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Systematic Analysis of Mobile Genetic Elements Mediating ß-Lactamase Gene Amplification in Noncarbapenemase-Producing Carbapenem-Resistant Enterobacterales Bloodstream Infections.
Shropshire, W C; Konovalova, A; McDaneld, P; Gohel, M; Strope, B; Sahasrabhojane, P; Tran, C N; Greenberg, D; Kim, J; Zhan, X; Aitken, S; Bhatti, M; Savidge, T C; Treangen, T J; Hanson, B M; Arias, C A; Shelburne, S A.
Afiliación
  • Shropshire WC; Department of Infectious Diseases and Infection Control, The University of Texas MD Anderson Cancer Centergrid.240145.6, Houston, Texas, USA.
  • Konovalova A; Department of Microbiology and Molecular Genetics, McGovern Medical School, The University of Texas Health Science Center at Houstongrid.267308.8, Houston, Texas, USA.
  • McDaneld P; Division of Pharmacy, The University of Texas MD Anderson Cancer Centergrid.240145.6, Houston, Texas, USA.
  • Gohel M; Department of Infectious Diseases and Infection Control, The University of Texas MD Anderson Cancer Centergrid.240145.6, Houston, Texas, USA.
  • Strope B; Department of Infectious Diseases and Infection Control, The University of Texas MD Anderson Cancer Centergrid.240145.6, Houston, Texas, USA.
  • Sahasrabhojane P; Department of Infectious Diseases and Infection Control, The University of Texas MD Anderson Cancer Centergrid.240145.6, Houston, Texas, USA.
  • Tran CN; Department of Infectious Diseases and Infection Control, The University of Texas MD Anderson Cancer Centergrid.240145.6, Houston, Texas, USA.
  • Greenberg D; Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA.
  • Kim J; Department of Microbiology, UT Southwestern Medical Center, Dallas, Texas, USA.
  • Zhan X; Department of Bioinformatics, UT Southwestern Medical Center, Dallas, Texas, USA.
  • Aitken S; Department of Bioinformatics, UT Southwestern Medical Center, Dallas, Texas, USA.
  • Bhatti M; Division of Pharmacy, Michigan Medicine at University of Michigan, Ann Arbor, Michigan, USA.
  • Savidge TC; Department of Laboratory Medicine, The University of Texas MD Anderson Cancer Centergrid.240145.6, Houston, Texas, USA.
  • Treangen TJ; Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA.
  • Hanson BM; Department of Pathology, Texas Children's Hospital, Houston, Texas, USA.
  • Arias CA; Department of Computer Science, Rice University, Houston, Texas, USA.
  • Shelburne SA; Center for Infectious Diseases, School of Public Health, University of Texas Health Science Center, Houston, Texas, USA.
mSystems ; 7(5): e0047622, 2022 10 26.
Article en En | MEDLINE | ID: mdl-36036505
Noncarbapenemase-producing carbapenem-resistant Enterobacterales (non-CP-CRE) are increasingly recognized as important contributors to prevalent carbapenem-resistant Enterobacterales (CRE) infections. However, there is limited understanding of mechanisms underlying non-CP-CRE causing invasive disease. Long- and short-read whole-genome sequencing was used to elucidate carbapenem nonsusceptibility determinants in Enterobacterales bloodstream isolates at MD Anderson Cancer Center in Houston, Texas. We investigated carbapenem nonsusceptible Enterobacterales (CNSE) mechanisms (i.e., isolates with carbapenem intermediate resistance phenotypes or greater) through a combination of phylogenetic analysis, antimicrobial resistance gene detection/copy number quantification, porin assessment, and mobile genetic element (MGE) characterization. Most CNSE isolates sequenced were non-CP-CRE (41/79; 51.9%), whereas 25.3% (20/79) were Enterobacterales with intermediate susceptibility to carbapenems (CIE), and 22.8% (18/79) were carbapenemase-producing Enterobacterales (CPE). Statistically significant copy number variants (CNVs) of extended-spectrum ß-lactamase (ESBL) genes (Wilcoxon Test; P-value < 0.001) were present in both non-CP-CR E. coli (median CNV = 2.6×; n = 17) and K. pneumoniae (median CNV = 3.2×, n = 17). All non-CP-CR E. coli and K. pneumoniae had predicted reduced expression of at least one outer membrane porin gene (i.e., ompC/ompF or ompK36/ompK35). Completely resolved CNSE genomes revealed that IS26 and ISEcp1 structures harboring blaCTX-M variants along with other antimicrobial resistance elements were associated with gene amplification, occurring in mostly IncFIB/IncFII plasmid contexts. MGE-mediated ß-lactamase gene amplifications resulted in either tandem arrays, primarily mediated by IS26 translocatable units, or segmental duplication, typically due to ISEcp1 transposition units. Non-CP-CRE strains were the most common cause of CRE bacteremia with carbapenem nonsusceptibility driven by concurrent porin loss and MGE-mediated amplification of blaCTX-M genes. IMPORTANCE Carbapenem-resistant Enterobacterales (CRE) are considered urgent antimicrobial resistance (AMR) threats. The vast majority of CRE research has focused on carbapenemase-producing Enterobacterales (CPE) even though noncarbapenemase-producing CRE (non-CP-CRE) comprise 50% or more of isolates in some surveillance studies. Thus, carbapenem resistance mechanisms in non-CP-CRE remain poorly characterized. To address this problem, we applied a combination of short- and long-read sequencing technologies to a cohort of CRE bacteremia isolates and used these data to unravel complex mobile genetic element structures mediating ß-lactamase gene amplification. By generating complete genomes of 65 carbapenem nonsusceptible Enterobacterales (CNSE) covering a genetically diverse array of isolates, our findings both generate novel insights into how non-CP-CRE overcome carbapenem treatments and provide researchers scaffolds for characterization of their own non-CP-CRE isolates. Improved recognition of mechanisms driving development of non-CP-CRE could assist with design and implementation of future strategies to mitigate the impact of these increasingly recognized AMR pathogens.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Bacteriemia / Sepsis Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: MSystems Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Bacteriemia / Sepsis Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: MSystems Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos