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: 10653094
• 负责人: Scott K Heysell
• 金额: $ 66.95万
• 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/10653094
• 关键词: Achievement; Admission activity; Adult; Adverse drug event; Africa; Africa South of the Sahara; Antibiotic Therapy; Antitubercular Agents; Area; Blood; Cessation of life; Clinical; 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; Life; Measures; Mycobacterium tuberculosis; Odds Ratio; Organ; Participant; Patients; Persons; Pharmaceutical Preparations; Pharmacodynamics; Phase; Polymerase Chain Reaction; Randomized; Recommendation; 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; clinical trial participant; conventional dosing; design; early phase clinical trial; global health; improved; isoniazid; lipoarabinomannan; microbial; mortality; open label; point-of-care diagnostics; primary endpoint; prospective; randomized, clinical trials; 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.

项目总结/摘要 脓毒症是一种危重病综合征，定义为由于宿主失调而导致的危及生命的器官功能障碍 是全球死亡率的主要原因。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， 南部非洲，特别是撒哈拉以南非洲，至少有120万至220万例败血症和650万例 每年因感染而死亡100万人。这些患者中的大多数是艾滋病毒感染者。我们已经确定 该地区败血症的主要原因是结核病（TB），其占血流的25- 30 脓毒症患者的感染。结核败血症与20-50%的死亡率相关，其中大多数死亡 发生在入院后的前4-5天内。然而，很难在临床上识别结核脓毒症， 诊断测试通常是不可用的并且具有有限的灵敏度。因此，结核病可能会被遗漏， 结核脓毒症患者可能不接受抗结核治疗，或者即使接受，也可能延迟治疗。但我们 发现经验性治疗未确诊结核病的脓毒症患者， 生存我们还研究了脓毒症患者的抗结核药代动力学/药效学， 相当低的循环药物浓度对于微生物杀灭是次优的。所以我们的 假设是与抗TB治疗相比，立即抗TB治疗将改善28天存活率， 仅在诊断后给药，并且优化的脓毒症特异性给药将改善28天 与传统的WHO推荐的基于体重的剂量相比， 局我们将通过随机2x2析因临床试验来检验这些假设， 患有HIV和脓毒症的受试者将被随机分配至1）经验性立即开始抗TB治疗加 标准治疗或诊断依赖性抗TB治疗和标准治疗，以及2）脓毒症特异性剂量抗TB 治疗加标准治疗或常规WHO基于体重的推荐剂量抗结核治疗， 标准护理这项随机2x2析因临床试验得到了坦桑尼亚和乌干达的强烈支持。 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方案。

项目成果

Decision Analytic Modeling for Global Clinical Trial Planning: A Case for HIV-Positive Patients at High Risk for Mycobacterium tuberculosis Sepsis in Uganda.

• DOI: 10.3390/ijerph20065041
• 发表时间: 2023-03-13
• 期刊: INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH
• 作者: Keim-Malpass, Jessica;Heysell, Scott K;Thomas, Tania A;Lobo, Jennifer M;Mpagama, Stellah G;Muzoora, Conrad;Moore, Christopher C
• 通讯作者: Moore, Christopher C

Whole-genome sequencing of SARS-CoV-2 isolates from symptomatic and asymptomatic individuals in Tanzania.

• DOI: 10.3389/fmed.2022.1034682
• 发表时间: 2022
• 期刊: FRONTIERS IN MEDICINE
• 影响因子: 3.9
• 作者: Mziray, Shabani Ramadhani;van Zwetselaar, Marco;Kayuki, Charles C.;Mbelele, Peter M.;Makubi, Abel N.;Magesa, Alex S.;Kisonga, Riziki M.;Sonda, Tolbert B.;Kibiki, Gibson S.;Githinji, George;Heysell, Scott K.;Chilongola, Jaffu O.;Mpagama, Stellah G.
• 通讯作者: Mpagama, Stellah G.

Early empiric anti-Mycobacterium tuberculosis therapy for sepsis in sub-Saharan Africa: a protocol of a randomised clinical trial.

• DOI: 10.1136/bmjopen-2022-061953
• 发表时间: 2022-06-06
• 期刊: BMJ OPEN
• 影响因子: 2.9
• 作者: Said, Bibie;Nuwagira, Edwin;Liyoyo, Alphonce;Arinaitwe, Rinah;Gitige, Catherine;Mushagara, Rhina;Buzaare, Peter;Chongolo, Anna;Jjunju, Samuel;Twesigye, Precious;Boulware, David R.;Conaway, Mark;Null, Megan;Thomas, Tania A.;Heysell, Scott K.;Moore, Christopher C.;Muzoora, Conrad;Mpagama, Stellah G.
• 通讯作者: Mpagama, Stellah G.

Outcomes of World Health Organization-defined Severe Respiratory Distress without Shock in Adults in Sub-Saharan Africa.

世界卫生组织定义的撒哈拉以南非洲成人无休克严重呼吸窘迫的结果。

• DOI: 10.1164/rccm.202304-0684le
• 发表时间: 2024
• 期刊: American journal of respiratory and critical care medicine
• 影响因子: 24.7
• 作者: Chang,BickeyH;Adakun,SusanA;Auma,MaryA;Banura,Patrick;Majwala,Albert;Mbonde,AmirA;McQuade,ElizabethRogawski;Ssekitoleko,Richard;Conaway,Mark;Moore,ChristopherC;SevereRespiratoryDistressinAfrica(SRDA)Investigators
• 通讯作者: SevereRespiratoryDistressinAfrica(SRDA)Investigators