This study evaluated the activity of cefiderocol and the combination of ceftazidime/avibactam (CZA) plus aztreonam against carbapenemase-producing extensively drug-resistant (XDR) Pseudomonas aeruginosa isolates. Nine clinical XDR P. aeruginosa isolates with different sequence types and class A (GES) or B (VIM, IMP or NDM) carbapenemases were analysed. Time-kill assays assessed bacterial load reduction for each treatment, while chemostat experiments on four isolates validated these findings. All isolates showed resistance to CZA, with four also resistant to aztreonam. Seven isolates were susceptible to cefiderocol, but two displayed borderline susceptibility (MIC 2-4 mg/L). Time-kill assays demonstrated bactericidal activity by cefiderocol in six isolates at 24 h, while CZA plus aztreonam showed bactericidal effects in three isolates and synergistic/additive effects in four isolates. In the chemostat model, cefiderocol and CZA plus aztreonam were bactericidal in all four tested isolates, with cefiderocol showing greater bacterial reduction in three of these isolates. Both cefiderocol and CZA plus aztreonam achieved significant reductions in bacterial counts compared to controls, but there was no significant difference between cefiderocol monotherapy and the combination. Both cefiderocol and CZA plus aztreonam demonstrated activity against XDR P. aeruginosa carrying metallo-β-lactamase (MBL) and/or serine-β-lactamase (SBL) carbapenemases. Cefiderocol was the only consistently effective monotherapy with a bactericidal effect across all tested isolates in the chemostat model.