Pharmacokinetic and pharmacodynamic relationships for antibacterial treatment of shigellosis

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212，000例腹泻死亡归因于志贺氏菌（占总数的12.5 疟疾死亡），在低资源国家造成不成比例的影响。对低资源国家的影响 全球肠道多中心研究（GEMS）的再分析表明，志贺氏菌具有 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 男男性行为者社区的志贺氏菌病病例证实，其影响不仅限于儿童 在低资源环境中。虽然明确需要新的志贺氏菌病治疗方法，但尚不清楚 当前疗法的特征有助于它们的功效和耐药性的出现。的目标 建议的工作是确定抗菌药物的安全性-反应关系，并建立一个严格的 临床前框架，其可用于鉴定和优化用于治疗志贺氏菌病的新疗法。 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功效的重要性。药代动力学/药效学 (PK抗隐孢子虫药物的体外和体内模型的特征在于， 隐孢子虫病我们对这一建议的中心假设是，可以使用类似的方法来建立 抗生素暴露与体内抗志贺氏菌功效之间的关系。此外，我们相信， 模型可用于鉴定与耐药性出现相关的抗菌剂浓度。 为了我们的假设，我们将使用我们建立的志贺氏菌感染小鼠模型来表征志贺氏菌在小鼠中的表达。 世卫组织推荐的志贺氏菌病抗菌治疗的体内疗效。此外，我们将采用创新的 中空纤维感染模型，以调查抗菌药物耐药性的出现。这一重要信息将 有助于合理化目前治疗的给药方案，并将支持发现和开发 未来的治疗我们建议通过以下方式评价抗菌药物的PK/PD关系 三个具体目标：（1）确定抗菌药物的体内抗菌-反应关系;（2） 用志贺氏菌中空纤维感染模型表征抗菌功效和耐药性的出现。 总之，这些研究将帮助我们更好地了解目前的志贺氏菌病治疗， 提供了一系列方法来识别和优化新的治疗方法。此外，工作成果将 为感染性疾病，特别是肠道感染领域的药物发现提供基础支持。

Project Summary/Abstract Enteric infection with Shigella spp. can lead to symptoms ranging from acute watery diarrhea to sudden, severe dysentery. Approximately 212,000 diarrheal deaths annually are attributed to Shigella (12.5% of total diarrheal deaths) with a disproportionate impact in low resource countries. The impact in low resource countries was 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 have sex with men community confirm that the impact is not limited to children in low resource settings. While there is a clear need for new shigellosis treatments, it is not clear what characteristics of current therapies contribute to their efficacy and emergence of resistance. The goals of the proposed work are to determine exposure-response relationships for antibacterials and to establish a rigorous preclinical framework which can be used to identify and optimize new therapeutics for treatment of shigellosis. Our previous innovative studies on the gut localized pathogen Cryptosporidium demonstrated the importance of gastrointestinal drug exposure for in vivo 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 can be used to establish the relationship between antibacterial exposure and in vivo efficacy against Shigella. In addition, we believe our models can be used to identify antibacterial concentrations associated with the emergence of resistance. Towards our hypothesis, we will use our established mouse model of Shigella infection to characterize the in vivo efficacy of WHO recommended antibacterial treatments for shigellosis. In addition, we will use an innovative hollow fiber infection model to investigate the emergence of antibacterial resistance. This crucial information will assist in rationalizing dosing regimens for current treatments and will support discovery and development of future therapeutics. We propose to evaluate the PK/PD relationship for antibacterials by undertaking the following three Specific Aims: (1) Determine in vivo exposure-response relationships for antibacterials and (2) Characterize antibacterial efficacy and emergence of resistance with a Shigella hollow fiber infection model. Taken together, these studies will help us better understand current shigellosis treatments and will provide a series of methods to identify and optimize new treatments. In addition, the results of the work will provide fundamental support for drug discovery in infectious disease, especially in the area of enteric infections.