Salvato Richard Steiner, Reis Ana Júlia, Schiefelbein Sun Hee, Gómez Michael Andrés Abril, Salvato Stéphanie Steiner, da Silva Larissa Vitória, Costa Elis Regina Dalla, Unis Gisela, Dias Claudia Fontoura, Viveiros Miguel, Portugal Isabel, von Groll Andrea, da Silva Pedro Eduardo Almeida, Kritski Afrânio Lineu, Perdigão João, Rossetti Maria Lucia Rosa
Programa de Pós-graduação em Biologia Celular e Molecular, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil; Centro de Desenvolvimento Científico e Tecnológico, Centro Estadual de Vigilância em Saúde, Secretaria Estadual da Saúde do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
Medical Microbiology Research Center, Faculdade de Medicina, Programa de Pós-graduação em Ciências da Saúde, Universidade Federal do Rio Grande, Rio Grande, Rio Grande do Sul, Brazil.
Int J Antimicrob Agents. 2021 Oct;58(4):106401. doi: 10.1016/j.ijantimicag.2021.106401. Epub 2021 Jul 18.
Genomic-based surveillance on the occurrence of drug resistance and its transmission dynamics has emerged as a powerful tool for the control of tuberculosis (TB). A whole-genome sequencing approach, phenotypic testing and clinical-epidemiological investigation were used to undertake a retrospective population-based study on drug-resistant (DR)-TB in Rio Grande do Sul, the largest state in Southern Brazil. The analysis included 305 resistant Mycobacterium tuberculosis strains sampled statewide from 2011 to 2014, and covered 75.7% of all DR-TB cases identified in this period. Lineage 4 was found to be predominant (99.3%), with high sublineage-level diversity composed mainly of 4.3.4.2 [Latin American and Mediterranean (LAM)/RD174], 4.3.3 (LAM/RD115) and 4.1.2.1 (Haarlem/RD182) sublineages. Genomic diversity was also reflected in resistance of the variants to first-line drugs. A large number of distinct resistance-conferring mutations, including variants that have not been reported previously in any other setting worldwide, and 22 isoniazid-monoresistant strains with mutations described as disputed in the rpoB gene but causing rifampicin resistance generally missed by automated phenotypic tests as BACTEC MGIT. Using a cut-off of five single nucleotide polymorphisms, the estimated recent transmission rate was 55.1%, with 168 strains grouped into 28 genomic clusters. The most worrying fact concerns multi-drug-resistant (MDR) strains, of which 73.4% were clustered. Different resistance profiles and acquisition of novel mutations intraclusters revealed important amplification of resistance in the region. This study described the diversity of M. tuberculosis strains, the basis of drug resistance, and ongoing transmission dynamics across the largest state in Southern Brazil, stressing the urgent need for MDR-TB transmission control state-wide.
基于基因组的耐药性发生及其传播动态监测已成为控制结核病（TB）的有力工具。采用全基因组测序方法、表型检测和临床流行病学调查，对巴西南部最大的州南里奥格兰德州的耐多药（DR）结核病进行了一项基于人群的回顾性研究。分析包括2011年至2014年在全州范围内采集的305株耐药结核分枝杆菌菌株，覆盖了该时期所有确诊的DR-TB病例的75.7%。发现4型谱系占主导地位（99.3%），亚谱系水平多样性高，主要由4.3.4.2[拉丁美洲和地中海（LAM）/RD174]、4.3.3（LAM/RD115）和4.1.2.1（哈勒姆/RD182）亚谱系组成。基因组多样性也反映在各变体对一线药物的耐药性上。大量不同的耐药性赋予突变，包括全球其他任何地方此前均未报道过的变体，以及22株异烟肼单耐药菌株，其rpoB基因中的突变被描述为有争议，但会导致利福平耐药，而自动化表型检测（如BACTEC MGIT）通常会遗漏这种耐药情况。以五个单核苷酸多态性为临界值，估计近期传播率为55.1%，168株菌株被分为28个基因组簇。最令人担忧的是耐多药（MDR）菌株，其中73.4%属于簇状。不同的耐药谱以及簇内新突变的获得揭示了该地区耐药性的重要扩增。本研究描述了巴西南部最大州结核分枝杆菌菌株的多样性、耐药性基础以及持续的传播动态，强调了全州范围内控制耐多药结核病传播的迫切需求。
