Pseudomonas aeruginosa is a major cause of infection in hospitalised patients, with a large genome which makes it highly versatile and resistant to most antimicrobial agents. Ceftazidime-avibactam (CZA) offers an alternative treatment, but resistance is quickly evolving. There is limited knowledge on the exact resistance mechanisms to this drug, or on cross-resistance to meropenem (MEM). This laboratory experiment aimed to decipher these mechanisms in order to provide guidance for the best treatment choice in meropenem pre-treated P. aeruginosa infections. Six clinical isolates of P. aeruginosa were subjected to multistep resistance selection in sub inhibitory concentrations of CZA and MEM. MICs were also determined in the presence of the efflux pump inhibitor phenyl-Arginine-β-Naphthylamide (PAβN). Molecular analyses were performed by whole genome sequencing, whole -gene- and -protein expression profiles. CRISPR/Cas9 genome editing was performed using a two-plasmid method for selected mutations