title: Role of the Outer Membrane and Porins in Susceptibility of β-Lactamase-Producing Enterobacteriaceae to Ceftazidime-Avibactam.
abstract: This study examined the activity of the novel antimicrobial combination ceftazidime-avibactam against Enterobacteriaceae exhibiting different outer membrane permeability profiles, specifically with or without porins and with or without expression of the main efflux pump (AcrAB-TolC). The addition of the outer membrane permeabilizer polymyxin B nonapeptide increased the antibacterial activities of avibactam alone, ceftazidime alone, and ceftazidime-avibactam against the characterized clinical isolates of Escherichia coli, Enterobacter aerogenes, and Klebsiella pneumoniae. This enhancement of activities was mainly due to increased passive penetration of compounds since inhibition of efflux by the addition of phenylalanine-arginine β-naphthylamide affected the MICs minimally. OmpF (OmpK35) or OmpC (OmpK36) pores were not the major route by which avibactam crossed the outer membranes of E. coli and K. pneumoniae. In contrast, Omp35 and Omp36 allowed diffusion of avibactam across the outer membrane of E. aerogenes, although other diffusion channels for avibactam were also present in that species. It was clear that outer membrane permeability and outer membrane pore-forming proteins play a key role in the activity of ceftazidime-avibactam. Nevertheless, the MICs of ceftazidime-avibactam (with 4 mg/liter avibactam) against the ceftazidime-resistant clinical isolates of the three species of Enterobacteriaceae studied were ≤ 8 mg/liter, regardless of outer membrane permeability changes resulting from an absence of defined porin proteins or upregulation of efflux.
authors.affiliation: UMR_MD-1, Aix-Marseille Université, IRBA, Transporteurs Membranaires, Chimiorésistance et Drug Design, Marseille, France jean-marie.pages@univ-amu.fr.
authors.forename: Jean-Marie
authors.identifier: http://orcid.org/0000-0001-7092-7977
authors.initials: JM
authors.lastname: Pagès
authors.affiliation: UMR_MD-1, Aix-Marseille Université, IRBA, Transporteurs Membranaires, Chimiorésistance et Drug Design, Marseille, France.
authors.forename: Sabine
authors.initials: S
authors.lastname: Peslier
authors.affiliation: AstraZeneca Infection Innovative Medicines, Waltham, Massachusetts, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Keating
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1047, Université Montpellier 1, Nîmes, France Department of Microbiology, University Hospital Caremeau, Nîmes, France.
authors.forename: Jean-Philippe
authors.identifier: http://orcid.org/0000-0002-9484-0304
authors.initials: JP
authors.lastname: Lavigne
authors.affiliation: AstraZeneca Infection Innovative Medicines, Waltham, Massachusetts, USA.
authors.forename: Wright W
authors.initials: WW
authors.lastname: Nichols
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D053961:Azabicyclo Compounds / Q000494:pharmacology*; D001425:Bacterial Outer Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D002442:Ceftazidime / Q000494:pharmacology*; D002463:Cell Membrane Permeability / Q000187:drug effects; D004338:Drug Combinations; D021902:Enterobacter aerogenes / Q000187:drug effects; D004755:Enterobacteriaceae / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D004926:Escherichia coli / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D011112:Polymyxin B / Q000494:pharmacology; D018272:Porins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D053961:Azabicyclo Compounds; D001425:Bacterial Outer Membrane Proteins; D004338:Drug Combinations; D018272:Porins; C000595613:avibactam, ceftazidime drug combination; D010649:Phenylalanine; C543519:avibactam; C079641:phenylalanine-beta-naphthylamide; D002442:Ceftazidime; D011112:Polymyxin B