Prevention/diagnosis/fungal infections/transplantation

描述(由申请人提供)：侵袭性真菌感染(IFI)的发病率在过去20年中急剧增加。接受骨髓移植(BMT)的患者以及接受实体器官移植的患者患这些通常是致命的感染的风险特别高。由于目前抗真菌药物有限且往往有毒，以及缺乏有助于早期诊断侵袭性真菌感染的灵敏、快速的测试，IFI与高死亡率有关。如果一种抗真菌方案能够安全地应用于发生真菌感染的高危患者，并在不引起耐药性发展的情况下预防真菌感染，移植领域将受益匪浅。同样，如果能够开发出一种在感染过程早期可靠地诊断侵袭性真菌病的方法，那么可以在感染更容易治疗的阶段开始有针对性的抗真菌方案。这项建议的具体目标是：1)评估预防高危移植人群侵袭性真菌感染的新预防方案；2)评估快速诊断高危人群侵袭性真菌感染的新实验室检测方法。这些目标将通过一系列临床试验来实现。吸入性两性霉素B脂复合体(ABLC)的安全性和耐受性将通过一项非随机开放标签试验在异基因骨髓移植人群中确定。随后将进行旨在评估疗效的大型多中心随机试验。与全身给药相比，吸入给药预防ABLC的毒性发生率可能会降低。不同快速抗原检测和聚合酶链式反应检测系列监测的性能特点和诊断价值将在涉及肺移植受者的前瞻性研究中进行评估。随后将进行旨在调查这些快速分析对更好的临床结果的贡献的试验。最后，将建立一个多中心移植数据登记处和标本库，以评估目前正在开发的快速诊断分析。这种方法将缩短治疗试验和指南从开发到临床实施的时间。

DESCRIPTION (provided by applicant): The incidence of invasive fungal infections (IFIs) has increased dramatically over the past twenty years. Patients undergoing bone marrow transplantation (BMT) as well as those receiving transplanted solid organs are at particularly high risk for these often lethal infections. IFIs are associated with high mortality owing to currently limited and often toxic antifungal drugs as well as the lack of sensitive, rapid tests to aid in the earlier diagnosis of invasive fungal infections. If an antifungal regimen could be given safely to patients at high risk for developing fungal infections and fungal infections prevented without inducing the development of resistance, the field of transplantation would benefit greatly. Similarly, if an assay could be developed that would reliably diagnose invasive mycoses early in the course of infection, targeted antifungal regimens could be started at a stage of infection more amenable to therapy. The specific aims of this proposal are 1) to assess new prophylactic regimens for the prevention of invasive fungal infections in high risk transplant populations and 2) to assess new laboratory assays for the rapid diagnosis of invasive fungal infections in high risk populations. These aims will be met through a series of clinical trials. The safety and tolerability of inhaled Amphotericin B Lipid Complex (ABLC) will be determined in the allogeneic BMT population through a non-randomized open-label trial. Large, multicenter randomized, trials designed to assess efficacy will follow. The inhaled route of administration of ABLC for prophylaxis may result in a decreased incidence of toxicity as compared with the systemic administration of the drug. The performance characteristics and the diagnostic value of serial monitoring with different rapid antigen assays and PCR assays will be assessed in prospective studies involving lung transplant recipients. Trials designed to investigate the contribution of these rapid assays to better clinical outcomes will follow. Finally, a multicenter transplant data registry and specimen bank will be established for the purpose of evaluating rapid diagnostic assays currently in development. This approach will shorten the time from development to clinical implementation in therapeutic trials and guidelines.