Baseline pRescription According to Direct from Sputum Sequencing and TArgeted drug Concentration Strategy (BRASS TACS)

根据直接痰测序和靶向药物浓度策略 (BRASS TACS) 进行基线处方

• 批准号: 10419566
• 负责人: Jeffrey Tornheim
• 金额: $ 70.6万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-07 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10419566
• 关键词: Adherence; Adult; Bacterial Infections; Biological Assay; Bone Marrow Suppression; COVID-19; Caring; Cellular Phone; Clinical; Collaborations; Communicable Diseases; Complex; Cycloserine; Data; Development; Diagnostic tests; Disease; Dose; Drug Kinetics; Drug Monitoring; Drug Targeting; Drug resistance; Drug resistance in tuberculosis; Electrocardiogram; Enrollment; Ensure; Evaluation; Frequencies; Future; Genotype; Goals; Guidelines; Hospitals; Hour; India; Individual; Infrastructure; Laboratories; Lead; Linezolid; Longitudinal cohort; Longitudinal cohort study; Lung; Measures; Methods; Minimum Inhibitory Concentration measurement; Modeling; Molecular; Monitor; Moxifloxacin; Multidrug-Resistant Tuberculosis; Mutation; National Institute of Allergy and Infectious Disease; Neuropathy; Oral; Outcome; Participant; Patient-Focused Outcomes; Patients; Persons; Pharmaceutical Preparations; Phenotype; Plasma; Predisposition; Preparation; Prospective, cohort study; Provider; Pulmonary Tuberculosis; Recommendation; Regimen; Reporting; Resistance; Rifampicin resistance; Rifampin; Safety; Sampling; Selection for Treatments; Severities; Site; Sputum; Strategic Planning; Test Result; Testing; Therapeutic; Time; Toxic effect; Treatment outcome; Tuberculosis; United States National Institutes of Health; Validation; Vision; Work; biomedical referral center; brass; clinical research site; cohort; diagnostic algorithm; diagnostic tool; drug testing; efficacy evaluation; efficacy outcomes; follow-up; implementation tool; improved; improved outcome; individualized medicine; ineffective therapies; innovation; liver injury; meetings; mortality; next generation sequencing; novel; novel diagnostics; novel therapeutics; observational cohort study; personalized strategies; pharmacokinetic model; prevent; prognostic assays; side effect; tool; transmission process; treatment response; treatment strategy; trial comparing; tuberculosis drugs; tuberculosis treatment

Project Summary Tuberculosis is the bacterial infection that kills the most people worldwide, especially in India, which has the highest burden in of multidrug-resistant tuberculosis (MDR-TB) in the world. Delays in adequate treatment due to slow diagnostic tests and the usual one-size-fits-all MDR-TB treatment strategy lead to additional drug resistance, terrible treatment-associated side effects, and high mortality. Rapid next generation sequencing (NGS) from uncultured samples is a novel diagnostic tool that can predict resistance and minimum inhibitory concentration (MIC) ranges for MDR-TB within 2 days of presentation–weeks before culture-based susceptibility tests provide results. NGS-predictions allow providers to tailor MDR-TB treatment and choose doses to target specific drug levels at the start of treatment. Most MDR-TB drugs reach steady state within 2 weeks, so early therapeutic drug monitoring (TDM) supported by direct observation of therapy could verify that predicted efficacy targets are achieved as soon as possible, ensuring that patients get the right drugs at the right dose as early as possible and before suffering side effects from poorly tailored treatment. This would be a dramatic improvement over current culture-based methods of regimen selection, where results return 2 months later, if at all. Our clinical site has previously enrolled ~800 participants with MDR-TB into cohort studies for longitudinal follow-up, monitored participants for side effects and treatment outcomes, and developed on-site workflows for phenotypic drug resistance, MIC testing, NGS from uncultured sputum, and plasma drug level testing of MDR-TB drugs. Each of these tools is available at our site, but they are only employed sporadically, are rarely used in the same patients, and have not been systematically analyzed for their relative contributions to patient outcomes. We will conduct a single-site observational cohort study of 210 adult participants with pulmonary smear-positive, rifampin-resistant TB to systematically evaluate the impact of a combination Baseline pRescription According to Direct from Sputum Sequencing and TArgeted drug Concentration Strategy (BRASS TACS) for personalized MDR-TB therapy as access to these tools expands. The specific aims of this proposal are to: 1) determine the proportion of patients with MDR-TB in Mumbai, India with resistance-associated mutations that would prevent treatment with moxifloxacin, linezolid, bedaquiline, clofazimine, or cycloserine using culture-free NGS; 2) identify the proportion of cohort participants with MDR-TB that achieve model-derived steady-state plasma levels meeting efficacy and toxicity targets; and 3) assess the time to final regimen, frequency of treatment-associated side effects, time to culture conversion, and final outcome of cohort participants who complete culture-free NGS and TDM. The results of this observational cohort will determine the combined benefit of these tools as they are deployed at a referral center with clinical and laboratory expertise in complex drug resistance. These data will describe the real-world outcomes of MDR-TB care using NGS and TDM for MDR-TB in a unique setting and will inform the future application of these tools to improved strategies for personalized MDR-TB treatment worldwide.

