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

OBJECTIVES

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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.

© The Author(s) 2025. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact [email protected] for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact [email protected].