Ceftazidime-Avibactam Resistance in Escherichia coli Primarily Mediated by blaNDM-5 with Emergent Ceftazidime-Avibactam/Aztreonam Resistance Linked to blaCMY-42 Variants

Ceftazidime-avibactam (CZA) has revolutionized care for carbapenem-resistant Enterobacterales infections, yet increasing New Delhi metallo-{beta}-lactamase (NDM) prevalence has driven use of CZA plus aztreonam (CZA/ATM). We performed a comprehensive analysis of CZA-resistant Escherichia coli (CZA-R-Ec) at a tertiary cancer center (2017-2024) by integrating clinical data, comparative genomics, and CZA/ATM susceptibility testing. CZA-R-Ec were isolated from forty-eight 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-{gamma}/K1) in distinct genomic contexts. Among 32 confirmed CZA-R and ATM-R index isolates, 21 (66%) were CZA/ATM synergy positive to CZA/ATM (MIC[≤]4 {micro}g/mL; SYN+). Compared to patients with SYN+ strains, patients with SYN-isolates (CZA/ATM MIC>4 {micro}g/mL) were significantly more likely to have had a prior E. coli infection (73% vs. 0%, P-value=1.6x10-5). SYN- isolates were strongly associated with blaCMY carriage (81% vs 9% in SYN+; adjusted P-value=4x10-4). Among 18 confirmed CZA-R-Ec bacteremias, 15 carried blaNDM; 14/15 (92%) received CZA/ATM and all responded clinically. In conclusion, CZA-R-Ec at our center are dominated by PBP3-insertion, blaNDM-5-positive lineages, for which CZA/ATM retains substantial in vitro activity and clinical efficacy. However, recent carbapenem exposure and prior E. coli infection identifies patients at risk for CZA/ATM non-synergy, frequently linked to blaCMY-42 variant positive isolates.