title: The postantibiotic effect and post-β-lactamase-inhibitor effect of ceftazidime, ceftaroline and aztreonam in combination with avibactam against target Gram-negative bacteria.
abstract: The magnitudes of the postantibiotic effect (PAE) and post-β-lactamase-inhibitory effect (PLIE) of ceftazidime-avibactam, ceftaroline-avibactam, and aztreonam-avibactam were determined against isolates of Enterobacteriaceae and Pseudomonas aeruginosa that either harboured genes encoding serine and/or metallo-β-lactamases, or did not harbour bla genes. The bla genes included ones that encoded extended spectrum β-lactamases, AmpC and KPC β-lactamases, and one metallo-β-lactamase, NDM-1. No substantial PAE was observed for any combination against any isolate. One substantial PLIE was found: a value of 1·9 h for ceftazidime-avibactam against Klebsiella pneumoniae (blaKPC-2 ). From comparison with results in the literature, we propose that the existence of a substantial PLIE depends on the bacterial isolate and on the specific β-lactamase inhibitor and β-lactam combination.
  
  
  CONCLUSIONS
  A wave of new β-lactamase inhibitors is entering either therapeutic use or clinical trials. The present work characterizes the postantibiotic effect (PAE) and post-β-lactamase-inhibitory effect (PLIE) of the clinically most advanced of these compounds, avibactam. We show that the existence of a measurable PLIE is strain- (and possibly compound-) dependent, and cannot be relied upon as a standard component of the primary pharmacology of a new β-lactamase inhibitor. This variability was not reported in earlier studies of clavulanic acid or sulbactam.
authors.affiliation: Micromyx, LLC, Kalamazoo, MI, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Pillar
authors.affiliation: Micromyx, LLC, Kalamazoo, MI, USA.
authors.forename: A
authors.initials: A
authors.lastname: Stoneburner
authors.affiliation: Micromyx, LLC, Kalamazoo, MI, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Shinabarger
authors.affiliation: Cerexa, Inc., Oakland, CA, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Krause
authors.affiliation: AstraZeneca, PLC, Waltham, MA, USA.
authors.forename: W W
authors.identifier: http://orcid.org/0000-0003-3305-6388
authors.initials: WW
authors.lastname: Nichols
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D053961:Azabicyclo Compounds / Q000494:pharmacology*; D001398:Aztreonam / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics*; D002442:Ceftazidime / Q000494:pharmacology*; D002511:Cephalosporins; D004338:Drug Combinations; D006801:Humans; D007711:Klebsiella pneumoniae / Q000187:drug effects* / Q000235:genetics; D008826:Microbial Sensitivity Tests; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000235:genetics; D013407:Sulbactam / Q000494:pharmacology; D065093:beta-Lactamase Inhibitors / Q000494:pharmacology*; D001618:beta-Lactamases / Q000235:genetics*; D000097583:Ceftaroline
chemical_list: D000900:Anti-Bacterial Agents; D053961:Azabicyclo Compounds; D001398:Aztreonam; D001426:Bacterial Proteins; D002442:Ceftazidime; D002511:Cephalosporins; D004338:Drug Combinations; D013407:Sulbactam; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases; D000097583:Ceftaroline; C000595613:avibactam, ceftazidime drug combination; C434283:beta-lactamase KPC-1; C048795:AmpC beta-lactamases; C552864:beta-lactamase NDM-1
keywords: antibacterial agents; post-β-lactamase-inhibitor effect; postantibiotic effect; primary pharmacodynamics; β-lactamase inhibitors; β-lactams