{"doi":"10.1093/infdis/jiaa319","title":"Mechanistic Insights Into the Differential Efficacy of Daptomycin Plus β-Lactam Combinations Against Daptomycin-Resistant Enterococcus faecium","abstract":"BACKGROUND: The combination of daptomycin (DAP) plus ampicillin (AMP), ertapenem (ERT), or ceftaroline has been demonstrated to be efficacious against a DAP-tolerant Enterococcus faecium strain (HOU503). However, the mechanism for the efficacy of these combinations against DAP-resistant (DAP-R) E. faecium strains is unknown. METHODS: We investigated the efficacy of DAP in combination with AMP, ERT, ceftaroline, ceftriaxone, or amoxicillin against DAP-R E. faecium R497 using established in vitro and in vivo models. We evaluated pbp expression, levels of penicillin-binding protein (PBP) 5 (PBP5) and β-lactam binding affinity in HOU503 versus R497. RESULTS: DAP plus AMP was the only efficacious regimen against DAP-R R497 and prevented emergence of resistance. DAP at 8, 6, and 4 mg/kg in combination with AMP was efficacious but showed delayed killing compared with 10 mg/kg. PBP5 of HOU503 exhibited amino acid substitutions in the penicillin-binding domain relative to R497. No difference in pbp mRNA or PBP5 levels was detected between HOU503 and R497. labeling of PBPs with Bocillin FL, a fluorescent penicillin derivative, showed increased β-lactam binding affinity of PBP5 of HOU503 compared with that of R497. CONCLUSIONS: Only DAP (10 mg/kg) plus AMP or amoxicillin was efficacious against a DAP-R E. faecium strain, and pbp5 alleles may be important contributors to efficacy of DAP plus β-lactam therapy.","journal":"The Journal of Infectious Diseases","year":2020,"id":70452,"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":19,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9564,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":373187,"name":"Kyle Stamper","orcid":null,"position":1,"is_corresponding":false},{"id":372459,"name":"Kavindra V. Singh","orcid":"0000-0003-3005-3982","position":2,"is_corresponding":false},{"id":372460,"name":"Ayesha Khan","orcid":"0000-0002-0489-0712","position":3,"is_corresponding":false},{"id":373188,"name":"Seth Rice","orcid":null,"position":4,"is_corresponding":false},{"id":232752,"name":"An Q Dinh","orcid":"0000-0002-2965-9269","position":5,"is_corresponding":false},{"id":343887,"name":"Truc T. Tran","orcid":"0000-0002-2696-4196","position":6,"is_corresponding":false},{"id":294610,"name":"Barbara E. Murray","orcid":"0000-0003-4461-6870","position":7,"is_corresponding":false},{"id":232742,"name":"César A. Arias","orcid":"0000-0001-9054-9774","position":8,"is_corresponding":false},{"id":348336,"name":"Michael J. Rybak","orcid":"0000-0003-2220-0081","position":9,"is_corresponding":false},{"id":372458,"name":"Razieh Kebriaei","orcid":"0000-0003-4019-2679","position":0,"is_corresponding":true}],"reference_count":39,"raw_metadata":null,"created_at":"2026-07-18T21:43:11.119231Z","pmid":"32514561","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":[]}