{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T16:45:59Z","timestamp":1781801159741,"version":"3.54.5"},"reference-count":72,"publisher":"American Society for Microbiology","issue":"5","license":[{"start":{"date-parts":[[2015,5,1]],"date-time":"2015-05-01T00:00:00Z","timestamp":1430438400000},"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":[[2015,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Azole resistance is an emerging problem in\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Aspergillus fumigatus<\/jats:named-content>\n            which translates into treatment failure. Alternative treatments with new azoles may improve therapeutic outcome in invasive aspergillosis (IA) even for strains with decreased susceptibility to current azoles. The\n            <jats:italic>in vivo<\/jats:italic>\n            efficacy of 0.25, 1, 4, 16, 64, 128, 256, and 512 mg\/kg of body weight\/day prodrug isavuconazonium sulfate (BAL8557) (isavuconazole [ISA]-equivalent doses of 0.12, 0.48, 1.92, 7.68, 30.7, 61.4, 122.9, and 245.8 mg\/kg\/day, respectively) administered by oral gavage was assessed in an immunocompetent murine model of IA against four clinical\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">A. fumigatus<\/jats:named-content>\n            isolates: a wild-type isolate (ISA MIC\n            <jats:sub>EUCAST<\/jats:sub>\n            , 0.5 mg\/liter) and three azole-resistant isolates harboring substitutions in the\n            <jats:italic>cyp51A<\/jats:italic>\n            gene: G54W (ISA MIC\n            <jats:sub>EUCAST<\/jats:sub>\n            , 0.5 mg\/liter), M220I (ISA MIC\n            <jats:sub>EUCAST<\/jats:sub>\n            , 4 mg\/liter), and TR\n            <jats:sub>34<\/jats:sub>\n            \/L98H (ISA MIC\n            <jats:sub>EUCAST<\/jats:sub>\n            , 8 mg\/liter). The maximum effect (100% survival) was reached at a prodrug isavuconazonium sulfate dose of 64 mg\/kg for the wild-type isolate, 128 mg\/kg for the G54W mutant, and 256 mg\/kg two times per day (q12) for the M220I mutant. A maximum response was not achieved with the TR\n            <jats:sub>34<\/jats:sub>\n            \/L98H isolates with the highest dose of prodrug isavuconazonium sulfate (256 mg\/kg q12). For a survival rate of 50%, the effective AUC\n            <jats:sub>0\u201324<\/jats:sub>\n            \/MIC\n            <jats:sub>EUCAST<\/jats:sub>\n            ratio for ISA total drug was 24.73 (95% confidence interval, 22.50 to 27.18). The efficacy of isavuconazole depended on both the drug exposure and the isavuconazole MIC of the isolates. The quantitative relationship between exposure and effect (AUC\n            <jats:sub>0\u201324<\/jats:sub>\n            \/MIC) can be used to optimize the treatment of human infections by\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">A. fumigatus<\/jats:named-content>\n            , including strains with decreased susceptibility.\n          <\/jats:p>","DOI":"10.1128\/aac.04907-14","type":"journal-article","created":{"date-parts":[[2015,3,10]],"date-time":"2015-03-10T02:03:07Z","timestamp":1425952987000},"page":"2855-2866","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":61,"title":["Pharmacodynamics of Isavuconazole in an Aspergillus fumigatus Mouse Infection Model"],"prefix":"10.1128","volume":"59","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6194-7447","authenticated-orcid":false,"given":"Seyedmojtaba","family":"Seyedmousavi","sequence":"first","affiliation":[{"name":"Department of Medical Microbiology and Infectious Diseases, Erasmus MC, Rotterdam, the Netherlands"},{"name":"Department of Medical Microbiology, Radboud UMC, Nijmegen, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger J. M.","family":"Br\u00fcggemann","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Radboud UMC, Nijmegen, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacques F.","family":"Meis","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology, Radboud UMC, Nijmegen, the Netherlands"},{"name":"Department of Medical Microbiology and Infectious Diseases, Canisius Wilhelmina Hospital, Nijmegen, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Willem J. G.","family":"Melchers","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology, Radboud UMC, Nijmegen, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul E.","family":"Verweij","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology, Radboud UMC, Nijmegen, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6736-4149","authenticated-orcid":false,"given":"Johan W.","family":"Mouton","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Infectious Diseases, Erasmus MC, Rotterdam, the Netherlands"},{"name":"Department of Medical Microbiology, Radboud