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

项目总结/摘要 志贺氏菌肠道感染。会导致从急性水样腹泻到突发性， 严重的痢疾每年约有164，000例腹泻死亡归因于志贺氏菌（占总数的12.5 疟疾死亡），对中低收入国家（LMIC）的影响不成比例。对LMIC的影响是 最近通过对全球肠道多中心研究（GEMS）的重新分析表明，志贺氏菌 60个月以下儿童腹泻的最高归因分数。虽然最近的研究强调， 由于疾病的负担，同时减少了治疗 志贺菌病作为耐药菌株的流行率增加。此外，越来越多的耐药报告 男男性接触者（MSM）社区的志贺氏菌病病例证实，其影响不仅限于 LMIC。展望未来，在新的志贺氏菌病治疗方法的开发方面存在重大差距。长期 拟议工作的目标是建立一个严格的临床前框架，可用于识别 重新利用治疗志贺氏菌病的机会或新的化学实体。 我们先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功效重要性药代动力学/ 采用体外和体内试验， 隐孢子虫病的体内模型。我们对这一建议的中心假设是，一个类似的方法，在体外 并且体内模型可用于建立药物暴露和体内功效之间的关系， 志贺氏菌病治疗。然而，虽然目前没有治疗隐孢子虫病的“金标准”， 在人类中，有一组批准的抗菌剂对人类志贺氏菌病具有不同的临床疗效。 为了我们的假设，我们已经开始了志贺氏菌感染的体外和体内模型的发展 其可用于表征抗志贺氏菌治疗剂的功效。令人兴奋的初步数据来自 这些模型表明，它们可用于确定用于治疗的抗菌药物的PK/PD关系， 志贺氏菌病。这一重要信息将有助于我们理解为什么抗菌药物的疗效不同， 诊所我们建议通过以下三个方面评价抗菌药物的PK/PD关系 具体目的：（1）用一组体外模型表征抗菌药物抗志贺氏菌的效力。（二） 探讨抗菌药物治疗细菌性痢疾的体内疗效和药代动力学。(3)以识别 体外抗菌效力、药代动力学和体内效力之间的关联。 总之，这些研究将帮助我们更好地了解目前的治疗志贺氏菌病， 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 为感染性疾病的药物发现提供基本支持，特别是在肠道感染领域。

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.