{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T11:14:44Z","timestamp":1789384484448,"version":"build-2803163510"},"reference-count":22,"publisher":"American Society for Microbiology","issue":"8","license":[{"start":{"date-parts":[[2012,8,1]],"date-time":"2012-08-01T00:00:00Z","timestamp":1343779200000},"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":[[2012,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Itraconazole is used for the prevention and treatment of infections caused by\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            . An understanding of the pharmacodynamics of itraconazole against wild-type and triazole-resistant strains provides a basis for innovative therapeutic strategies for treatment of infections. An\n            <jats:italic>in vitro<\/jats:italic>\n            model of the human alveolus was used to define the pharmacodynamics of itraconazole. Galactomannan was used as a biomarker. The effect of systemic and airway administration of itraconazole was assessed, as was a combination of itraconazole administered to the airway and systemically administered 5FC. Systemically administered itraconazole against the wild type induced a concentration-dependent decline in galactomannan in the alveolar and endothelial compartments. No exposure-response relationships were apparent for the L98H, M220T, or G138C mutant. The administration of itraconazole to the airway resulted in comparable exposure-response relationships to those observed with systemic therapy. This was achieved without detectable concentrations of drug within the endothelial compartment. The airway administration of itraconazole resulted in a definite but submaximal effect in the endothelial compartment against the L98H mutant. The administration of 5FC resulted in a concentration-dependent decline in galactomannan in both the alveolar and endothelial compartments. The combination of airway administration of itraconazole and systemically administered 5FC was additive. Systemic administration of itraconazole is ineffective against Cyp51 mutants. The airway administration of itraconazole is effective for the treatment of wild-type strains and appears to have some activity against the L98H mutants. Combination with other agents, such as 5FC, may enable the attainment of near-maximal antifungal activity.\n          <\/jats:p>","DOI":"10.1128\/aac.00141-12","type":"journal-article","created":{"date-parts":[[2012,5,22]],"date-time":"2012-05-22T02:55:06Z","timestamp":1337655306000},"page":"4146-4153","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":13,"title":["Pharmacodynamics of Itraconazole against Aspergillus fumigatus in an\n            <i>In Vitro<\/i>\n            Model of the Human Alveolus: Perspectives on the Treatment of Triazole-Resistant Infection and Utility of Airway Administration"],"prefix":"10.1128","volume":"56","author":[{"given":"Zaid","family":"Al-Nakeeb","sequence":"first","affiliation":[{"name":"School of Translational Medicine, The University of Manchester, and Manchester Academic Health Science Centre, National Institute for Health Research Translational Research Facility in Respiratory Medicine, University Hospital of South Manchester National Health Service, Foundation Trust, Manchester, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajay","family":"Sudan","sequence":"additional","affiliation":[{"name":"School of Translational Medicine, The University of Manchester, and Manchester Academic Health Science Centre, National Institute for Health Research Translational Research Facility in Respiratory Medicine, University Hospital of South Manchester National Health Service, Foundation Trust, Manchester, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam R.","family":"Jeans","sequence":"additional","affiliation":[{"name":"School of Translational Medicine, The University of Manchester, and Manchester Academic Health Science Centre, National Institute for Health Research Translational Research Facility in Respiratory Medicine, University Hospital of South Manchester National Health Service, Foundation Trust, Manchester, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lea","family":"Gregson","sequence":"additional","affiliation":[{"name":"School of Translational Medicine, The University of Manchester, and Manchester Academic Health Science Centre, National Institute for Health Research Translational Research Facility in Respiratory Medicine, University Hospital of South Manchester National Health Service, Foundation Trust, Manchester, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanne","family":"Goodwin","sequence":"additional","affiliation":[{"name":"School of Translational Medicine, The University of Manchester, and Manchester Academic Health Science Centre, National Institute for Health Research Translational Research Facility in Respiratory Medicine, University Hospital of South Manchester National Health Service, Foundation Trust, Manchester, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter A.","family":"Warn","sequence":"additional","affiliation":[{"name":"School of Translational Medicine, The University of Manchester, and Manchester Academic Health Science Centre, National Institute for Health Research Translational Research Facility in Respiratory Medicine, University Hospital of South Manchester National Health Service, Foundation Trust, Manchester, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy W.","family":"Felton","sequence":"additional","affiliation":[{"name":"School of Translational Medicine, The University of Manchester, and Manchester Academic Health Science Centre, National Institute for Health Research Translational Research Facility in Respiratory Medicine, University Hospital of South Manchester National Health Service, Foundation Trust, Manchester, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan J.","family":"Howard","sequence":"additional","affiliation":[{"name":"School of Translational Medicine, The University of Manchester, and Manchester Academic Health Science Centre, National Institute for Health Research Translational Research Facility in Respiratory Medicine, University Hospital of South Manchester National Health Service, Foundation Trust, Manchester, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William W.","family":"Hope","sequence":"additional","affiliation":[{"name":"School of Translational Medicine, The University of Manchester, and Manchester Academic Health Science Centre, National Institute for Health Research Translational Research Facility in Respiratory Medicine, University Hospital of South Manchester National Health Service, Foundation Trust, Manchester, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-0691.2012.03890.x"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00637-11"},{"key":"e_1_3_2_4_2","volume-title":"Approved standard. M38-A.","author":"Clinical Laboratory Sciences Institute","year":"2002","unstructured":"Clinical Laboratory Sciences Institute. 2002. Reference method for broth dilution antifungal susceptibility testing of filamentous fungi. Approved standard. M38-A. CLSI, Wayne, PA."},{"key":"e_1_3_2_5_2","unstructured":"D'ArgenioDZ\nSchumitzkyA\nWangX. 2009. ADAPT 5 user's guide: pharmacokinetic\/pharmacodynamic systems analysis software. Biomedical Simulations Resource Los Angeles CA."},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tim.2010.02.004"},{"key":"e_1_3_2_7_2","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/0002-9343(94)90023-X","article-title":"NIAID Mycoses Study Group multicenter trial of oral itraconazole therapy for invasive aspergillosis","volume":"97","author":"Denning DW","year":"1994","unstructured":"DenningDW. 1994. NIAID Mycoses Study Group multicenter trial of oral itraconazole therapy for invasive aspergillosis. Am. J. Med. 97:135\u2013144.","journal-title":"Am. J. Med."},{"key":"e_1_3_2_8_2","doi-asserted-by":"crossref","first-page":"4615","DOI":"10.1200\/JCO.2003.04.052","article-title":"Itraconazole prevents invasive fungal infections in neutropenic patients treated for hematologic malignancies: evidence from a meta-analysis of 3,597 patients","volume":"21","author":"Glasmacher A","year":"2003","unstructured":"GlasmacherA. 2003. Itraconazole prevents invasive fungal infections in neutropenic patients treated for hematologic malignancies: evidence from a meta-analysis of 3,597 patients. J. Clin. Oncol. 21:4615\u20134626.","journal-title":"J. Clin. Oncol."},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.50.4.1552-1554.2006"},{"key":"e_1_3_2_10_2","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1086\/510535","article-title":"Pathogenesis of Aspergillus fumigatus and the kinetics of galactomannan in an in vitro model of early invasive pulmonary aspergillosis: implications for antifungal therapy","volume":"195","author":"Hope WW","year":"2007","unstructured":"HopeWW. 2007. Pathogenesis of Aspergillus fumigatus and the kinetics of galactomannan in an in vitro model of early invasive pulmonary aspergillosis: implications for antifungal therapy. J. Infect. Dis. 195:455\u2013466.","journal-title":"J. Infect. 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