{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T20:55:13Z","timestamp":1790283313812,"version":"4.1.0"},"reference-count":69,"publisher":"American Society for Microbiology","issue":"12","license":[{"start":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T00:00:00Z","timestamp":1765324800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T00:00:00Z","timestamp":1765324800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100006710","name":"Wayne State University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100006710","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2025,12,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      The rise of bacterial resistance has driven the exploration of novel therapies, such as bacteriophage-antibiotic cocktails (PACs), which have shown\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      promise against resistant pathogens, including daptomycin non-susceptible-methicillin-resistant\n                      <jats:italic toggle=\"yes\">Staphylococcus aureus<\/jats:italic>\n                      (DNS-MRSA) strains. While daptomycin has been a cornerstone for treating MRSA bacteremia and vancomycin-refractory infective endocarditis, the emergence of DNS-MRSA presents a significant challenge due to high morbidity, mortality, and rapid intrinsic resistance development. Phages, Intesti13 and Sb-1, were selected for their unique host range and activity against sixteen DNS-MRSA strains. Synergy with antibiotics was assessed via growth suppression curves and 24-hour time-kill assays (TKAs) across varying administration sequences and minimum inhibitory concentration (MIC) increments. Selected regimens were further assessed in an\n                      <jats:italic toggle=\"yes\">ex vivo<\/jats:italic>\n                      simulated endocardial vegetation (SEV) model, with pharmacokinetic analyses confirming target antibiotic concentrations. In the\n                      <jats:italic toggle=\"yes\">ex vivo<\/jats:italic>\n                      SEV model, simultaneous PAC administration using daptomycin \u00b1 phage showed superior bactericidal activity over sequential treatments in isolate C6 (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &lt; 0.01). Similarly, in the same model, C2 reached detection limits within 48 h and remained suppressed for 120 h (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &lt; 0.0037). Sequential outcomes varied by phage-antibiotic order and antibiotic choice. Simultaneous and phage-first regimens outperformed antibiotic-first, especially in 24 h TKAs, but showed variability at lower MICs and between\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">ex vivo<\/jats:italic>\n                      settings. This study highlights PAC\u2019s potential for DNS-MRSA treatment, emphasizing the importance of administration timing. The observed differences across clinical strains emphasize the need for strain-specific evaluations and a deeper understanding of phage-antibiotic interactions to optimize therapy. Future research must focus on expanding phage diversity, refining protocols, and clinically validating sequential strategies to enhance PAC efficacy.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/aac.00699-25","type":"journal-article","created":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T13:00:36Z","timestamp":1763470836000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":2,"title":["Optimizing phage-antibiotic combinations: impact of administration order against daptomycin non-susceptible (DNS) MRSA clinical isolates"],"prefix":"10.1128","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-6232-6804","authenticated-orcid":false,"given":"Callan R.","family":"Bleick","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01070mq45","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pharmacy Practice, Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University","place":["Detroit, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2277-7089","authenticated-orcid":true,"given":"Sean R.","family":"Van Helden","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01070mq45","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pharmacy Practice, Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University","place":["Detroit, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5658-1973","authenticated-orcid":true,"given":"Andrew D.","family":"Berti","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01070mq45","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pharmacy Practice, Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University","place":["Detroit, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Richa","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01070mq45","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pharmacy Practice, Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University","place":["Detroit, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5831-8148","authenticated-orcid":true,"given":"Susan M.","family":"Lehman","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01070mq45","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Biologics Evaluation and Research, US Food and Drug Administration","place":["Silver Spring, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1968-0192","authenticated-orcid":true,"given":"Arnold S.","family":"Bayer","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01e4byj08","id-type":"ROR","asserted-by":"publisher"}],"name":"The Department of Medicine, David Geffen School of Medicine at UCLA","place":["Los Angeles, USA"]},{"id":[{"id":"https:\/\/ror.org\/01070mq45","id-type":"ROR","asserted-by":"publisher"}],"name":"The Lundquist Institution for Biomedical Innovation at Harbor-UCLA","place":["Torrance, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2220-0081","authenticated-orcid":true,"given":"Michael J.","family":"Rybak","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01070mq45","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pharmacy Practice, Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University","place":["Detroit, USA"]},{"name":"Department of Pharmacy Services, Detroit Receiving Hospital, Detroit Medical Center","place":["Detroit, USA"]},{"id":[{"id":"https:\/\/ror.org\/025j2nd68","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Medicine, Division of Infectious Diseases, Wayne State University","place":["Detroit, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13054-017-1801-3"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.05022-11"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkq050"},{"key":"e_1_3_3_5_2","unstructured":"CDC. 2023. Antimicrobial resistance and patient safety portal: daptomycin-resistant MRSA 2011-2021. Available from: