Evaluation of novel in vitro and in vivo models to characterize anti-Shigella therapeutic PK/PD relationships

项目摘要/摘要 肠源性志贺氏菌感染。会导致各种症状，从急性水样腹泻到突发性， 严重的痢疾。每年约有164,000人死于腹泻(占总数的12.5% 腹泻死亡)，对中低收入国家的影响不成比例。对LMIC的影响是 最近对全球肠道多中心研究(GEMS)的重新分析表明，志贺氏菌具有 儿童腹泻的最高可归因率&60个月。虽然最近的研究强调了 随着疾病负担的增加，治疗方法的选择也同时减少 志贺氏菌病作为耐药菌株的患病率有所增加。此外，越来越多的抗药性报告 男男性接触者(MSM)社区中的志贺氏菌病病例证实，其影响不仅限于 LMIC。展望未来，在开发新的志贺氏菌病治疗方法方面存在严重差距。长期的 拟议工作的目标是建立一个严格的临床前框架，可以用来确定 改变治疗志贺氏菌病的机会或新的化学物质。 我们之前对肠道局部病原体隐孢子虫的创新性研究表明 胃肠道药物暴露对体内抗隐孢子虫疗效的重要性。药代动力学/ 体外和体外研究了抗隐孢子虫药物的药效学(PK/PD)关系 隐孢子虫病的活体模型。我们对这一提议的中心假设是，类似的体外实验方法 体内模型可用于建立药物暴露与体内疗效之间的关系 志贺氏菌病的治疗。然而，尽管目前还没有治疗隐孢子虫病的“黄金标准”， 在人类身上，有一套被批准的抗菌药，对人类的志贺氏菌病具有不同的临床疗效。 根据我们的假设，我们已经开始了志贺氏菌感染的体外和体内模型的发展。 可用于表征抗志贺氏菌治疗药物的疗效。令人振奋的初步数据来自 这些模型表明，它们可以用来确定用于治疗的抗菌药的PK/PD关系 志贺氏菌病。这一关键信息将有助于我们理解为什么抗菌药的疗效在 诊所。我们建议通过以下三个方面来评估抗菌药的PK/PD关系 具体目的：(1)通过一组体外模型来表征抗菌药的抗志贺氏菌效果。(2) 目的：研究抗菌药治疗志贺氏菌病的体内疗效和药代动力学。(3)识别 体外抗菌效果、药代动力学和体内疗效之间的关系。 综上所述，这些研究将有助于我们更好地了解目前志贺氏菌病的治疗方法和 将提供一系列方法来确定新的治疗方案。此外，工作成果将提供 为传染病，特别是肠道感染领域的药物发现提供基本支持。

PROJECT SUMMARY/ABSTRACT Enteric infection with Shigella spp. can lead to symptoms ranging from acute watery diarrhea to sudden, severe dysentery. Approximately 164,000 diarrheal deaths annually are attributed to Shigella (12.5% of total diarrheal deaths) with a disproportionate impact in low-middle income countries (LMIC). The impact in LMIC was recently illustrated by a reanalysis of the Global Enteric Multicenter Study (GEMS) which found that Shigella has the highest attributable fraction for diarrhea in children < 60 months. While recent studies have highlighted the burden of the disease, there has been a concurrent reduction in therapeutic options for the treatment of shigellosis as drug resistant strains increase in prevalence. In addition, increasing reports of drug resistant shigellosis cases in the men who has sex with men (MSM) community confirm that the impact isn’t limited to LMIC. Moving forward, there are critical gaps in the development of new shigellosis treatments. The long-term goals of the proposed work are to establish a rigorous pre-clinical framework which can be used to identify repurposing opportunities or new chemical entities for the treatment of shigellosis. Our previous innovative studies on the gut localized pathogen Cryptosporidium demonstrated the importance of gastrointestinal drug exposure for in vivo anti-Cryptosporidium efficacy. The pharmacokinetic/ pharmacodynamic (PK/PD) relationship for anti-Cryptosporidium drugs was characterized with in vitro and in vivo models of cryptosporidiosis. Our central hypothesis for this proposal is that a similar approach with in vitro and in vivo models can be used to establish the relationship between drug exposure and in vivo efficacy for shigellosis treatments. However, while there currently is no “gold standard” for the treatment of cryptosporidiosis in humans, there are a set of approved antibacterials with variable clinical efficacy against shigellosis in humans. Towards our hypothesis, we have initiated the development of in vitro and in vivo models of Shigella infection which can be used to characterize the efficacy of anti-Shigella therapeutics. The exciting preliminary data from these models suggest that they can be used to identify PK/PD relationships for antibacterials used to treat shigellosis. This crucial information will assist in our understanding of why the efficacy of antibacterials differ in the clinic. We propose to evaluate the PK/PD relationship for antibacterials by undertaking the following three Specific Aims: (1) To characterize the anti-Shigella efficacy of antibacterials with a panel of in vitro models. (2) To investigate the in vivo efficacy and pharmacokinetics of antibacterials to treat shigellosis. (3) To identify associations between antibacterial in vitro efficacy, pharmacokinetics, and in vivo efficacy. Taken together, these studies will help us better understand the current treatments for shigellosis and will provide a series of methods to identify new treatment options. In addition, the results of the work will provide fundamental support for drug discovery in infectious disease, especially in the area of enteric infections.