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Pharmacodynamic Modelling of β-lactam/β-lactamase Inhibitor Checkerboard Data: Illustration with Aztreonam–Avibactam

Abstract. Objectives. Checkerboard experiments followed by fractional inhibitory concentration (FIC) index determinations are commonly used to assess in vitro pharmacodynamic interactions between combined antibiotics, but FIC index cannot be determined in case of antibiotic/non-active compound combinations. The aim of this study was to use a simple modelling approach to quantify the in vitro activity of aztreonam-avibactam, a new β-lactam–β-lactamase inhibitor combination.

Methods

MIC checkerboard experiments were performed with 12 Enterobacteriaceae with diverse β-lactamases profiles. Aztreonam MICs in the absence and presence of avibactam at different concentrations (ranging from 0.0625 to 4 mg/L) were determined. Aztreonam MIC versus avibactam concentrations were fitted by an inhibitory Emax model with a baseline effect parameter.

Results

A concentration-dependent relationship was observed with a steep initial reduction of aztreonam MIC at low avibactam concentrations and reaching a maximum at higher avibactam concentrations that was adequately fitted by the model. Maximum avibactam effect was characterized by the ratio of aztreonam MICs in the absence of avibactam (MIC0) and when avibactam concentration tends toward infinity (MIC), and this ratio ranged between 90 and 10 068 depending on the strain. Avibactam potency was characterized by avibactam concentrations corresponding to 50% of the maximum effect (IC50 values between 0.00022 and 0.053 mg/L).

Conclusions

An inhibitory Emax model with a baseline effect could quantify maximum avibactam effect and potency among various strains. This simple modelling approach can be used to compare the activity of other combinations of antibiotics with non-antibiotic drugs when FIC index is inappropriate.

November 02, 2019

Profile of the SeptiCyte™ LAB Gene Expression Assay to Diagnose Infection in Critically Ill Patients

Abstract. Sepsis is a severe and frequently occurring clinical syndrome, caused by the inflammatory response to infections. Recent studies on the huma...

December 11, 2018

Detection and Prevalence of Carbapenem-resistant Gram-negative Bacteria Among European Laboratories Part of the COMBACTE Network: A COMBACTE LAB-Net Survey

Abstract: Antimicrobial resistance (AMR) represents a global public health threat which jeopardizes the progress that modern medicine has made over th...

April 05, 2020

EURECA - Substudy of Infections Due to Carbapenem-resistant Enterobacteriacea (CRE) Along Europe. Inside COMBACTE Network; Global Information for a Global Problem

IMI Symposium_COMBACTE-CARE_EURECA_Maria Paniagua