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首页> 外文期刊>Antimicrobial agents and chemotherapy. >Pharmacodynamics of itraconazole against Aspergillus fumigatus in an in vitro model of the human alveolus: Perspectives on the treatment of triazole-resistant infection and utility of airway administration
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Pharmacodynamics of itraconazole against Aspergillus fumigatus in an in vitro model of the human alveolus: Perspectives on the treatment of triazole-resistant infection and utility of airway administration

机译：伊曲康唑在人肺泡体外模型中对烟曲霉的药效学：对三唑耐药性感染的治疗观点和气道给药的实用性

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摘要

Itraconazole is used for the prevention and treatment of infections caused by Aspergillus fumigatus. 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 in vitro 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.
机译：伊曲康唑用于预防和治疗由烟曲霉引起的感染。对伊曲康唑针对野生型和三唑耐药菌株的药效学的了解为创新的感染治疗策略提供了基础。人类肺泡的体外模型用于定义伊曲康唑的药效学。半乳甘露聚糖被用作生物标记。评估了伊曲康唑的全身和气道给药效果，以及伊曲康唑向气道给药和全身5FC给药的联合作用。对野生型全身施用伊曲康唑可引起肺泡和内皮区室中半乳甘露聚糖的浓度依赖性下降。对于L98H，M220T或G138C突变体，没有明显的暴露-反应关系。将伊曲康唑施用于气道可导致与全身治疗观察到的暴露-反应关系相当。这是在内皮区室中没有可检测到的药物浓度的情况下实现的。对伊曲康唑进行气道给药可在内皮区室中对L98H突变体产生明确但次最大的作用。 5FC的给药导致在肺泡和内皮区室中半乳甘露聚糖的浓度依赖性下降。伊曲康唑的气道给药与全身性5FC给药相加。伊曲康唑的全身给药对Cyp51突变体无效。依曲康唑的气道给药对野生型菌株有效，并且似乎对L98H突变体具有一定的活性。与其他药物（例如5FC）的组合可实现接近最大的抗真菌活性。

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