{"doi":"10.1093/cid/ciab888","title":"Progressive Development of Cefiderocol Resistance in <i>Escherichia coli</i> During Therapy is Associated With an Increase in <i>bla</i>NDM-5 Copy Number and Gene Expression","abstract":"BACKGROUND: As cefiderocol is increasingly being prescribed in clinical practice, it is critical that we understand key mechanisms contributing to acquired resistance to this agent. METHODS: We describe a patient with acute lymphoblastic leukemia and a New Delhi metallo-ß-lactamase (NDM)-5-producing Escherichia coli intra-abdominal infection in whom resistance to cefiderocol evolved approximately 2 weeks after the start of treatment. Through whole-genome sequencing (WGS), messenger RNA expression studies, and ethylenediaminetetraacetic acid inhibition analysis, we investigated the role of increased NDM-5 production and genetic mutations contributing to the development of cefiderocol resistance, using 5 sequential clinical E. coli isolates obtained from the patient. RESULTS: In all 5 isolates, blaNDM-5 genes were identified. The minimum inhibitory concentrations for cefiderocol were 2, 4, and >32 μg/mL for isolates 1-2, 3, and 4-5, respectively. WGS showed that isolates 1-3 contained a single copy of the blaNDM-5 gene, whereas isolates 4 and 5 had 5 and 10 copies of the blaNDM-5 gene, respectively, on an IncFIA/FIB/IncFII plasmid. These findings were correlated with those of blaNDM-5 messenger RNA expression analysis, in which isolates 4 and 5 expressed blaNDM-5 1.7- and 2.8-fold, respectively, compared to, isolate 1. Synergy testing with the combination of ceftazidime-avibactam and aztreonam demonstrated expansion of the zone of inhibition between the disks for all isolates. The patient was successfully treated with this combination and remained infection free 1 year later. CONCLUSIONS: The findings in our patient suggest that increased copy numbers of blaNDM genes through translocation events are used by Enterobacterales to evade cefiderocol-mediated cell death. The frequency of increased blaNDM-5 expression in contributing to cefiderocol resistance needs investigation.","journal":"Clinical Infectious Diseases","year":2021,"id":148985,"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":115,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9624,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":251887,"name":"Heba H. Mostafa","orcid":"0000-0002-0274-8966","position":1,"is_corresponding":false},{"id":573746,"name":"Yehudit Bergman","orcid":"0000-0002-4262-7173","position":2,"is_corresponding":false},{"id":634110,"name":"Michael Ante","orcid":"0000-0001-5803-2409","position":3,"is_corresponding":false},{"id":604328,"name":"Tsigereda Tekle","orcid":null,"position":4,"is_corresponding":false},{"id":635366,"name":"Ayomikun Adebayo","orcid":null,"position":5,"is_corresponding":false},{"id":634111,"name":"Stephan Beisken","orcid":"0000-0002-2412-4118","position":6,"is_corresponding":false},{"id":634112,"name":"Kathryn Dzintars","orcid":"0000-0003-4407-2826","position":7,"is_corresponding":false},{"id":287739,"name":"Pranita D. Tamma","orcid":"0000-0002-4143-6324","position":8,"is_corresponding":false},{"id":305631,"name":"Patricia J. Simner","orcid":"0000-0001-6134-151X","position":0,"is_corresponding":true}],"reference_count":34,"raw_metadata":null,"created_at":"2026-07-18T23:42:51.282401Z","pmid":"34618008","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":[]}