期刊
JOURNAL OF INFECTIOUS DISEASES
卷 206, 期 3, 页码 442-452出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/infdis/jis372
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资金
- National Centre for Replacement, Refinement and Reduction of Animals in Research (NC3Rs)
- Anti-Infective Research (AIR) Foundation
- Pfizer Inc.
- National Institute of Health Research (NIHR)
- Pfizer
- Astellas
- Merck
- Gilead
- Fungal Research Trust
- Schering-Plough
- Astellas Pharma
- bioMerieux
- Gilead Sciences
- Merck Sharp and Dohme
- Schering Plough
- Soria Melguizo SA
- Ferrer International
- European Union
- ALBAN program
- Spanish Agency for International Cooperation
- Spanish Ministry of Culture and Education
- Spanish Health Research Fund
- Instituto de Salud Carlos III
- Ramon Areces Foundation
- Mutua Madrile a Foundation
- National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) [G0700599/1] Funding Source: researchfish
Background. Voriconazole is a first-line agent for the treatment of invasive pulmonary aspergillosis (IPA). There are increasing reports of Aspergillus fumigatus isolates with reduced susceptibility to voriconazole. Methods. An in vitro dynamic model of IPA was developed that enabled simulation of human-like voriconazole pharmacokinetics. Galactomannan was used as a biomarker. The pharmacodynamics of voriconazole against wild-type and 3 resistant strains of A. fumigatus were defined. The results were bridged to humans to provide decision support for setting breakpoints for voriconazole using Clinical Laboratory Standards Institute (CLSI) and European Committee of Antimicrobial Susceptibility Testing (EUCAST) methodologies. Results. Isolates with higher minimum inhibitory concentrations (MICs) required higher area under the concentration time curves (AUCs) to achieve suppression of galactomannan. Using CLSI and EUCAST methodologies, the AUC:MIC values that achieved suppression of galactomannan were 55 and 32.1, respectively. Using CLSI and EUCAST methodologies, the trough concentration: MIC values that achieved suppression of galactomannan were 1.68 and 1, respectively. Potential CLSI breakpoints for voriconazole are <= 0.5 mg/L for susceptible and >1 mg/L for resistant. Potential EUCAST breakpoints for voriconazole are <= 1 mg/L for susceptible and >2 mg/L for resistant. Conclusions. This dynamic model of IPA is a useful tool to address many remaining questions related to antifungal treatment of Aspergillus spp.
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