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

基本信息

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
项目类别：
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

项目摘要

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使粘膜和皮下真菌病衰弱。目前的抗真菌疗法存在严重缺陷包括有限的活性谱、患者毒性以及带有遗传基因的真菌分离株的出现编码电阻。更大的担忧是所有三大类抗真菌药物的功效均不高，因为这可能是 IFI 患者死亡率过高和持续存在的一个主要驱动因素。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了新冠病毒的患者身上。根据体外测定，似乎对所选抗真菌治疗敏感的真菌分离株敏感性测试。例如，大约三分之一的患者患有播散性念珠菌感染涉及根据当前临床断点被认为敏感的分离株，未能对治疗做出反应唑类抗真菌药。一些与宿主相关的因素被提出来解释宿主之间的不一致。体外药敏试验和患者结果，例如感染部位的药物分布不充分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。虽然药物间相互作用是人们严重关注的问题从患者毒性角度、大多数联合用药对真菌生理学的影响以及抗真菌药物的敏感性，很大程度上是未知的。使用主要非专利药物的简单筛选，我们最近发现，在所检测的 1280 种化合物中，惊人的 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发挥作用。我们的初步研究还表明非抗真菌药物可以对真菌生理学和结果产生深远的影响小鼠感染。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它们对 IFI 患者治疗结果的潜在临床影响。目标1 我们将进行一套全面、系统的筛选，以确定目前批准的药物在四种最常见的人类真菌中拮抗最相关的抗真菌药物的活性病原体。然后将选择那些在药理学相关浓度下起作用的药物，并确定作用的程度相比之下，其抗真菌活性有所减弱。目标 2 将侧重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小鼠模型并对患者结果进行回顾性分析以确定拮抗药物的联合使用是否足以影响抗真菌治疗的临床疗效。这长期目标是通过建立综合治疗方案来改善患者的治疗结果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。