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。症状包括发烧、发冷、出汗、头痛、肌痛和厌食。在年轻、健康的情况下 对于个人来说，症状往往很少且轻微。年龄 >50 岁且免疫功能低下的个体 患者的症状可能很严重，需要住院治疗。尽管进行了医疗护理，但并发症如 由于严重贫血，可能会出现成人呼吸窘迫综合征和肾功能不全或衰竭。死亡是 2-3% 的住院病例出现这种结果。预防仅限于避开流行区和接触蜱虫 减少。这些措施未能有效遏制巴贝斯虫病的出现。没有疫苗 已有可用的药物，并且尚未测试过针对巴贝斯虫病的化学预防方法。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 旅行。治疗方案是单剂量与氯喹一起服用。他非诺喹从来没有 经测试可预防巴贝斯虫病。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 连续几天。在最近的一份病例报告中，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 广泛的抗菌药物耐药性。开始使用他非诺喹后，治愈了。我们假设 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 由于高龄或严重的免疫抑制而削弱。在目标 #1 中，我们将使用 DBA/2J 小鼠品系 模拟老年的严重巴贝斯虫病。我们将通过感染年轻的 DBA/2J 小鼠来开始我们的研究， 这样做，确定了有可能在老年进行预防的治疗方案。简而言之，我们将管理 从感染后第 3 天开始，在“窗口期”连续三天服用他非诺喹。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。我们将确定是否 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。我们将 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，我们将使用缺乏破布的年轻人 BALB/c 小鼠用于模拟严重的免疫抑制。我们将测试是否可以对有缺陷的小鼠进行预防 需要的每日剂量高于用于年轻和年老 DBA/2J 小鼠预防的剂量。如果成功的话， 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。