Evaluation of tafenoquine for prophylaxis of babesiosis caused by Babesia microti

他非诺喹预防田鼠巴贝斯虫引起的巴贝斯虫病的评价

基本信息

批准号：
10648698
负责人：
Edouard G Vannier
金额：
$ 8.9万
依托单位：
TUFTS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-17 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10648698
关键词：
Acute Respiratory Distress Syndrome Adoptive Transfer Age Age Years Anemia Anorexia Antimicrobial Resistance Area Babesia microti Babesiosis Bite Black-legged Tick Blood Borrelia microti Caring Case Study Cessation of life Chemoprophylaxis Chills Chloroquine Clinical Trials Data Dose Drug Exposure Drug Kinetics Elderly Emerging Communicable Diseases Evaluation Exposure to FDA approved Feeds Fever Glucosephosphate Dehydrogenase Deficiency Headache Hospitalization Human Immune response Immunocompromised Host Immunosuppression Inbred BALB C Mice Incidence Individual Infection Kidney Failure Maintenance Malaria Measures Medical Modeling Monitor Mouse Strains Mus Myalgia Outcome Parasitemia Plasma Plasmodium vivax Prophylactic treatment Protocols documentation Regimen Relapse Research Resolution Risk Factors Symptoms Testing Therapeutic Tick-Borne Diseases Ticks Travel United States Vaccines Work enzootic human old age (65+)liquid chromatography mass spectrometry pre-exposure prophylaxis preclinical study prophylactic vector

项目摘要

PROJECT SUMMARY/ABSTRACT Human babesiosis caused by the hemoparasite Babesia microti is an emerging tick-borne disease in the United States. Symptoms include fever, chills, sweats, headache, myalgia and anorexia. In young and healthy individuals, symptoms tend to be few and mild. In individuals >50 years of age and in immunocompromised patients, symptoms can be severe and hospital admission required. Despite medical care, complications such as severe anemia, adult respiratory distress syndrome and renal insufficiency or failure can develop. Death is the outcome in 2-3% of hospitalized cases. Prophylaxis is limited to endemic area avoidance and tick exposure reduction. These measures have been ineffective in curtailing the emergence of babesiosis. No vaccine is available and no chemoprophylaxis has been tested for babesiosis. Tafenoquine is approved for pre-exposure prophylaxis of malaria and radical cure of Plasmodium vivax infection. The prophylactic regimen consists of a loading dose taken for three consecutive days followed by a weekly maintenance dose until one week after travel. The therapeutic regimen is a single dose taken along with chloroquine. Tafenoquine has never been tested as prophylaxis for babesiosis. Pre-clinical studies indicate that i) prompt resolution of B. microti infection is achieved by single dose tafenoquine but ii) radical cure is attained only if tafenoquine is administered over several consecutive days. In a recent case report, we were the first to document the therapeutic benefit of tafenoquine in an elderly immunocompromised patient who suffered from relapsing babesiosis in the context of broad antimicrobial resistance. Cure was achieved following initiation of tafenoquine. We hypothesize that tafenoquine can be used for the prophylaxis of babesiosis, including when the host immune response is weakened by advanced age or severe immune suppression. In Aim #1, we will use the DBA/2J mouse strain to model the severe babesiosis of old age. We will initiate our studies by infecting young DBA/2J mice and, in doing so, identify regimens that offer a prospect of conferring prophylaxis in old age. Briefly, we will administer tafenoquine for three consecutive days during the “window period”, starting on day 3 post-infection. We will monitor the course of parasitemia from its onset (day 7) until day 35 post-infection. We will ascertain whether radical cure is achieved by adoptive transfer of blood to rag-deficient mice. We identify the protective regimen that uses the lowest daily dose and test whether this regimen confers prophylaxis to old DBA/2J mice. We will detect tafenoquine in plasma by use of LC/MS/MS and identify the maximal concentration and the overall drug exposure required for prophylaxis in young and old DBA/2J mice. In Aim #2, we will use young rag-deficient BALB/c mice to model severe immune suppression. We will test whether prophylaxis of rag-deficient mice requires a daily dose higher than those used for prophylaxis of young and old DBA/2J mice. If successful, the work will lay the ground for a clinical trial that will test tafenoquine for post-exposure prophylaxis of babesiosis.

项目概要/摘要由血液寄生虫微小巴贝斯虫引起的人类巴贝斯虫病是一种新出现的蜱传疾病美国年轻人和健康人的症状包括发烧、发冷、出汗、头痛、肌痛和厌食。对于年龄 > 50 岁且免疫功能低下的个体，症状往往较少且轻微。患者，尽管接受医疗护理，但症状可能很严重，需要住院治疗，出现并发症等。严重贫血、成人呼吸窘迫综合征和肾功能不全或衰竭可能导致死亡。 2-3% 的住院病例的结果仅限于避免流行区和接触蜱虫。这些措施对于减少巴贝斯虫病的出现没有效果。他非诺喹已被批准用于暴露前治疗，并且尚未对巴贝西虫病进行化学预防测试。预防疟疾和根治间日疟原虫感染。预防方案包括：连续三天服用负荷剂量，然后每周服用维持剂量，直到一周后治疗方案是与氯喹一起服用的单剂量。临床前研究表明 i) 迅速解决田鼠芽孢杆菌感染可以通过单剂量他非诺喹实现，但是 ii) 只有在服用他非诺喹超过在最近的连续几天的病例报告中，我们是第一个记录了治疗益处的人。他非诺喹治疗一位免疫功能低下的老年患者，该患者患有复发性巴贝虫病开始使用他非诺喹后，实现了广泛的抗菌药物耐药性。他非诺喹可用于预防巴贝斯虫病，包括当宿主免疫反应减弱时因高龄或严重免疫抑制而减弱在目标 #1 中，我们将使用 DBA/2J 小鼠品系来我们将通过感染年轻的 DBA/2J 小鼠来建立老年严重巴贝斯虫病模型。这样做，确定了可以在老年进行预防的治疗方案。简而言之，我们将进行管理。从感染后第 3 天开始，我们将在“窗口期”连续三天服用他非诺喹。监测寄生虫血症从发病（第 7 天）到感染后第 35 天的过程。通过将血液过继转移到有缺陷的小鼠体内，可以实现根治。我们确定了保护方案。使用最低每日剂量并测试该方案是否对老年 DBA/2J 小鼠具有预防作用。使用 LC/MS/MS 检测血浆中他非诺喹并确定最大浓度和总体药物年轻和年老 DBA/2J 小鼠预防所需的暴露量在目标 #2 中，我们将使用年轻的 rag 缺陷小鼠。 BALB/c 小鼠模拟严重的免疫抑制我们将测试是否对 rag 缺陷小鼠进行预防。需要高于年轻和年老 DBA/2J 小鼠预防剂量的每日剂量。这项工作将为一项临床试验奠定基础，该试验将测试他非诺喹对巴贝斯虫病暴露后预防的作用。