Clinical and genomic determinants associated with emergent ceftazidime-avibactam plus aztreonam non-susceptibility in ceftazidime-avibactam resistant Escherichia coli

  • Antimicrob Agents Chemother. 2026 May 6;70(5):e0186025. doi: 10.1128/aac.01860-25.
William C Shropshire  1 ,  Jovan Borjan  2 ,  Iris Y Fonseca  3 ,  Kathlyn Pham  3 ,  Melanie Guerrero  3 ,  Karl Liboro  3 ,  Allyson Young  1 ,  Jovelle K Chung  2 ,  Chin-Ting Wu  1  4 ,  Ambrocio Manzanares Jr  5 ,  Micah M Bhatti  5 ,  Nancy N Vuong  2 ,  Guy Handley  1  4 ,  Amy Spallone  1  4 ,  Roy F Chemaly  1 ,  Ayesha Khan  3 ,  Samuel Shelburne  1  6  7
Affiliations
  • 1. Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
  • 2. Division of Pharmacy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
  • 3. Department of Pathology and Laboratory Medicine, School of Medicine, University of California Irvine, Irvine, California, USA.
  • 4. Department of Infection Control, Chief Quality Office, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
  • 5. Department of Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
  • 6. Program in Diagnostic Genetics and Genomics, The University of Texas MD Anderson Cancer Center School of Health Professions, Houston, Texas, USA.
  • 7. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
PMID: 41870042 DOI: 10.1128/aac.01860-25
Abstract

Ceftazidime-avibactam (CZA) has revolutionized care for carbapenem-resistant Enterobacterales infections, yet increasing New Delhi Metallo-β-lactamase (NDM) prevalence has driven use of CZA plus aztreonam (ATM/CZA). We performed a comprehensive clinical and genomic analysis of ceftazidime-avibactam-resistant Escherichia coli (CZA-R-Ec) collected at a tertiary Cancer center (2017-2024) to identify patient- and isolate-level factors associated with reduced susceptibility to ATM/CZA and aztreonam-avibactam (AZA). CZA-R-Ec were isolated from 48 unique patients of whom 28 (58%) had confirmed Infection. Oxford Nanopore Technologies long-read Sequencing performed on 34 isolates from unique patients showed a diverse population enriched for ST167 (35%). Most sequenced isolates carried blaNDM-5 (26/34, 76%); among blaNDM-5 strains, 88% (23/26) harbored PBP3 YRI(K/N) insertions. Eleven isolates (32%) carried blaCMY variants, predominantly blaCMY-42. BlaNDM-5 and blaCMY genes were largely plasmid-borne (IncF-type and IncI-γ/K1) in distinct genomic contexts. Among 32 confirmed CZA-R and ATM-R index isolates, 21 (66%) were ATM/CZA susceptible (MIC≤4 µg/mL; ATM/CZA-S). Compared to patients with ATM/CZA-S strains, patients with ATM/CZA non-susceptible (ATM/CZA-NS) isolates (ATM/CZA MIC>4 µg/mL) were significantly more likely to have had a prior E. coli Infection (73% vs 0%, P-value = 1.6 × 10-5). ATM/CZA-NS isolates were strongly associated with blaCMY carriage (81% vs 9% in ATM/CZA-S; adjusted P-value = 4 × 10-4). Among 18 confirmed CZA-R-Ec bacteremias, 15 carried blaNDM; 14/15 (92%) received ATM/CZA and all responded clinically. In conclusion, CZA-R-Ec at our center are dominated by PBP3-insertion, blaNDM-5-positive lineages, for which ATM/CZA retains substantial in vitro activity and clinical efficacy. However, prior E. coli Infection and blaCMY-42 variant positivity identify patients at risk for ATM/CZA non-susceptible infections.

Keywords
avibactam/aztreonam; ceftazidime/avibactam; ceftazidime/avibactam plus aztreonam; metallo-beta-lactamases; novel beta-lactam/beta-lactamase inhibitors; plasmid mediated AmpC genes.
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