Molecular and epidemiological characteristics of cefiderocol-resistant Klebsiella pneumoniae: Insights from genomic analysis

OBJECTIVE: To characterize reported cefiderocol (FDC)-resistant Klebsiella pneumoniae through a systematic review and reanalysis of available whole-genome sequencing (WGS) data. METHODS: PubMed, Embase, and Web of Science were searched for original reports of FDC-resistant K. pneumoniae. Epidemiological, susceptibility, molecular, and available WGS data were extracted and reanalysed. Iron-related disruptive events were compared between high- and lower-minimum inhibitory concentration (MIC) groups among eligible non-outbreak isolates. RESULTS: Seventy-five studies reported 779 FDC-resistant K. pneumoniae isolates from 24 countries or regions. Forty-four studies provided WGS data, yielding 145 non-duplicate genomes. The WGS subset comprised 31 sequence types (STs), most commonly ST147, ST16, ST512, and ST307. Carbapenemase genes were detected in 143 genomes, most frequently blaNDM (71/145, 49.0%), blaKPC (65/145, 44.8%), and blaOXA-48-like (31/145, 21.4%); 31 genomes (21.4%) carried carbapenemase genes from two groups. Iron uptake- or regulation-related disruptive events were identified in 59 isolates (40.7%). Among 71 non-outbreak isolates with MIC data, these events were more frequent in the high-MIC group than in the lower-MIC group (78.3% vs. 22.9%; odds ratio = 12.1, 95% confidence interval 3.82-36.18; P < 0.0001), and disruption involving two or more iron-related genes was observed only in the high-MIC group. Among isolates with available data, resistance to ceftazidime-avibactam (105/129, 81.4%) and ceftolozane-tazobactam (75/75, 100%) was frequent, whereas aztreonam-avibactam resistance was detected in 4 of 60 isolates (6.7%). CONCLUSIONS: Available WGS data indicate that reported FDC-resistant K. pneumoniae isolates are genetically diverse, commonly carry complex β-lactamase backgrounds, and harbour candidate iron-related genomic alterations associated with higher FDC MICs.