Observational studyThe Lancet. Microbe2022
Investigating resistance in clinical Mycobacterium tuberculosis complex isolates with genomic and phenotypic antimicrobial susceptibility testing: a multicentre observational study.
Observational study in The Lancet. Microbe, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers, 1 of them a synthesis that pooled it.
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Who cites it
25 citing papers in PubMed, 1 synthesis or guideline pooled it, 48 citations in OpenAlex.
- MIC-based tuberculosis drug susceptibility testing using Sensititre MYCOTB: a diagnostic accuracy meta-analysis.Journal of clinical microbiology · 2026Pooled it
- Recent advances in antituberculosis drugs and therapeutics: from mechanistic breakthroughs to clinical translation.Molecular biomedicine · 2026Review
- [Molecular mechanisms underlying the development and spread of antibiotic resistance].Bundesgesundheitsblatt, Gesundheitsforschung, Gesundheitsschutz · 2026Review
- Extensive Endemic Transmission of Multidrug-ResistantOpen forum infectious diseases · 2026Article
- Genomic characterization of XDR Mycobacterium tuberculosis isolates in Argentina (2006-2015).BMC infectious diseases · 2025Article
- Molecular Indicator for Distinguishing Multi-drug-Resistant Tuberculosis from Drug Sensitivity Tuberculosis and Potential Medications for Treatment.Molecular biotechnology · 2025Article
- UShER-TB: Scalable, Comprehensive, Accessible Phylogenomic Analysis ofmedRxiv : the preprint server for health sciences · 2025Article
- Machine learning-based prediction of antimicrobial resistance and identification of AMR-related SNPs in Mycobacterium tuberculosis.BMC genomic data · 2025Article
- Advantages of updated WHO mutation catalog combined with existing whole-genome sequencing-based approaches for Mycobacterium tuberculosis resistance prediction.Genome medicine · 2025Article
- Performance of a broth microdilution assay for routine minimum inhibitory concentration determination of 14 anti-tuberculous drugs against theAntimicrobial agents and chemotherapy · 2025Article
- A duplex one-step recombinase aided PCR assay for the rapid and sensitive detection of the isoniazid resistance genes katG and inhA inFrontiers in microbiology · 2025Article
- Mutations inAntibiotics (Basel, Switzerland) · 2024Article
- Limitations of current techniques in clinical antimicrobial resistance diagnosis: examples and future prospects.npj antimicrobials and resistance · 2024Review
- Article
- Implementation of Whole Genome Sequencing of Tuberculosis Isolates in a Referral Center in Rome: Six Years' Experience in Characterizing Drug-Resistant TB and Disease Transmission.Antibiotics (Basel, Switzerland) · 2024Article
- Plasmid-encoded gene duplications of extended-spectrum β-lactamases in clinical bacterial isolates.Frontiers in cellular and infection microbiology · 2024Article
- Rapid detection of multidrug resistance in tuberculosis using nanopore-based targeted next-generation sequencing: a multicenter, double-blind study.Frontiers in microbiology · 2024Article
- Use of Whole Genome Sequencing for Mycobacterium tuberculosis Complex Antimicrobial Susceptibility Testing: From Sequence Data to Resistance Profiles.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Lineage classification and antitubercular drug resistance surveillance ofMicrobiology spectrum · 2023Article
- The Mycobacterium tuberculosis genome at 25 years: lessons and lingering questions.The Journal of clinical investigation · 2023Review
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Authors and funding
30 authors at 15 institutions in 11 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundWhole-genome sequencing (WGS) of Mycobacterium tuberculosis complex has become an important tool in diagnosis and management of drug-resistant tuberculosis. However, data correlating resistance genotype with quantitative phenotypic antimicrobial susceptibility testing (AST) are scarce.
methodsIn a prospective multicentre observational study, 900 clinical M tuberculosis complex isolates were collected from adults with drug-resistant tuberculosis in five high-endemic tuberculosis settings around the world (Georgia, Moldova, Peru, South Africa, and Viet Nam) between Dec 5, 2014, and Dec 12, 2017. Minimum inhibitory concentrations (MICs) and resulting binary phenotypic AST results for up to nine antituberculosis drugs were determined and correlated with resistance-conferring mutations identified by WGS.
findingsConsidering WHO-endorsed critical concentrations as reference, WGS had high accuracy for prediction of resistance to isoniazid (sensitivity 98·8% [95% CI 98·5-99·0]; specificity 96·6% [95% CI 95·2-97·9]), levofloxacin (sensitivity 94·8% [93·3-97·6]; specificity 97·1% [96·7-97·6]), kanamycin (sensitivity 96·1% [95·4-96·8]; specificity 95·0% [94·4-95·7]), amikacin (sensitivity 97·2% [96·4-98·1]; specificity 98·6% [98·3-98·9]), and capreomycin (sensitivity 93·1% [90·0-96·3]; specificity 98·3% [98·0-98·7]). For rifampicin, pyrazinamide, and ethambutol, the specificity of resistance prediction was suboptimal (64·0% [61·0-67·1], 83·8% [81·0-86·5], and 40·1% [37·4-42·9], respectively). Specificity for rifampicin increased to 83·9% when borderline mutations with MICs overlapping with the critical concentration were excluded. Consequently, we highlighted mutations in M tuberculosis complex isolates that are often falsely identified as susceptible by phenotypic AST, and we identified potential novel resistance-conferring mutations.
interpretationThe combined analysis of mutations and quantitative phenotypes shows the potential of WGS to produce a refined interpretation of resistance, which is needed for individualised therapy, and eventually could allow differential drug dosing. However, variability of MIC data for some M tuberculosis complex isolates carrying identical mutations also reveals limitations of our understanding of the genotype and phenotype relationships (eg, including epistasis and strain genetic background).
fundingBill & Melinda Gates Foundation, German Centre for Infection Research, German Research Foundation, Excellence Cluster Precision Medicine of Inflammation (EXC 2167), and Leibniz ScienceCampus EvoLUNG.
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