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: 10163798
• 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/10163798
• 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 在高结核病（TB）事件的国家中，结核病是心包积液的最常见原因。 心包结核病（PCTB）是一种严重的肺外结核病形式，导致血液动力学不稳定和 心脏填塞需要心脏穿刺术3。尽管抗结核治疗（ATT），并发症 保持频繁和死亡率高（8-34％，在艾滋病毒共同感染的人中最差）。 PCTB死亡有助于 两者均通过高质心包液（PCF）细菌负荷，这可能是由于ATT渗透不足而产生的 心包，通过免疫激素的失调，试图清除感染。那是 在细菌杀戮的效率方面，改善当前PCTB治疗方法的重要需求 以及可以专门调节的有害炎症途径的识别。这项合作 因此将确定： 1：高剂量利福平是否会增加PCF的药物暴露，从而导致更大的下降 MTB负载。假设是PCF中的利福平（RIF）暴露会随着剂量较高（35mg/kg， RIF35）与标准（RIF 10mg/kg，RIF10），而细菌的下降将与PCF中的RIF暴露有关 和等离子体。每天的35mg/kg RIF的随机对照临床试验与标准剂量相结合 其他3种抗结核药物（吡嗪酰胺，ethambutol和Isoniaiazid）与护理标准相比 实施。这将评估0和72小时的PCF细菌燃烧的安全性和主要效率终点。 次要终点将是临床测量和精确心血管磁共振的综合 （CMR）心包炎症，增厚，废物，纤维化或收缩的证据。药代动力学 还将确定PCF中抗结核药物的药效学。 2：心包MTB特异性T细胞与细菌负荷和治疗结果之间的关系 PCTB。在PCF中发现了多种类型的T细胞，但尚不清楚哪些子集有助于保护 和/或病理。常规和供体的表型和功能不受限制（例如Mait细胞，CD1- 受限制的T细胞，γδT细胞）MTB特异性T细胞亚群，来自感染HIV和未感染的HIV的配对血液和PCF PCTB患者将进行调查。 CD4+ T细胞生物标志物PCF的关系（CD153，HLA-DR， 还将进行带有细菌载荷和结果的CD38，KI67）。 3：MTB诱导的宿主细胞死亡途径标记与PCTB中细菌负荷之间的关系。 在模型系统中，坏死（细胞溶解）细胞死亡益处MTB，而凋亡细胞死亡 与宿主细菌对照相关。尚不清楚诱导不同的细胞死亡途径如何与 结核病患者的疾病。因此 血液）将被确定，并与临床终点的相关性。