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.

项目摘要/摘要 由血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由壁虱传播的疾病。 美国。症状包括发烧、发冷、出汗、头痛、肌肉疼痛和食欲不振。在年轻和健康中 对于个人来说，症状往往很少，而且很轻微。50岁和免疫功能低下的个人 患者，症状可能很严重，需要住院治疗。尽管有医疗护理，但并发症如 由于严重的贫血，成人呼吸窘迫综合征和肾功能不全或衰竭可能会发展。死亡就是 2-3%的住院病例的转归。预防措施仅限于避免流行地区和接触壁虱。 还原。这些措施在遏制巴贝斯虫病的出现方面效果不佳。没有疫苗是 目前还没有针对巴贝斯虫病的化学预防措施进行测试。他芬诺喹被批准用于预暴露 预防疟疾和根治间日疟原虫感染。预防方案包括一种 连续三天服用负荷量，然后每周服用维持剂，直到一周后 旅行。治疗方案是与氯喹一起服用的单剂量。他芬诺喹从来没有 被测试为预防巴贝斯虫病的药物。临床前研究表明，i)微小杆菌感染的迅速解决 是通过单剂他非诺喹达到的，但ii)只有当他非诺喹使用超过 连续几天。在最近的一份病例报告中，我们首先记录了阿司匹林的治疗益处 他非诺喹用于1例老年免疫功能低下的患者，患者患有复发性巴贝斯虫病 广泛的抗菌素耐药性。他非诺喹起效后即可治愈。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 因高龄或严重的免疫抑制而虚弱。在目标1中，我们将使用DBA/2J小鼠品系来 制作老年严重巴贝斯虫病的模型。我们将通过感染年轻的DBA/2J小鼠开始我们的研究，在 要做到这一点，就必须确定能够在老年时提供预防措施的养生法。简而言之，我们将管理 从感染后第三天开始，在“窗口期”内连续三天服用他非诺喹。我们会 监测寄生虫血症从发病(第7天)到感染后第35天的病程。我们将确定是否 根治是通过向RAG缺陷小鼠过继输血来实现的。我们确定了保护方案 这使用了最低的每日剂量，并测试了这种方案是否对老年DBA/2J小鼠提供了预防。我们会 LC/MS/MS法测定血浆中他苯喹的最大血药浓度和总药物浓度 对年轻和老年DBA/2J小鼠进行预防所需的暴露。在目标2中，我们将使用衣衫不整的年轻人 建立BALB/c小鼠严重免疫抑制模型。我们将测试RAG缺陷小鼠的预防 需要的日剂量高于用于预防年轻和老年DBA/2J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，该试验将测试他苯喹对暴露后预防巴贝斯虫病的作用。