Semimechanistic Pharmacodynamic Modeling of Aztreonam‐Avibactam Combination to Understand Its Antimicrobial Activity Against Multidrug‐Resistant Gram‐Negative Bacteria

Alexia Chauzy (1, 2) , Bruna Gaelzer Silva Torres (1, 2) , Julien Buyck (1, 2) , Boudewijn Jonge (3) , Christophe Adier (1, 4) , Sandrine Marchand (1, 2, 4) , William Couet (1, 2, 4) , Nicolas Grégoire (1, 2)

1 PHAR [Poitiers] - Pharmacologie des anti-infectieux
2 Université de Poitiers - Faculté de Médecine et de Pharmacie
3 Pfizer
4 POITIERS - Pharmacocinétique - Laboratoire de Pharmacocinétique

Aztreonam-avibactam (ATM-AVI) is a promising combination to treat serious infections caused by multidrug-resistant (MDR) pathogens. Three distinct mechanisms of action have been previously characterized for AVI: inhibition of ATM degradation by β-lactamases, proper bactericidal effect, and enhancement of ATM bactericidal activity. The aim of this study was to quantify the individual contribution of each of the three AVI effects. In vitro static time-kill studies were performed on four MDR Enterobacteriaceae with different β-lactamase profiles. β-Lactamase activity was characterized by measuring ATM concentrations over 27 hours. Data were analyzed by a semimechanistic pharmacodynamics modeling approach. Surprisingly, even though AVI prevented ATM degradation, the combined bactericidal activity was mostly explained by the enhancement of ATM effect within clinical range of ATM (5-125 mg/L) and AVI concentrations (0.9-22.5 mg/L). Therefore, when selecting a β-lactamase inhibitor for combination with a β-lactam, its capability to enhance the β-lactam activity should be considered in addition to the spectrum of β-lactamases inhibited.

Mots clés: semi-mechanistic pharmacodynamic modeling; aztreonam-avibactam; multi-drug resistant bacteria

Domaines: Sciences du Vivant [q-bio]; Sciences pharmaceutiques

Alexia Chauzy, Bruna Gaelzer Silva Torres, Julien Buyck, Boudewijn Jonge, Christophe Adier, et al.. Semimechanistic Pharmacodynamic Modeling of Aztreonam‐Avibactam Combination to Understand Its Antimicrobial Activity Against Multidrug‐Resistant Gram‐Negative Bacteria. CPT: Pharmacometrics and Systems Pharmacology, 2019, ⟨10.1002/psp4.12452⟩. ⟨hal-02320523⟩