Mutations Leading to Ceftolozane/Tazobactam and Imipenem/Cilastatin/Relebactam Resistance Duringin vivoexposure to Ceftazidime/Avibactam inPseudomonas aeruginosa

Abstract

ABSTRACTIdentifying 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 longitudinalPseudomonas aeruginosathat developed imipenem/cilastatin/relebactam and ceftolozane/tazobactam resistance during ceftazidime/avibactam treatment, we determined mutations resulting in cross-resistance. Penicillin-binding proteinftsI, transcriptional repressorbepR, and virulence regulatorpvdSwere found in resistant isolates. We conclude that peptidoglycan synthesis gene mutations can alter the efficacy of multiple antimicrobials.