Emergence of cefiderocol resistance during therapy in NDM-5-producing Klebsiella pneumoniae isolates harboring siderophore receptors mutations

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Cefiderocol, a siderophore-conjugated cephalosporine, is a promising drug used to treat infection with carbapenem-resistant Gram-negative bacteria. Here, we report a case of pneumonia induced by multiple Gram-negative pathogens including a carbapenem-resistant Klebsiella pneumoniae developing cefiderocol resistance within 32 days of cefiderocol therapy. Whole genome sequencing of 3 consecutive K. pneumoniae isolates revealed the bacteria were isogenic and were carrying several broad-spectrum β-lactamases (blaNDM5 and blaCTX-M-15). Two isolates with elevated MIC against cefiderocol harbored mutations in genes encoding siderophore: one in the cirA gene, and one in both the cirA and the fiu genes. The combination of a metallo-β-lactamase background and mutations in siderophore receptors was associated with phenotypic resistance to cefiderocol.