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. 2023 May 17;10(7):ofad276.
doi: 10.1093/ofid/ofad276. eCollection 2023 Jul.

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  1 , Yehudit Bergman  1 , Rick Conzemius  2 , Emily Jacobs  1 , Tsigereda Tekle  1 , Stephan Beisken  2 , Pranita D Tamma  3
Affiliations

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 et al. Open Forum Infect Dis. .

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-γ 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 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.

Keywords: PBP3; antimicrobial resistance; aztreonam; cefiderocol; ceftazidime-avibactam.

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Conflict of interest statement

Potential conflicts of interest. P.J.S. reports grants and personal fees from Accelerate Diagnostics, OpGen, Inc., and BD Diagnostics; grants from bioMerieux, Inc., Affinity Biosensors, and Hardy Diagnostics; and personal fees from Roche Diagnostics, Shionogi, Inc., GeneCapture, outside the submitted work. R.C. and S.B. are employees of Ares Genetics. All other authors have nothing to disclose.

Figures

Figure 1.
Figure 1.
Disk approximation method evaluating for increased activity of ceftazidime-avibactam and aztreonam, compared to aztreonam alone.
Figure 2.
Figure 2.
Broth disk elution results testing for susceptibility of (A) growth control in the absence of any disks, (B) aztreonam (30 µg), (C) ceftazidime-avibactam (30/20 µg), and (D) the combination of ceftazidime-avibactam (30/20 µg) and aztreonam (30 µg), inoculated with the patient's clinical Escherichia coli isolate, from left to right.
See this image and copyright information in PMC

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