UMC, Nijmegen, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200401-093OC"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1093\/clinids\/23.3.608"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0891-5520(02)00035-1"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.3201\/eid1710.110226"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa020191"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1086\/525258"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1080\/13693780802545600"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.3201\/eid1507.090043"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.0050219"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1086\/597465"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(07)61055-1"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200212263472618"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.2807\/ese.17.36.20262-en"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01017-12"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.riam.2012.09.002"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.2217\/fmb.14.27"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkr443"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1003633"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dku259"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.3201\/eid1905.130075"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.2217\/fmb.11.118"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00980-12"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dks402"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00833-13"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1586\/14787210.2015.990382"},{"key":"e_1_3_3_27_2","first-page":"O230a","author":"Maertens J","year":"2013","unstructured":"Maertens J, Patterson T, Rahav G, Kontoyiannis D, Marr K, Maher R, Lee M, Zeiher B, Ullmann A. 2013. A phase 3 randomised, double-blinded trial evaluating isavuconazole vs. voriconazole for the primary treatment of invasive fungal disease caused by Aspergillus spp. or other filamentous fungi (SECURE), p O230a. 23rd Eur Congr Clin Microbiol Infect Dis (ECCMID), Barcelona, Spain.","journal-title":"A phase 3 randomised, double-blinded trial evaluating isavuconazole vs. voriconazole for the primary treatment of invasive fungal disease caused by Aspergillus spp. or other filamentous fungi (SECURE)"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01355-13"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1086\/588660"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.43.8.4112-4120.2005"},{"key":"e_1_3_3_31_2","doi-asserted-by":"crossref","unstructured":"Rodriguez-Tudela JL Arendrup MC Arikan S Barchiesi F Bille J Chryssanthou E Cuenca-Estrella M Dannaoui E Denning DW Donnelly JP Fegeler W Lass-Fl\u00f6rl C Moore C Richardson M Gaustad P Schmalreck A Velegraki A Verweij P. 2008. EUCAST definitive document E.DEF 9.1: method for the determination of broth dilution minimum inhibitory concentrations of antifungal agents for conidia forming moulds. Subcommittee on Antifungal Susceptibility Testing (AFST) of the ESCMID European Committee for Antimicrobial Susceptibility Testing (EUCAST). http:\/\/www.eucast.org\/.","DOI":"10.1111\/j.1469-0691.2007.01935.x"},{"key":"e_1_3_3_32_2","volume-title":"Reference method for broth dilution antifungal susceptibility testing of filamentous fungi; approved standard\u20142nd ed","author":"CLSI","year":"2008","unstructured":"CLSI. 2008. Reference method for broth dilution antifungal susceptibility testing of filamentous fungi; approved standard\u20142nd ed. CLSI document M38-A2, vol 28, no 16. Clinical and Laboratory Standards Institute, Wayne, PA."},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.drup.2009.09.002"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02226-12"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01430-12"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.coph.2011.08.001"},{"key":"e_1_3_3_37_2","first-page":"125","article-title":"Targeting 28S rDNA-gene of Aspergillus fumigatus for pharmacokinetics and pharmacodynamics (PK\/PD) studies of voriconazole in a non-neutropenic murine model of invasive aspergillosis","volume":"55","author":"Seyedmousavi S","year":"2012","unstructured":"Seyedmousavi S, Melchers WJG, Bakkers J, Verweij PE, Mouton JW. 2012. Targeting 28S rDNA-gene of Aspergillus fumigatus for pharmacokinetics and pharmacodynamics (PK\/PD) studies of voriconazole in a non-neutropenic murine model of invasive aspergillosis. Mycoses 