Progressive Development of Cefiderocol Resistance in Escherichia coli During Therapy is Associated With an Increase in 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 describe a patient with acute lymphoblastic leukemia and a New Delhi metallo-ss-lactamase (NDM)-5-producing Escherichia coli intra-abdominal infection in whom resistance to cefiderocol evolved approximately 2 weeks after the start of treatment. Through whole-genome sequencing (WGS), messenger RNA expression studies, and ethylenediaminetetraacetic acid inhibition analysis, we investigated 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 In all 5 isolates, bla(NDM-5) genes were identified. The minimum inhibitory concentrations for cefiderocol were 2, 4, and >32 mu g/mL for isolates 1-2, 3, and 4-5, respectively. WGS showed that isolates 1-3 contained a single copy of the bla(NDM-5) gene, whereas isolates 4 and 5 had 5 and 10 copies of the bla(NDM-5) gene, respectively, on an IncFIA/FIB/IncFII plasmid. These findings were correlated with those of bla(NDM-5) messenger RNA expression analysis, in which isolates 4 and 5 expressed bla(NDM-5) 1.7- and 2.8-fold, respectively, compared to, 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 successfully treated with this combination and remained infection free 1 year later. Conclusions The findings in our patient suggest that increased copy numbers of bla (NDM) genes through translocation events are used by Enterobacterales to evade cefiderocol-mediated cell death. The frequency of increased bla(NDM-5) expression in contributing to cefiderocol resistance needs investigation. In a patient infected with a New Delhi metallo-ss-lactamase-producing Escherichia coliisolate, whole-genome sequencing, messenger RNA expression studies, and ethylenediaminetetraacetic acid inhibition work uncovered the mechanisms that led to relatively rapid development of cefiderocol resistance.

Automated summary

This study revealed the mechanisms by which New Delhi metallo-β-lactamase-producing Escherichia coli isolate developed relatively rapid resistance to cefiderocol through increased copy numbers of bla(NDM) genes. The findings highlight the importance of investigating increased bla(NDM-5) expression frequency in contributing to cefiderocol resistance.