Mechanisms leading to In vivo ceftazidime/avibactam resistance development during treatment of GES-5-producing Pseudomonas aeruginosa infections

The mechanisms underlying ceftazidime/avibactam resistance development in 4 ceftazidime/avibactam susceptible/resistant pairs of GES-5-producing Pseudomonas aeruginosa clinical isolates was investigated through susceptibility profiling and whole genome sequencing. All isolates belonged to ST235. In 3 of the cases ceftazidime/avibactam resistance was driven by a single mutation leading to GES-27 (P162A), GES-29 (P162Q) or the novel GES-60 (N136S), as confirmed through cloning experiments. Moreover, these mutations were associated with increased cefiderocol MICs but reduced carbapenem, and particularly imipenem/relebactam, resistance. This emerging scenario in which development of resistance to novel cephalosporin ß-lactamase inhibitor combinations (and eventually cefiderocol) restores carbapenem (and/or combinations with ?-lactamase inhibitors such as imipenem/relebactam) susceptibility and vice versa offers a unique opportunity for innovative treatment strategies such as antibiotic rotations and highlights the importance of antimicrobial stewardship measures to combat infections by MDR Gram negative pathogens.