-resistance, rpoB I491F, bedaquiline resistance, Eswatini.

Study Highlights:
tNGS detected rifampicin resistance in 159/234 strains, substantially more than Xpert Ultra, LPA, or MGIT pDST, and identified 101 strains with the rpoB I491F mutation (96 solo). Mutations in Rv0678 associated with bedaquiline/clofazimine resistance were found in 87 strains, occurring in 55% of rifampicin-resistant isolates and frequently co-occurring with rpoB I491F. Routine diagnostics under-classified resistance leading to incorrect regimen selection for many patients. In a subset of 59 patients with clinical data, tNGS-informed changes were made for 53% and treatment success was 88%.

Conclusion:
Programmatic tNGS in Eswatini closed a major diagnostic gap by identifying rifampicin resistance due to rpoB I491F and widespread Rv0678-associated bedaquiline resistance undetected by routine tests, enabling regimen changes and prompting reconsideration of current treatment algorithms and resistance classifications.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
Targeted next-generation sequencing implementation in Eswatini identifies rifampicin and bedaquiline resistance undetected by routine diagnostic testing

First author:
Vambe D

Journal:
Nature Communications

DOI:
10.1038/s41467-026-73551-w

Reference:
Vambe D, Kay A, Ziyane M, et al. Targeted next-generation sequencing implementation in Eswatini identifies rifampicin and bedaquiline resistance undetected by routine diagnostic testing. Nat Commun. 2026. https://doi.org/10.1038/s41467-026-73551-w

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/hidden-resistance-tngs-eswatini

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-06-17.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the main results and implications discussed in the transcript: programmatic tNGS implementation, diagnostic gaps (I491F), BDQ resistance via Rv0678, comparison with routine diagnostics, regimen changes and outcomes, and WHO classification implications.
- transcript topics: Diagnostic escape and rpoB I491F; tNGS programmatic implementation in Eswatini; BDQ resistance and Rv0678 mutations; Comparison of tNGS with Xpert Ultra, LPA, and MGIT pDST; Clinical impact: treatment changes and outcomes; WHO tuberculosis resistance classifications and implications

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 6
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
-...