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

Patricia J. Simner, Yehudit Bergman, Rick Conzemius, Emily Jacobs, Tsigereda Tekle, Stephan Beisken, Pranita D. Tamma*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Background: Cefiderocol and ceftazidime-avibactam plus aztreonam (CZA-ATM) are preferred treatment regimens for New Delhi metallo-β-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 β-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 blaNDM-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 blaNDM-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 blaCMY-59 gene was harbored on an IncI-γreplicon 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 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.

Original languageAmerican English
Article numberofad276
JournalOpen Forum Infectious Diseases
Volume10
Issue number7
DOIs
StatePublished - 1 Jul 2023
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2023 The Author(s).

Keywords

  • PBP3
  • antimicrobial resistance
  • aztreonam
  • cefiderocol
  • ceftazidime-avibactam

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