Improving rapid phenotypic drug susceptibility testing for drug resistant tuberculosis in high-burden areas

完善高负担地区耐药结核病快速表型药敏检测

• 批准号: 10658013
• 负责人: BLANCA I RESTREPO
• 金额: $ 95.64万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-06 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658013
• 关键词: Acceleration; Agar; Agreement; Area; Blinded; Bovine Tuberculosis; Cause of Death; Chlorhexidine; Clinical; Collection; Color; Communicable Diseases; Communities; Data; Decontaminant; Decontamination; Democratic Republic of the Congo; Diagnosis; Digestion; Drug Costs; Drug Prescriptions; Drug resistance; Drug resistance in tuberculosis; Drug resistant Mycobacteria Tuberculosis; Early Diagnosis; Epidemiology; Equipment; Ethambutol; Evaluation; Eye; Generations; Genotype; Goals; Growth; Health; Income; Laboratories; Linezolid; Liquid substance; Methods; Mexican; Mexico; Moxifloxacin; Multidrug-Resistant Tuberculosis; Mycobacterium tuberculosis; National Institute of Allergy and Infectious Disease; Notification; Oral; Oral Tuberculosis; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Power Sources; Predisposition; Process; Protocols documentation; Provider; Pyrazinamide; Recommendation; Regimen; Resistance; Resource-limited setting; Rifampin; Sampling; Sensitivity and Specificity; Sodium Chloride; Solid; Specimen; Sputum; Surrogate Markers; Test Result; Testing; Thinness; Time; Tuberculosis; Tuberculosis diagnosis; United States National Institutes of Health; World Health Organization; biobank; cost; design; directed attention; drug testing; field study; flexibility; improved; individualized medicine; innovation; isoniazid; low and middle-income countries; meetings; mortality; novel; novel therapeutics; point of care; point of care testing; rifapentine; sample collection; transmission process; tuberculosis drugs; tuberculosis treatment; usability

ABSTRACT Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb), is a leading infectious disease and cause of death worldwide. The growing burden of drug-resistant (DR)-TB is complicating TB treatment. Early diagnosis of TB with drug susceptibility testing (DST) is critical for successful treatment and is the first pillar of the World Health Organization’s (WHO) End TB Strategy. DST is achieved via phenotypic or genotypic methods. Traditionally, phenotypic DST is performed on solid (Löwenstein Jensen) or liquid media (MGIT) in a two-step process: first a culture to identify M.tb growth, and then re-culture of the isolate with the drugs to be tested. In addition to requiring biosafety level II-plus labs, the DST process, if available in low-middle income settings, can take 42 to ~6 months from sample collection to notification of results to the clinical provider resulting in treatment delays, continued transmission, and higher mortality. Conversely, genotypic DST has many advantages, including a reduced time to result (< 2h for GeneXpert) and the possibility of deployment to at or near point of care (POC). However, its widespread use in high TB burden resource-limited settings is hindered by the need for regular power supply and importantly cost. Thus, NIH/NIAID is redirecting attention to innovative and simple phenotypic DST solutions to be deployed at or near POC. The goal of this application is to develop the 1G test into the 2G test, providing higher flexibility to perform DST for 1st and 2nd frontline drugs, including drugs prescribed for DS- and DR-TB regimens such RIPE (DS-TB oral regimen composed of RIF/INH/PZA/Ethambutol), HPMZ (DS-TB 4-month short course oral drug regimen composed of INH/Rifapentine/MFX/PZA) and BPaL [MDR- and pre-XDR oral drug regimen composed of bedaquiline (BDQ), pretomanid (PMD) and linezolid (LNZ)], as well as clofazimine (CFZ) and delamanid (DLM), other WHO recommended oral agents for DR-TB. Because the 2G test is non-proprietary, its cost is expected to be extremely low (< $8) and mainly driven by the cost of drugs. Further, for the 1G test we tested a simple step to digest/decontaminate sputa that does not require equipment, meeting the near to POC test definition. We will optimize this sputum-processing protocol for use with the 2G test. We propose to: Aim 1) Develop and validate the 2G test by defining the stability and critical concentration (CC) for new drugs against known DR-M.tb strains, and optimize appropriate sputum digestion and decontamination protocols for this test; Aim 2) Determine the agreement of the 2G test with current gold standard methods for phenotypic DST for each of the 11 drugs, and Aim 3) Determine the accuracy of the 2G test against reference phenotypic DST protocols using freshly collected sputa in field settings and assess its usability, acceptability, and feasibility. We expect that the novel, simple, affordable and sustainable 2G test will provide a significant improvement when compared to current phenotypic DST reference methods, allowing rapid and tailored treatment for DS-/DR-TB in low- and middle-income countries with high TB burden.

抽象的 结核分枝杆菌（M.TB）引起的结核病（结核病）是一种领先的不确定疾病，原因是 全世界的死亡 具有药物敏感性测试（DST）的结核病对于成功治疗至关重要，并且是世界上的第一个支柱 卫生组织（WHO）结束结核病策略。 传统上，表型DST在固体（LöwensteinJensen）或液体培养基（MGIT）上进行两步 过程：首先是识别M.TB生长的培养物，并与要测试的药物重新培养 除了需要在低矮的收入设置中可用的情况下，DST过程还需要生物安全级II-Plus实验室 从样本收集到临床提供者的结果42到6个月，导致对临床提供者进行治疗 延迟，持续传播和更高的死亡率，基因型DST具有许多优势 包括减少结果的时间（GenExpert的2H）以及部署到或接近点的可能性 护理（POC）。 为了定期电源，重要的是，NIH/NIAID正在重定向到创新和简单 表型DST溶液将在POC或附近部署。 该应用程序的目的是将1G测试开发到2G测试中，从而更高的灵活性执行DST 对于第一和第二二次前线药物，包括针对DS和TB方案开处方的药物（DS-TB口服） 由RIF/INH/PZA/Ethambutol组成的方案HPMZ（DS-TB 4个月短期课程口服药物方案 由INH/Rifapentine/MFX/PZA）和BPAL [MDR和XDR前口服药物方案 Bedaquiline（BDQ），Pipomanid（PMD）和LineZolid（LNZ），以及氯富氮胺（CFZ）和Delamanid（DLM） 其他建议使用DR-TB的口服剂。 非常低（<$ 8），主要由毒品成本驱动。 要消化/净化不需要设备的痰液，请符合POC测试定义。 优化此痰液概述，以与2G测试一起使用。 通过定义针对已知DR-M.TB菌株的新药物的稳定性和关键概念（CC），通过定义2G测试， 并优化适当的痰液消化和该测试的净化协议； 2G测试与目前的11种药物表型DST的当前黄金标准方法以及 目标3）使用新鲜收集器确定针对参考表型DST方案的2G测试的准确性 现场设置和评估中的痰液是USAVISIOS，可接受性和效率。 我们希望小说，简单，负担得起和可持续的2G测试将在 与当前的表型DST参考方法相比 在中低收入国家，结核病负担很高。