Ceftazidime-avibactam resistance evolution in Pseudomonas aeruginosa and implications for cross-resistance to other novel β-lactams

Twelve pairs of baseline and post-exposure Pseudomonas aeruginosa isolates from patients treated with ceftazidime-avibactam were evaluated to define mechanisms of treatment-emergent resistance. Resistance was associated with amino acid substitutions in ampC and OXA β-lactamases, or mutations in regulatory genes conferring hyper-production of AmpC and MexAB-OprM efflux pumps. Cross-resistance was common between ceftazidime-avibactam and ceftolozane-tazobactam, less common for imipenem-relebactam and cefepime-zidebactam, and lowest for cefiderocol. These findings have important implications for sequential treatment of P. aeruginosa infections.