title: The pharmacodynamics of avibactam in combination with ceftaroline or ceftazidime against β-lactamase-producing Enterobacteriaceae studied in an in vitro model of infection.
abstract: Pharmacodynamics of β-lactamase inhibitors are an area of intense interest as new β-lactam/β-lactamase inhibitor combinations enter clinical development and clinical practice. Avibactam, a non-β-lactam β-lactamase inhibitor, has been combined with ceftaroline or ceftazidime but these two combinations have not been directly compared.
  
  
  
  Using an in vitro pharmacokinetic model we simulated human drug concentration-time courses associated with ceftaroline 600 mg every 8 h and ceftazidime 2000 mg every 8 h. Avibactam was given by continuous infusion at a range of concentrations up to 10 mg/L and antibacterial effect assessed against a CTX-M-producing Escherichia coli , AmpC-hyperproducing Enterobacter cloacae and KPC-producing Klebsiella pneumoniae. Simulations were performed over 72 h.
  
  
  
  Avibactam, at a concentration of 1-2 mg/L, produced maximum bacterial clearance over 72 h for the E. coli and E. cloacae strains with both ceftaroline and ceftazidime. Avibactam (4 mg/L) was required for maximum reduction in bacterial load with the KPC-producing K. pneumoniae. A series of dose fractionation experiments were performed with avibactam against each of the three strains and AUC, C max or T  >   avibactam concentration of 1, 2 or 4 mg/L related to antibacterial effect as measured by change in bacterial count at 24 h. AUC or C max were best related to 24 h antibacterial effect for avibactam though there was no consistent pattern favouring one over the other.
  
  
  
  As AUC is a much easier and more reliable pharmacokinetic measure than C max , it would be useful to explore how AUC-based indices for avibactam exposures could be used for translating the results of the present study into patients' therapy.
authors.forename: Alasdair
authors.initials: A
authors.lastname: MacGowan
authors.forename: Sharon
authors.initials: S
authors.lastname: Tomaselli
authors.forename: Alan
authors.initials: A
authors.lastname: Noel
authors.forename: Karen
authors.initials: K
authors.lastname: Bowker
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D053961:Azabicyclo Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D002442:Ceftazidime / Q000493:pharmacokinetics* / Q000494:pharmacology; D002511:Cephalosporins / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D003198:Computer Simulation; D004359:Drug Therapy, Combination; D016972:Enterobacter cloacae / Q000187:drug effects; D004755:Enterobacteriaceae / Q000187:drug effects*; D004756:Enterobacteriaceae Infections / Q000188:drug therapy / Q000382:microbiology; D004926:Escherichia coli / Q000187:drug effects; D006801:Humans; D007711:Klebsiella pneumoniae / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D065093:beta-Lactamase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D001618:beta-Lactamases / Q000378:metabolism; D000097583:Ceftaroline
chemical_list: D000900:Anti-Bacterial Agents; D053961:Azabicyclo Compounds; D002442:Ceftazidime; D002511:Cephalosporins; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases; D000097583:Ceftaroline; C543519:avibactam