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Imipenem/Relebactam Resistance in Clinical Isolates of Extensively Drug Resistant Pseudomonas aeruginosa: Inhibitor-Resistant ß-Lactamases and Their Increasing Importance.
Hujer, Andrea M; Bethel, Christopher R; Taracila, Magdalena A; Marshall, Steven H; Rojas, Laura J; Winkler, Marisa L; Painter, Ronald E; Domitrovic, T Nicholas; Watkins, Richard R; Abdelhamed, Ayman M; D'Souza, Roshan; Mack, Andrew R; White, Richard C; Clarke, Thomas; Fouts, Derrick E; Jacobs, Michael R; Young, Katherine; Bonomo, Robert A.
Afiliação
  • Hujer AM; Department of Medicine, Case Western Reserve Universitygrid.67105.35 School of Medicine, Cleveland, Ohio, USA.
  • Bethel CR; Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA.
  • Taracila MA; Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA.
  • Marshall SH; Department of Medicine, Case Western Reserve Universitygrid.67105.35 School of Medicine, Cleveland, Ohio, USA.
  • Rojas LJ; Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA.
  • Winkler ML; Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA.
  • Painter RE; Department of Medicine, Case Western Reserve Universitygrid.67105.35 School of Medicine, Cleveland, Ohio, USA.
  • Domitrovic TN; Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA.
  • Watkins RR; Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA.
  • Abdelhamed AM; Department of Molecular Biology and Microbiology, Case Western Reserve Universitygrid.67105.35 School of Medicine, Cleveland, Ohio, USA.
  • D'Souza R; Merck & Co., Inc., Kenilworth, New Jersey, USA.
  • Mack AR; Department of Medicine, Case Western Reserve Universitygrid.67105.35 School of Medicine, Cleveland, Ohio, USA.
  • White RC; Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA.
  • Clarke T; Division of Infectious Diseases, Cleveland Clinic Akron General, Akron, Ohio, USA.
  • Fouts DE; Department of Pathology, Case Western Reserve Universitygrid.67105.35, Cleveland, Ohio, USA.
  • Jacobs MR; Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA.
  • Young K; J. Craig Venter Institute, Rockville, Maryland, USA.
  • Bonomo RA; Department of Molecular Biology and Microbiology, Case Western Reserve Universitygrid.67105.35 School of Medicine, Cleveland, Ohio, USA.
Antimicrob Agents Chemother ; 66(5): e0179021, 2022 05 17.
Article em En | MEDLINE | ID: mdl-35435707
Multidrug-resistant (MDR) Pseudomonas aeruginosa infections are a major clinical challenge. Many isolates are carbapenem resistant, which severely limits treatment options; thus, novel therapeutic combinations, such as imipenem-relebactam (IMI/REL), ceftazidime-avibactam (CAZ/AVI), ceftolozane-tazobactam (TOL/TAZO), and meropenem-vaborbactam (MEM/VAB) were developed. Here, we studied two extensively drug-resistant (XDR) P. aeruginosa isolates, collected in the United States and Mexico, that demonstrated resistance to IMI/REL. Whole-genome sequencing (WGS) showed that both isolates contained acquired GES ß-lactamases, intrinsic PDC and OXA ß-lactamases, and disruptions in the genes encoding the OprD porin, thereby inhibiting uptake of carbapenems. In one isolate (ST17), the entire C terminus of OprD deviated from the expected amino acid sequence after amino acid G388. In the other (ST309), the entire oprD gene was interrupted by an ISPa1328 insertion element after amino acid D43, rendering this porin nonfunctional. The poor inhibition by REL of the GES ß-lactamases (GES-2, -19, and -20; apparent Ki of 19 ± 2 µM, 23 ± 2 µM, and 21 ± 2 µM, respectively) within the isolates also contributed to the observed IMI/REL-resistant phenotype. Modeling of REL binding to the active site of GES-20 suggested that the acylated REL is positioned in an unstable conformation as a result of a constrained Ω-loop.
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Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Pseudomonas aeruginosa / Infecções por Pseudomonas Limite: Humans País/Região como assunto: America do norte Idioma: En Revista: Antimicrob Agents Chemother Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Pseudomonas aeruginosa / Infecções por Pseudomonas Limite: Humans País/Região como assunto: America do norte Idioma: En Revista: Antimicrob Agents Chemother Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Estados Unidos