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

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 three consecutive K. pneumoniae isolates revealed that the bacteria were isogenic and were carrying several broad-spectrum beta-lactamases (blaNDM5 and blaCTX-M-15). Two isolates with elevated minimum inhibitory concentration against cefiderocol harbored mutations in genes encoding siderophore: one in the cirA gene and one in both the cirA and the flu genes. The combination of a metallo-beta-lactamase background and mutations in siderophore receptors was associated with phenotypic resistance to cefiderocol. (c) 2024 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)