An NDM-Producing Escherichia coli Clinical Isolate Exhibiting Resistance to Cefiderocol and the Combination of Ceftazidime-Avibactam and Aztreonam: Another Step Toward Pan--Lactam Resistance

We report the case of a United States patient who traveled to India for a renal transplant and developed pyelonephritis from an NDM-producing Escherichia coli isolate. Mechanisms leading to resistance to cefiderocol and the combination of ceftazidime-avibactam and aztreonam are described. Background Cefiderocol and ceftazidime-avibactam plus aztreonam (CZA-ATM) are preferred treatment regimens for New Delhi metallo-& beta;-lactamase (NDM)-producing infections. Methods We report the case of a US 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 & beta;-lactams, including cefiderocol and CZA-ATM. Whole-genome sequencing investigations were undertaken to identify resistance mechanisms. Results An E. coli isolate belonging to sequence type (ST) 167 containing a bla(NDM-5) gene was identified on a plasmid of the IncFIA/IncFIB/IncFIC replicon groups. When compared with the genome of another ST167 E. coli clinical isolate containing bla(NDM-5) and exhibiting susceptibility to cefiderocol and CZA-ATM, a 12-base pair insertion in ftsI, translating to a 4-amino acid duplication in PBP3, was identified. Moreover, a bla(CMY-59) gene was harbored on an IncI-& gamma; replicon type, and frameshift mutations were identified in the cirA iron transport gene. Conclusions This is the first clinical case of a US patient harboring an NDM-producing isolate exhibiting resistance to all available & beta;-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 bla(CMY) gene (reduced CZA-ATM activity). E. coli ST167 clinical isolates harboring bla(NDM-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-& beta;-lactam resistance may occur.