Rapid Emergence of Cefiderocol Resistance Associated with Mutation of EnvZ Gene in a VIM-Producing ST307 Klebsiella pneumoniae Strain

Infections caused by carbapenem-resistant Enterobacterales (CRE), particularly those harboring metallo-β-lactamases (MBLs) such as VIM, constitute a significant public health threat due to the paucity of effective therapeutic options. Cefiderocol (CFD), a novel siderophore-conjugated cephalosporin, exhibits potent activity against CRE by exploiting bacterial iron uptake systems. Nevertheless, the emergence of CFD resistance has been recently documented. This study aimed to characterize the development of CFD resistance in a VIM-producing Klebsiella pneumoniae isolate during antimicrobial treatment. Antimicrobial susceptibility was assessed by broth microdilution using iron-depleted medium according to EUCAST guidelines. Whole-genome sequencing and comparative genomic analyses focused on mutations in genes related to iron transport and CFD resistance, using Illumina MiSeq. Initial isolates (RS, BA1) were susceptible to CFD (MIC 2 mg/L), whereas the isolate recovered after 9 days of CFD therapy (BA2) was resistant (MIC 8 mg/L). In conclusion, this study illustrates for the first time the rapid emergence of CFD resistance in a VIM-producing ST307 K. pneumoniae isolate linked to a missense variant in envZ gene, arising after a 9-day CFD treatment.