Development of azole resistance in Aspergillus fumigatus during azole therapy associated with change in virulence.

Four sequential Aspergillus fumigatus isolates from a patient with chronic granulomatous disease (CGD) eventually failing azole-echinocandin combination therapy were investigated. The first two isolates (1 and 2) were susceptible to antifungal azoles, but increased itraconazole, voriconazole and pos...

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Autores principales:	Maiken Cavling Arendrup, Eleftheria Mavridou, Klaus Leth Mortensen, Eveline Snelders, Niels Frimodt-Møller, Humara Khan, Willem J G Melchers, Paul E Verweij
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/34a422c5b83d4335a86546298a249e3f
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spelling	oai:doaj.org-article:34a422c5b83d4335a86546298a249e3f2021-11-25T06:24:40ZDevelopment of azole resistance in Aspergillus fumigatus during azole therapy associated with change in virulence.1932-620310.1371/journal.pone.0010080https://doaj.org/article/34a422c5b83d4335a86546298a249e3f2010-04-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20404915/?tool=EBIhttps://doaj.org/toc/1932-6203Four sequential Aspergillus fumigatus isolates from a patient with chronic granulomatous disease (CGD) eventually failing azole-echinocandin combination therapy were investigated. The first two isolates (1 and 2) were susceptible to antifungal azoles, but increased itraconazole, voriconazole and posaconazole MICs were found for the last two isolates (3 and 4). Microsatellite typing showed that the 4 isolates were isogenic, suggesting that resistance had been acquired during azole treatment of the patient. An immunocompromised mouse model confirmed that the in vitro resistance corresponded with treatment failure. Mice challenged with the resistant isolate 4 failed to respond to posaconazole therapy, while those infected by susceptible isolate 2 responded. Posaconazole-anidulafungin combination therapy was effective in mice challenged with isolate 4. No mutations were found in the Cyp51A gene of the four isolates. However, expression experiments of the Cyp51A showed that the expression was increased in the resistant isolates, compared to the azole-susceptible isolates. The microscopic morphology of the four isolates was similar, but a clear alteration in radial growth and a significantly reduced growth rate of the resistant isolates on solid and in broth medium was observed compared to isolates 1 and 2 and to unrelated wild-type controls. In the mouse model the virulence of isolates 3 and 4 was reduced compared to the susceptible ones and to wild-type controls. For the first time, the acquisition of azole resistance despite azole-echinocandin combination therapy is described in a CGD patient and the resistance demonstrated to be directly associated with significant change of virulence.Maiken Cavling ArendrupEleftheria MavridouKlaus Leth MortensenEveline SneldersNiels Frimodt-MøllerHumara KhanWillem J G MelchersPaul E VerweijPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 5, Iss 4, p e10080 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Maiken Cavling Arendrup Eleftheria Mavridou Klaus Leth Mortensen Eveline Snelders Niels Frimodt-Møller Humara Khan Willem J G Melchers Paul E Verweij Development of azole resistance in Aspergillus fumigatus during azole therapy associated with change in virulence.
description	Four sequential Aspergillus fumigatus isolates from a patient with chronic granulomatous disease (CGD) eventually failing azole-echinocandin combination therapy were investigated. The first two isolates (1 and 2) were susceptible to antifungal azoles, but increased itraconazole, voriconazole and posaconazole MICs were found for the last two isolates (3 and 4). Microsatellite typing showed that the 4 isolates were isogenic, suggesting that resistance had been acquired during azole treatment of the patient. An immunocompromised mouse model confirmed that the in vitro resistance corresponded with treatment failure. Mice challenged with the resistant isolate 4 failed to respond to posaconazole therapy, while those infected by susceptible isolate 2 responded. Posaconazole-anidulafungin combination therapy was effective in mice challenged with isolate 4. No mutations were found in the Cyp51A gene of the four isolates. However, expression experiments of the Cyp51A showed that the expression was increased in the resistant isolates, compared to the azole-susceptible isolates. The microscopic morphology of the four isolates was similar, but a clear alteration in radial growth and a significantly reduced growth rate of the resistant isolates on solid and in broth medium was observed compared to isolates 1 and 2 and to unrelated wild-type controls. In the mouse model the virulence of isolates 3 and 4 was reduced compared to the susceptible ones and to wild-type controls. For the first time, the acquisition of azole resistance despite azole-echinocandin combination therapy is described in a CGD patient and the resistance demonstrated to be directly associated with significant change of virulence.
format	article
author	Maiken Cavling Arendrup Eleftheria Mavridou Klaus Leth Mortensen Eveline Snelders Niels Frimodt-Møller Humara Khan Willem J G Melchers Paul E Verweij
author_facet	Maiken Cavling Arendrup Eleftheria Mavridou Klaus Leth Mortensen Eveline Snelders Niels Frimodt-Møller Humara Khan Willem J G Melchers Paul E Verweij
author_sort	Maiken Cavling Arendrup
title	Development of azole resistance in Aspergillus fumigatus during azole therapy associated with change in virulence.
title_short	Development of azole resistance in Aspergillus fumigatus during azole therapy associated with change in virulence.
title_full	Development of azole resistance in Aspergillus fumigatus during azole therapy associated with change in virulence.
title_fullStr	Development of azole resistance in Aspergillus fumigatus during azole therapy associated with change in virulence.
title_full_unstemmed	Development of azole resistance in Aspergillus fumigatus during azole therapy associated with change in virulence.
title_sort	development of azole resistance in aspergillus fumigatus during azole therapy associated with change in virulence.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/34a422c5b83d4335a86546298a249e3f
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Development of azole resistance in Aspergillus fumigatus during azole therapy associated with change in virulence.

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