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

Abstract

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. 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. 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 blaOXA-181 and blaKPC carbapenemases. Specifically, 4 out of 10 isolates carried blaKPC-3, while 6 harboured mutated blaKPC. Of note, KPC producers resistant to ceftazidime/avibactam and harbouring mutated blaKPC exhibited higher MICs of cefiderocol (median MIC 16 mg/L, IQR 16-16) than strains harbouring WT blaKPC-3 (cefiderocol 9 mg/L, IQR 1.5-16). Our results highlight the need for continuous monitoring of CPE to limit widespread MDR pathogens carrying multiple mechanisms conferring resistance to novel antimicrobial molecules.