Influence of high-dose rifampin on Mycobacterial load and inflammatory mediators in pericardial TB patients

大剂量利福平对心包结核患者分枝杆菌负荷及炎症介质的影响

• 批准号: 10397595
• 负责人: Daniel Leo Barber
• 金额: $ 20万
• 依托单位: UNIVERSITY OF CAPE TOWN
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-13 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10397595
• 关键词: Acute; Africa; Antibiotic Therapy; Antitubercular Agents; Apoptosis; Apoptotic; Bacteria; Bacteriology; Biological Markers; Biological Models; Blood; CD4 Positive T Lymphocytes; Cardiac Tamponade; Cardiovascular system; Cell Death; Cell Death Induction; Cells; Cessation of life; Clinical; Clinical Trials; Collaborations; Constrictive Pericarditis; Country; Data; Development; Diagnostic tests; Disease; Disease Outcome; Dose; Drug Exposure; Drug usage; Ethambutol; Fibrosis; Growth; HIV; HLA-DR Antigens; Host resistance; Hour; Human; Immune; Immune response; Immunologics; In Vitro; Incidence; Individual; Infection; Inflammation; Inflammation Mediators; Inflammatory; Interferons; Investigation; Liquid substance; Localized Disease; Magnetic Resonance; Measures; Microbiology; Minimum Inhibitory Concentration measurement; Monitor; Mycobacterium tuberculosis; Necrosis; Outcome; Participant; Pathogenesis; Pathology; Pathway interactions; Patients; Penetration; Pericardial body location; Pericardial effusion; Persons; Pharmacology; Pharmacotherapy; Phenotype; Plasma; Pulmonary Pathology; Pulmonary Tuberculosis; Pyrazinamide; Randomized Clinical Trials; Randomized Controlled Clinical Trials; Randomized Controlled Trials; Rapid diagnostics; Research; Rifampin; Role; Safety; Serum; Site; Syndrome; T-Lymphocyte; T-Lymphocyte Subsets; Time; Tissues; Treatment outcome; Tuberculosis; Tuberculous Pericarditis; constriction; cytokine; drug standard; effusion; hemodynamics; immunopathology; improved; insight; isoniazid; macrophage; mortality; mouse model; mycobacterial; novel; pericardial sac; pharmacokinetics and pharmacodynamics; pre-clinical; primary endpoint; response; secondary endpoint; standard of care; treatment response; tuberculosis drugs; tuberculosis treatment; γδ T cells

SUMMARY/ABSTRACT In countries with high tuberculosis (TB) incidence, TB is the most common cause of pericardial effusion. Pericardial tuberculosis (PCTB) is a severe form of extrapulmonary TB causing hemodynamic instability and cardiac tamponade requiring pericardiocentesis3. Despite anti-tuberculosis treatment (ATT), complications remain frequent and mortality high (8-34%, worst in HIV co-infected persons). Death in PCTB is contributed to both by a high pericardial fluid (PCF) bacillary load that may arise from inadequate penetration of ATT into pericardium, and by dysregulation of the immune response, which attempts to clear the infection. Thus there is an important need to improve the current PCTB treatment approach both in terms of efficiency of bacterial killing and identification of deleterious inflammatory pathways that could be specifically modulated. This collaboration will therefore determine: 1: Whether high dose rifampin increases drug exposure in PCF and thus results in a greater decline in Mtb load. The hypothesis is that rifampin (RIF) exposure in PCF will increase with a higher dose (35mg/kg, RIF35) versus standard (RIF 10mg/kg, RIF10) and that decline in bacteria will correlate with RIF exposure in PCF and plasma. A randomized controlled clinical trial of 35mg/kg RIF daily in combination with standard doses of the 3 other antitubercular drugs (pyrazinamide, ethambutol and isoniazid), versus standard of care will be conducted. This will assess safety and the primary efficacy endpoint of PCF bacillary burden at 0 and 72 hrs. Secondary endpoints will be a composite of clinical measures and precise cardiovascular magnetic resonance (CMR) evidence of pericardial inflammation, thickening, effusion, fibrosis or constriction. The pharmacokinetics and pharmacodynamics of antitubercular drugs in PCF will also be determined. 2: Relationships between pericardial Mtb-specific T cells with bacterial load and treatment outcome in PCTB. Multiple types of T cells are found in PCF, but it remains unknown which subsets contribute to protection and/or pathology. The phenotype and function of conventional and donor unrestricted (e.g. MAIT cells, CD1- restricted T cells, γδ T cells) Mtb-specific T cell subsets in paired blood and PCF from HIV infected and uninfected persons with PCTB will be investigated. The relationship in PCF of CD4+ T cell biomarkers (CD153, HLA-DR, CD38, Ki67) with bacillary load and outcome will also be undertaken. 3: Relationships between Mtb-induced markers of host cell death pathways and bacterial load in PCTB. In model systems, necrotic (cytolytic) cell death benefits dissemination of Mtb, while apoptotic cell death associates with host bacterial control. It is unknown how the induction of varying cell death pathways relate to disease in TB patients. Therefore well-defined markers of cytolytic macrophage cell death pathways in PCF (and blood) will be determined and their correlation with clinical endpoints explored.

