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

• 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
• 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

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.

项目总结/摘要 人类巴贝虫病是由血寄生虫田鼠巴贝虫引起的一种新出现的蜱传疾病， 美国的症状包括发烧、发冷、出汗、头痛、肌痛和厌食。在年轻和健康的 个体而言，症状往往很少且轻微。>50岁和免疫功能低下的个体 患者，症状可能严重，需要住院治疗。尽管有医疗护理， 如严重贫血、成人呼吸窘迫综合征和肾功能不全或衰竭。死亡是 2-3%的住院病例的结局。预防措施仅限于避开流行区和蜱暴露 还原这些措施在减少巴贝斯虫病的出现方面没有效果。没有一种疫苗是 目前尚无此类药物，但尚未对巴贝虫病进行过化学预防试验。他非诺喹被批准用于暴露前 预防疟疾和根治间日疟原虫感染。预防性方案包括： 连续三天接受负荷剂量，然后每周接受维持剂量，直至治疗后一周 出行治疗方案是沿着服用一剂氯喹。他非诺喹从来没有 作为预防巴贝斯虫病的试验临床前研究表明，i）迅速解决B。霉菌感染 但是ii）只有当他非诺喹超过 连续几天。在最近的一份病例报告中，我们首次记录了 他非诺喹治疗1例复发性巴贝虫病的老年免疫功能低下患者， 广泛的抗菌素耐药性。开始他非诺喹治疗后治愈。我们假设 他非诺喹可用于预防巴贝虫病，包括当宿主免疫应答被破坏时， 由于年老或严重的免疫抑制而变得虚弱。在目标1中，我们将使用DBA/2 J小鼠品系， 模拟老年人的严重巴贝斯虫病。我们将通过感染年轻的DBA/2 J小鼠来启动我们的研究，并在 这样做，确定方案，提供一个前景赋予预防老年。简单地说，我们将管理 在感染后第3天开始的“窗口期”期间连续三天给予他非诺喹。我们将 监测寄生虫血症从发病（第7天）到感染后第35天的过程。我们将查明 通过将血液过继转移到Rag缺陷小鼠中实现根治。我们确定了保护方案 使用最低日剂量，并测试该方案是否对老年DBA/2 J小鼠提供预防。我们将 通过使用LC/MS/MS检测血浆中的他非诺喹，并确定最大浓度和总体药物 在年轻和年老的DBA/2 J小鼠中预防所需的暴露。在目标#2中，我们将使用年轻的缺乏拉格的 BALB/c小鼠以建立严重免疫抑制模型。我们将测试预防Rag缺陷小鼠 需要的日剂量高于用于预防年轻和年老DBA/2 J小鼠的剂量。如果成功，则 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用于巴贝斯虫病的接触后预防。