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Whole genomic sequencing as a tool for diagnosis of drug and multidrug-resistance tuberculosis in an endemic region in Mexico

By Carlos Francisco Madrazo-Moya, Irving Cancino-Muñoz, Betzaida Cuevas-Cordoba, Vanessa Gonzalez-Covarrubias, Martín Barbosa-Amezcua, Xavier Soberón, Raquel Muñiz-Salazar, Armando Martínez-Guarneros, Claudia Backer, José Zarrabal-Meza, Clara Sampieri-Ramirez, Antonio Enciso-Moreno, Michael Lauzardo, Iñaki Comas, Roberto Zenteno-Cuevas

Posted 15 Feb 2019
bioRxiv DOI: 10.1101/551481 (published DOI: 10.1371/journal.pone.0213046)

Background: Whole genome sequencing (WGS) has been proposed as a tool for diagnosing drug resistance in tuberculosis. However, reports of its effectiveness in endemic countries with important numbers of drug resistance are scarce. The goal of this study was to evaluate the effectiveness of this procedure in isolates from a tuberculosis endemic region in Mexico. Methods: WGS analysis was performed in 81 tuberculosis positive clinical isolates with a known phenotypic profile of resistance against first-line drugs (isoniazid, rifampin, ethambutol, pyrazinamide and streptomycin). Mutations related to drug resistance were identified for each isolate; drug resistant genotypes were predicted and compared with the phenotypic profile. Genotypes and transmission clusters based on genetic distances were also characterized. Findings:. Prediction by WGS analysis of resistance against isoniazid, rifampicin, ethambutol, pyrazinamide and streptomycin showed sensitivity values of 84%, 96%, 71%, 75% and 29%, while specificity values were 100%, 94%, 90%, 90% and 98%, respectively. Prediction of multidrug resistance showed a sensitivity of 89% and specificity of 97%. Moreover, WGS analysis revealed polymorphisms related to second-line drug resistance, enabling classification of eight and two clinical isolates as pre- and extreme drug-resistant cases, respectively. Four lineages were identified in the population (L1, L2, L3 and L4). The most frequent of these was L4, which included 90% (77) of the isolates. Six transmission clusters were identified; the most frequent was TC6, which included 13 isolates with a L4.1.1 and a predominantly multidrug-resistant condition. Conclusion: The results illustrate the utility of WGS for establishing the potential for prediction of resistance against first and second line drugs in isolates of tuberculosis from the region. They also demonstrate the feasibility of this procedure for use as a tool to support the epidemiological surveillance of drug- and multidrug-resistant tuberculosis.

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