Progressive Development of Cefiderocol Resistance in Escherichia coli During Therapy Is Associated with Increased blaNDM-5 Copy Number and Gene Expression.

BACKGROUND As cefiderocol is increasingly being prescribed in clinical practice, it is critical that we understand key mechanisms contributing to acquired resistance to this agent. METHODS We report the case of a patient with acute lymphoblastic leukemia with an NDM-5 producing Escherichia coli intra-abdominal infection where resistance to cefiderocol evolved approximately 2 weeks after initiating cefiderocol therapy. Through WGS investigations, mRNA expression studies, and EDTA inhibition analysis, we investigate the role of increased NDM-5 production and genetic mutations contributing to the development of cefiderocol resistance using 5 sequential clinical E. coli isolates obtained from the patient. RESULTS blaNDM-5 genes were identified in all 5 isolates. Cefiderocol MICs were 2, 4, and >32 mcg/mL for isolates 1-2, 3, 4-5, respectively. WGS showed that isolates 1-3 contained a single copy of the blaNDM-5 gene, whereas isolates 4 and 5 had 5 copies and 10 copies of the blaNDM-5 gene on an IncFIA/FIB/IncFII plasmid, respectively. These findings correlated with NDM-5 mRNA expression analysis in which isolates 4 and 5 expressed NDM 1.7x and 2.8x greater than isolate 1. Synergy testing with the combination of ceftazidime-avibactam and aztreonam demonstrated expansion of the zone of inhibition between the disks for all isolates. The patient was eventually successfully treated with this combination and remained infection free 10 months later. CONCLUSIONS Our patient's case suggests that increased copy numbers of bla NDM genes through translocation events is used by Enterobacterales to evade cefiderocol-mediated cell death. The frequency of increased NDM expression in contributing to cefiderocol resistance needs investigation.