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

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.