Multi-carbapenemase-producing Klebsiella pneumoniae: Genomic characterization and In Vitro evaluation of cefiderocol and novel β-lactam/β-lactamase inhibitor combinations.

BACKGROUND: Multi-carbapenemase-producing Klebsiella pneumoniae (MCP-Kp) represents an emerging threat due to its extensive drug resistance and the scarcity of effective therapeutic options. This study characterizes the epidemiology, genomic features, and in vitro activity of novel antimicrobial agents against MCP-Kp isolates recovered from bloodstream infections in Italy.

METHODS AND RESULTS: From 2022 to 2023, a total of 414 non-duplicate carbapenemase-producing K. pneumoniae isolates were collected from 14 Italian hospitals. Antimicrobial susceptibility testing of the MCP-Kp isolates included cefiderocol, aztreonam/avibactam, cefepime/zidebactam, cefepime/enmetazobactam and relevant comparators. Whole-genome sequencing was performed to determine multilocus sequence types (STs), capsule loci, plasmid replicons, resistance determinants, and virulence-associated genes. MCP isolates accounted for 2.4% of all carbapenemase producers and displayed six distinct carbapenemase combinations. Genomic analysis revealed a polyclonal population (ST512, ST147, ST383, ST35, ST320, ST6668) characterized by heterogeneous capsule loci, diverse plasmid replicons, extensive β-lactamase repertoires, porin alterations, and widespread non-β-lactam resistance determinants. Two isolates carried mgrB disruptions associated with colistin resistance. MCP isolates exhibited high-level resistance to most β-lactams and to first- and second-generation β-lactam/β-lactamase inhibitor combinations. Aztreonam/avibactam, cefepime/zidebactam, and cefiderocol retained potent in vitro activity, with susceptibility rates of 100%, 100%, and 80%, respectively. Synergy was consistently observed between aztreonam and ceftazidime/avibactam, meropenem/vaborbactam, or cefepime/enmetazobactam across all aztreonam-resistant, metallo-β-lactamase-producing MCP-Kp isolates.

CONCLUSIONS: MCP-Kp in Italy exhibited substantial genomic diversity and multidrug resistance, driven by horizontal gene transfer and plasmid-mediated dissemination. The preserved activity of aztreonam/avibactam and cefepime/zidebactam, alongside the observed synergistic combinations, underscores promising therapeutic strategies for managing infections caused by these highly resistant pathogens.