{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:12:26Z","timestamp":1791295946861,"version":"4.1.0"},"reference-count":38,"publisher":"American Society for Microbiology","issue":"7","license":[{"start":{"date-parts":[[2014,7,1]],"date-time":"2014-07-01T00:00:00Z","timestamp":1404172800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2014,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Candidemia is the fourth most common kind of microbial bloodstream infection, with\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Candida albicans<\/jats:named-content>\n            being the most common causative species. Echinocandins are employed as the first-line treatment for invasive candidiasis until the fungal species is determined and confirmed by clinical diagnosis. Echinocandins block the\n            <jats:italic>FKS<\/jats:italic>\n            glucan synthases responsible for embedding \u03b2-(1,3)-\n            <jats:sc>d<\/jats:sc>\n            -glucan in the cell wall. The increasing use of these drugs has led to the emergence of antifungal resistance, and elevated MICs have been associated with single-residue substitutions in specific hot spot regions of\n            <jats:italic>FKS1<\/jats:italic>\n            and\n            <jats:italic>FKS2<\/jats:italic>\n            . Here, we show for the first time the caspofungin-mediated\n            <jats:italic>in vivo<\/jats:italic>\n            selection of a double mutation within one allele of the\n            <jats:italic>FKS1<\/jats:italic>\n            hot spot 1 in a clinical isolate. We created a set of isogenic mutants and used a hematogenous murine model to evaluate the\n            <jats:italic>in vivo<\/jats:italic>\n            outcomes of echinocandin treatment. Heterozygous and homozygous double mutations significantly enhance the\n            <jats:italic>in vivo<\/jats:italic>\n            resistance of\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">C. albicans<\/jats:named-content>\n            compared with the resistance seen with heterozygous single mutations. The various\n            <jats:italic>FKS1<\/jats:italic>\n            hot spot mutations differ in the degree of their MIC increase, substance-dependent\n            <jats:italic>in vivo<\/jats:italic>\n            response, and impact on virulence. Our results demonstrate that echinocandin EUCAST breakpoint definitions correlate with the\n            <jats:italic>in vivo<\/jats:italic>\n            response when a standard dosing regimen is used but cannot predict the\n            <jats:italic>in vivo<\/jats:italic>\n            response after a dose escalation. Moreover, patients colonized by a\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">C. albicans<\/jats:named-content>\n            strain with multiple mutations in\n            <jats:italic>FKS1<\/jats:italic>\n            have a higher risk for therapeutic failure.\n          <\/jats:p>","DOI":"10.1128\/aac.00123-14","type":"journal-article","created":{"date-parts":[[2014,4,15]],"date-time":"2014-04-15T03:30:53Z","timestamp":1397532653000},"page":"3626-3635","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":72,"title":["Positions and Numbers of\n            <i>FKS<\/i>\n            Mutations in Candida albicans Selectively Influence\n            <i>In Vitro<\/i>\n            and\n            <i>In Vivo<\/i>\n            Susceptibilities to Echinocandin Treatment"],"prefix":"10.1128","volume":"58","author":[{"given":"M.","family":"Lackner","sequence":"first","affiliation":[{"name":"Division of Hygiene and Medical Microbiology, Innsbruck Medical University, Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Tscherner","sequence":"additional","affiliation":[{"name":"Medical University of Vienna, Department for Medical Biochemistry, Max F. Perutz Laboratories, Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Schaller","sequence":"additional","affiliation":[{"name":"Universit\u00e4ts-Hautklinik T\u00fcbingen, Eberhard-Karls-Universit\u00e4t T\u00fcbingen, T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K.","family":"Kuchler","sequence":"additional","affiliation":[{"name":"Medical University of Vienna, Department for Medical Biochemistry, Max F. Perutz Laboratories, Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Mair","sequence":"additional","affiliation":[{"name":"Division of Hygiene and Medical Microbiology, Innsbruck Medical University, Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B.","family":"Sartori","sequence":"additional","affiliation":[{"name":"Division of Hygiene and Medical Microbiology, Innsbruck Medical University, Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F.","family":"Istel","sequence":"additional","affiliation":[{"name":"Medical University of Vienna, Department for Medical Biochemistry, Max F. Perutz Laboratories, Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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