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

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 <i>Escherichia coli</i> (CZA-R-<i>Ec</i>) 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-<i>Ec</i> 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 <i>bla</i>_NDM-5 (26/34, 76%); among <i>bla</i>_NDM-5 strains, 88% (23/26) harbored PBP3 YRI(K/N) insertions. Eleven isolates (32%) carried <i>bla</i>_CMY variants, predominantly <i>bla</i>_CMY-42. <i>Bla</i>_NDM-5 and <i>bla</i>_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 <i>E. coli</i> infection (73% vs 0%, <i>P</i>-value = 1.6 × 10^-5). ATM/CZA-NS isolates were strongly associated with <i>bla</i>_CMY carriage (81% vs 9% in ATM/CZA-S; adjusted <i>P</i>-value = 4 × 10^-4). Among 18 confirmed CZA-R-<i>Ec</i> bacteremias, 15 carried <i>bla</i>_NDM; 14/15 (92%) received ATM/CZA and all responded clinically. In conclusion, CZA-R-<i>Ec</i> at our center are dominated by PBP3-insertion, <i>bla</i>_NDM-5-positive lineages, for which ATM/CZA retains substantial <i>in vitro</i> activity and clinical efficacy. However, prior <i>E. coli</i> infection and <i>bla</i>_CMY-42 variant positivity identify patients at risk for ATM/CZA non-susceptible infections.