55:125\u2013126.","journal-title":"Mycoses"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00053-14"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchromb.2012.01.015"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00133-06"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.2165\/11594090-000000000-00000"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00009.2003"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1986.60.2.532"},{"key":"e_1_3_3_44_2","first-page":"L617","article-title":"Quantitative assessment of epithelial lining fluid in the lung","volume":"263","author":"Chinard FP","year":"1992","unstructured":"Chinard FP. 1992. Quantitative assessment of epithelial lining fluid in the lung. Am J Physiol 263:L617\u2013L618.","journal-title":"Am J Physiol"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm\/147.1.148"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.00535-08"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2006.08.017"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jir023"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01354-13"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00606-10"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00931-09"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkm428"},{"key":"e_1_3_3_53_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11046-010-9324-3"},{"key":"e_1_3_3_54_2","doi-asserted-by":"publisher","DOI":"10.2147\/IDR.S51340"},{"key":"e_1_3_3_55_2","doi-asserted-by":"publisher","DOI":"10.1517\/17425255.2012.683859"},{"key":"e_1_3_3_56_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkn076"},{"key":"e_1_3_3_57_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.diagmicrobio.2011.08.006"},{"key":"e_1_3_3_58_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1439-0507.2010.01996.x"},{"key":"e_1_3_3_59_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01530-08"},{"key":"e_1_3_3_60_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01512-07"},{"key":"e_1_3_3_61_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dki399"},{"key":"e_1_3_3_62_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00636-13"},{"key":"e_1_3_3_63_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01141-13"},{"key":"e_1_3_3_64_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01384-07"},{"key":"e_1_3_3_65_2","first-page":"M-1936","volume-title":"Abstr 52nd Intersci Conf Antimicrob Agents Chemother (ICAAC)","author":"Desai A","year":"2012","unstructured":"Desai A, Zadeikis N, Pearlman H, Kowalski D, Townsend R. 2012. Effect of multiple doses of isavuconazole on the pharmacokinetics of CYP3A4 substrate midazolam in healthy volunteers, p M-1936. Abstr 52nd Intersci Conf Antimicrob Agents Chemother (ICAAC), San Francisco, CA."},{"key":"e_1_3_3_66_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkl396"},{"key":"e_1_3_3_67_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01601-08"},{"key":"e_1_3_3_68_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkn431"},{"key":"e_1_3_3_69_2","first-page":"A-1874","volume-title":"14th Eur Congr Clin Microbiol Infect Dis (ESCMID)","author":"Te Dorsthorst DT","year":"2004","unstructured":"Te Dorsthorst DT, Verweij PE, Meis JF, Mouton JW. 2004. Pharmacodynamics of BAL4815 a new azole antifungal in a mouse model of systemic infection, p A-1874. 14th Eur Congr Clin Microbiol Infect Dis (ESCMID), Prague, Czech Republic."},{"key":"e_1_3_3_70_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02301-13"},{"key":"e_1_3_3_71_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.50.1.286-293.2006"},{"key":"e_1_3_3_72_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.50.1.279-285.2006"},{"key":"e_1_3_3_73_2","volume-title":"Abstr 48th Intersci Conf Antimicrob Agents Chemother (ICAAC)-Infect Dis Soc Am (IDSA) 46th Annu Meet","author":"Schmitt-Hoffman A","year":"2008","unstructured":"Schmitt-Hoffman A, Roos B, Roehrle M, Spickermann J, Schoetzau A, Simmen U, Heep M. 2008. No relevant food effect in man on isavuconazole oral pharmacokinetics preliminary data. Abstr 48th Intersci Conf Antimicrob Agents Chemother (ICAAC)-Infect Dis Soc Am (IDSA) 46th Annu Meet, Washington, DC."}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.04907-14","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.04907-14","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T22:59:36Z","timestamp":1645484376000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/AAC.04907-14"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,5]]},"references-count":72,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2015,5]]}},"alternative-id":["10.1128\/AAC.04907-14"],"URL":"https:\/\/doi.org\/10.1128\/aac.04907-14","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,5]]},"assertion":[{"value":"2014-11-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2015-02-28","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2015-04-10","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}