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.

摘要 由结核分枝杆菌（Mycobacterium tuberculosis，M.tb）引起的结核病（tuberculosis，TB）是一种主要的传染病， 全世界的死亡耐药（DR）结核病的负担日益加重，使结核病治疗复杂化。早期诊断 结核病的药物敏感性测试（DST）是成功治疗的关键，是世界结核病的第一支柱。 世界卫生组织（WHO）终止结核病战略。DST通过表型或基因型方法实现。 传统上，表型DST在固体（Löwenstein詹森）或液体培养基（MGIT）上以两步进行 过程：首先进行培养以鉴定结核分枝杆菌的生长，然后用待测药物对分离株进行再培养。在 除了要求生物安全二级以上的实验室外，如果在中低收入环境中可用，DST过程还可以 从样本采集到将结果通知临床提供者，需要42至约6个月的时间进行治疗 延迟、持续传播和更高的死亡率。相反，基因型DST具有许多优点， 包括缩短获得结果的时间（GeneXpert <2小时），以及部署到或接近 护理（POC）。然而，在结核病高负担、资源有限的环境中， 定期供电和重要的成本。因此，NIH/NIAID正在将注意力转向创新和简单 表型DST解决方案将部署在POC或接近POC。 此应用程序的目标是将1G测试扩展到2G测试，为执行DST提供更高的灵活性 第一和第二一线药物，包括为DS-和DR-TB方案处方的药物，如RIPE（DS-TB口服 RIF/INH/PZA/乙胺丁醇组成的方案）、HPMZ（DS-TB 4个月短程口服药物方案 由INH/利福喷丁/MFX/PZA组成）和BPaL [MDR-和pre-XDR口服药物方案， 贝达喹啉（BDQ）、普瑞托马尼（PMD）和利奈唑胺（LNZ）]，以及氯法齐明（CFZ）和地拉马尼（DLM）， 其他世卫组织推荐的耐药结核口服药物。由于2G测试是非专有的，其成本预计将 价格极低（<8美元），主要受药物成本的影响。此外，对于1G测试，我们测试了一个简单的步骤 用于消化/净化不需要设备的粪便，满足接近POC测试定义。我们将 优化这种用于2G测试的语音处理协议。我们建议：目标1）开发和验证 2G测试通过定义针对已知DR-M.tb菌株的新药的稳定性和临界浓度（CC）， 并优化适当的痰液消化和净化方案，用于该测试;目的2）确定 2G试验与11种药物中每种药物表型DST的现行金标准方法的一致性，以及 目的3）使用新鲜收集的样本，确定2G测试相对于参考表型DST方案的准确性。 在现场环境中进行测试，并评估其可用性，可接受性和可行性。 我们预计，新颖、简单、经济实惠和可持续的2G测试将在以下方面提供重大改进： 与目前的表型DST参考方法相比，允许对DS-/DR-TB进行快速和定制的治疗 在结核病负担高的低收入和中等收入国家。