Electrochemical Assay to Monitor Anti-TB Antibiotics

项目总结/摘要 结核病（TB）是全球十大死亡原因之一，也是第二大单一死因。 艾滋病毒/艾滋病背后的传染源。虽然结核病的发病率每年持续下降， 耐药结核病（DR-TB）显著增加，10%的病例发展为广泛耐药结核病。 TB（XDR TB）。由于毒性，这些耐药结核形式的治疗结果出乎意料地差 由于缺乏血液监测，二线抗生素和治疗方案的疗效低下。尽管 大量的证据表明浓度非常重要，它们是高度可变的，治疗药物 结核病监测被认为是一种奢侈，而不是必需品。此外，血液中的 抗生素只能在高度专业化的实验室中使用复杂的仪器进行测量， 成本和周转时间，并且使得在全球临床领域中基本上不可能进行监测。 目前还没有一种快速、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，三种药物NIX-TB方案（利奈唑胺、Pretomanid和 贝达喹啉）具有巨大的潜力，在治疗后仅6个月就能显著治愈约90%的广泛耐药结核病患者。 治疗然而，许多患者由于高剂量利奈唑胺而发生副作用， 需要治疗药物水平监测。这仍然是结核病治疗中的一个主要差距，因为这种检测目前需要 即使在资源充足的环境中，也需要一周的时间，而在大多数结核病高发国家，这是不可用的。一种快速 一个简单的电化学测试来量化血液中抗结核抗生素的水平满足了一个关键的需求 在结核病治疗中。Giner的目标是证明这三种抗生素的电化学分析的可行性 用于NIX-TB方案中的人血清样本，样本要求低（<100 µl）， 结果时间<10分钟。将在0.05 µg/mL的广泛相关临床范围内证明定量 至100 µg/mL。第一阶段可行性方案的目的是：1）开发一种电化学测定法， NIX-TB方案中的每种药物（利奈唑胺、Pretomanid和贝达喹啉）; 2）验证灵敏度、特异性， 和同时测量能力;和3）评价人血清中的测定性能， 以黄金标准分析方法为基准。

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.