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

Year: 2026

Type: article

Abstract: 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 bla NDM-5 (26/34, 76%); among bla NDM-5 strains, 88% (23/26) harbored PBP3 YRI(K/N) insertions. Eleven isolates (32%) carried bla CMY variants, predominantly bla CMY-42 . Bla NDM-5 and bla CMY 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 bla CMY carriage (81% vs 9% in ATM/CZA-S; adjusted P -value = 4 × 10 −4 ). Among 18 confirmed CZA-R- Ec bacteremias, 15 carried bla NDM ; 14/15 (92%) received ATM/CZA and all responded clinically. In conclusion, CZA-R- Ec at our center are dominated by PBP3-insertion, bla NDM-5 –positive lineages, for which ATM/CZA retains substantial in vitro activity and clinical efficacy. However, prior E. coli infection and bla CMY-42 variant positivity identify patients at risk for ATM/CZA non-susceptible infections.

Source: Antimicrobial Agents and Chemotherapy

DOI: 10.1128/aac.01860-25