A Culture-Free Platform for Rapid Fungal Pathogen Identification

快速真菌病原体鉴定的无培养平台

• 批准号: 10374805
• 负责人: Alon Singer
• 金额: $ 100万
• 依托单位: HELIXBIND, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10374805
• 关键词: Address; Adopted; Adoption; Affect; American; Antifungal Agents; Automation; Automobile Driving; Autopsy; Biological Assay; Blinded; Blood; Budgets; Candida; Candida auris; Caring; Centers for Disease Control and Prevention (U.S.); Clinical; Clinical Microbiology; Clinical Research; Communities; Critical Care; Critical Illness; Detection; Development; Diagnosis; Diagnostic; Disease; Disease Outbreaks; Ensure; Etiology; Fungemia; Future; Hospitals; Hour; Indiana; Infection; Infection Control; Intervention; Laboratories; Length of Stay; Life; Liquid substance; Medical center; Memorial Sloan-Kettering Cancer Center; Methods; Morbidity - disease rate; Multi-Drug Resistance; National Institute of Allergy and Infectious Disease; Outcome; Patients; Performance; Phase; Process; Prognosis; Readiness; Research Design; Resistance; Risk; Sampling; Sepsis; Septicemia; Small Business Innovation Research Grant; Specificity; Specimen; Sterility; Surface; Symptoms; Techniques; Temperature; Testing; Time; TimeLine; Traction; Universities; University Hospitals; Validation; Whole Blood; Work; antimicrobial; assay development; candidemia; clinically relevant; combat; cost; design; diagnostic strategy; emerging pathogen; evidence base; experience; global health; improved; institutional financing; instrument; internal control; member; microbial; mortality; multi-drug resistant pathogen; novel; novel diagnostics; pathogen; pathogenic fungus; prevent; side effect; success; systemic inflammatory response; usability; verification and validation

PROJECT SUMMARY Septicemia is a serious, life-threatening systemic inflammatory response to a bloodstream infection (BSI). Of particular concern are BSIs caused by fungal pathogens (fungemia) which affects over 100,000 Americans annually and is characterized by exceedingly high mortality rates (~40%). The optimal strategy to combat these infections is well known; immediate administration of appropriate antifungals. Due to their high cost and serious side-effects, though, antifungals are generally withheld until confirmation of infection. Unfortunately, standard techniques for confirmation still rely on antiquated blood cultures, which requires 1-3 days or longer leading to poor outcomes. More poignantly, it is estimated that 30% of fungemia patients never receive appropriate care, as diagnosis was only confirmed post-mortem. It is therefore critical to advance new diagnostic approaches, which do not rely on culturing, to rapidly transition to personalized antimicrobial interventions. To address this unmet need, HelixBind has developed RaPID/F, a test which characterizes fungal BSIs, directly from blood in ~2.5 hours, without cultures. Implemented on the RaPID (Resistance and Pathogen IDentification) platform, appropriate for placement anywhere in the hospital, RaPID/F detects (and discriminates between) both fungal and bacterial bloodstream infections. Species level detail is provided along with single CFUs/ml sensitivity for the most common Candida infections, enabling selection of appropriate antimicrobials. The test menu also includes Candida auris, an emerging multi-drug resistant pathogen considered a global health threat. Importantly, RaPID/F can be used not only for detection of C. auris in blood, but also on surfaces or instruments – addressing an urgent need to control hospital outbreaks of this deadly pathogen. Combined, RaPID/F not only enables the confirmation of fungemia days faster than currently possible by standard techniques, but also addresses use cases identified by customers as crucial to drive adoption. HelixBind has met and exceeded each of the Specific Aims defined in the Phase II NIAID SBIR. This included verification of the test menu, incorporating five key Candida species and an Internal Control, to which we added coverage of additional pathogens, automation of this test onto a single-use plastic disposable, and demonstration of >90% sensitivity and 95% specificity with clinical samples as well as a subset spiked at clinically relevant loads. Given the success of this Phase II work, HelixBind proposes in this Phase IIB to advance RaPID/F toward readiness for regulatory clearance. Specific Aims proposed, each with quantifiable deliverables, serve to address and de-risk manufacturing, usability, and analytical and clinical performance aspects of the product. This proposed Phase IIB will culminate in a blinded, in-hospital, study challenging our proposed FDA pivotal study design. Upon completion of this project, we will be well placed to initiate formal Analytical and Clinical studies for FDA clearance of RaPID/F and scale manufacturing for product launch.

项目概要 败血症是对血流感染 (BSI) 的一种严重的、危及生命的全身炎症反应。 特别值得关注的是由真菌病原体（真菌血症）引起的 BSI，影响了超过 100,000 名美国人 每年都会发生这种情况，其特点是死亡率极高（~40%）。 感染是众所周知的；由于其成本高且需要立即施用适当的抗真菌药物。 然而，由于存在严重的副作用，因此在确认感染之前通常不会使用抗真菌药物。 确认的标准技术仍然依赖于过时的血培养，这需要 1-3 天或更长时间 更令人心酸的是，估计有 30% 的真菌血症患者从未接受过治疗。 适当的护理，因为诊断只能在尸检后得到确认，因此推进新的诊断至关重要。 不依赖培养的方法可以快速过渡到个性化抗菌干预措施。 为了解决这一未满足的需求，HelixBind 开发了 RaPID/F，这是一种表征真菌 BSI 的测试， 约 2.5 小时内直接从血液中进行，无需在 RaPID（耐药性和病原体）上进行。 识别）平台，适合放置在医院的任何地方，RaPID/F 检测（和 还提供了（区分）真菌和细菌血流感染的物种级别详细信息。 对最常见的念珠菌感染具有单 CFU/ml 的敏感性，从而能够选择合适的 测试菜单还包括耳念珠菌，一种被认为是新兴的多重耐药病原体。 重要的是，RaPID/F 不仅可以用于检测血液中的耳念珠菌，还可以用于检测耳念珠菌。 表面或仪器——解决控制这种致命病原体在医院爆发的迫切需要。 结合起来，RaPID/F 不仅能够比目前更快地确认真菌血症天数 标准技术，还解决了客户认为对推动采用至关重要的用例。 HelixBind 已达到并超过了 II 期 NIAID SBIR 中定义的每一项具体目标。 验证测试菜单，包括五个关键念珠菌物种和一个内部对照，我们添加了 覆盖其他病原体、在一次性塑料一次性用品上自动化测试以及演示 临床样本以及临床相关子集的灵敏度 >90%，特异性 >95% 鉴于第二阶段工作的成功，HelixBind 建议在第二阶段推进 RaPID/F。 提出的具体目标，每个目标都有可量化的可交付成果，旨在解决问题 降低产品的制造、可用性以及分析和临床性能方面的风险。 拟议的 IIB 期研究将最终形成一项盲法、住院研究，挑战我们拟议的 FDA 关键研究 设计完成后，我们将能够启动正式的分析和临床研究。 FDA 批准 RaPID/F 并进行产品上市的规模生产。

项目成果

Duplex DNA-Invading γ-Modified Peptide Nucleic Acids Enable Rapid Identification of Bloodstream Infections in Whole Blood.

• DOI: 10.1128/mbio.00345-16
• 发表时间: 2016-04-19
• 期刊: mBio
• 影响因子: 6.4
• 作者: Nölling J;Rapireddy S;Amburg JI;Crawford EM;Prakash RA;Rabson AR;Tang YW;Singer A
• 通讯作者: Singer A