Molecular Detection of Invasive Fungal Infections

 描述（由申请人提供）：侵袭性真菌感染的发生率，特别是念珠菌感染（第四大常见医院病原体），在过去40年中持续增加。这一增加是由于移植手术、化疗方案、内科和外科治疗的进步以及侵入性器械（如血管内中心静脉导管）的使用增加导致严重免疫抑制的患者数量增加。虽然大多数侵袭性真菌病（IFD）是 由念珠菌属和曲霉属引起，其他罕见的真菌病原体如隐球菌属、球孢子菌属和接合菌属在最近几十年变得更加普遍，并与极高的死亡率相关（念珠菌病20%;曲霉病17%;接合菌属14%;隐球菌属11%;球孢子菌病6%和芽生菌病5%）。由于目前诊断方法的周转时间缓慢，IFD的适当治疗往往被延迟，导致与这种疾病相关的高死亡率。目前的诊断标准微生物培养平均需要48-72小时才能完成，并且无法检测到大约50%的真菌物种。由于IFD的适当治疗需要迅速和准确的诊断，真菌诊断领域中未满足的需求是可以提供1）早期检测2）敏感结果，3）物种水平区分和4）多重能力的平台。已经开发了几种分子方法来解决这一需求，但未能满足所有这些要求。Immunetics的真菌微阵列检测（IFM检测）使用PCR，然后在微阵列上与物种特异性探针杂交，通过使用全血样本而不是血液培养物以多重形式提供一系列真菌病原体的灵敏和快速（约5小时）检测，为这种未满足的需求提供了解决方案。在该II期申请中，我们建议进一步开发和临床验证IFM检测方法，用于检测和诊断27种侵袭性真菌的感染。该临床研究将与两家专门从事护理和治疗的医疗机构合作进行。 真菌感染，并将包括前瞻性和回顾性评价的临床血液样本获得的患者在高风险或已知的真菌感染。在成功完成临床研究后，将寻求FDA对IFM检测试剂盒体外诊断用途的监管批准，之后IFM试剂盒将作为独立的分子诊断检测试剂盒进行商业化。该产品提供了一种快速、灵敏和多路复用的方法，满足了理想的IFD诊断平台的要求。通过显著缩短检测时间，这一创新平台将导致IFD治疗的变化，最值得注意的是，使用靶向抗真菌药物进行更快的治疗。

 DESCRIPTION (provided by applicant): The incidence of invasive fungal infections and, in particular, Candida infections, the fourth most common nosocomial pathogen, has continued to increase over the past 40 years. This increase is due to the increasing numbers of patients subjected to severe immunosuppression as a result of transplant procedures, chemotherapy regimens, advances in medical and surgical therapies, and the increased use of invasive devices such as intravascular central lines. While the majority of invasive fungal disease (IFD) is caused by species of Candida and Aspergillus, other rare fungal pathogens such as Cryptococcus, Coccidioides, and Zygomycetes have become more prevalent in recent decades and are associated with exceedingly high mortalities (Candidiasis 20%; Aspergillosis 17%; Zygomycetes 14%; Cryptococcus 11%; Coccidioidomycosis 6%, and Blastomycosis 5%). Due to the slow turnaround time of current diagnostic methods, proper treatment of IFD is often delayed, contributing to the high mortality rates associated with this disease. Microbiologic culture, the current diagnostic standard, requires, on average, 48-72 hours for completion, and fails to detect roughly 50% of fungal species. As proper treatment of IFD calls for prompt and accurate diagnosis, an unmet need in the area of fungal diagnostics is a platform that can provide 1) early detection 2) sensitive results, 3) species level discrimination and 4) multiplex capability. Several molecular approaches have been developed to address this need but have failed to meet all these requirements. Immunetics' fungal microarray assay (IFM assay) uses PCR followed by hybridization on a microarray with species-specific probes, offering a solution to this unmet need by providing a sensitive and rapid (~5 hour) test for a range of fungal pathogens in a multiplex format, using whole blood samples rather than blood cultures. In this Phase II application we propose further development and clinical validation of the IFM assay for the detection and diagnosis of infection with 27 invasive fungal species. The clinical study will be carried out in collaboration with two medical institutions specializing in care and treatment of fungal infections, and will comprise prospective and retrospective evaluations on clinical blood samples obtained from patients at high risk for or with known fungal infections. Regulatory approval from FDA for in-vitro diagnostic use of the IFM assay will be sought upon successful completion of the clinical study, upon which the IFM kit will be commercialized as a standalone molecular diagnostic assay. This product offers a rapid, sensitive and multiplexed approach that meets the requirements of an ideal diagnostic platform for IFD. By significantly reducing time to detection, this innovative platform will lead to changes in the treatment of IFD, most notably, faster treatment with a targeted anti-fungal.