{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T22:04:42Z","timestamp":1790719482938,"version":"4.1.0"},"reference-count":33,"publisher":"SAGE Publications","issue":"4","license":[{"start":{"date-parts":[[2022,4,1]],"date-time":"2022-04-01T00:00:00Z","timestamp":1648771200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2022,4,1]],"date-time":"2022-04-01T00:00:00Z","timestamp":1648771200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Microbial Drug Resistance"],"published-print":{"date-parts":[[2022,4,1]]},"abstract":"<jats:p>\n                    The objective of this study was to characterize isolates with reduced susceptibility to cefiderocol in patients receiving cefiderocol for nosocomial pneumonia or carbapenem-resistant infections in the Phase 3 APEKS-NP and CREDIBLE-CR studies. Susceptibility testing of isolates was conducted at a central laboratory, and post-treatment changes were evaluated according to available breakpoints for cefiderocol. Whole-genome sequencing and multilocus sequence typing were performed for isolates to confirm their origin and identify mutations. Five (APEKS-NP) and nine (CREDIBLE-CR) isolates demonstrated a\u2009\u2265\u20094-fold minimum inhibitory concentration (MIC) increase compared with genetically related baseline isolates; most remained susceptible to cefiderocol despite the \u22654-fold MIC increase. Mutations in \u03b2-lactamases or penicillin-binding protein (PBP) were identified in 4\/14 isolates: one\n                    <jats:italic toggle=\"yes\">Enterobacter cloacae<\/jats:italic>\n                    (amino acid [AA] substitution [A313P] in ACT-17); two\n                    <jats:italic toggle=\"yes\">Acinetobacter baumannii<\/jats:italic>\n                    (one PBP3 AA substitution [H370Y], one with OXA-23 substitutions [N85I and P225S]); and one\n                    <jats:italic toggle=\"yes\">Pseudomonas aeruginosa<\/jats:italic>\n                    (PDC-30 [4AA deletion \u201cTPMA\u201d position 316\u2013319]). Cloning experiments using isogenic\n                    <jats:italic toggle=\"yes\">Escherichia coli<\/jats:italic>\n                    strains containing wild-type and those mutant cephalosporinase enzymes show that the mutant enzymes may contribute to decreased susceptibility to cefiderocol. Pharmacokinetic data were available for nine patients, for whom cefiderocol exposures exceeded 100%\n                    <jats:italic toggle=\"yes\">f<\/jats:italic>\n                    T\u2009&gt;\u20094\u2009\u00d7\u2009MIC\n                    <jats:sub>.<\/jats:sub>\n                    No clear pattern between mutations and development or extent of MIC increases was observed. No mutations were identified in genes related to iron transport, including\n                    <jats:italic toggle=\"yes\">fiu<\/jats:italic>\n                    ,\n                    <jats:italic toggle=\"yes\">cirA<\/jats:italic>\n                    ,\n                    <jats:italic toggle=\"yes\">piuA\/C<\/jats:italic>\n                    , and\n                    <jats:italic toggle=\"yes\">pirA<\/jats:italic>\n                    , among recovered Gram-negative isolates.\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/Clinicaltrials.gov:\">Clinicaltrials.gov:<\/jats:ext-link>\n                    APEKS-NP: NCT03032380; CREDIBLE-CR: NCT02714595.\n                  <\/jats:p>","DOI":"10.1089\/mdr.2021.0180","type":"journal-article","created":{"date-parts":[[2022,1,25]],"date-time":"2022-01-25T08:56:31Z","timestamp":1643100991000},"page":"398-407","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":71,"title":["Mechanisms of Reduced Susceptibility to Cefiderocol Among Isolates from the CREDIBLE-CR and APEKS-NP Clinical Trials"],"prefix":"10.1177","volume":"28","author":[{"given":"Patrice","family":"Nordmann","sequence":"first","affiliation":[{"name":"Medical and Molecular Microbiology, Department of Medicine, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan K.","family":"Shields","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, University of Pittsburgh, Pittsburgh, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yohei","family":"Doi","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, University of Pittsburgh, Pittsburgh, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miki","family":"Takemura","sequence":"additional","affiliation":[{"name":"Pharmaceutical Research Division, Shionogi &amp; Co., Ltd., Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger","family":"Echols","sequence":"additional","affiliation":[{"name":"Infectious