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Up to 35% of SAB patients fail to clear infection with gold-standard anti-MRSA antibiotics, even if the isolate meets susceptibility breakpoints in conventional assays in vitro. Such outcomes are termed persistent and may involve small colony variant (SCV) adaptation of SA in vivo. Methods: In this study, we assessed virulence phenotypes and mechanisms in persistent (PB) vs. resolving (RB) MRSA isolates from SAB. Results: Overall, PB isolates caused less hemolysis or biofilm formation than RB isolates, but proteolysis was equivalent. Attenuation of these virulence phenotypes increased longitudinally during the course of SAB. Although PB vs. RB isolates had similar human endothelial cell invasion rates, PB isolates more frequently formed SCVs intracellularly and inversely correlated with pH. Study PB and RB isolates exhibited distinct susceptibilities to prototypic human host defense peptides (HDPs), which were influenced by antibiotics and pH. Furthermore, mechanistic signatures of HDPs differed between PB and RB isolates. Conclusions: Together, these results reveal that MRSA isolates from PB vs. RB outcomes of SAB have differential virulence profiles that suggest coordinated immune subversion in PB. Understanding MRSA adaptations that promote persistence in SAB may enable innovative agents and strategies to address these challenging infections.<\/jats:p>","DOI":"10.3390\/antibiotics15040332","type":"journal-article","created":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T12:05:49Z","timestamp":1775563549000},"page":"332","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Virulence Phenotypes Differentiate Persistent vs. Resolving Isolates of Human Staphylococcus aureus Bacteremia"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2567-4418","authenticated-orcid":false,"given":"Liana C.","family":"Chan","sequence":"first","affiliation":[{"name":"Harbor-UCLA Medical Center, Division of Molecular Medicine, Torrance, CA 90502, USA"},{"name":"Harbor-UCLA Medical Center, Division of Infectious Diseases, Torrance, CA 90502, USA"},{"name":"Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90024, USA"},{"name":"The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Institute for Infection and Immunity, Torrance, CA 90502, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong K.","family":"Lee","sequence":"additional","affiliation":[{"name":"Harbor-UCLA Medical Center, Division of Molecular Medicine, Torrance, CA 90502, USA"},{"name":"The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Institute for Infection and Immunity, Torrance, CA 90502, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Wang","sequence":"additional","affiliation":[{"name":"Harbor-UCLA Medical Center, Division of Molecular Medicine, Torrance, CA 90502, USA"},{"name":"The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Institute for Infection and Immunity, Torrance, CA 90502, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiyuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Harbor-UCLA Medical Center, Division of Molecular Medicine, Torrance, CA 90502, USA"},{"name":"The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Institute for Infection and Immunity, Torrance, CA 90502, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott G.","family":"Filler","sequence":"additional","affiliation":[{"name":"Harbor-UCLA Medical Center, Division of Infectious Diseases, Torrance, CA 90502, USA"},{"name":"Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90024, USA"},{"name":"The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Institute for Infection and Immunity, Torrance, CA 90502, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Ciranna","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases and International Health, Department of Medicine, Duke University School of Medicine, Durham, NC 27708, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wessam","family":"Abdelhady","sequence":"additional","affiliation":[{"name":"Harbor-UCLA Medical Center, Division of Infectious Diseases, Torrance, CA 90502, USA"},{"name":"The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Institute for Infection and Immunity, Torrance, CA 90502, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan Q.","family":"Xiong","sequence":"additional","affiliation":[{"name":"Harbor-UCLA Medical Center, Division of Infectious Diseases, Torrance, CA 90502, USA"},{"name":"Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90024, USA"},{"name":"The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Institute for Infection and Immunity, Torrance, CA 90502, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Li","sequence":"additional","affiliation":[{"name":"Harbor-UCLA Medical Center, Division of Infectious Diseases, Torrance, CA 90502, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachelle A.","family":"Gonzales","sequence":"additional","affiliation":[{"name":"Harbor-UCLA Medical Center, Division of Infectious Diseases, Torrance, CA 90502, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2176-6462","authenticated-orcid":false,"given":"Felicia","family":"Ruffin","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases and International Health, Department of Medicine, Duke University School of Medicine, Durham, NC 27708, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"Vance G.","family":"Fowler","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases and International Health, Department of Medicine, Duke University School of Medicine, Durham, NC 27708, USA"},{"name":"Duke Clinical Research Institute, Durham, NC 27708, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1968-0192","authenticated-orcid":false,"given":"Arnold S.","family":"Bayer","sequence":"additional","affiliation":[{"name":"Harbor-UCLA Medical Center, Division of Infectious Diseases, Torrance, CA 90502, USA"},{"name":"Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90024, USA"},{"name":"The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Institute for Infection and Immunity, Torrance, CA 90502, 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