{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T18:59:36Z","timestamp":1792004376649,"version":"4.4.0"},"reference-count":10,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T00:00:00Z","timestamp":1752710400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"PRIN 2022"},{"name":"2022WBPFSC"},{"name":"MIUR-Italy"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,9,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>We describe the clinical and microbiological features of four cases of bacteraemia caused by cefiderocol-resistant NDM-producing Klebsiella pneumoniae (NDM-KP), observed at Padua University Hospital, Italy, in four immunocompromised hosts not previously exposed to cefiderocol.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Three out of the four cefiderocol-resistant NDM-KP isolates also co-produced OXA-48-like carbapenemases. Cefiderocol susceptibility testing was performed both alone or in combination with EDTA or xeruborbactam, used as NDM inhibitors, following reference microdilution methods in iron-depleted Mueller\u2013Hinton broth. Whole-genome sequencing was conducted to investigate the resistome, virulome, MLST and plasmidome.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>All patients reported isolates with a primary resistance to cefiderocol. In two cases, clinical failure to cefiderocol occurred before susceptibility results were available. All patients were successfully treated with the aztreonam-avibactam combination. MLST revealed that two isolates belonged to ST14 and two to ST147. No known alterations in iron uptake systems were detected by whole-genome sequencing. However, both ST14 NDM-KP carried a fec operon located on an IncFIIK-IncFIBk plasmid. The addiction of EDTA or xeruborbactam restored cefiderocol susceptibility, suggesting a key role of NDM-1 production in mediating resistance.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>This case series highlights the urgent need of new therapeutic agents that will overcome the diffusion of NDM-KP resistant to FDC. The emergence of NDM-KP with an acquired fec operon in nosocomial settings, even without a previous drug exposure, may further compromise cefiderocol efficacy. Further studies will be necessary to assess the in vivo activity of xeruborbactam, a new cyclic boronate \u03b2-lactamase inhibitor, which may restore cefiderocol susceptibility in NDM-KP isolates.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/jac\/dkaf238","type":"journal-article","created":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T05:13:37Z","timestamp":1752729217000},"page":"2442-2446","source":"Crossref","is-referenced-by-count":5,"title":["Clinical and microbiological analysis of bloodstream infections by four cefiderocol-resistant and not previously exposed NDM-producing <i>Klebsiella pneumoniae<\/i>"],"prefix":"10.1093","volume":"80","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0263-0703","authenticated-orcid":false,"given":"Maria","family":"Mazzitelli","sequence":"first","affiliation":[{"name":"Infectious and Tropical Diseases Unit, Padua University Hospital , Padua ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Coppi","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, University of Florence , Florence ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Scaglione","sequence":"additional","affiliation":[{"name":"Infectious and Tropical Diseases Unit, Padua University Hospital , Padua ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo","family":"Paci","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, University of Florence , Florence ,","place":["Italy"]},{"name":"Microbiology and Virology Unit, Careggi University Hospital , Florence ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ignazio","family":"Castagliuolo","sequence":"additional","affiliation":[{"name":"Microbiology and Virology Unit, Padua University Hospital , Padua ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Franchin","sequence":"additional","affiliation":[{"name":"Microbiology and Virology Unit, Padua University Hospital , Padua ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gian Maria","family":"Rossolini","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, University of Florence , Florence ,","place":["Italy"]},{"name":"Microbiology and Virology Unit, Careggi University Hospital , Florence ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annamaria","family":"Cattelan","sequence":"additional","affiliation":[{"name":"Infectious and Tropical Diseases Unit, Padua University Hospital , Padua ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,7,17]]},"reference":[{"key":"2025090413114140600_dkaf238-B1","doi-asserted-by":"publisher","first-page":"777","DOI":"10.1007\/s40121-023-00773-6","article-title":"Cefiderocol, a siderophore cephalosporin, as a treatment option for infections caused by carbapenem-resistant Enterobacterales","volume":"12","author":"Kaye","year":"2023","journal-title":"Infect Dis Ther"},{"key":"2025090413114140600_dkaf238-B2","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1080\/23744235.2023.2226709","article-title":"Higher rates of cefiderocol resistance among NDM producing Klebsiella bloodstream isolates applying EUCAST over CLSI breakpoints","volume":"55","author":"Isler","year":"2023","journal-title":"Infect Dis (Lond)"},{"key":"2025090413114140600_dkaf238-B3","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1016\/j.cmi.2023.11.005","article-title":"In vivo evolution to high-level cefiderocol resistance of NDM-1-producing Klebsiella pneumoniae, followed by intra-hospital cross-transmission","volume":"30","author":"Tascini","year":"2024","journal-title":"Clin Microbiol Infect"},{"key":"2025090413114140600_dkaf238-B4","doi-asserted-by":"publisher","first-page":"2200795","DOI":"10.2807\/1560-7917.ES.2022.27.43.2200795","article-title":"Nosocomial outbreak by NDM-1-producing Klebsiella pneumoniae highly resistant to cefiderocol, Florence, Italy, August 2021 to June 2022","volume":"27","author":"Coppi","year":"2022","journal-title":"Euro Surveill"},{"key":"2025090413114140600_dkaf238-B5","doi-asserted-by":"publisher","first-page":"3487","DOI":"10.1093\/jac\/dkac347","article-title":"The acquisition of transferable extrachromosomal fec operon is associated with a cefiderocol MIC increase in Enterobacterales","volume":"77","author":"Kocer","year":"2022","journal-title":"J Antimicrob Chemother"},{"key":"2025090413114140600_dkaf238-B6","doi-asserted-by":"publisher","first-page":"e0349622","DOI":"10.1128\/spectrum.03496-22","article-title":"Cefiderocol resistance in Klebsiella pneumoniae is linked to SHV extended-spectrum beta-lactamase activities and functional loss of the outer membrane porin OmpK35","volume":"11","author":"Moon","year":"2023","journal-title":"Microbiol Spectr"},{"key":"2025090413114140600_dkaf238-B7","doi-asserted-by":"publisher","first-page":"e0044023","DOI":"10.1128\/aac.00440-23","article-title":"In vitro potency of xeruborbactam in combination with multiple beta-lactam antibiotics in comparison with other beta-lactam\/beta-lactamase inhibitor (BLI) combinations against carbapenem-resistant and extended-spectrum beta-lactamase-producing Enterobacterales","volume":"67","author":"Lomovskaya","year":"2023","journal-title":"Antimicrob Agents Chemother"},{"key":"2025090413114140600_dkaf238-B8","doi-asserted-by":"publisher","first-page":"1253160","DOI":"10.3389\/fmicb.2023.1253160","article-title":"Genomic characterization of an NDM-9-producing Acinetobacter baumannii clinical isolate and role of Glu152Lys substitution in the enhanced cefiderocol hydrolysis of NDM-9","volume":"14","author":"Gaillot","year":"2023","journal-title":"Front Microbiol"},{"key":"2025090413114140600_dkaf238-B9","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1093\/cid\/ciab888","article-title":"Progressive development of cefiderocol resistance in Escherichia coli during therapy is associated with an increase in blaNDM-5 copy number and gene expression","volume":"75","author":"Simner","year":"2022","journal-title":"Clin Infect Dis"},{"key":"2025090413114140600_dkaf238-B10","doi-asserted-by":"publisher","first-page":"ciae403","DOI":"10.1093\/cid\/ciae403","article-title":"Infectious Diseases Society of America 2024 guidance on the treatment of antimicrobial-resistant Gram-negative infections","author":"Tamma","year":"2024","journal-title":"Clin Infect Dis"}],"container-title":["Journal of Antimicrobial Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jac\/article-pdf\/80\/9\/2442\/63780537\/dkaf238.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jac\/article-pdf\/80\/9\/2442\/63780537\/dkaf238.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T17:11:46Z","timestamp":1757005906000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jac\/article\/80\/9\/2442\/8203697"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,17]]},"references-count":10,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,7,17]]},"published-print":{"date-parts":[[2025,9,3]]}},"URL":"https:\/\/doi.org\/10.1093\/jac\/dkaf238","relation":{},"ISSN":["0305-7453","1460-2091"],"issn-type":[{"value":"0305-7453","type":"print"},{"value":"1460-2091","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,9]]},"published":{"date-parts":[[2025,7,17]]}}}