Innovating anti-tuberculosis drug susceptibility testing with a novel and rapid non-culture based phenotypic test using MPT64 biomarker
使用 MPT64 生物标志物,通过新型、快速的非培养表型测试来创新抗结核药物敏感性测试
基本信息
- 批准号:10663034
- 负责人:
- 金额:$ 67.68万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-04-04 至 2028-03-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAntibioticsAntitubercular AgentsBiological AssayBiological MarkersCellsClinicalClinical SensitivityCollectionColony-forming unitsCountryCulture MediaDNA Sequence AlterationDataDetectionDiagnosisDrug ExposureDrug resistanceDrug resistance in tuberculosisEarly DiagnosisEnzyme ImmunoassayEpidemicFluoroquinolonesGoalsGrowthHourInfrastructureIntermediate resistanceIsoniazid resistanceJapanLaboratoriesLinezolidLiquid substanceMeasuresMethodsMolecularMutationMycobacterium tuberculosisOralPatient-Focused OutcomesPatientsPerformancePharmaceutical PreparationsPhenotypePhilippinesPredispositionProtein SecretionProtocols documentationPulmonary TuberculosisRegimenResistanceResistance profileRifampinSamplingSensitivity and SpecificitySpecificitySpeedSputumTestingTimeTuberculosisValidationWorld Health Organizationbiobankdetection limiteffective therapyimmunogenicimprovedin vitro Assayinnovationisoniazidnovelnovel therapeuticsprospectiverapid techniquerapid testtuberculosis drugstuberculosis treatment
项目摘要
Summary/Abstract: 30 lines
Drug-resistant tuberculosis (TB) threatens our goal of ending the global TB epidemic by 2035.
Early diagnosis of drug-resistant TB for timely initiation of appropriate treatment remains a
challenge. Phenotypic drug susceptibility testing (DST) requires Mycobacterium tuberculosis
(MTB) culture and takes 8-12 weeks. Molecular-based methods are rapid but require previously
identified and validated resistance-conferring mutations. Unfortunately, mutations are not
completely known for key drugs included in newer all-oral regimens. Our long-term goal is to
develop a non-culture-based method for phenotypic DST that provides results in 48-72
hours from sputum collection and that can be used directly on sputum. Our innovative
approach is based on MPT64, a protein secreted only during active growth that is highly specific
for MTB. We demonstrated that MPT64 secretion in MTB cultures decreases significantly within
48–72 hours of anti-TB drug exposure for drug-susceptible but not drug-resistant MTB isolates.
We have previously measured MPT64 directly in sputum samples with a limit of detection
comparable with Xpert MTB/RIF Ultra (Cepheid, Sunnyvale, CA, USA). In this study we will
validate culture MPT64 DST chemiluminescence-enzyme immunoassay (CLEA) for isoniazid
(INH), rifampin (RIF), fluoroquinolones (FQs), bedaquiline (BDQ), linezolid (LZD), and delamanid
(DLM). Our proposed approach will provide results within 72 hours of the time the culture is
identified as MTB, compared to the 2-3 weeks required to obtain results from conventional DST
(Aim 1). We will use the principles of culture MPT64 DST to develop a sputum MPT64 DST
CLEIA, which will provide results in 48-72 hours from the time of sputum collection. We will identify
protocols for sputum liquefaction, antibiotic exposure times, and CLEIA that result in the lowest
limit of detection (LOD) for resistant MTB cells (Aim 2). We will prospectively evaluate sputum
MPT64 DST in 860 patients with TB in the Philippines and in the country of Georgia (Aim 3). We
hypothesize that both culture MPT64 DST and sputum MPT64 DST will meet or exceed minimum
sensitivity (>95%) and specificity (>98%), which are the WHO high priority target product profiles
for rapid DST. The innovative MPT64 DST assays will transform TB management by enabling
early initiation of effective treatment based on rapid drug susceptibility data, thus improving patient
outcomes and curtailing the spread of drug resistant TB that is critical if TB is to be eliminated by
2035.
摘要/摘要:30行
项目成果
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