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Unexpected challenges in treating multidrug-resistant Gram-negative bacteria: resistance to ceftazidime-avibactam in archived isolates of Pseudomonas aeruginosa.
Winkler, Marisa L; Papp-Wallace, Krisztina M; Hujer, Andrea M; Domitrovic, T Nicholas; Hujer, Kristine M; Hurless, Kelly N; Tuohy, Marion; Hall, Geraldine; Bonomo, Robert A.
Afiliação
  • Winkler ML; Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, Ohio, USA Research Service, Louis Stokes Veterans Affairs Medical Center, Cleveland, Ohio, USA.
  • Papp-Wallace KM; Research Service, Louis Stokes Veterans Affairs Medical Center, Cleveland, Ohio, USA Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
  • Hujer AM; Research Service, Louis Stokes Veterans Affairs Medical Center, Cleveland, Ohio, USA Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
  • Domitrovic TN; Research Service, Louis Stokes Veterans Affairs Medical Center, Cleveland, Ohio, USA.
  • Hujer KM; Research Service, Louis Stokes Veterans Affairs Medical Center, Cleveland, Ohio, USA Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
  • Hurless KN; Research Service, Louis Stokes Veterans Affairs Medical Center, Cleveland, Ohio, USA.
  • Tuohy M; Department of Clinical Pathology, Cleveland Clinic Foundation, Cleveland, Ohio, USA.
  • Hall G; Department of Clinical Pathology, Cleveland Clinic Foundation, Cleveland, Ohio, USA.
  • Bonomo RA; Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, Ohio, USA Research Service, Louis Stokes Veterans Affairs Medical Center, Cleveland, Ohio, USA Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA Department of Pharmacology, Case
Antimicrob Agents Chemother ; 59(2): 1020-9, 2015 Feb.
Article em En | MEDLINE | ID: mdl-25451057
Pseudomonas aeruginosa is a notoriously difficult-to-treat pathogen that is a common cause of severe nosocomial infections. Investigating a collection of ß-lactam-resistant P. aeruginosa clinical isolates from a decade ago, we uncovered resistance to ceftazidime-avibactam, a novel ß-lactam/ß-lactamase inhibitor combination. The isolates were systematically analyzed through a variety of genetic, biochemical, genomic, and microbiological methods to understand how resistance manifests to a unique drug combination that is not yet clinically released. We discovered that avibactam was able to inactivate different AmpC ß-lactamase enzymes and that blaPDC regulatory elements and penicillin-binding protein differences did not contribute in a major way to resistance. By using carefully selected combinations of antimicrobial agents, we deduced that the greatest barrier to ceftazidime-avibactam is membrane permeability and drug efflux. To overcome the constellation of resistance determinants, we show that a combination of antimicrobial agents (ceftazidime/avibactam/fosfomycin) targeting multiple cell wall synthetic pathways can restore susceptibility. In P. aeruginosa, efflux, as a general mechanism of resistance, may pose the greatest challenge to future antibiotic development. Our unexpected findings create concern that even the development of antimicrobial agents targeted for the treatment of multidrug-resistant bacteria may encounter clinically important resistance. Antibiotic therapy in the future must consider these factors.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pseudomonas aeruginosa / Ceftazidima / Compostos Azabicíclicos / Antibacterianos Limite: Humans Idioma: En Ano de publicação: 2015 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pseudomonas aeruginosa / Ceftazidima / Compostos Azabicíclicos / Antibacterianos Limite: Humans Idioma: En Ano de publicação: 2015 Tipo de documento: Article