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Semi-mechanistic pharmacokinetic/pharmacodynamics modeling of aztreonam-avibactam combination against multidrug resistant Gram(-) organisms
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International audience. Background: Aztreonam-avibactam (ATM-AVI) is a promising combination to treat serious infections caused by multi-drug resistant (MDR) pathogens including those producing metallo-β-lactamases (MBLs). The aim of this study was to apply a semi-mechanistic PK/PD modelling approach (Sy et al., CPT Pharmacometrics Syst. Pharmacol., 2016) to evaluate the in vitro synergistic activity of ATM-AVI combination against 4 MDR Enterobacteriaceae with different β-lactamase profiles.Materials/methods: ATM MICs were determined both in the absence and presence of AVI at different concentrations (from 0.004 to 32 mg/L). For static time-kill studies, ATM concentrations were set at 0.25, 0.5, 1, 2 and 4 times the MIC, and were combined with different AVI concentrations ranging from 0 to 8 mg/L. The effect of AVI alone was also evaluated. The presence of pre-existing resistant bacteria (R) in the initial inoculum was investigated. In order to take into account ATM degradation by β-lactamases, the actual concentrations of ATM and AVI were determined by LC-MS/MS. The time course of bacteria response was first modeled and, thereafter, ATM degradation was integrated into the model.Results: A common structural model with 2 sub-populations, slightly different from the one developed by Sy et al., was applied for all strains (Fig .1). There was no transformation between bacterial states and the fraction of resistant bacteria was fixed at the value determined experimentally. ATM bactericidal effect was modeled as an increase in the killing rate for both subpopulations, according to a sigmoidal Emax model with a higher EC50 for the resistant state. AVI was modeled having three effects: a concentration-dependent inhibition of ATM degradation; an enhancement of ATM bactericidal activity with a reduction of the ATM EC50; and a bactericidal effect observed for high concentrations. Conclusions: The three previously reported effects of AVI: β-lactamase inhibition, bactericidal activity and ATM enhancing activity could be well characterized by the PK/PD model for the 4 strains evaluated in this study. Enabling ATM effect in both subpopulations, the model succeeded in capturing the bacterial growth, regrowth and killing kinetics for all strains.
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