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To date,\n                      <jats:italic toggle=\"yes\">E. faecium<\/jats:italic>\n                      strains with low minimum inhibitory concentrations (MICs) of CPH have only been described following genetic manipulation. At Parc Taul\u00ed University Hospital, we identified a clinical isolate of ampicillin-susceptible\n                      <jats:italic toggle=\"yes\">E. faecium<\/jats:italic>\n                      (Efm5) that exhibited unusually low MICs to cefotaxime (1 mg\/L), ceftriaxone (3 mg\/L), and ceftaroline (0.19 mg\/L). Upon single exposure to ceftriaxone (100 mg\/L), Efm5 rapidly yielded variants with markedly increased MICs of ceftriaxone (&gt;256 mg\/L) and cefotaxime (&gt;32 mg\/L), while MICs of ampicillin and ceftaroline were unaffected. Whole-genome sequencing revealed that the high-MIC variants carried single-nucleotide polymorphisms leading to non-synonymous mutations in\n                      <jats:italic toggle=\"yes\">croS<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">nusG<\/jats:italic>\n                      , or\n                      <jats:italic toggle=\"yes\">rpoB<\/jats:italic>\n                      genes. Phenotypic assays confirmed that these mutations were associated with ceftriaxone resistance, and immunoblots revealed increased expression of penicillin-binding protein 5 (PBP5) in all the high-MIC variants. Transcriptional profiling showed upregulation of the\n                      <jats:italic toggle=\"yes\">pbp5<\/jats:italic>\n                      operon, which includes\n                      <jats:italic toggle=\"yes\">ftsW<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">psr<\/jats:italic>\n                      , and\n                      <jats:italic toggle=\"yes\">pbp5<\/jats:italic>\n                      , in the\n                      <jats:italic toggle=\"yes\">croS<\/jats:italic>\n                      variants. This study provides evidence that\n                      <jats:italic toggle=\"yes\">E. faecium<\/jats:italic>\n                      isolates with low MICs to CPH can arise in clinical settings without laboratory manipulation, enabling further investigation of resistance pathways.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/aac.01948-25","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T13:01:26Z","timestamp":1774270886000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Single point mutations in global regulatory genes restore cephalosporin resistance in a low-MIC\n                    <i>Enterococcus faecium<\/i>\n                    natural 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