Measuring Intralesional Bedaquiline Exposures in Cavitary TB Using Noninvasive In Vivo PET Imaging
使用无创体内 PET 成像测量空洞结核病灶内贝达喹啉暴露
基本信息
- 批准号:9894300
- 负责人:
- 金额:$ 24.56万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-02-11 至 2022-01-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAftercareAnimal ModelAnimalsAntibiotic TherapyAntibioticsArea Under CurveAutopsyAutoradiographyBacteriaBiodistributionBlood VesselsBrainBromineCardiacCerebrospinal FluidChemicalsClinicalClinical ResearchClinical TrialsComplementComplexDataDevelopmentDisease ProgressionDoseDrug KineticsDrug resistanceEventExcisionFutureGoalsGranulomaHourHumanImageIn SituInfectionKineticsKnowledgeLeadLesionLungMass Spectrum AnalysisMeasurementMeasuresMethodsModelingMorphologic artifactsMulti-Drug ResistanceMultidrug-Resistant TuberculosisMusMycobacterium InfectionsMycobacterium tuberculosisNational Institute of Allergy and Infectious DiseaseNecrosisNecrotic LesionOrganOrganismOryctolagus cuniculusParentsPathologicPathologyPatientsPenetrationPerformancePharmaceutical PreparationsPhasePhysiologyPlasmaPneumoniaPositronPositron-Emission TomographyPredispositionPulmonary TuberculosisRadiolabeledRecommendationRelapseReportingResearchResistanceResolutionResourcesRifampinRisk FactorsSafetySamplingSampling BiasesSiteStrategic PlanningTechnologyThickTimeTissuesToxic effectTreatment FailureTreatment ProtocolsTuberculosisUnited States Food and Drug Administrationappropriate dosebasebioimagingbrain tissuecapsuleclinically translatablecohortcostdrug developmentdrug distributionfirst-in-humanimprovedimproved outcomein vivonovelnovel therapeuticspharmacokinetic modelpreclinical studyradiochemicaltooltransmission processtreatment optimizationtreatment responsetuberculosis drugstuberculosis treatment
项目摘要
Current antibiotic dosing recommendations and breakpoints for drug susceptibility are based on plasma
concentrations and historic measures of efficacy, without specific information at the infection sites. Since
inappropriate antibiotic concentrations in target tissues can lead to treatment failure, selection of resistant
organisms, or toxicity, several studies and the U.S. Food and Drug Administration (FDA) support measuring
drug concentrations in infected tissues. However, current tools to detect tissue drug levels are invasive (require
tissue resection), which is difficult in humans and generally limited to a single time point even in animals.
Our overarching hypothesis is that multiple, heterogeneous pathological states, e.g. cavitation, pneumonia,
and necrotic lesions in pulmonary tuberculosis (TB), occur simultaneously in the same patient. Moreover, these
lesions can also have distinct bacterial burdens and antibiotic exposures, which also change with disease
progression and antibiotic treatment. Cavitation is a key pathological feature of human TB and a well-
recognized risk factor for transmission of infection, relapse, and emergence of drug resistance after treatment.
While cavitary walls have high bacterial burden (107-109), they are poorly vascularized with thick fibrous
capsules. Therefore, while adequately high antibiotic levels are need to effectively kill bacteria in cavities, using
PET bioimaging in patients with pulmonary TB, we have demonstrated that rifampin exposure is paradoxically
the lowest in cavitary walls.
Bedaquiline, a bromine-containing diarylquinoline, was recently approved for the treatment of multi-drug
resistant (MDR) tuberculosis (TB). However, bedaquiline distribution into infected tissues (e.g. granulomas and
cavitary lesions) has not been studied extensively whilst preliminary preclinical studies have reported variability
in the treatment response in mice with caseous necrotic granulomas. While highly effective in treating MDR-
TB, bedaquiline can also cause cardiac events (QT-interval prolongation) leading to safety warnings by
regulatory agencies. Therefore, there is a need for noninvasive methods to measure the biodistribution of
bedaquiline in infected tissues (e.g. cavities) and other target organs to inform appropriate dosing and develop
effective, antibiotic treatments with minimal toxicities. The overall goals of this project are to leverage our
expertise in animal models of TB and in vivo PET, a clinically translatable technology. We will develop efficient
radiolabeling methods for 76Br-bedaquiline. Using Mycobacterium tuberculosis infections as a model for
heterogeneous necrotic-lesions in multiple-compartments, quantitative 76Br-bedaquiline PET in live animals
and post-mortem high-resolution / sensitivity autoradiography (<10 µm resolution, sub-nanogram sensitivity)
will be utilized in animal models of cavitary TB to provide detailed biodistribution and temporal kinetics of
intralesional bedaquiline exposures in multiple-compartments. This proposal fulfills an important research gap
in TB drug development and aligned with the NIAID Strategic Plan for TB Research.
目前的抗生素剂量建议和药物敏感性断点是基于血浆的
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Sanjay Jain其他文献
Sanjay Jain的其他文献
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{{ truncateString('Sanjay Jain', 18)}}的其他基金
A Computational IMage Analysis Platform (CIMAP) for HuBMAP
HuBMAP 的计算图像分析平台 (CIMAP)
- 批准号:
10841858 - 财政年份:2023
- 资助金额:
$ 24.56万 - 项目类别:
Kidney single cell and spatial molecular atlas project - KIDSSMAP
肾脏单细胞和空间分子图谱项目 - KIDSSMAP
- 批准号:
10531101 - 财政年份:2022
- 资助金额:
$ 24.56万 - 项目类别:
National Institute of Diabetes and Digestive and Kidney Diseases ATLAS (D2K-ATLAS) Center as an accessible, comprehensive data portfolio for renal and genitourinary development and disease
国家糖尿病、消化和肾脏疾病研究所 ATLAS (D2K-ATLAS) 中心作为肾脏和泌尿生殖发育和疾病的可访问、全面的数据组合
- 批准号:
10910532 - 财政年份:2022
- 资助金额:
$ 24.56万 - 项目类别:
Kidney single cell and spatial molecular atlas project - KIDSSMAP
肾脏单细胞和空间分子图谱项目 - KIDSSMAP
- 批准号:
10867926 - 财政年份:2022
- 资助金额:
$ 24.56万 - 项目类别:
Kidney single cell and spatial molecular atlas project - KIDSSMAP
肾脏单细胞和空间分子图谱项目 - KIDSSMAP
- 批准号:
10531099 - 财政年份:2022
- 资助金额:
$ 24.56万 - 项目类别:
Kidney single cell and spatial molecular atlas project - KIDSSMAP
肾脏单细胞和空间分子图谱项目 - KIDSSMAP
- 批准号:
10705737 - 财政年份:2022
- 资助金额:
$ 24.56万 - 项目类别:
National Institute of Diabetes and Digestive and Kidney Diseases ATLAS (D2K-ATLAS) Center as an accessible, comprehensive data portfolio for renal and genitourinary development and disease
国家糖尿病、消化和肾脏疾病研究所 ATLAS (D2K-ATLAS) 中心作为肾脏和泌尿生殖发育和疾病的可访问、全面的数据组合
- 批准号:
10605033 - 财政年份:2022
- 资助金额:
$ 24.56万 - 项目类别:
Research Project 1: A Multidimensional Molecular Atlas of Healthy and Diseased Human Pediatric Kidney
研究项目 1:健康和患病人类儿童肾脏的多维分子图谱
- 批准号:
10530270 - 财政年份:2022
- 资助金额:
$ 24.56万 - 项目类别:
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