title: Prediction of in vivo and in vitro infection model results using a semimechanistic model of avibactam and aztreonam combination against multidrug resistant organisms.
abstract: The combination of aztreonam-avibactam is active against multidrug-resistant Enterobacteriaceae that express metallo-β-lactamases. A complex synergistic interaction exists between aztreonam and avibactam bactericidal activities that have not been quantitatively explored. A two-state semimechanistic pharmacokinetic/pharmacodynamic (PK/PD) logistic growth model was developed to account for antimicrobial activities in the combination of bacteria-mediated degradation of aztreonam and the inhibition of aztreonam degradation by avibactam. The model predicted that changing regimens of 2 g aztreonam plus 0.375 and 0.6 g avibactam as a 1-hour infusion were qualitatively similar to that observed from in vivo murine thigh infection and hollow-fiber infection models previously reported in the literature with 24-hour log kill ≥1. The current approach to characterize the effect of avibactam in enhancing aztreonam activity from time-kill study was accomplished by shifting the half-maximal effective concentration (EC50) of aztreonam in increasing avibactam concentration using a nonlinear equation as a function of avibactam concentration, providing a framework for translational predictions.
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida, USA.
authors.forename: Skb
authors.initials: S
authors.lastname: Sy
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida, USA.
authors.forename: L
authors.initials: L
authors.lastname: Zhuang
authors.affiliation: Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, Florida, USA.
authors.forename: H
authors.initials: H
authors.lastname: Xia
authors.affiliation: AstraZeneca, Waltham, Massachusetts, USA.
authors.forename: M-E
authors.initials: ME
authors.lastname: Beaudoin
authors.affiliation: AstraZeneca, Waltham, Massachusetts, USA.
authors.forename: V J
authors.initials: VJ
authors.lastname: Schuck
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida, USA.
authors.forename: H
authors.initials: H
authors.lastname: Derendorf
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage; D053961:Azabicyclo Compounds / Q000008:administration & dosage*; D001398:Aztreonam / Q000008:administration & dosage*; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects* / Q000502:physiology; D004359:Drug Therapy, Combination; D004756:Enterobacteriaceae Infections / Q000188:drug therapy; D005544:Forecasting; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests / Q000379:methods; D008954:Models, Biological; D011552:Pseudomonas Infections / Q000188:drug therapy; D065093:beta-Lactamase Inhibitors / Q000008:administration & dosage
chemical_list: D000900:Anti-Bacterial Agents; D053961:Azabicyclo Compounds; D065093:beta-Lactamase Inhibitors; C543519:avibactam; D001398:Aztreonam