{"doi":"10.1093/jacamr/dlae141","title":"Emergence of high-level aztreonam–avibactam and cefiderocol resistance following treatment of an NDM-producing <i>Escherichia coli</i> bloodstream isolate exhibiting reduced susceptibility to both agents at baseline","abstract":"Abstract Background Cefiderocol (FDC) or ceftazidime-avibactam with aztreonam (CZA-ATM) are frontline agents for New Delhi metallo-β-lactamase (NDM)-producing Enterobacterales; however, clinical data are scarce, and mechanisms of treatment-emergent resistance are ill-defined. Our objectives were to characterize serial isolates and stool microbiota from a liver transplant recipient with NDM-producing Escherichia coli bacteraemia. Methods Isolates collected pre- and post-CZA–ATM treatment underwent broth microdilution susceptibility testing and whole-genome sequencing. Longitudinal stool collected during CZA–ATM therapy underwent metagenomic sequencing (Nanopore MinION). Results The baseline isolate exhibited elevated MICs for ATM–AVI (16/4 µg/mL) and FDC (8 µg/mL). Posttreatment, a rectal surveillance isolate exhibited high-level resistance to ATM–AVI (&amp;gt; 128/4 µg/mL) and FDC (32 µg/mL). Both isolates belonged to ST361 and harboured WT blaNDM-5. The baseline isolate contained wild type (WT) blaCMY-145 and mutations in ftsI (which encodes PBP3), including a YRIN insertion at residue 338 and the non-synonymous substitutions Q227H, E353K and I536L. The posttreatment isolate harboured new mutations in ftsI (A417 V) and blaCMY-145 (L139R and N366Y). Analysis of four stool samples collected during CZA–ATM treatment revealed high E. coli abundance. E. coli relative abundance increased from 34.5% (first sample) to 61.9% (last sample). Conclusions Baseline mutations in ftsI were associated with reduced susceptibility to ATM–AVI and FDC in an ST361 NDM-5-producing E. coli bloodstream isolate. High-level resistance was selected after CZA–ATM treatment, resulting in new ftsl and blaCMY-145 mutations. These findings underscore the need for ATM–AVI susceptibility testing for NDM producers, and the potential for PBP3 mutations to confer cross-resistance to ATM–AVI and FDC, which can emerge after CZA–ATM treatment.","journal":"JAC-Antimicrobial Resistance","year":2024,"id":422339,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":27,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.954,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":282878,"name":"Ellen G Kline","orcid":"0009-0006-7167-6368","position":1,"is_corresponding":false},{"id":16243,"name":"Georgios D. Kitsios","orcid":"0000-0002-1018-948X","position":2,"is_corresponding":false},{"id":1216020,"name":"Xiaohong Wang","orcid":"0000-0002-8755-2531","position":3,"is_corresponding":false},{"id":346506,"name":"E.J. Kwak","orcid":null,"position":4,"is_corresponding":false},{"id":896662,"name":"Anthony Newbrough","orcid":null,"position":5,"is_corresponding":false},{"id":1216644,"name":"Kelly Friday","orcid":null,"position":6,"is_corresponding":false},{"id":645856,"name":"Kailey Hughes Kramer","orcid":"0000-0002-7028-6062","position":7,"is_corresponding":false},{"id":282876,"name":"Ryan K. Shields","orcid":"0000-0001-9794-5665","position":8,"is_corresponding":false},{"id":536897,"name":"Ghady Haidar","orcid":"0000-0003-0634-8211","position":0,"is_corresponding":true}],"reference_count":22,"raw_metadata":null,"created_at":"2026-07-19T01:57:46.393290Z","pmid":"39239090","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}