Prevention/diagnosis/fungal infections/transplantation

描述（由申请人提供）：侵袭性真菌感染（IFIs）的发病率在过去二十年中急剧增加。接受骨髓移植（BMT）的患者以及接受移植实体器官的患者患这些通常致命的感染的风险特别高。IFIs与高死亡率相关，这是由于目前有限且通常有毒的抗真菌药物以及缺乏敏感、快速的检测来帮助早期诊断侵袭性真菌感染。如果抗真菌治疗方案能够安全地给予真菌感染高危患者，并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检测方法，在感染过程的早期可靠地诊断侵袭性真菌病，则可以在感染阶段开始靶向抗真菌治疗，更适合治疗。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。将通过一项非随机开放标签试验在同种异体BMT人群中确定吸入两性霉素B脂质复合物（ABLC）的安全性和耐受性。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，ABLC预防性吸入给药途径可能导致毒性发生率降低。将在涉及肺移植受者的前瞻性研究中评估不同快速抗原检测和PCR检测系列监测的性能特征和诊断价值。旨在研究这些快速测定对更好临床结果的贡献的试验将随后进行。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检测方法。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.