Rapid Tests for Drug Resistance to Detect Extensively Drug-Resistant Tuberculosis

快速耐药检测以检测广泛耐药结核病

• 批准号: 8138539
• 负责人: ANTONINO CATANZARO
• 金额: $ 234.29万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-27 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8138539
• 关键词: Academia; Achievement; Advanced Development; Agreement; Amikacin; Base Sequence; Biological Assay; California; Capromycin; Clinical Data; Databases; Detection; Development; Drug Delivery Systems; Drug Resistant Tuberculosis; Drug resistance; Enrollment; Epidemiology; Evaluation; Extreme drug resistant tuberculosis; Family; Future; Gene Targeting; Genes; Genetic; Genome; Genomics; Geographic Locations; Gold; Growth; Health system; India; Industry; Instruction; International; Kanamycin; Laboratories; Liquid substance; Measures; Methods; Microscopic; Moldova; Molecular; Molecular Probes; Multi-Drug Resistance; Mutation; Mycobacterium tuberculosis; Ofloxacin; Oligonucleotides; Patients; Performance; Pharmaceutical Preparations; Philippines; Predisposition; Procedures; Process; Public Health; Publishing; Research Personnel; Resistance; Rifampin; Risk; Risk Factors; Site; South Africa; Sputum; System; Testing; Time; Universities; base; biosecurity; clinical research site; cost; cost effectiveness; design; drug standard; drug testing; isoniazid; mycobacterial; novel; programs; repository; technology development; tuberculosis drugs

DESCRIPTION (provided by applicant): The emergence of extensively drug-resistant tuberculosis (XDR-TB) poses a growing threat to national and international biosecurity and to TB control achievements. Current standard indirect drug susceptibility testing (DST) takes up to 3 months to identify XDR-TB, undermining efforts to control XDR-TB. The University of California at San Diego has assembled an international team of TB experts from academia, public health, and industry to advance the development and evaluation of 3 rapid tests (i.e., Main strip, molecular beacon, microscopic-observation drug-susceptibility assays) to detect resistance to 6 drugs defining XDR-TB (i.e., isoniazid, rifampin, ofloxacin, amikacin, kanamycin, and capreomycin) directly from sputa. The specific aims are (1) to reduce the average XDR-TB detection time from months to a week, (2) to demonstrate agreement between the rapid tests and standard DST, (3) to identify the genetic basis of discordant results in Aim 2, (4) to characterize global XDR-TB strains and the epidemiology of drug resistance, and (5) to study cost- effectiveness. In Year 1, creation of new probes and assay procedures for the rapid tests (Version-1) will be based on published information, publicly-available genomic databases and new information from genotypic analysis of existing XDR and drug-susceptible strains from four study sites (i.e., South Africa, Moldova, India, the Philippines). These study sites will enroll 2,475 TB patients in Years 2-4; collect clinical data, sputa, and culture isolates; and perform the three rapid tests and DST onsite. Strains identified as drug resistant by the DST but not by the rapid tests will be further examined through sequencing target genes, neighboring genes, or whole genomes to find new regions or points of difference compared to drug-susceptible strains. New mutations discovered through this process will inform creation of probes for Version-2 rapid tests, as needed, to be tested onsite along with Version-1. This 5-year study will result in novel tests to rapidly detect XDR-TB in a broad range of laboratory settings as well as a repository of diverse well-characterized TB strains for future studies. The long-term implication is the development of technologies and methods that can be adapted to rapidly detect new drug-resistant TB strains and to test for resistance to other anti-TB drugs. RELEVANCE (See instructions): XDR-TB is associated with high fatality rates, is highly communicable, and has the potential to cause massive disruption to public-health systems and economies at a local, national and global scale if not detected and treated rapidly. The study proposes to develop and evaluate three novel rapid tests to reduce XDR-TB detection time to better guide public health measures and patient management decisions.

描述（由申请人提供）：广泛耐药结核病（XDR-TB）的出现对国家和国际生物安全以及结核病控制成就构成日益严重的威胁。目前的标准间接药物敏感性测试（DST）需要长达3个月的时间来识别广泛耐药结核病，这削弱了控制广泛耐药结核病的努力。位于圣地亚哥的加州大学组建了一个由来自学术界、公共卫生界和工业界的结核病专家组成的国际小组，以推进3种快速检测方法的开发和评估（即，主要测试条、分子信标、显微镜观察药物敏感性测定），以检测对6种定义广泛耐药结核的药物的耐药性（即，异烟肼、利福平、氧氟沙星、阿米卡星、卡那霉素和卷曲霉素）。具体目标是：（1）将广泛耐药结核病的平均检测时间从几个月缩短到一周;（2）证明快速检测与标准DST之间的一致性;（3）确定目标2中不一致结果的遗传基础;（4）描述全球广泛耐药结核菌株和耐药性流行病学的特征;（5）研究成本效益。在第1年，快速检测（第1版）的新探针和检测程序的创建将基于已发表的信息、公开可用的基因组数据库以及来自四个研究中心（即，南非、摩尔多瓦、印度、菲律宾）。这些研究中心将在第2-4年招募2，475名结核病患者;收集临床数据、结核分枝杆菌和培养分离株;并在现场进行三种快速检测和DST。通过DST而不是快速测试确定为耐药的菌株将通过测序靶基因、邻近基因或整个基因组进行进一步检查，以发现与药物敏感菌株相比的新区域或差异点。通过此过程发现的新突变将根据需要为版本2快速检测创建探针，并与版本1沿着进行现场检测。这项为期5年的研究将产生新的检测方法，用于在广泛的实验室环境中快速检测广泛耐药结核病，并为未来的研究建立各种特征良好的结核菌株库。长期影响是开发可用于快速检测新的耐药结核菌株和检测对其他抗结核药物的耐药性的技术和方法。相关性（参见说明）：广泛耐药结核病与高死亡率有关，具有高度传染性，如果不迅速发现和治疗，有可能在地方、国家和全球范围内对公共卫生系统和经济造成大规模破坏。该研究建议开发和评估三种新的快速检测方法，以缩短广泛耐药结核病的检测时间，从而更好地指导公共卫生措施和患者管理决策。