Antifungal antagonism as a cause of treatment failure for invasive mycoses

据估计，每年有150万人死于侵袭性真菌感染（IFIs）， 通过使粘膜和皮下真菌病衰弱。目前的抗真菌治疗存在严重缺陷 包括有限的活性谱、患者毒性和出现具有遗传毒性的真菌分离物， 编码抵抗一个更大的问题是所有三个主要类别的抗真菌药物的疗效适中， 这可能是IFIs患者死亡率过高的主要驱动因素， 粘膜感染由于无法解释的原因，大多数治疗失败发生在感染 真菌分离株似乎对所选抗真菌治疗敏感，如体外试验确定的 敏感性试验例如，大约三分之一的播散性念珠菌感染患者 涉及根据当前临床折点被视为敏感的分离株，对以下药物治疗无效 唑类抗真菌剂。已经提出了几个与宿主相关的因素来解释这些差异。 体外药敏试验和患者结局，如感染部位药物分布不足，或 患者免疫功能障碍的严重程度。然而，只有有限的证据支持这些论点， 许多治疗失败仍然无法解释。虽然药物相互作用是一个严重的问题， 从患者毒性的角度来看，大多数联合用药对真菌生理学的影响， 抗真菌敏感性，在很大程度上是未知的。使用一个简单的主要是非专利药物的筛选，我们 最近发现，在1280种化合物中，有139种化合物表现出与 氟康唑在至少一种医学上重要的念珠菌属中。我们的初步研究还显示 非抗真菌药物可以对真菌生理学和真菌感染的结果产生深远的影响。 感染小鼠。本研究的目的是揭示抗真菌药物-药物拮抗剂的全部范围 相互作用，并评估其对IFIs患者治疗结局的潜在临床影响。在aim 1中 我们将进行一套全面和系统的筛选，以确定目前批准的药物， 拮抗最相关的抗真菌药物的活性，在四个最流行的人类真菌 病原体然后将选择那些在相关浓度下起作用的化合物， 其抗真菌活性相比之下降低。目标2将集中于定义分子机制， 其中抗真菌拮抗剂起作用并检查它们对真菌生理学的影响。最后，在目标3中，我们将使用 侵袭性念珠菌病的小鼠模型，并对患者结局进行回顾性分析，以确定 如果同时使用拮抗药物足以影响抗真菌治疗的临床疗效。的 长期目标是通过建立综合治疗方案， 最大限度地减少临床相关的拮抗药物相互作用，从而最大限度地提高抗真菌功效。

An estimated 1.5 million people die each year from invasive fungal infections (IFIs), with millions more afflicted by debilitating mucosal and subcutaneous mycoses. Current antifungal therapies have serious deficiencies including limited spectrum of activity, patient toxicity and the emergence of fungal isolates with genetically encoded resistance. A larger concern is the modest efficacy of all three major classes of antifungal drug, as this is likely a major driver of the excessively high rates of mortality in patients with IFIs, and persistence of mucosal infections. For unexplained reasons, the majority of treatment failures occur in patients infected by fungal isolates that are seemingly sensitive to the selected antifungal therapy, as determined by in vitro susceptibility testing. For example, approximately one-third of patients with a disseminated Candida infection involving isolates deemed susceptible according to current clinical breakpoints, fail to respond to treatment with an azole antifungal. Several host-related factors have been proposed to explain the discordance between in vitro susceptibility tests and patient outcomes, such as inadequate drug distribution to the site of infection or severity of patient immune dysfunction. However, there is only limited evidence to support these arguments, and many treatment failures remain unexplained. While drug-drug interactions are a serious concern from the perspective of patient toxicity, the effect of most co-administered medications upon fungal physiology and antifungal susceptibility, is largely unknown. Using a simple screen of mainly off-patent medications, we recently found that a staggering 139 of the 1280 compounds examined exhibit antagonistic interactions with fluconazole in at least one medically important Candida species. Our preliminary studies have also revealed that non-antifungal medications can have a profound impact upon fungal physiology and upon the outcome of infection in mice. The objective of this study is to uncover the full scope of antifungal drug-drug antagonistic interactions and assess their potential clinical impact upon treatment outcomes in patients with IFIs. In aim 1 we will conduct a comprehensive and systematic set of screens to identify currently approved medications that antagonize the activity of the most relevant antifungal drugs, in four of the most prevalent human fungal pathogens. Those acting at pharmacologically relevant concentrations will then be selected, and the extent to which antifungal activity is diminished compared. Aim 2 will focus upon defining the molecular mechanisms by which antifungal antagonists act and examine their effects upon fungal physiology. Finally, in aim 3 we will use a mouse model of invasive candidiasis and conduct a retrospective analysis of patient outcomes to determine if coadministration of antagonistic drugs is sufficient to influence the clinical efficacy of antifungal therapy. The long-term goal is to improve patient outcomes through establishing integrated treatment protocols that minimize clinically relevant antagonistic drug-interactions to and therefore maximize antifungal efficacy.