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The development of resistance against linezolid necessitates the exploration of novel therapies.\u00a0 Aim: This study aims to investigate the synergistic activity of various combinations of linezolid with non-antibiotic through in vitro and in vivo approaches.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and Results<\/jats:title>\n                    <jats:p>\n                      In our research, 44\n                      <jats:italic>S. aureus<\/jats:italic>\n                      isolates were obtained from various clinical sources.\n                      <jats:italic>S. aureus<\/jats:italic>\n                      isolates presented high levels of resistance to \u03b2-lactams and moderate resistance to doxycycline and erythromycin. Among the isolates, 43 (97.73%) were MRSA, 10 (22.73%) were linezolid resistant\n                      <jats:italic>S. aureus<\/jats:italic>\n                      (LRSA), and 17 (38.64%) were classified as VRSA. A total of 97.73% of the isolates presented the\n                      <jats:italic>mecA<\/jats:italic>\n                      gene (MRSA), whereas the\n                      <jats:italic>optrA<\/jats:italic>\n                      gene was detected in 9.09% of the isolates (LRSA). \u00a0The synergistic activity of nine compounds with linezolid was assessed in vitro against LRSA isolates using broth microdilution and checkerboard microdilution methods. Linezolid\/cyclizine and linezolid\/piroxicam combinations showed fractional inhibitory concentration indexes (FICIs) ranging from 0.28 to 0.5 against LRSA isolates. Time-kill curves were used to confirm their bactericidal activity. Promising combinations (linezolid\/cyclizine and linezolid\/piroxicam) were further evaluated in vivo LRSA-induced lung infection murine animal model. Compared with monotherapy, combination therapies significantly enhance bacterial eradication and increase sensitivity to linezolid, resulting in superior bacterial eradication. Linezolid\/cyclizine and linezolid\/piroxicam combinations provided complete protection (100% survival), improved lung pathology, and enhanced clinical scores.\u00a0\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study presents two novel combination therapies (linezolid\/cyclizine and linezolid\/piroxicam) with promising applications in treating severe LRSA infections.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>\n                            <jats:italic>optrA gene was detected in four linezolid S. aureus\u2013resistant isolates (LRSA)<\/jats:italic>\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            <jats:italic>Linezolid\/cyclizine and linezolid\/piroxicam synergism was detected against LRSA.<\/jats:italic>\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            <jats:italic>Combinations revealed complete lung protection in lung-infected LRSA murine model.<\/jats:italic>\n                          <\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00253-026-13738-9","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T20:32:11Z","timestamp":1773952331000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["In vitro and in vivo synergistic effects of cyclizine and piroxicam in combination with linezolid against methicillin-resistant Staphylococcus aureus"],"prefix":"10.1007","volume":"110","author":[{"given":"Mai A.","family":"Moawad","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abeer M.","family":"Abd El-Aziz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mona I.","family":"Shaaban","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,3,19]]},"reference":[{"key":"13738_CR1","first-page":"172","volume":"4","author":"M Aamir","year":"2015","unstructured":"Aamir M, Abu El-Wafa W, Ali A, Hamouda H, Mourad F (2015) Prevalence of multidrug resistant bacteria causing late-onset neonatal sepsis. 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