Lab-on-a-Film Multiplexed Test for Respiratory Mycobacterial Infections
呼吸道分枝杆菌感染的胶片实验室多重检测
基本信息
- 批准号:10689261
- 负责人:
- 金额:$ 99.94万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-04-21 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:AcademyAcid Fast Bacillae Staining MethodAddressAlgorithmsAmericanAminoglycoside resistanceAntibioticsAntimicrobial ResistanceAntimicrobial susceptibilityAzithromycinBacillusBacteriaBiological AssayBronchiectasisCause of DeathChronicChronic Obstructive Pulmonary DiseaseClarithromycinClinicClinicalClinical MicrobiologyClinical ResearchCollaborationsCombination Drug TherapyCompanionsComplexComputer softwareConsumptionDNADNA Sequence AlterationDetectionDevelopmentDiagnosisDiagnosticDiagnostic testsDiseaseDrug resistanceElementsErythromycinEtiologyFilmFreeze DryingGeneral PopulationGenesGenetic PolymorphismGenomicsGenus MycobacteriumGlassGoalsHealthIncidenceIndividualInfectionJournalsLaboratoriesLaboratory DiagnosisLaboratory StudyLifeLiquid substanceLow PrevalenceLung diseasesLung infectionsMacrolide-resistanceMagnetismMethodologyMethyltransferaseMicrobeMicrobial BiofilmsMicrobiologyMicrofluidicsMolecularMolecular Diagnostic TestingMycobacterium InfectionsMycobacterium abscessusMycobacterium avium ComplexMycobacterium tuberculosis complexNucleic AcidsOrganismPatientsPerformancePharmaceutical PreparationsPhasePhenotypePoint MutationPolymorphism AnalysisPorosityPositioning AttributePrevalenceProcessProtocols documentationPulmonary EmphysemaPulmonary TuberculosisReagentRegimenRelapseResistanceResistance to infectionRespiratory Tract InfectionsRibosomesRisk FactorsRoboticsRotationSamplingSensitivity and SpecificitySoilSpecificitySpecimenSputumStep TestsTestingTimeTuberculosisVeteransViscosityWaterautomated analysisclinical diagnosisclinically relevantdiagnostic algorithmdrug testingeditorialfollower of religion Jewishimagerinstrumentmembermycobacterialnew epidemicnon-tuberculosis mycobacterianovel therapeuticsoptimal treatmentsportabilityrRNA Genesradiological imagingrapid testrespiratorytest striptuberculosis treatmentvirtualworking group
项目摘要
ABSTRACT
Nontuberculous mycobacteria lung disease (NTM-LD) is a silent and emerging epidemic in the U.S. and many
parts of the world.1-3 The incidence and prevalence of NTM-LD is increasing yearly and now far exceeds that of
tuberculosis (TB) caused by Mycobacterium tuberculosis complex in the U.S.4 Two of the greatest known risk
factors for NTM-LD are chronic obstructive pulmonary disease (COPD) and pre-existing bronchiectasis.3 In the
U.S., approximately 12 million individuals have COPD, the third leading cause of death in the U.S.5 In addition,
the co-occurrence of bronchiectasis in patients with known COPD is up to ~70%.6 Like TB, the requirement for
prolonged combination drug therapy is a central tenet of NTM-LD treatment. Consequently, it is essential that
several drugs be administered concurrently to maximize sterilizing activity. While TB has benefited from the
development of rapid molecular diagnostic tests to simultaneously detect infection and antimicrobial resistance
and from recently approved new drugs, the diagnosis and treatment of NTM-LD have not experienced similar
advances.7,8 The diagnosis of NTM-LD is complicated by the fact that clinical manifestations and radiographic
findings for pulmonary TB and NTM-LD may be virtually indistinguishable. Thus, it is important when
diagnosing NTM-LD to “rule out” TB even in regions of lower prevalence of the disease, such as the U.S.,
because treatment for TB and NTM-LD are substantially different. To differentiate TB from NTM-LD, clinicians
must rely on a combination of phenotypic assays and molecular tests to identify the etiological agent and to
detect resistance to key antibiotics. Hence, the algorithm for contemporary NTM diagnostic testing is complex,
requiring varied testing methodologies, which are either insensitive (acid-fast bacilli smear), inherently slow to
obtain the results (culture; up to 6 weeks), or insufficiently comprehensive (lack of molecular tests).