Disease Drug Development Consulting, LLC, Easton, Connecticut, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuko","family":"Matsunaga","sequence":"additional","affiliation":[{"name":"Shionogi, Inc., Florham Park, New Jersey, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshinori","family":"Yamano","sequence":"additional","affiliation":[{"name":"Pharmaceutical Research Division, Shionogi &amp; Co., Ltd., Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2022,4,18]]},"reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01454-17"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciz827"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00097-18"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciz825"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciz826"},{"key":"e_1_3_5_7_2","unstructured":"2020. Fetroja (cefiderocol) for injection for intravenous use. In Prescribing information. Shionogi Inc. Florham Park NJ. Available at https:\/\/www.shionogi.com\/content\/dam\/shionogi\/si\/products\/pdf\/fetroja.pdf Accessed December20 2021."},{"key":"e_1_3_5_8_2","unstructured":"2020. Fetcroja (cefiderocol 1\u2009g powder for concentrate for solution for infusion). In Shionogi B.V. Summary of product characteristics. Amsterdam Netherlands. Available at https:\/\/www.ema.europa.eu\/en\/documents\/product-information\/fetcroja-epar-product-information_en.pdf Accessed December20 2021."},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2018.10.007"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.03098-15"},{"key":"e_1_3_5_11_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cix182"},{"key":"e_1_3_5_12_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2016.11764"},{"key":"e_1_3_5_13_2","first-page":"e02097","article-title":"Emergence of ceftazidime-avibactam resistance due to plasmid-borne blaKPC-3 mutations during treatment of carbapenem-resistant Klebsiella pneumoniae infections","volume":"61","author":"Shields R.K.","year":"2017","unstructured":"Shields R.K., , Chen L., , Cheng S., et al. 2017. Emergence of ceftazidime-avibactam resistance due to plasmid-borne blaKPC-3 mutations during treatment of carbapenem-resistant Klebsiella pneumoniae infections. Antimicrob. Agents. Chemother. 61:e02097-16.","journal-title":"Antimicrob. Agents. Chemother"},{"key":"e_1_3_5_14_2","doi-asserted-by":"crossref","unstructured":"Waglechner N. and Wright G.D.. 2017. Antibiotic resistance: it's bad but why isn't it worse? BMC Biol. 15:84.","DOI":"10.1186\/s12915-017-0423-1"},{"key":"e_1_3_5_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(20)30731-3"},{"key":"e_1_3_5_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(20)30796-9"},{"key":"e_1_3_5_17_2","unstructured":"Clinical and Laboratory Standards Institute. 2020. Performance standards for antimicrobial susceptibility testing. 30th ed. CLSI supplement M100-S30. CLSI Wayne PA."},{"key":"e_1_3_5_18_2","unstructured":"European Committee on Antimicrobial Susceptibility Testing. 2021. Clinical breakpoints. Available at https:\/\/www.eucast.org\/clinical_breakpoints\/ Accessed April6 2021."},{"key":"e_1_3_5_19_2","unstructured":"Food US and Administration. Drug. 2021. Antibiotic Susceptibility Test Interpretive Criteria. Available at https:\/\/www.fda.gov\/drugs\/development-resources\/antibacterial-susceptibility-test-interpretive-criteria Accessed April6 2021."},{"key":"e_1_3_5_20_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkz123"},{"key":"e_1_3_5_21_2","unstructured":"Center for Genomic Epidemiology. 2018. ResFinder. Available at https:\/\/cge.cbs.dtu.dk\/services\/ResFinder\/ Accessed December20 2021."},{"key":"e_1_3_5_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jgar.2020.07.009"},{"key":"e_1_3_5_23_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01221-20"},{"key":"e_1_3_5_24_2","volume-title":"in vitro","author":"Yamano Y.","year":"2020","unstructured":"Yamano Y., , Takemura M., , and Echols R.. 2020. Potential mechanisms of cefiderocol MIC increase in Enterobacterales in in vitro resistance acquisition studies. Open Forum Infect. Dis. 7(Suppl 1):S730 (abstract)."},{"key":"e_1_3_5_25_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01437-20"},{"key":"e_1_3_5_26_2","volume-title":"et al","author":"Katsube T.","unstructured":"Katsube T., T. Wajima, R. Echols, et al. 2020. Intrapulmonary pharmacokinetics of cefiderocol in hospitalized and ventilated patients receiving standard of care antibiotics for bacterial pneumonia. Open Forum Infect. 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