{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T23:41:49Z","timestamp":1789429309225,"version":"build-2803163510"},"reference-count":32,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,7,1]],"date-time":"2019-07-01T00:00:00Z","timestamp":1561939200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,7,1]],"date-time":"2019-07-01T00:00:00Z","timestamp":1561939200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Pulmocide Ltd."}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Invasive pulmonary Aspergillosis is a leading cause of morbidity and mortality in immunosuppressed patients and treatment outcomes using oral antifungal triazoles remain suboptimal. Here we show that combining topical treatment using PC945, a novel inhaled triazole, with systemic treatment using known triazoles demonstrated synergistic antifungal effects against\n                    <jats:italic>Aspergillus fumigatus<\/jats:italic>\n                    (AF) in an\n                    <jats:italic>in vitro<\/jats:italic>\n                    human alveolus bilayer model and in the lungs of neutropenic immunocompromised mice. Combination treatment with apical PC945 and either basolateral posaconazole or voriconazole resulted in a synergistic interaction with potency improved over either compound as a monotherapy against both azole-susceptible and resistant AF invasion\n                    <jats:italic>in vitro<\/jats:italic>\n                    . Surprisingly there was little, or no synergistic interaction observed when apical and basolateral posaconazole or voriconazole were combined. In addition, repeated prophylactic treatment with PC945, but not posaconazole or voriconazole, showed superior effects to single prophylactic dose, suggesting tissue retention and\/or accumulation of PC945. Furthermore, in mice infected with AF intranasally, 83% of animals treated with a combination of intranasal PC945 and oral posaconazole survived until day 7, while little protective effects were observed by either compound alone. Thus, the combination of a highly optimised topical triazole with oral triazoles potentially induces synergistic effects against AF infection.\n                  <\/jats:p>","DOI":"10.1038\/s41598-019-45890-w","type":"journal-article","created":{"date-parts":[[2019,7,1]],"date-time":"2019-07-01T06:02:54Z","timestamp":1561960974000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["Antifungal synergy of a topical triazole, PC945, with a systemic triazole against respiratory Aspergillus fumigatus infection"],"prefix":"10.1038","volume":"9","author":[{"given":"Thomas","family":"Colley","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gurpreet","family":"Sehra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leah","family":"Daly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Genki","family":"Kimura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiro","family":"Nakaoki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Nishimoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuo","family":"Kizawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pete","family":"Strong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Garth","family":"Rapeport","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9320-2717","authenticated-orcid":false,"given":"Kazuhiro","family":"Ito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,7,1]]},"reference":[{"key":"45890_CR1","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1128\/cmr.00055-08","volume":"22","author":"TRT Dagenais","year":"2009","unstructured":"Dagenais, T. R. T. & Keller, N. P. Pathogenesis of Aspergillus fumigatus in Invasive Aspergillosis. Clin Microbiol Rev 22, 447\u2013465, https:\/\/doi.org\/10.1128\/cmr.00055-08 (2009).","journal-title":"Clin Microbiol Rev"},{"key":"45890_CR2","doi-asserted-by":"publisher","first-page":"e1","DOI":"10.1093\/cid\/ciw326","volume":"63","author":"TF Patterson","year":"2016","unstructured":"Patterson, T. F. et al. Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America. 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J. et al. In Vivo Efficacy of Aerosolized Nanostructured Itraconazole Formulations for Prevention of Invasive Pulmonary Aspergillosis. Antimicrob Agents Chemother 50, 1552\u20131554, https:\/\/doi.org\/10.1128\/aac.50.4.1552-1554.2006 (2006).","journal-title":"Antimicrob Agents Chemother"},{"key":"45890_CR5","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1183\/09031936.00163511","volume":"40","author":"O Hilberg","year":"2012","unstructured":"Hilberg, O. et al. Remarkably efficient inhaled antifungal monotherapy for invasive pulmonary aspergillosis. The European respiratory journal 40, 271\u2013273, https:\/\/doi.org\/10.1183\/09031936.00163511 (2012).","journal-title":"The European respiratory journal"},{"key":"45890_CR6","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1097\/01.tp.0000101516.08327.a9","volume":"77","author":"RH Drew","year":"2004","unstructured":"Drew, R. H. et al. Comparative safety of amphotericin B lipid complex and amphotericin B deoxycholate as aerosolized antifungal prophylaxis in lung-transplant recipients. Transplantation 77, 232\u2013237, https:\/\/doi.org\/10.1097\/01.tp.0000101516.08327.a9 (2004).","journal-title":"Transplantation"},{"key":"45890_CR7","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1111\/bcpt.12820","volume":"121","author":"CU Andersen","year":"2017","unstructured":"Andersen, C. U. et al. Voriconazole Concentrations in Plasma and Epithelial Lining Fluid after Inhalation and Oral Treatment. Basic & clinical pharmacology & toxicology 121, 430\u2013434, https:\/\/doi.org\/10.1111\/bcpt.12820 (2017).","journal-title":"Basic & clinical pharmacology & toxicology"},{"key":"45890_CR8","doi-asserted-by":"publisher","first-page":"e02280","DOI":"10.1128\/aac.02280-16","volume":"61","author":"T Colley","year":"2017","unstructured":"Colley, T. et al. In vitro and in vivo antifungal profile of a novel and long acting inhaled azole, PC945, on Aspergillus fumigatus infection. Antimicrob Agents Chemother 61, e02280\u201302216, https:\/\/doi.org\/10.1128\/aac.02280-16 (2017).","journal-title":"Antimicrob Agents Chemother"},{"key":"45890_CR9","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1086\/510535","volume":"195","author":"WW Hope","year":"2007","unstructured":"Hope, W. W. et al. Pathogenesis of Aspergillus fumigatus and the kinetics of galactomannan in an in vitro model of early invasive pulmonary aspergillosis: implications for antifungal therapy. The Journal of infectious diseases 195, 455\u2013466, https:\/\/doi.org\/10.1086\/510535 (2007).","journal-title":"The Journal of infectious diseases"},{"key":"45890_CR10","doi-asserted-by":"publisher","first-page":"e00124","DOI":"10.1128\/aac.00124-17","volume":"61","author":"G Kimura","year":"2017","unstructured":"Kimura, G. et al. 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T.C. and L.D. are\u00a0employees of Pulmocide Ltd. P.S., G.R. and K.I. are Pulmocide employees and (co-)founders of Pulmocide Ltd. Other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"9482"}}