An automated, scalable, and rapid AST system for Gonorrhea STIs

用于淋病性传播感染的自动化、可扩展且快速的 AST 系统

• 批准号: 10327731
• 负责人: Roy R Swiger
• 金额: $ 96.73万
• 依托单位: ACENXION BIOSYSTEMS, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-15 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10327731
• 关键词: Agar; Agreement; Anatomy; Antibiotic Therapy; Antibiotic susceptibility; Antibiotics; Antimicrobial Resistance; Bacteria; Behavior; Carbon Dioxide; Categories; Centers for Disease Control and Prevention (U.S.); Clinical; Clinical Research; Code; Computer software; Computers; Contracts; Data; Data Analyses; Development; Devices; Ensure; Environment; Feedback; Funding; Future; Genetic Materials; Genitourinary system; Gonorrhea; Growth; Healthcare; Hospitals; Hour; Human; Human Resources; Incidence; Intermediate resistance; Investments; Laboratories; Liquid substance; Location; Manuals; Methods; Microfluidics; Minimum Inhibitory Concentration measurement; Molecular; Monitor; Neisseria gonorrhoeae; Optics; Organism; Patients; Phase; Phenotype; Predisposition; Preparation; Price; Protocols documentation; Public Health; Reader; Reading; Recording of previous events; Reporting; Reproducibility; Sampling; Savings; Sensitivity and Specificity; Sexually Transmitted Diseases; Single-Blind Study; Small Business Innovation Research Grant; Speed; Spottings; Surveillance Program; Surveys; System; Testing; Time; Work; base; co-infection; commercialization; cost; design; experimental study; field study; hospital laboratories; instrument; laboratory facility; practical application; programs; prototype; resistance mechanism; response; success

Gonorrhea is a sexually transmitted infection (STI) caused by the bacterium Neisseria gonorrhoeae (NG) that infects the urogenital, anorectal and pharyngeal tracts in humans. In 2018, there were an estimated 1.14M cases in the US, and 86.9M cases worldwide. Of concern is the growing incidence of antimicrobial resistance not only due to inappropriate use of antibiotics, but also because NG interacts with and acquires genetic material from other co-infections in the anatomical sites that it infects. This wide range of resistance mechanisms that NG isolates can potentially harbor makes it very challenging to develop rapid molecular methods of Antibiotic Susceptibility Testing (AST). Even among phenotypic AST methods, it has so far not been considered feasible to perform automated broth microdilution based ASTs on NG: principally because it is a fastidious organism in liquid culture. As a result, the primary method used to perform ASTs for NG is the manual agar dilution method, which (because it is so labor intensive) is currently conducted in only a very limited number of public health labs. Even these labs test only 200-300 samples a month. Acenxion Biosystems proposes to develop the first fully automated NG phenotypic AST platform that both satisfies the current CDC guidance for surveillance and fulfils an unmet clinical need for AST-guided “directed” antibiotic therapy. Our instrument will provide Minimum Inhibitory Concentration (MIC) and Susceptible/ Intermediate /Resistance (S/I/R) interpretation in < 6 hours with minimal sample preparation (<5 min per sample) at a reasonable price. The instrument will consist of stackable, cassette reader units with up to eight microfluidic cassette capacity; software/PC Controller; and single-use consumable (50-well microfluidic cassette pre-spotted with candidate antibiotics). Optimized broth and rapid stirring are employed for NG growth, enabling automated broth microdilution. With prior funding from the CDC, we have demonstrated proof-of-concept for the proposed instrument by building a partly-automated system to perform broth micro- dilution experiments on a single 16-well cassette, and used it monitor the growth (or lack thereof) of 3 NG strains (1 ATTC QC strain, and 2 AR isolate strains) in the presence of multiple candidate antibiotics with 100% sensitivity & specificity. We seek “Direct to Phase II” funds to expand this earlier work: build a fully automated instrument and test it against the CDC’s challenge AR bank panel of 50 clinical isolates (which span multiple resistance mechanisms and yield wide range of phenotypic responses). We chose this set of organisms in lieu of patient samples from 2 - 3 locations to ensure better chances of success in the real world. Our commercialization strategy aims to first bring efficiencies to the existing market (regional labs participating in the Gonococcal Isolate Survey Program) and then to expand the user (customer) base to hospital labs, clinical laboratory networks and clinical labs by enabling AST-guided directed antibiotic therapy for gonorrhea.

淋病是一种由淋病奈瑟菌 (NG) 引起的性传播感染 (STI)， 感染人类的​​泌尿生殖道、肛门直肠和咽道。 2018年估计有114万 美国有 8690 万例，全球有 8690 万例。令人担忧的是抗菌素耐药性的发生率不断上升 不仅是由于抗生素使用不当，还因为 NG 与遗传相互作用并获得遗传 来自其感染的解剖部位的其他合并感染的物质。这种宽范围的电阻 NG 分离株可能具有的机制使得开发快速分子 抗生素敏感性测试（AST）的方法。即使在表型 AST 方法中，迄今为止也没有 被认为在 NG 上进行基于自动肉汤微量稀释的 AST 是可行的：主要是因为它 是液体培养中的挑剔生物。因此，针对 NG 执行 AST 的主要方法是 手动琼脂稀释方法（因为它是劳动密集型的）目前仅在非常有限的情况下进行 公共卫生实验室数量有限。即使这些实验室每月也只测试 200-300 个样本。 Acenxion Biosystems 提议开发第一个全自动 NG 表型 AST 平台 满足当前 CDC 的监测指南，并满足 AST 引导“定向”的未满足的临床需求 抗生素治疗。我们的仪器将提供最低抑制浓度 (MIC) 和敏感/ 在 < 6 小时内完成中间/电阻 (S/I/R) 解释，只需最少的样品制备（每次<5 分钟） 样品）以合理的价格。该仪器将由可堆叠的盒式磁带读取器单元组成，最多可容纳 8 个单元 微流体盒容量；软件/PC控制器；和一次性消耗品（50 孔微流体 盒内预先点有候选抗生素）。 NG 采用优化肉汤和快速搅拌 生长，实现自动肉汤微量稀释。在疾病预防控制中心的先前资助下，我们已经证明 通过构建一个半自动化系统来执行肉汤微量分析，对拟议仪器进行概念验证 在单个 16 孔盒上进行稀释实验，并用它监测 3 NG 的生长（或缺乏） 存在多种候选抗生素时的菌株（1 个 ATTC QC 菌株和 2 个 AR 分离菌株） 100% 敏感性和特异性。我们寻求“直接进入第二阶段”资金来扩展这项早期工作：建立一个完全 自动化仪器，并针对 CDC 的挑战 AR 库小组（由 50 个临床分离株（涵盖 多种耐药机制并产生广泛的表型反应）。我们选择了这一套 生物体代替来自 2 - 3 个地点的患者样本，以确保在现实世界中获得更好的成功机会。 我们的商业化战略旨在首先提高现有市场的效率（参与的区域实验室） 在淋球菌分离调查计划中），然后将用户（客户）基础扩展到医院实验室， 通过启用 AST 引导的淋病定向抗生素治疗来建立临床实验室网络和临床实验室。