Prevention/diagnosis/fungal infections/transplantation

描述（由申请人提供）：在过去的二十年中，侵袭性真菌感染（IFIs）的发病率急剧增加。接受骨髓移植（BMT）的患者以及接受实体器官移植的患者发生这些通常致命的感染的风险特别高。国际金融机构与高死亡率有关，因为目前抗真菌药物有限，而且往往有毒，而且缺乏敏感、快速的检测方法，以帮助早期诊断侵袭性真菌感染。如果一种抗真菌方案能够安全地给予真菌感染高风险患者，并且在不诱导耐药性的情况下预防真菌感染，那么移植领域将受益匪浅。同样，如果能够开发出一种能够在感染过程的早期可靠地诊断出侵袭性真菌病的检测方法，则可以在更适合治疗的感染阶段开始靶向抗真菌方案。本提案的具体目的是：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)评估快速诊断高风险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。吸入两性霉素B脂质复合物（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体BMT人群中确定。随后将进行大型、多中心随机试验，以评估疗效。与全身给药相比，用于预防的ABLC吸入给药途径可能导致毒性发生率降低。在涉及肺移植受者的前瞻性研究中，将评估不同快速抗原检测和PCR检测串行监测的性能特点和诊断价值。随后将进行旨在调查这些快速检测方法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和标本库，以评估目前正在开发的快速诊断分析方法。这种方法将缩短从开发到临床实施治疗试验和指南的时间。

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.