Clinical and microbiological analysis of bloodstream infections by four cefiderocol-resistant and not previously exposed NDM-producing Klebsiella pneumoniae.

We describe the clinical and microbiological features of four cases of bacteraemia caused by cefiderocol-resistant NDM-producing Klebsiella pneumoniae (NDM-KP), observed at Padua University Hospital, Italy, in four immunocompromised hosts not previously exposed to cefiderocol. Three out of the four cefiderocol-resistant NDM-KP isolates also co-produced OXA-48-like carbapenemases. Cefiderocol susceptibility testing was performed both alone or in combination with EDTA or xeruborbactam, used as NDM inhibitors, following reference microdilution methods in iron-depleted Mueller-Hinton broth. Whole-genome sequencing was conducted to investigate the resistome, virulome, MLST and plasmidome. All patients reported isolates with a primary resistance to cefiderocol. In two cases, clinical failure to cefiderocol occurred before susceptibility results were available. All patients were successfully treated with the aztreonam-avibactam combination. MLST revealed that two isolates belonged to ST14 and two to ST147. No known alterations in iron uptake systems were detected by whole-genome sequencing. However, both ST14 NDM-KP carried a fec operon located on an IncFIIK-IncFIBk plasmid. The addiction of EDTA or xeruborbactam restored cefiderocol susceptibility, suggesting a key role of NDM-1 production in mediating resistance. This case series highlights the urgent need of new therapeutic agents that will overcome the diffusion of NDM-KP resistant to FDC. The emergence of NDM-KP with an acquired fec operon in nosocomial settings, even without a previous drug exposure, may further compromise cefiderocol efficacy. Further studies will be necessary to assess the in vivo activity of xeruborbactam, a new cyclic boronate β-lactamase inhibitor, which may restore cefiderocol susceptibility in NDM-KP isolates.