https:\/\/arpsp.cdc.gov\/profile\/antibiotic-resistance\/daptomycin-resistant-mrsa"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciq146"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000000296"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10096-016-2581-4"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijmm.2013.02.009"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.3390\/antibiotics12010087"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2024.1453233"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00284-023-03579-4"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.3390\/antibiotics11050570"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1093\/ofid\/ofad500.136"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1093\/ofid\/ofad500.1734"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/spectrum.00679-24"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.3390\/antibiotics11070839"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1128\/aac.01388-23"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.03396-23"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02071-21"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.3390\/antibiotics11030392"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.3390\/antibiotics12081329"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01863-20"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.3390\/antibiotics12030593"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.3390\/antibiotics10070849"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1128\/spectrum.03212-23"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1128\/spectrum.00411-22"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.01462-20"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2018.00127"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.3390\/v14071542"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1128\/spectrum.04918-22"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.3390\/v15010017"},{"key":"e_1_3_3_33_2","volume-title":"Genome assembly ASM755669v1","author":"(NCBI) NCfBI","year":"2019","unstructured":"(NCBI) NCfBI. 2019. Genome assembly ASM755669v1. UC, San Diego."},{"key":"e_1_3_3_34_2","volume-title":"Genome assembly ASM420859v1","author":"(NCBI) NCfBI","year":"2016","unstructured":"(NCBI) NCfBI. 2016. Edited by G. Sakoulas. Genome assembly ASM420859v1. National Center for Biotechnology Information (NCBI), San Diego."},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.3390\/v11010088"},{"key":"e_1_3_3_36_2","first-page":"100","article-title":"Characteristics of the primary and secondary DNA structure of staphylococcal phage SB-1","volume":"1981","author":"Andriashvili IA","year":"1981","unstructured":"Andriashvili IA, Kvachadze LI, Adamiia RS, Tushishvili DG, Kalandarishvili LL. 1981. Characteristics of the primary and secondary DNA structure of staphylococcal phage SB-1. Vopr Virusol 1981:100\u2013103.","journal-title":"Vopr Virusol"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.3390\/v15010017"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00890-20"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00536-10"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2006.05.030"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00422-06"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2180-8-39"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dky148"},{"key":"e_1_3_3_44_2","unstructured":"Clinical and Laboratory Standards Institute (CLSI). 2025. CLSI M100: performance standards for antimicrobial susceptibility testing (35th ed.). https:\/\/clsi.org\/standards\/products\/microbiology\/documents\/m100\/."},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1007\/s40121-014-0023-0"},{"key":"e_1_3_3_46_2","volume-title":"Bacteriophages: methods and protocols","author":"Clokie MRJ","year":"2009","unstructured":"Clokie MRJ, Kropinski AM. 2009. Bacteriophages: methods and protocols. Humana Press, New York."},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.micpath.2023.106061"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00088-14"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.06439-11"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00101-18"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00386-19"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00315-18"},{"key":"e_1_3_3_53_2","doi-asserted-by":"publisher","DOI":"10.1128\/spectrum.00340-23"},{"key":"e_1_3_3_54_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dku378"},{"key":"e_1_3_3_55_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01586-12"},{"key":"e_1_3_3_56_2","doi-asserted-by":"publisher","DOI":"10.1093\/ofid\/ofaa072"},{"key":"e_1_3_3_57_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2021.106310"},{"key":"e_1_3_3_58_2","doi-asserted-by":"publisher","DOI":"10.1093\/ofid\/ofz538"},{"key":"e_1_3_3_59_2","doi-asserted-by":"publisher","DOI":"10.1128\/spectrum.00427-24"},{"key":"e_1_3_3_60_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.virusres.2022.198909"},{"key":"e_1_3_3_61_2","doi-asserted-by":"publisher","DOI":"10.1128\/AEM.00468-21"},{"key":"e_1_3_3_62_2","unstructured":"(NCBI) NCfBI. 2024. CUBIST-2 BioSample (SAMN41318537) 2024 [Clinical bloodstream isolate CUBIST-2 from a patient with endovascular staphylococcal infection daptomycin-resistant ST5-DNS MRSA-II CC.]. Available from: https:\/\/www.ncbi.nlm.nih.gov\/biosample\/41318537"},{"key":"e_1_3_3_63_2","unstructured":"(NCBI) NCfBI. 2024. CUBIST-6 biosample (SAMN43213404): National Library of Medicine National Center for Biotechnology Information; 2024 [Clinical bloodstream isolate CUBIST-6 part of the CUBIST Pharmaceuticals Isolate Collection is a daptomycin-resistant strain obtained from a patient with endovascular staphylococcal infection following daptomycin treatment failure. It belongs to ST5-MRSA-II CC and has sequence variations in walK (L494V) and mprF (T345A) compared to CUBIST-5.]. Available from: https:\/\/www.ncbi.nlm.nih.gov\/biosample\/43213404"},{"key":"e_1_3_3_64_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2024.107144"},{"key":"e_1_3_3_65_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2018.02705"},{"key":"e_1_3_3_66_2","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.02262-23"},{"key":"e_1_3_3_67_2","doi-asserted-by":"publisher","DOI":"10.1021\/acscentsci.2c00125"},{"key":"e_1_3_3_68_2","doi-asserted-by":"publisher","DOI":"10.1128\/aac.00895-23"},{"key":"e_1_3_3_69_2","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.01990-23"},{"key":"e_1_3_3_70_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tim.2020.05.017"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/aac.00699-25","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/aac.00699-25","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T14:05:38Z","timestamp":1765375538000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/aac.00699-25"}},"subtitle":[],"editor":[{"given":"Sarah","family":"Doernberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,12,10]]},"references-count":69,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2025,12,10]]}},"alternative-id":["10.1128\/aac.00699-25"],"URL":"https:\/\/doi.org\/10.1128\/aac.00699-25","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2025.05.19.654851","asserted-by":"object"}]},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,10]]},"assertion":[{"value":"2025-05-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-12","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-18","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e00699-25"}}