摘要/摘要 在结核病(TB)发病率高的国家，结核病是心包积液的最常见原因。 心包结核(PCTB)是一种严重的肺外结核病，可导致血流动力学不稳定和 需要心包穿刺术的心脏压塞3。尽管接受了抗结核治疗(ATT)，但并发症 仍然很频繁，死亡率很高(8-34%，在艾滋病毒合并感染者中最严重)。PCTB的死亡是由 两者均由高心包液(PCF)细菌负荷引起，这可能是由于ATT未充分穿透到 通过心包和免疫反应的失调，试图清除感染。因此，有 在细菌杀灭效率方面改进目前的PCTB治疗方法是一项重要的需要 以及识别可能被特定调节的有害炎症途径。此协作 因此，将决定： 1：大剂量利福平是否会增加PCF中的药物暴露，从而导致更大的降幅 MTB装载。假设PCF中的利福平(RIF)暴露会随着较高剂量(35 mg/kg， RIF35)与标准(RIF 10 mg/kg，RIF10)相比，细菌的下降将与PCF中的RIF暴露相关 和血浆。RIF每日35 mg/kg联合标准剂量的随机对照临床试验 其他3种抗结核药物(吡嗪酰胺、乙胺丁醇和异烟肼)，与护理标准相比将是 指挥。这将评估0小时和72小时PCF细菌负荷的安全性和主要疗效终点。 次要终点将是临床措施和精确的心血管磁共振的组合 (CMR)心包炎、增厚、渗出、纤维化或狭窄的证据。药代动力学 此外，还将测定PCF中抗结核药物的药效学。 心包结核分枝杆菌特异性T细胞与细菌载量及治疗结果的关系 PCTB。在PCF中发现了多种类型的T细胞，但尚不清楚哪些亚群起到了保护作用 和/或病理学。常规和供者不受限制的表型和功能(如MAIT细胞、CD1- γδ感染者和未感染者外周血和外周血中MTB特异性T细胞亚群 患有肺结核病的人将受到调查。CD_4~+T细胞生物标志物(CD153、HL A-DR、CD_4~+)与外周血中的关系 CD38，Ki67)，细菌载量和结果也将被接受。 3：结核分枝杆菌诱导的宿主细胞死亡途径标志物与细菌载量的关系。 在模型系统中，坏死性(溶细胞性)细胞死亡有利于结核分枝杆菌的传播，而凋亡性细胞死亡有利于结核分枝杆菌的传播。 与宿主细菌控制有关。目前尚不清楚不同细胞死亡途径的诱导如何与 结核病患者中的疾病。因此，PCF中明确的细胞溶解巨噬细胞死亡途径的标志物(和 血液)，并探讨其与临床终点的相关性。