Mutations Leading to Ceftolozane/Tazobactam and Imipenem/Cilastatin/Relebactam Resistance During in vivo exposure to Ceftazidime/Avibactam in Pseudomonas aeruginosa

Identifying resistance mechanisms to novel antimicrobials informs treatment and antimicrobial development, but frequently identifies multiple candidate resistance mutations without resolving the driver mutation. Using whole genome sequencing of longitudinal Pseudomonas aeruginosa that developed imipenem/cilastatin/relebactam and ceftolozane/tazobactam resistance during ceftazidime/avibactam treatment, we determined mutations resulting in cross-resistance. Penicillin-binding protein ftsI, transcriptional repressor bepR, and virulence regulator pvdS were found in resistant isolates. We conclude that peptidoglycan synthesis gene mutations can alter the efficacy of multiple antimicrobials.