Insertion of IS Pa1635 in IS CR1 Creates a Hybrid Promoter for bla PER-1 Resulting in Resistance to Novel β-lactam/β-lactamase Inhibitor Combinations and Cefiderocol.

Eleven bla PER-1 -positive Pseudomonas aeruginosa clinical isolates showed variable susceptibility to ceftazidime-avibactam (CZA). The genetic contexts of bla PER-1 were identical (IS CR1 - bla PER-1 - gst ) except for the ST697 isolate HS204 (IS CR1 -IS Pa1635 - bla PER-1 - gst ). The insertion of IS Pa1635 in IS CR1 upstream of bla PER-1 created a hybrid promoter, which elevated the bla PER-1 transcription level and resulted in increased resistance to CZA, ceftolozane-tazobactam, cefepime-zidebactam, and cefiderocol. Diversity in the promoter activity of bla PER-1 partially explains the variable susceptibility to CZA in PER-producing isolates.