Assessing the in vitro activity of ceftazidime/avibactam and aztreonam among carbapenemase-producing Enterobacteriaceae: Defining the zone of hope.

Ceftazidime/avibactam plus aztreonam (CZA+ATM) is an emerging option to combat carbapenemase-producing Enterobacteriaceae (CPE) expressing resistance via multiple β-lactamases within Ambler classes A, B, C, and D. The benefit of this combination is apparent when the pathogen-specific resistance genotype is characterized. However, rapid molecular diagnostic systems may be unavailable to allow this precision medicine-based approach. Using synergy tests with antibiotic gradient diffusion strips (GDSs), we aimed to prove that the defined phenotypic profile of CPE is reliably predicted by the genotype to confirm the utility of this method as a phenotypic profiling tool for use in the clinical setting. Synergy assessments for CPE (n=10) that co-produce serine- and metallo-β-lactamases were performed by crossing CZA and ATM antibiotic GDSs (Liofilchem® and Etest®). The minimum inhibitory concentration (MIC):MIC ratio method was also conducted for five CPE. All CPE were resistant to CZA and ATM when tested alone. Using classical fractional inhibitory concentration definitions, synergy (9/10) and additivity (1/10) was detected by at least one method for all isolates. As predicted by cross-coverage of genotypically defined serine- and metallo-β-lactamases, for all isolates CZA+ATM produced a phenotypic profile distinguished by sizeable zones of inhibited growth which we term the 'zone of hope'. In conclusion, simple procedures utilizing antibiotic GDSs were concordant with the known genotypic profile of the CPE selected for study. This approach appears to be a valuable tool for guiding therapy in the absence of molecular diagnostic systems. Furthermore, this study confirms potent in vitro activity of CZA+ATM against CPE expressing multiple β-lactamases.