Cefiderocol activity is compromised by acquired extended-spectrum oxacillinases in Pseudomonas aeruginosa

Objectives: Cefiderocol has an excellent in vitro activity on clinical strains of Pseudomonas aeruginosa ( P. aeruginosa ). However, the resistance of some isolates has been associated with the production of some ,B-lactamases. Whether some acquired extended-spectrum oxacillinases (ES-OXA) common in this species may compromise the susceptibility of P. aeruginosa to cefiderocol has not been evaluated so far. Methods: Eighteen genes encoding OXA belonging to the major subgroups identified in P. aeruginosa OXA-1 (n = 3); - 2 (n = 5); - 10 (n = 8), and - 46 (n = 2) were cloned into pUCP24 shuttle vector and transferred into reference strain PAO1. Results: Although production of the OXA-1 subgroup enzymes did not alter cefiderocol MICs, the ,B- lactamases of OXA-2, OXA-46, and four variants of the OXA-10 subgroup resulted in an 8-fold to 32-fold decrease in susceptibility in the PAO1 background. Interestingly, point mutations Ala149Pro and Asp150Gly in OXA-2 subgroup, Trp154Cys and Gly157Asp in OXA-10 subgroup (all located in the Q loop), and the duplication of a Thr206 and a Gly207 in the ,B5 -,B6 loop of OXA-10 subgroup were related to de-creased susceptibility to cefiderocol. We also showed that some ES-OXA, including the most frequent ES-OXA in P. aeruginosa strains, OXA-19 (derived from OXA-10 subgroup), significantly compromised activity of cefiderocol in addition to ceftazidime, ceftolozane/tazobactam, and ceftazidime/avibactam in clinical strains. Conclusion: This work shows that several ES-OXA have a significant effect on cefiderocol susceptibility. Of concern are the Trp154Cys and Gly157Asp mutations that occur in some of these ,B-lactamases, as they are associated with a decreased activity of the most recent cephalosporins introduced to combat P. aeruginosa infections. & COPY; 2023 Published by Elsevier Ltd.

Automated summary

This study evaluated the impact of certain acquired extended-spectrum oxacillinases (ES-OXA) on the susceptibility of Pseudomonas aeruginosa to cefiderocol. It was found that certain variant ES-OXA significantly decreased the susceptibility of Pseudomonas aeruginosa to cefiderocol.