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We performed a comprehensive clinical and genomic analysis of ceftazidime\u2013avibactam-resistant\n Escherichia coli<\/jats:italic>\n (CZA-R-\n Ec<\/jats:italic>\n ) collected at a tertiary cancer center (2017\u20132024) to identify patient- and isolate-level factors associated with reduced susceptibility to ATM\/CZA and aztreonam\u2013avibactam (AZA). CZA-R-\n Ec<\/jats:italic>\n 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\n bla<\/jats:italic>\n NDM-5<\/jats:sub>\n (26\/34, 76%); among\n bla<\/jats:italic>\n NDM-5<\/jats:sub>\n strains, 88% (23\/26) harbored PBP3 YRI(K\/N) insertions. Eleven isolates (32%) carried\n bla<\/jats:italic>\n CMY<\/jats:sub>\n variants, predominantly\n bla<\/jats:italic>\n CMY-42<\/jats:sub>\n .\n Bla<\/jats:italic>\n NDM-5<\/jats:sub>\n and\n bla<\/jats:italic>\n CMY<\/jats:sub>\n genes were largely plasmid-borne (IncF-type and IncI-\u03b3\/K1) in distinct genomic contexts. Among 32 confirmed CZA-R and ATM-R index isolates, 21 (66%) were ATM\/CZA susceptible (MIC\u22644 \u00b5g\/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 \u00b5g\/mL) were significantly more likely to have had a prior\n E. coli<\/jats:italic>\n infection (73% vs 0%,\n P<\/jats:italic>\n -value = 1.6 \u00d7 10\n \u22125<\/jats:sup>\n ). ATM\/CZA-NS isolates were strongly associated with\n bla<\/jats:italic>\n CMY<\/jats:sub>\n carriage (81% vs 9% in ATM\/CZA-S; adjusted\n P<\/jats:italic>\n -value = 4 \u00d7 10\n \u22124<\/jats:sup>\n ). Among 18 confirmed CZA-R-\n Ec<\/jats:italic>\n bacteremias, 15 carried\n bla<\/jats:italic>\n NDM<\/jats:sub>\n ; 14\/15 (92%) received ATM\/CZA and all responded clinically. In conclusion, CZA-R-\n Ec<\/jats:italic>\n at our center are dominated by PBP3-insertion,\n bla<\/jats:italic>\n NDM-5<\/jats:sub>\n \u2013positive lineages, for which ATM\/CZA retains substantial\n in vitro<\/jats:italic>\n activity and clinical efficacy. However, prior\n E. coli<\/jats:italic>\n infection and\n bla<\/jats:italic>\n CMY-42<\/jats:sub>\n variant positivity identify patients at risk for ATM\/CZA non-susceptible infections.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1128\/aac.01860-25","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T13:01:53Z","timestamp":1774270913000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["Clinical and genomic determinants associated with emergent ceftazidime\u2013avibactam plus aztreonam non-susceptibility in ceftazidime-avibactam resistant\n Escherichia coli<\/i>"],"prefix":"10.1128","volume":"70","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8556-3248","authenticated-orcid":true,"given":"William C.","family":"Shropshire","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04twxam07","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Infectious 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