title: Activity of ceftazidime-avibactam against multidrug-resistance Enterobacteriaceae expressing combined mechanisms of resistance.
abstract: BACKGROUND
  Antimicrobial resistance in Enterobacteriaceae is increasing worldwide and is making treating infections caused by multidrug-resistant Enterobacteriaceae a challenge. The use of β-lactam agents is compromised by microorganisms harboring extended-spectrum β-lactamases (ESBLs) and other mechanisms of resistance. Avibactam is a non β-lactam agent that inhibits clinically relevant β-lactamases, such as ESBL and AmpC. The ceftazidime-avibactam combination (CAZ-AVI) was recently approved for use in certain complicated infections, and may provide a therapeutic alternative for infections caused by these microorganisms.
  
  
  METHODS
  The in vitro activity of CAZ and CAZ-AVI (AVI at a fixed concentration of 4mg/L) was tested against 250 clinical isolates of Enterobacteriaceae using broth microdilution. EUCAST breakpoint criteria were used for CAZ, and FDA criteria for CAZ-AVI. Clinical isolates included bacteria producing extended-spectrum β-lactamases (ESBLs) and acquired AmpC β-lactamases (AACBLs). Porin loss in Klebsiella pneumoniae was also evaluated.
  
  
  RESULTS
  The combination of AVI with CAZ displayed excellent activity against clinical isolates of ESBL-producing Escherichia coli and Klebsiella pneumoniae, rendering all the ceftazidime-resistant isolates susceptible to ceftazidime. CAZ-AVI retained activity against porin-deficient isolates of K. pneumoniae producing ESBLs, AACBLs, or both, although MIC values were higher compared to porin-expressing isolates. CAZ-AVI rendered all the ceftazidime-resistant AACBL-producing Enterobacteriaceae tested susceptible to ceftazidime.
  
  
  CONCLUSIONS
  CAZ-AVI showed potent in vitro activity against clinical isolates of Enterobacteriaceae producing ESBLs and/or AACBLs, including K. pneumoniae with loss of porins.
authors.affiliation: Intercentre Unit of Infectious Diseases, Microbiology and Preventive Medicine, University Hospital Virgen Macarena-Virgen del Rocío, Spain. Electronic address: inlopezh@us.es.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: López-Hernández
authors.affiliation: Santa Creu i Sant Pau Hospital, Barcelona, Spain.
authors.forename: Noemí
authors.initials: N
authors.lastname: Alonso
authors.affiliation: University Hospital Marqués de Valdecilla, Santander, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Fernández-Martínez
authors.affiliation: Son Espases Hospital, Palma de Mallorca, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Zamorano
authors.affiliation: Santa Creu i Sant Pau Hospital, Barcelona, Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: Rivera
authors.affiliation: Son Espases Hospital, Palma de Mallorca, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Oliver
authors.affiliation: School of Medicine, University of Sevilla, Spain.
authors.forename: M Carmen
authors.initials: MC
authors.lastname: Conejo
authors.affiliation: University Hospital Marqués de Valdecilla, Santander, Spain; Department of Molecular Biology, University of Cantabria, Santander, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Martínez-Martínez
authors.affiliation: Santa Creu i Sant Pau Hospital, Barcelona, Spain.
authors.forename: Ferrán
authors.initials: F
authors.lastname: Navarro
authors.affiliation: Intercentre Unit of Infectious Diseases, Microbiology and Preventive Medicine, University Hospital Virgen Macarena-Virgen del Rocío, Spain; School of Medicine, University of Sevilla, Spain.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Pascual
mesh_terms: D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D053961:Azabicyclo Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D001692:Biological Transport; D002442:Ceftazidime / Q000493:pharmacokinetics / Q000494:pharmacology*; D004338:Drug Combinations; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics*; D004357:Drug Synergism; D004755:Enterobacteriaceae / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D004756:Enterobacteriaceae Infections / Q000382:microbiology*; D006801:Humans; D018272:Porins / Q000172:deficiency / Q000378:metabolism; D018440:beta-Lactam Resistance; D001618:beta-Lactamases / Q000235:genetics / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D053961:Azabicyclo Compounds; D001426:Bacterial Proteins; D004338:Drug Combinations; D018272:Porins; C000595613:avibactam, ceftazidime drug combination; D002442:Ceftazidime; D001618:beta-Lactamases
keywords: AmpC; Avibactam; Ceftazidima; Ceftazidime; Enterobacteriaceae; Enterobacterias; Porinas; Porins; Resistance; Resistencia