Antifungal antagonism as a cause of treatment failure for invasive mycoses

抗真菌拮抗作用是侵袭性真菌病治疗失败的一个原因

• 批准号: 10378060
• 负责人: Glen Palmer
• 金额: $ 60.84万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10378060
• 关键词: Affect; Antifungal Agents; Antifungal Therapy; Antipsychotic Agents; Aspergillus; Aspergillus fumigatus; Azoles; Biological Assay; Candida; Candida albicans; Candida glabrata; Candidiasis; Cause of Death; Chemicals; Clinical; Collection; Cryptococcus; Cryptococcus neoformans; Drug Efflux; Drug Interactions; Enzymes; Exhibits; FDA approved; Failure; Fluconazole; Frequencies; Fungal Drug Resistance; Gene Expression Profile; Goals; Growth; Human; Immune System Diseases; In Vitro; Incidence; Individual; Infection; Investigation; Life; Medical; Microbiology; Molecular; Mucous Membrane; Mus; Mycoses; Outcome; Patient-Focused Outcomes; Patients; Persons; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiological; Physiology; Polyenes; Population; Predisposition; Regimen; Resistance; Retrospective cohort study; Risk; Severities; Site; Testing; Therapeutic; Toxic effect; Treatment Failure; Treatment Protocols; Treatment outcome; Virulence; antagonist; aripiprazole; clinical efficacy; clinically relevant; comorbidity; drug distribution; efflux pump; follow-up; improved; improved outcome; insight; mortality; mouse model; off-patent; pathogenic fungus; patient response; subcutaneous; success

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.

据估计，每年有150万人死于侵袭性真菌感染(IFI)，还有数百万人受到影响 通过削弱粘膜和皮下真菌病。目前的抗真菌疗法存在严重的缺陷。 包括有限的活性范围、患者的毒性和遗传上的真菌分离株的出现 编码抵抗力。一个更大的担忧是，所有三大类抗真菌药物的疗效都不是很好，因为 这可能是导致IFIS患者死亡率过高的主要原因，而且持续的 粘膜感染。由于不明原因，大多数治疗失败发生在感染了 体外测定对所选抗真菌药物似乎敏感的真菌分离株 药敏试验。例如，大约三分之一的播散性念珠菌感染患者 涉及根据当前临床断点被认为易感的菌株，对以下治疗没有反应 一种唑类抗真菌药物。已经提出了几个与宿主有关的因素来解释 体外药敏试验和患者结局，如感染或感染部位药物分配不充分 患者免疫功能障碍的严重程度。然而，支持这些论点的证据有限， 许多治疗失败仍然无法解释。虽然药物与药物的相互作用是来自 患者毒性的观点，大多数联合用药对真菌生理和 抗真菌敏感性，在很大程度上是未知的。使用主要是非专利药物的简单筛选，我们 最近发现，在所研究的1280种化合物中，有139种表现出与 至少一种医学上重要的念珠菌属中的氟康唑。我们的初步研究也揭示了 非抗真菌药物可以对真菌生理学和疾病结局产生深远的影响 小鼠的感染。本研究的目的是全面揭示抗真菌药物-药物拮抗剂。 并评估其对IFIS患者治疗结果的潜在临床影响。在目标1中 我们将进行一套全面和系统的筛查，以确定目前批准的药物 拮抗最相关的抗真菌药物的活性，在四种最流行的人类真菌中 病原体。然后将选择那些在药理上相关的浓度起作用的药物，并在一定程度上 与之相比，其抗真菌活性减弱。目标2将集中于通过以下方式定义分子机制 哪些抗真菌拮抗剂起作用并检测它们对真菌生理学的影响。最后，在目标3中，我们将使用 建立侵袭性念珠菌病的小鼠模型，并对患者的预后进行回顾性分析，以确定 联合应用拮抗药物是否足以影响抗真菌治疗的临床疗效。这个 长期目标是通过建立综合治疗方案来改善患者结果 将临床相关的拮抗药物相互作用降至最低，从而最大限度地提高抗真菌效果。