Molecular detection of NTM and its antimicrobial resistance from respiratory samples is challenging. The
specimen type (sputum) is viscous and highly heterogeneous; bacterial burden is often low but significant;
mycobacteria are difficult to lyse; the number of clinically relevant NTM species is considerable; and the
polymorphisms that confer drug resistance are numerous. To address these challenges, we propose to
automate and integrate the following into a one user-step test: chaotic mixing of glass beads using a rotating
magnetic disc to homogenize sputa and lyse bacilli, a porous disc in a pipette tip to purify and concentrate
nucleic acid, and a Lab-on-a-Film test to speciate and detect polymorphisms that confer drug resistance. For
Phase 2, we propose to develop a test that can rule in/out TB, speciate clinically-relevant NTM, and detect
NTM-LD drug resistance markers. To evaluate this test, we propose to perform clinical studies at Mayo Clinic,
National Jewish Health, and Wadsworth Center in collaboration with clinical NTM-LD experts, which includes
members of: the Journal of Clinical Microbiology Editorial Board, Clinical Laboratory Standards Institute
Working Group, fellows of the American Academy of Microbiology and Board of Governors of the Academy.
摘要
非结核分枝杆菌肺病(NTM-LD)在美国和许多国家是一种默默无闻的新兴流行病。
世界部分地区1-3非霍奇金淋巴瘤的发病率和流行率每年都在增加,现在远远超过
由结核分枝杆菌复合体引起的结核病在美国是已知风险最大的两个
慢性阻塞性肺疾病(COPD)和既往存在的支气管扩张是NTM-LD的因素。
在美国,大约有1200万人患有慢性阻塞性肺病,这是美国第三大死因。
在已知的COPD患者中,支气管扩张的并存比例高达~70%。6与结核病一样,要求
长期联合用药是NTM-LD治疗的核心原则。因此,至关重要的是
同时给药几种药物,以最大限度地发挥杀菌作用。虽然结核病受益于
同时检测感染和耐药性的快速分子诊断试验的发展
从最近批准的新药来看,NTM-LD的诊断和治疗没有经历过类似的经历
NTM-LD的诊断因其临床表现和X线表现而变得复杂。
肺结核和NTM-LD的诊断结果可能几乎无法区分。因此,重要的是什么时候
即使在疾病发病率较低的地区,如美国,诊断NTM-LD时也要“排除”结核病,
因为结核病和NTM-LD的治疗有很大的不同。为了区分结核病和NTM-LD,临床医生
必须依靠表型分析和分子测试相结合的方法来确定病原体和
检测对关键抗生素的耐药性。因此,当代NTM诊断测试的算法是复杂的,
需要不同的测试方法,这些方法要么不敏感(抗酸杆菌涂片),固有地缓慢
获得结果(培养;长达6周),或不够全面(缺乏分子测试)。
从呼吸道样本中检测NTM及其耐药性的分子检测是具有挑战性的。这个
标本类型(痰)是粘性和高度异质性的;细菌负荷通常很低,但很明显;
分支杆菌很难分解;临床上相关的NTM种类数量相当多;以及
导致耐药性的基因多态有很多。为应付这些挑战,我们建议
自动化以下内容并将其集成到一个用户步骤测试中:使用旋转的
用于均质痰和裂解杆菌的磁盘,用于提纯和浓缩吸管尖端的多孔盘
核酸,以及一种膜上实验室测试,以确定和检测导致耐药性的多态。为
第二阶段,我们建议开发一种测试,可以排除/排除结核病,指定与临床相关的NTM,并检测
NTM-LD耐药标志物。为了评估这项测试,我们建议在梅奥诊所进行临床研究,
国家犹太人健康和沃兹沃斯中心与NTM-LD临床专家合作,其中包括
成员:临床微生物学杂志编辑委员会,临床实验室标准研究所
工作组、美国微生物学会院士和该学会理事会成员。
项目成果
期刊论文数量(0)
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Christopher Gerard Cooney其他文献
Christopher Gerard Cooney的其他文献
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{{ truncateString('Christopher Gerard Cooney', 18)}}的其他基金
Lab-on-a-Film Multiplexed Test for Respiratory Mycobacterial Infections
呼吸道分枝杆菌感染的胶片实验室多重检测
- 批准号:
10256602 - 财政年份:2021
- 资助金额:
$ 99.94万 - 项目类别:
Lab-on-a-Film Multiplexed Test for Respiratory Mycobacterial Infections
呼吸道分枝杆菌感染的胶片实验室多重检测
- 批准号:
10546793 - 财政年份:2021
- 资助金额:
$ 99.94万 - 项目类别:
A low-cost instrument for nucleic acid isolation.
一种用于核酸分离的低成本仪器。
- 批准号:
8393862 - 财政年份:2012
- 资助金额:
$ 99.94万 - 项目类别: