Electrochemical Assay to Monitor Anti-TB Antibiotics

监测抗结核抗生素的电化学测定

• 批准号: 10010646
• 负责人: Avni A Argun
• 金额: $ 21.21万
• 依托单位: GINER, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10010646
• 关键词: AIDS/HIV problem; Address; Adverse effects; Algorithms; Antibiotics; Antitubercular Agents; BCL2/Adenovirus E1B 19kd Interacting Protein 3-Like; Benchmarking; Biological Assay; Biological Availability; Biosensor; Blood; Blood Volume; Blood specimen; Boston; Caring; Cause of Death; Cessation of life; Chemicals; Clinical; Clinical Research; Communicable Diseases; Consult; Country; Detection; Development; Diagnosis; Dose; Drug Interactions; Drug Monitoring; Drug resistance; Drug resistance in tuberculosis; Electrodes; Equipment; Essential Drugs; Evaluation; Extreme drug resistant tuberculosis; Failure; Frequencies; Gold; Health system; Hematologic Agents; Human; In Vitro; Incidence; Individual; Infectious Agent; Israel; Laboratories; Linezolid; Measurement; Measures; Medical center; Methods; Monitor; Mycobacterium Infections; Overdose; Patients; Performance; Pharmaceutical Preparations; Phase; Regimen; Reporting; Resistance development; Resources; Risk; Sampling; Sensitivity and Specificity; Serum; Specificity; System; Technology; Testing; Therapeutic; Therapeutic Intervention; Time; Toxic effect; Treatment Cost; Treatment Efficacy; Treatment Failure; Treatment outcome; Tuberculosis; United States; Validation; World Health Organization; analytical method; clinically relevant; cost; cost effective; cross reactivity; design; effective therapy; experience; global health; improved; instrument; low and middle-income countries; non-tuberculosis mycobacteria; pill; prevent; programs; research and development; sensor; side effect; success; therapy outcome; transmission process; tuberculosis drugs; tuberculosis treatment

PROJECT SUMMARY/ABSTRACT Tuberculosis (TB) is one of the top ten causes of death globally and is the second most powerful single infectious agent behind HIV/AIDS. While the incidence of TB continues to decrease every year, there has been a significant rise in drug resistant TB (DR-TB), with 10% of the cases developing into extensively drug resistant TB (XDR TB). The therapeutic outcome of these drug resistant TB forms are unexpectedly poor due to toxicity of second line antibiotics and low efficacy of therapeutic regimes due to lack of blood monitoring. Despite tremendous evidence that concentrations matter enormously and they are highly variable, therapeutic drug monitoring in TB has been perceived as a luxury, rather than a necessity. Additionally, blood levels of antibiotics can only be measured using sophisticated instruments in highly specialized laboratories, increasing the cost and turnaround times and making the monitoring essentially impossible in the global clinical field. Currently there is no rapid and cost-effective method capable of monitoring anti-TB antibiotics in blood. A recent landmark clinical study showed that a three-drug NIX-TB regimen (Linezolid, Pretomanid and Bedaquiline) has great potential, remarkably curing ~90% of patients with XDR-TB after only six months of treatment. However, many patients experienced side effects due to high dose linezolid and patients often require therapeutic drug level monitoring. This remains a major gap in TB care since this testing currently takes one week even in high resource settings and is unavailable in most high TB incidence countries. A rapid and simple electrochemical test to quantify the levels of anti-tuberculous antibiotics in blood meets a critical need within TB care. Giner aims to demonstrate the feasibility of an electrochemical assay for the three antibiotics used in NIX-TB regimen in human serum samples with low (<100 µl) sample requirements and a sample-to- result time of <10 minutes. Quantification will be demonstrated at a broad relevant clinical range of 0.05 µg/mL to 100 µg/mL. The Aims of the Phase I feasibility program are: 1) Development of an electrochemical assay for each drug in NIX-TB regimen (Linezolid, Pretomanid and Bedaquiline); 2) Validation of sensitivity, specificity, and simultaneous measurement capability; and 3) Evaluation of assay performance in human blood serum and benchmarking against the gold standard analytical method.

项目概要/摘要 结核病（TB）是全球十大死亡原因之一，也是第二大死因 尽管结核病的发病率逐年下降，但艾滋病毒/艾滋病背后的传染源仍然存在。 耐药结核病 (DR-TB) 显着增加，10% 的病例发展为广泛耐药 由于毒性，这些耐药结核病的治疗效果出乎意料地差。 尽管二线抗生素的使用和由于缺乏血液监测而导致的治疗方案疗效较低。 大量证据表明浓度非常重要并且它们是高度可变的治疗药物 结核病监测一直被认为是一种奢侈，而不是必需品。 抗生素只能在高度专业化的实验室中使用精密仪器进行测量，这增加了 成本和周转时间，使得在全球临床领域基本上不可能进行监测。 目前尚无快速且经济有效的方法能够监测血液中的抗结核抗生素。 最近一项具有里程碑意义的临床研究表明，三药 NIX-TB 方案（利奈唑胺、Pretomanid 和 Bedaquiline）具有巨大的潜力，令人惊讶的是，仅六个月后就治愈了约 90% 的广泛耐药结核病患者 然而，许多患者因高剂量利奈唑胺而出现副作用，而且患者经常出现副作用。 需要治疗药物水平监测，这仍然是结核病护理的一个主要差距，因为目前需要进行这种测试。 即使在资源丰富的环境中，也需要一周的时间，并且在大多数结核病高发国家都无法实现。 量化血液中抗结核抗生素水平的简单电化学测试满足了关键需求 Giner 旨在证明电化学检测三种抗生素的可行性。 用于 NIX-TB 方案中的人血清样品，样品要求低（<100 µl），并且样品到 定量结果时间<10 分钟，将在 0.05 µg/mL 的广泛相关临床范围内得到证明。 至 100 µg/mL。 第一阶段可行性计划的目标是： 1) 开发电化学检测方法 NIX-TB 方案中的每种药物（利奈唑胺、Pretomanid 和 Bedaquiline）；2) 敏感性、特异性的验证； 和同时测量能力；以及 3) 人体血清和检测性能的评估 以金标准分析方法为基准。