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However, the functional consequences of\n                      <jats:italic toggle=\"yes\">rpoB<\/jats:italic>\n                      mutations leading to RIF resistance remain poorly characterized, particularly their impact on bacterial fitness and treatment response. We analyzed clinical RIF-R and RIF-susceptible (RIF-S) MRSE isolates from a single-center IAI cohort. RIF-R strains showed delayed exponential growth and exhibited a reduced growth rate during the exponential phase, while biofilm formation remained largely unchanged. To investigate resistance-associated phenotypes, we induced RIF resistance in three clinical RIF-S strains using subinhibitory exposure in a murine tissue cage model. Sequencing revealed\n                      <jats:italic toggle=\"yes\">rpoB<\/jats:italic>\n                      mutations in cluster I, frequently at codons 481 and 486. One mutant, R\n                      <jats:sub>611<\/jats:sub>\n                      (Ser486Tyr), mirrored mutations from a clinical isolate and exhibited slower growth, reduced cell density, and markedly increased biofilm production with unchanged susceptibilities to vancomycin or daptomycin compared to its RIF-S parent, S\n                      <jats:sub>611<\/jats:sub>\n                      .\n                      <jats:italic toggle=\"yes\">In vivo<\/jats:italic>\n                      , R\n                      <jats:sub>611<\/jats:sub>\n                      was more competitive in the planktonic phase, while S\n                      <jats:sub>611<\/jats:sub>\n                      dominated the adherent fraction. Time-kill assays demonstrated strong bactericidal activity of daptomycin combined with ceftaroline or fosfomycin. In the murine model, ceftaroline monotherapy was partially effective, whereas daptomycin\/ceftaroline achieved the highest cure rates even against clinical RIF-R strains at the minimum infective dose, with efficacy decreasing markedly at higher bacterial inocula. These findings reveal fitness trade-offs linked to\n                      <jats:italic toggle=\"yes\">rpoB<\/jats:italic>\n                      -mediated resistance and support ceftaroline-based combinations as a potential treatment strategy for RIF-R MRSE in IAIs, particularly when bacterial burden can be reduced.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/aac.00876-26","type":"journal-article","created":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T15:10:55Z","timestamp":1792595455000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Rifampicin-resistant\n                    <i>Staphylococcus epidermidis<\/i>\n                    implant-associated infections: the therapeutic potential of ceftaroline and daptomycin 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