Pharmacokinetic and pharmacodynamic relationships for antibacterial treatment of shigellosis

抗菌治疗志贺氏菌病的药代动力学和药效学关系

• 批准号: 10656116
• 负责人: Samuel L Arnold
• 金额: $ 43.63万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-06 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656116
• 关键词: Acceleration; Acute; Africa; Animal Experiments; Anti-Bacterial Agents; Area; Asia; Azithromycin; Bacterial Drug Resistance; Cefixime; Cell Line; Cessation of life; Characteristics; Child; Ciprofloxacin; Clinic; Clinical; Colon; Communicable Diseases; Communities; Country; Cryptosporidiosis; Cryptosporidium; Data; Development; Diarrhea; Dose; Dose Fractionation; Drug Exposure; Drug Kinetics; Drug resistance; Dysentery; Enteral; Environment; Fatty Acids; Fiber; Foundations; Future; Gastrointestinal Agents; Gastrointestinal tract structure; Goals; Growth; Human; In Vitro; Infection; Invaded; Knowledge; Large Intestine; Link; Methods; Modeling; Multicenter Studies; Mus; Oral Administration; Pharmaceutical Preparations; Pharmacodynamics; Physiological; Plasma; Population Attributable Risks; Prevalence; Property; Rationalization; Recommendation; Reducing Agents; Regimen; Reporting; Research; Resistance; Resistance development; Resource-limited setting; Resources; Series; Shigella; Shigella Infections; Site; Symptoms; Therapeutic; Therapeutic Effect; Time; Toxic effect; Virulence; Work; bile salts; burden of illness; design; diarrheal disease; drug development; drug discovery; enteric infection; enteric pathogen; gastrointestinal; improved; in vivo; in vivo Model; indexing; innovation; mass spectrometric imaging; men who have sex with men; mortality; mouse model; new chemical entity; novel therapeutics; pathogen; pharmacodynamic model; pharmacokinetic model; pharmacokinetics and pharmacodynamics; physiologically based pharmacokinetics; pre-clinical; preclinical development; resistant strain; response; tool

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.

项目概要/摘要 志贺氏菌属肠道感染。可能导致从急性水样腹泻到突发的症状， 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%） 腹泻死亡），对资源匮乏国家的影响尤为严重。对资源匮乏国家的影响 全球肠道多中心研究 (GEMS) 的重新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 随着疾病负担的增加，治疗选择也同时减少 志贺氏菌病随着耐药菌株的流行而增加。此外，越来越多的耐药性报道 男男性行为者群体中的志贺氏菌病例证实其影响不仅限于儿童 在低资源环境中。虽然显然需要新的志贺氏菌病治疗方法，但尚不清楚是什么 当前疗法的特点有助于其疗效和耐药性的出现。的目标 拟议的工作是确定抗菌药物的暴露-反应关系并建立严格的 临床前框架可用于识别和优化治疗志贺氏菌病的新疗法。 我们之前对肠道本地病原体隐孢子虫的创新研究证明了 胃肠道药物暴露对于体内疗效的重要性。药代动力学/药效学 通过体外和体内模型表征抗隐孢子虫药物的（PK/PD）关系 隐孢子虫病。我们对该提案的中心假设是，可以使用类似的方法来建立 抗菌药物暴露与体内志贺氏菌功效之间的关系。此外，我们相信我们的 模型可用于识别与耐药性出现相关的抗菌浓度。 根据我们的假设，我们将使用我们建立的志贺氏菌感染小鼠模型来表征 世界卫生组织推荐的志贺氏菌病抗菌治疗的体内疗效。此外，我们将使用创新的 中空纤维感染模型研究抗菌药物耐药性的出现。这一重要信息将 协助合理化当前治疗的给药方案，并将支持发现和开发 未来的治疗方法。我们建议通过以下方式评估抗菌药物的 PK/PD 关系 三个具体目标：(1) 确定抗菌药物的体内暴露-反应关系，以及 (2) 使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。 总而言之，这些研究将帮助我们更好地了解当前的志贺氏菌病治疗方法，并将 提供一系列方法来识别和优化新的治疗方法。此外，工作成果将 为传染病特别是肠道感染领域的药物发现提供基础支持。