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Xeruborbactam is a boronic acid \u03b2-lactamase inhibitor with potent activity against serine- and metallo-\u03b2-lactamases and is currently under clinical development in combination with cefiderocol. We evaluated the\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      activity of cefiderocol\/xeruborbactam against a panel of clinical\n                      <jats:italic toggle=\"yes\">Klebsiella pneumoniae<\/jats:italic>\n                      isolates and isogenic\n                      <jats:italic toggle=\"yes\">Escherichia coli<\/jats:italic>\n                      transformants (including both wild-type and porin-deficient backgrounds) producing KPC variants. Xeruborbactam and taniborbactam activities were compared using ceftazidime, cefepime, and cefiderocol as reporter substrates. Inhibitory activity was analyzed by determining the IC\u2085\u2080 values for both inhibitors against KPC variants. Most clinical isolates producing KPC variants showed increased MIC values and substantial cross-resistance to ceftazidime\/avibactam, cefiderocol, and cefepime\/taniborbactam. Cefiderocol\/xeruborbactam retained potent activity against all clinical isolates, regardless of the KPC variant produced or the outer membrane permeability status. These findings were confirmed in wild-type and porin-deficient isogenic\n                      <jats:italic toggle=\"yes\">E. coli<\/jats:italic>\n                      models, in which the combination of KPC variants and porin loss synergistically increased resistance to multiple \u03b2-lactams, while cefiderocol\/xeruborbactam consistently restored susceptibility to wild-type levels. Comparative MIC analyses showed that xeruborbactam enhanced the activity of all \u03b2-lactam partners to a greater extent than taniborbactam. IC\u2085\u2080 determinations revealed a 17-fold to 73-fold greater inhibitory potency of xeruborbactam, which was maintained across structurally diverse KPC variants. Overall, cefiderocol\/xeruborbactam exhibited potent activity against KPC-producing Enterobacterales, including isolates producing KPC variants associated with reduced susceptibility or resistance to ceftazidime\/avibactam, cefiderocol, and cefepime\/taniborbactam.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/aac.00897-26","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T14:12:32Z","timestamp":1790777552000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Relative inhibitory activities of taniborbactam and xeruborbactam against KPC variants conferring reduced susceptibility or resistance to ceftazidime\/avibactam, cefiderocol, and cefepime\/taniborbactam"],"prefix":"10.1128","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8270-0259","authenticated-orcid":true,"given":"Salud","family":"Rodr\u00edguez-Pallares","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01qckj285","id-type":"ROR","asserted-by":"publisher"}],"name":"Servicio de Microbiolog\u00eda Cl\u00ednica & Grupo de Investigaci\u00f3n en Microbiolog\u00eda, Instituto de Investigaci\u00f3n Biom\u00e9dica de A Coru\u00f1a (INIBIC), Complexo Hospitalario Universitario de A Coru\u00f1a (CHUAC), SERGAS. Universidade da Coru\u00f1a (UDC)","place":["A Coru\u00f1a, Spain"]},{"id":[{"id":"https:\/\/ror.org\/00ca2c886","id-type":"ROR","asserted-by":"publisher"}],"name":"CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III","place":["Madrid, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5455-5576","authenticated-orcid":true,"given":"Christophe","family":"Le Terrier","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/022fs9h90","id-type":"ROR","asserted-by":"publisher"}],"name":"Medical and Molecular Microbiology, Faculty of Science and Medicine, University of Fribourg","place":["Fribourg, Switzerland"]},{"name":"Department of Anaesthesiology, Pharmacology, Intensive Care and Emergency Medicine, Faculty of Medicine, University of Geneva","place":["Geneva, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1636-6429","authenticated-orcid":true,"given":"Tania","family":"Blanco-Mart\u00edn","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01qckj285","id-type":"ROR","asserted-by":"publisher"}],"name":"Servicio de Microbiolog\u00eda Cl\u00ednica & Grupo de Investigaci\u00f3n en Microbiolog\u00eda, Instituto de Investigaci\u00f3n Biom\u00e9dica de A Coru\u00f1a (INIBIC), Complexo Hospitalario Universitario de A Coru\u00f1a (CHUAC), SERGAS. 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