Progressive Development of Cefiderocol Resistance in Escherichia coli During Therapy is Associated With an Increase in blaNDM-5 Copy Number and Gene Expression

Abstract

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.

New Delhi Metallo-Beta-Lactamase Facilitates the Emergence of Cefiderocol Resistance in Enterobacter cloacae

“…S1). Besides cirA mutation, cefiderocol resistance in Enterobacterales, specifically in Escherichia coli , has been attributed to the increased copy number and expression of the bla NDM gene ( 16 ). Therefore, we investigated the abundance of the bla NDM gene copy number using gene coverage from whole-genome sequencing (WGS) data normalized to the chromosomal gyrB as a proxy.…”

“…Although cefiderocol resistance in Enterobacterales can still be considered rare, reports on the emergence of cefiderocol resistance Enterobacterales are cumulating ( 11 , 16 , 24 ). In Klebsiella pneumoniae and E. cloacae , the acquisition of cefiderocol resistance has been linked with mutations in the cirA gene, whereas, in E. coli , the emergence of cefiderocol resistance was associated with an increase in the bla NDM-5 copy number and gene expression.…”

“…Still, it did not entirely reduce the cefiderocol MIC to the baseline level so that both cirA mutation and NDM-5 activity may have an additive influence on the resistance phenotype. Of note, the emergence of cefiderocol resistance in Enterobacterales so far has been associated with the presence of bla NDM-5 on multiple occasions ( 11 , 16 , 24 ). Indeed, NDM-5 has been described to have increased hydrolysis activity toward β-lactam antibiotics than the NDM-1 variant ( 25 ).…”

Place in Therapy of the Newly Available Armamentarium for Multi-Drug-Resistant Gram-Negative Pathogens: Proposal of a Prescription Algorithm

“…Moreover, a case of a NDM producing E. col i intra-abdominal infection in a hematopoietic stem cell transplant recipient was reported where CFDC resistance evolved after 19 days of administration. Whole genome sequencing analysis indicated a bla NDM-5 copy number increase that reduced CFDC susceptibility [ 66 ].…”

Treatment of Severe Infections Due to Metallo-Betalactamases Enterobacterales in Critically Ill Patients

“…In vivo acquired resistance to cefiderocol has been already reported [ 36 ] due to an increase in the copies of blaNDM5 gene of E. coli, resulting in a clinical failure to treat an intra-abdominal infection, which was eventually successfully treated by a combination of CZA/ATM.…”