项目摘要 结核病是杀死全球大多数人的细菌感染，尤其是在印度，有 世界上抗多药的结核病（MDR-TB）的最高燃烧。应得的适当治疗延迟 减慢诊断测试和通常的一小大适合所有MDR-TB治疗策略导致其他药物 阻力，可怕的治疗相关副作用和高死亡率。快速下一代测序 （NGS）来自未培养的样品是一种新型的诊断工具，可以预测耐药性和最小抑制性 MDR-TB的浓度（MIC）在介绍后的2天内 - 基于培养的敏感性之前 测试提供结果。 NGS预测允许提供者量身定制MDR-TB治疗并选择剂量以靶向 治疗开始时的特定药物水平。大多数MDR-TB药物在2周内达到稳态，因此 通过直接观察治疗支持的治疗药物监测（TDM）可以验证预测效率 尽快实现靶标，以确保患者最早以正确的剂量获得正确的药物 可能并在造成副作用的副作用之前。这将是一个巨大的进步 在当前基于培养的方案选择方法上，如果有的话，结果在2个月后返回。我们的临床 以前，现场已将约800名MDR-TB参与者纳入队列研究，以进行纵向随访， 监视参与者以获取副作用和治疗结果，并开发了现场工作流程的表型 耐药性，麦克风测试，未培养痰的NG和MDR-TB药物的血浆药物水平测试。 这些工具中的每一个都可以在我们的网站上找到，但是它们仅在偶发地使用，很少在同一中使用 患者，尚未系统地分析其对患者预后的相对贡献。我们将 对210名成年参与者进行肺涂片阳性， 抗利福平的结核病，以系统地评估组合基线处方的影响 直接从痰液测序和针对性的药物浓度策略（黄铜TAC）直接用于个性化 MDR-TB疗法随着这些工具的访问而扩展。该提案的具体目的是：1）确定 印度孟买的MDR-TB患者比例具有与阻力相关的突变，这将阻止 使用无培养的NGS治疗莫西沙星，linezolid，bedaquiline，clofazimine或celloserine； 2）识别 获得模型衍生稳态血浆水平的MDR-TB的队列参与者的比例 达到效率和毒性目标； 3）评估最终方案的时间，治疗相关的频率 副作用，培养时间转化的时间以及完成无文化NG的队列参与者的最终结果 和TDM。该观察队列的结果将确定这些工具的综合益处 部署在具有复杂耐药性的临床和实验室专业知识的推荐中心。这些数据将 在独特的环境中，使用NGS和TDM描述MDR-TB护理的现实结果，并将 告知这些工具的未来应用，以改善全球个性化MDR-TB治疗的策略。