LAUSR

Cefiderocol and ceftazidime-avibactam plus aztreonam (CZA-ATM) are preferred treatment regimens for NDM-producing infections. We report the case of a United States patient who traveled to India to receive a renal transplant. He subsequently experienced pyelonephritis by an NDM-producing Escherichia coli. Broth microdilution and the broth disk elution method indicated resistance to all β-lactams, including cefiderocol and CZA-ATM. WGS investigations were undertaken to identify resistance mechanisms. An E. coli isolate belonging to sequence type (ST) 167 containing a blaNDM-5 gene was identified on a plasmid of the IncFIA/IncFIB/IncFIC replicon groups. When compared to the genome of another ST167 E. coli clinical isolate containing blaNDM-5 and exhibiting susceptibility to cefiderocol and CZA-ATM, a 12 base pair insertion in ftsI, translating to a four amino acid duplication in PBP3 was identified. Moreover, a blaCMY-59 gene was harbored on an IncI-γ replicon type and frameshift mutations were identified in the cirA iron transport gene. This is the first clinical case of a United States patient harboring an NDM-producing isolate exhibiting resistance to all available β-lactam agents. The isolate’s unexpected resistance to cefiderocol and CZA-ATM was likely due to a combination of (1) a modified PBP3 (increased MICs to both regimens), (2) truncated iron-binding protein (increased cefiderocol MIC), and (3) a blaCMY gene (reduced CZA-ATM activity). E. coli ST167 clinical isolates harboring blaNDM-5 genes are a recognized international high-risk clone. When coupled with the additional mechanisms identified in our patient’s isolate, which is not uncommon for this high-risk clone, pan-β-lactam resistance may occur.