Clonal dissemination of Klebsiella pneumoniae resistant to cefiderocol, ceftazidime/avibactam, meropenem/vaborbactam and imipenem/relebactam co-producing KPC and OXA-181 carbapenemase

OBJECTIVES: Herein, we describe the epidemiology of carbapenemase-producing Enterobacterales (CPE) before and during the COVID-19 pandemic. Also, we report the emergence of an outbreak of Klebsiella pneumoniae strains co-producing KPC and OXA-181 carbapenemase, resistant to novel β-lactam/β-lactamase inhibitors (βL-βLICs) and cefiderocol. METHODS: CPE were collected during a period of 3 years from 2019 to 2021. Antimicrobial susceptibility testing for novel βL-βLICs and cefiderocol was performed by MIC test strips and microdilution with iron-depleted broth. WGS was performed on 10 selected isolates using the Illumina platform, and resistome analysis was carried out by a web-based pipeline. RESULTS: Between January 2019 and December 2021, we collected 1430 carbapenemase producers from 957 patients with infections due to CPE. KPC was the most common carbapenemase, followed by VIM, OXA-48 and NDM. During 2021, we identified 78 K. pneumoniae co-producing KPC and OXA-181 carbapenemases in 60 patients, resistant to meropenem/vaborbactam and imipenem/relebactam. Resistance to ceftazidime/avibactam and cefiderocol was observed respectively in 7 and 8 out of the 10 sequenced K. pneumoniae. Genome analysis showed that all isolates were clonally related, shared a common porin and plasmid content, and carried bla(OXA-181) and bla(KPC) carbapenemases. Specifically, 4 out of 10 isolates carried bla(KPC-3), while 6 harboured mutated bla(KPC). Of note, KPC producers resistant to ceftazidime/avibactam and harbouring mutated bla(KPC) exhibited higher MICs of cefiderocol (median MIC 16 mg/L, IQR 16–16) than strains harbouring WT bla(KPC-3) (cefiderocol 9 mg/L, IQR 1.5–16). CONCLUSIONS: Our results highlight the need for continuous monitoring of CPE to limit widespread MDR pathogens carrying multiple mechanisms conferring resistance to novel antimicrobial molecules.