title: Pharmacokinetics/pharmacodynamics of a β-lactam and β-lactamase inhibitor combination: a novel approach for aztreonam/avibactam.
abstract: OBJECTIVE
  The combination of aztreonam/avibactam has promising activity against MDR Gram-negative pathogens producing metallo-β-lactamases (MBLs), such as New Delhi MBL-1. Pharmacokinetic (PK)/pharmacodynamic (PD) understanding of this combination is critical for optimal clinical dose selection. This study focuses on the determination of an integrated PK/PD approach for aztreonam/avibactam across multiple clinical Enterobacteriaceae strains.
  
  
  METHODS
  Six clinical Enterobacteriaceae isolates expressing MBLs and ESBLs were studied in an in vitro hollow-fibre infection model (HFIM) using various dosing regimens simulating human-like PK for aztreonam/avibactam. The neutropenic murine thigh infection model was used for in vivo validation against two bacterial strains.
  
  
  RESULTS
  MIC values of aztreonam/avibactam for the isolates ranged from 0.125 to 8 mg/L. Using a constant infusion of avibactam at 4 mg/L, the aztreonam PK/PD index was observed as % fT >MIC. Studies performed in the presence of a fixed dose of aztreonam revealed that the efficacy of avibactam correlates best with percentage of time above a critical threshold concentration of 2-2.5 mg/L. These conclusions translated well to the efficacy observed in the murine thigh model, demonstrating in vivo validation of the in vitro PK/PD target.
  
  
  CONCLUSIONS
  PK/PD evaluations for aztreonam/avibactam in HFIM yielded a single target across strains with a wide MIC range. This integrated approach could be easily applied for forecasting clinically efficacious doses for β-lactam/β-lactamase inhibitor combinations.
authors.affiliation: AstraZeneca Infection Innovative Medicines, 35 Gatehouse Drive, Waltham, MA 02451, USA renusingh2@gmail.com.
authors.forename: Renu
authors.initials: R
authors.lastname: Singh
authors.affiliation: AstraZeneca Infection Innovative Medicines, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Aryun
authors.initials: A
authors.lastname: Kim
authors.affiliation: AstraZeneca Infection Innovative Medicines, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: M Angela
authors.initials: MA
authors.lastname: Tanudra
authors.affiliation: AstraZeneca Infection Innovative Medicines, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Harris
authors.affiliation: AstraZeneca Infection Innovative Medicines, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: McLaughlin
authors.affiliation: AstraZeneca Infection Innovative Medicines, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Patey
authors.affiliation: AstraZeneca Infection Innovative Medicines, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: O'Donnell
authors.affiliation: AstraZeneca Infection Innovative Medicines, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Bradford
authors.affiliation: AstraZeneca Infection Innovative Medicines, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Ann E
authors.initials: AE
authors.lastname: Eakin
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000494:pharmacology; D053961:Azabicyclo Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000494:pharmacology; D001398:Aztreonam / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000494:pharmacology; D004195:Disease Models, Animal; D004755:Enterobacteriaceae / Q000187:drug effects; D004756:Enterobacteriaceae Infections / Q000188:drug therapy*; D005260:Female; D051379:Mice; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D016896:Treatment Outcome; D065093:beta-Lactamase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D047090:beta-Lactams / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D053961:Azabicyclo Compounds; D065093:beta-Lactamase Inhibitors; D047090:beta-Lactams; C543519:avibactam; D001398:Aztreonam
keywords: NDM-1; PK/PD; hollow-fibre infection model