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Effects of intranasally dosed posaconazole on fungal load and biomarkers in Aspergillus fumigatus infected immunocompromised mice
Author(s) -
Kimura Genki,
Nakaoki Takahiro,
Nishimoto Yuki,
Suzuki Yuto,
Rapeport Garth,
Strong Pete,
Ito Kazuhiro,
Kizawa Yasuo
Publication year - 2017
Publication title -
mycoses
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.13
H-Index - 69
eISSN - 1439-0507
pISSN - 0933-7407
DOI - 10.1111/myc.12653
Subject(s) - posaconazole , aspergillus fumigatus , nasal administration , bronchoalveolar lavage , itraconazole , pharmacology , medicine , aspergillosis , lung , immunology , antifungal , dermatology
Summary Although anti‐fungal triazoles are dosed orally or systemically for Aspergillus fumigatus infection, systemic adverse events and limited exposure of the lung cavity would make a topical treatment for the lung an attractive option. In this study, we examined the effects of intranasally dosed posaconazole on survival rates and biomarkers in A. fumigatus (itraconazole susceptible: ATCC 13073 [Af]; or resistant: NCPF 7100 [AfR]) infected, temporarily neutropenic A/J mice. Once daily treatment produced a dose‐dependent improvement of survival of Af‐infected mice ( ED 50 : 0.019 mg/mouse [approx. 0.755 mg/kg, in]), similar to its potency ( ED 50 : 0.775 mg/kg, po) after once daily oral dosing. For AfR infection, either intranasal or oral posaconazole was largely ineffective on survival, although the highest dose of intranasal treatment (0.35 mg/mouse) achieved 75% survival rate. Early intervention (treated on days 0, 1, 2 and 3 postinfection) and late intervention (treated on days 1, 2 and 3) with intranasal posaconazole (0.014‐0.35 mg/mouse) demonstrated potent inhibition of lung fungal load and galactomannan levels in both bronchoalveolar lavage fluid ( BALF ) and serum as well as inflammatory cells, IFN ‐γ, IL ‐17 and malondialdehyde ( MDA ) in BALF . Thus, posaconazole when dosed intranasally once daily showed an improvement of survival equivalent to or better than oral treatment, and produced potent inhibition of fungal load and biomarkers.