A randomized clinical trial of early empiric anti-Mycobacterium tuberculosis therapy for sepsis in sub-Saharan Africa

撒哈拉以南非洲地区早期经验性抗结核杆菌治疗败血症的随机临床试验

• 批准号: 10443820
• 负责人: Scott K Heysell
• 金额: $ 65.78万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-18 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10443820
• 关键词: Achievement; Admission activity; Adult; Adverse drug event; Africa; Africa South of the Sahara; Antibiotics; Antitubercular Agents; Area; Blood; Cessation of life; Clinical; Clinical Microbiology; Clinical Trials; Communities; Critical Illness; Diagnosis; Diagnostic tests; Dose; Drug Kinetics; Early treatment; Etiology; Functional disorder; Goals; HIV; HIV-2; HIV/TB; Health Priorities; Hospital Mortality; Hospitalization; Immune response; Infection; Karnofsky Performance Status; Knowledge; Lead; Life; Measures; Mycobacterium tuberculosis; Odds Ratio; Organ; Participant; Patients; Persons; Pharmaceutical Preparations; Pharmacodynamics; Phase; Polymerase Chain Reaction; Randomized; Randomized Clinical Trials; Regimen; Rifampin; Risk Reduction; Sample Size; Sepsis; Serum; Side; Site; Sputum; Syndrome; Tanzania; Temperature; Testing; Time; Tuberculosis; Tuberculosis diagnosis; Uganda; Undifferentiated; Vulnerable Populations; Weight; World Health Organization; antimicrobial; base; clinical trial participant; design; early phase clinical trial; global health; improved; isoniazid; lipoarabinomannan; microbial; mortality; open label; point-of-care diagnostics; primary endpoint; prospective; secondary endpoint; septic patients; standard care; standard of care; tuberculosis drugs; tuberculosis treatment; urinary

PROJECT SUMMARY/ABSTRACT Sepsis is a syndrome of critical illness defined as life-threatening organ dysfunction due to a dysregulated host response to infection and is a leading cause of global mortality. In May of 2017, the World Health Organization (WHO) made sepsis a global health priority. Yet, little is known about sepsis in the global South and specifically sub-Saharan Africa where there are at least 1.2-2.2 million cases of sepsis and 6.5 million deaths due to infection annually. The majority of these patients are living with HIV. We have determined the leading cause of sepsis in this region is tuberculosis (TB) which is responsible for 25-30% of bloodstream infections in septic patients. TB sepsis is associated with 20-50% mortality rates with the majority of deaths occurring within the first 4-5 days of admission. However, it is difficult to identify TB sepsis clinically or with diagnostic tests which are often unavailable and have limited sensitivity. Therefore, TB can be missed and patients with TB sepsis may not receive anti-TB therapy, or if they do, it may be delayed. However, we have found that empiric treatment of TB in septic patients without a confirmed diagnosis of TB improves 28 day survival. We have also studied anti-TB pharmacokinetics/pharmacodynamics in septic patients and discovered considerably low circulating drug concentrations that are suboptimal for microbial kill. Therefore, our hypotheses are that immediate anti-TB therapy will improve 28 day survival compared to anti-TB therapy that is administered only after a diagnosis is made, and that optimized sepsis-specific dosing will improve 28 day mortality compared to conventional WHO recommended weight-based dosing regardless of the timing of administration. We will test these hypotheses through a randomized 2x2 factorial clinical trial where participants with HIV and sepsis will be randomized to 1) empiric immediate initiation of anti-TB therapy plus standard care or diagnosis dependent anti-TB therapy and standard care and 2) sepsis-specific dose anti-TB therapy plus standard care or conventional WHO weight-based recommended dose anti-TB therapy and standard care. This randomized 2x2 factorial clinical trial is strongly endorsed by Tanzanian and Ugandan community advisory boards and will be the first to determine the optimal content, dosing, and timing of the antimicrobial regimen for adult sepsis in sub-Saharan Africa.

项目摘要/摘要 脓毒症是一种危重疾病综合征，定义为由于宿主调节失调而导致的危及生命的器官功能障碍。 它是对感染的反应，是全球死亡的主要原因。2017年5月，世界卫生组织 世界卫生组织(WHO)将脓毒症列为全球卫生优先事项。然而，全球对脓毒症知之甚少。 南部，特别是撒哈拉以南非洲，那里至少有120万至220万例脓毒症病例和650万例 每年有数百万人死于感染。这些患者中的大多数都是艾滋病毒携带者。我们已经决定 该地区败血症的主要原因是结核病，它占血液总量的25%-30%。 败血症患者的感染。肺结核败血症与20%-50%的死亡率有关，其中大多数死亡 在入院的头4-5天内发生的。然而，在临床或临床上很难识别结核败血症。 通常无法获得且灵敏度有限的诊断测试。因此，结核病可能会被漏掉，而且 肺结核败血症患者可能不会接受抗结核治疗，或者如果他们接受了，治疗可能会推迟。然而，我们有 发现对未确诊为结核病的脓毒症患者进行经验性治疗可改善28天 生死存亡。我们还研究了败血症患者的抗结核药代动力学/药效学，并发现 相当低的循环药物浓度，对微生物杀灭不是最理想的。因此，我们的 假设与立即抗结核治疗相比，立即抗结核治疗将提高28天存活率。 只有在做出诊断后才能给予，优化的脓毒症特异性剂量将改善28天 死亡率与世卫组织建议的传统重量剂量的比较，无论何时 行政管理。我们将通过一项随机的2x2析因临床试验来检验这些假设 患有艾滋病毒和脓毒症的参与者将被随机分配到1)经验性立即开始抗结核治疗加 标准护理或诊断依赖的抗结核治疗和标准护理以及2)脓毒症特异性剂量抗结核 治疗加标准护理或传统世卫组织以体重为基础的推荐剂量抗结核治疗和 标准护理。这项随机的2x2因子临床试验得到了坦桑尼亚和乌干达的大力支持 社区咨询委员会，并将是第一个确定最佳内容、剂量和时间的 撒哈拉以南非洲成人败血症的抗菌疗法。