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; 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.

项目摘要/摘要 由疾病虫babesia microti引起的人类Babesiosis是一种新兴的tick传播疾病 美国。症状包括发烧，发冷，汗水，标头，肌痛和厌食症。年轻健康 在个人中，症状往往很少且温和。在> 50岁的个人和免疫功能低下 患者，症状可能很严重，需要住院。尽管医疗护理，并发症 由于严重的贫血，会发展成人呼吸窘迫综合征和肾功能不全或失败。死亡是 2-3％的住院病例的结果。预防仅限于内在区域的回避和tick虫暴露 减少。这些措施在减少巴布西病的出现方面无效。没有疫苗 可用，没有化学预防症进行了巴氏菌病测试。 tafenoquine被批准用于暴露前 疟疾的预防和疟原虫植虫感染的根治治疗。预防性方案包括 连续三天服用的加载剂量，然后每周维护剂量直到一周后 旅行。治疗方案是与氯喹一起服用的单剂量。 tafenoquine从未 被测试为预防性的巴氏病。临床前研究表明i）迅速解决微杆菌感染 通过单剂量tafenoquine来实现，但ii）只有在将tafenoquine施用时就附着自由基治疗 连续几天。在最近的一份案件报告中，我们是第一个记录治疗益处的人 tafenoquine在一名较早的免疫功能低下的患者中 广泛的抗菌素耐药性。在Tafenoquine的主动性之后，可以实现治愈。我们假设这一点 tafenoquine可用于预防性巴氏症，包括宿主免疫反应是何时 因年龄或严重的免疫抑制而减弱。在AIM＃1中，我们将使用DBA/2J鼠标应变 建模严重的老年人。我们将通过感染的年轻DBA/2J小鼠开始研究，并在 这样做，确定可以在老年内提供预防前景的方案。简而言之，我们将管理 从感染后第3天开始，在“窗户期”中连续三天连续三天。我们将 从发病（第7天）到感染后第35天，监测寄生虫病的过程。我们将确定是否 通过将血液自适应转移到抹布缺陷的小鼠中来实现根本治愈。我们确定受保护的方案 使用最低的每日剂量并测试该方案是否承认对旧DBA/2J小鼠的预防。我们将 通过使用LC/MS/MS检测血浆中的Tafenoquine，并鉴定最大浓度和整体药物 在年轻和老年DBA/2J小鼠中进行预防所需的暴露。在AIM＃2中，我们将使用年轻的抹布缺陷 BALB/C小鼠对严重的免疫抑制进行建模。我们将测试抹布缺陷小鼠的预防 需要每天的剂量高于用于预防年轻人和老年DBA/2J小鼠的剂量。如果成功， 工作将为一项临床试验奠定基础，该试验将测试tafenoquine的暴露后预防bab虫病。