Walker, Timothy M; Miotto, Paolo; Köser, Claudio U; Fowler, Philip W; Knaggs, Jeff; Iqbal, Zamin; Hunt, Martin; Chindelevitch, Leonid; Farhat, Maha; Cirillo, Daniela Maria; +16 more... Comas, Iñaki; Posey, James; Omar, Shaheed V; Peto, Timothy Ea; Suresh, Anita; Uplekar, Swapna; Laurent, Sacha; Colman, Rebecca E; Nathanson, Carl-Michael; Zignol, Matteo; Walker, Ann Sarah; CRyPTIC Consortium; Seq&Treat Consortium; Crook, Derrick W; Ismail, Nazir; Rodwell, Timothy C; (2022) The 2021 WHO catalogue of Mycobacterium tuberculosis complex mutations associated with drug resistance: A genotypic analysis. The Lancet Microbe, 3 (4). e265-e273. ISSN 2666-5247 DOI: https://doi.org/10.1016/S2666-5247(21)00301-3
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Abstract
BACKGROUND: Molecular diagnostics are considered the most promising route to achieving rapid, universal drug susceptibility testing for Mycobacterium tuberculosiscomplex (MTBC). We aimed to generate a WHO endorsed catalogue of mutations to serve as a global standard for interpreting molecular information for drug resistance prediction. METHODS: A candidate gene approach was used to identify mutations as associated with resistance, or consistent with susceptibility, for 13 WHO endorsed anti-tuberculosis drugs. 38,215 MTBC isolates with paired whole-genome sequencing and phenotypic drug susceptibility testing data were amassed from 45 countries. For each mutation, a contingency table of binary phenotypes and presence or absence of the mutation computed positive predictive value, and Fisher's exact tests generated odds ratios and Benjamini-Hochberg corrected p-values. Mutations were graded as Associated with Resistance if present in at least 5 isolates, if the odds ratio was >1 with a statistically significant corrected p-value, and if the lower bound of the 95% confidence interval on the positive predictive value for phenotypic resistance was >25%. A series of expert rules were applied for final confidence grading of each mutation. FINDINGS: 15,667 associations were computed for 13,211 unique mutations linked to one or more drugs. 1,149/15,667 (7·3%) mutations were classified as associated with phenotypic resistance and 107/15,667 (0·7%) were deemed consistent with susceptibility. For rifampicin, isoniazid, ethambutol, fluoroquinolones, and streptomycin, the mutations' pooled sensitivity was >80%. Specificity was over 95% for all drugs except ethionamide (91·4%), moxifloxacin (91·6%) and ethambutol (93·3%). Only two resistance mutations were classified for bedaquiline, delamanid, clofazimine, and linezolid as prevalence of phenotypic resistance was low for these drugs. INTERPRETATION: This first WHO endorsed catalogue of molecular targets for MTBC drug susceptibility testing provides a global standard for resistance interpretation. Its existence should encourage the implementation of molecular diagnostics by National Tuberculosis Programmes. FUNDING: UNITAID, Wellcome, MRC, BMGF.
Item Type | Article |
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Faculty and Department |
Faculty of Infectious and Tropical Diseases > Dept of Clinical Research Faculty of Infectious and Tropical Diseases > Department of Infection Biology |
Research Centre |
TB Centre Antimicrobial Resistance Centre (AMR) |
PubMed ID | 35373160 |
Elements ID | 176283 |
Official URL | http://dx.doi.org/10.1016/s2666-5247(21)00301-3 |
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