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.