{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T20:59:21Z","timestamp":1793134761074,"version":"4.5.0"},"reference-count":39,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2020,6,8]],"date-time":"2020-06-08T00:00:00Z","timestamp":1591574400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 AI121400"],"award-info":[{"award-number":["R01 AI121400"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["K24-AI121296"],"award-info":[{"award-number":["K24-AI121296"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AI134637"],"award-info":[{"award-number":["R01AI134637"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21AI143229"],"award-info":[{"award-number":["R21AI143229"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>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 \u03b2-lactam binding affinity in HOU503 versus R497.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>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 \u03b2-lactam binding affinity of PBP5 of HOU503 compared with that of R497.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>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 \u03b2-lactam therapy.<\/jats:p><\/jats:sec>","DOI":"10.1093\/infdis\/jiaa319","type":"journal-article","created":{"date-parts":[[2020,6,2]],"date-time":"2020-06-02T19:09:59Z","timestamp":1591124999000},"page":"1531-1539","source":"Crossref","is-referenced-by-count":20,"title":["Mechanistic Insights Into the Differential Efficacy of Daptomycin Plus \u03b2-Lactam Combinations Against Daptomycin-Resistant Enterococcus faecium"],"prefix":"10.1093","volume":"222","author":[{"given":"Razieh","family":"Kebriaei","sequence":"first","affiliation":[{"name":"Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy & Health Sciences, Detroit, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle C","family":"Stamper","sequence":"additional","affiliation":[{"name":"Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy & Health Sciences, Detroit, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kavindra V","family":"Singh","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, UTHealth McGovern Medical School, Houston, Texas, USA"},{"name":"Center for Antimicrobial Resistance and Microbial Genomics, UTHealth McGovern Medical School, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayesha","family":"Khan","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, UTHealth McGovern Medical School, Houston, Texas, USA"},{"name":"Center for Antimicrobial Resistance and Microbial Genomics, UTHealth McGovern Medical School, Houston, Texas, USA"},{"name":"Department of Microbiology and Molecular Genetics, UTHealth McGovern Medical School, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seth A","family":"Rice","sequence":"additional","affiliation":[{"name":"Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy & Health Sciences, Detroit, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"An Q","family":"Dinh","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, UTHealth McGovern Medical School, Houston, Texas, USA"},{"name":"Center for Antimicrobial Resistance and Microbial Genomics, UTHealth McGovern Medical School, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Truc T","family":"Tran","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, UTHealth McGovern Medical School, Houston, Texas, USA"},{"name":"Center for Antimicrobial Resistance and Microbial Genomics, UTHealth McGovern Medical School, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara E","family":"Murray","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, UTHealth McGovern Medical School, Houston, Texas, USA"},{"name":"Center for Antimicrobial Resistance and Microbial Genomics, UTHealth McGovern Medical School, Houston, Texas, USA"},{"name":"Department of Microbiology and Molecular Genetics, UTHealth McGovern Medical School, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cesar A","family":"Arias","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, UTHealth McGovern Medical School, Houston, Texas, USA"},{"name":"Center for Antimicrobial Resistance and Microbial Genomics, UTHealth McGovern Medical School, Houston, Texas, USA"},{"name":"Department of Microbiology and Molecular Genetics, UTHealth McGovern Medical School, Houston, Texas, USA"},{"name":"Center for Infectious Diseases, UTHealth School of Public Health, Houston, Texas, USA"},{"name":"Molecular Genetics and Antimicrobial Resistance Unit, International Center for Microbial Genomics; Universidad El Bosque, Bogot\u00e1, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J","family":"Rybak","sequence":"additional","affiliation":[{"name":"Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy & Health Sciences, Detroit, Michigan, USA"},{"name":"School of Medicine, Wayne State University, Detroit, Michigan, 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