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

评估新型体外和体内模型以表征抗志贺氏菌治疗 PK/PD 关系

• 批准号: 10436402
• 负责人: Samuel L Arnold
• 金额: $ 44.32万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-23 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10436402
• 关键词: Acute; Animal Experiments; Anti-Bacterial Agents; Area; Bacteria; Cells; Cessation of life; Chemicals; Child; Clinic; Clinical; Clinical Data; Clinical Microbiology; Coculture Techniques; Communicable Diseases; Communities; Complex; Cryptosporidiosis; Cryptosporidium; Data; Development; Diarrhea; Dose; Dose Fractionation; Drug Combinations; Drug Exposure; Drug Kinetics; Drug resistance; Dysentery; Enteral; Evaluation; Foundations; Gastrointestinal Agents; Gastrointestinal tract structure; Goals; Gold; Human; In Vitro; Infection; Kinetics; Lead; Methodology; Methods; Modeling; Multicenter Studies; Mus; Outcome; Pathogenesis; Pharmaceutical Preparations; Pharmacodynamics; Physiology; Plasma; Population Attributable Risks; Prevalence; Process; Property; Protocols documentation; Publishing; Randomized Controlled Trials; Reporting; Research; Resistance; Series; Shigella; Shigella Infections; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Symptoms; Therapeutic; Time; Work; animal efficacy; bactericide; base; burden of illness; cell type; clinical efficacy; cohesion; design; drug development; drug discovery; enteric infection; enteric pathogen; extracellular; gastrointestinal; improved; in vitro Assay; in vitro Model; in vivo; in vivo Model; innovation; low and middle-income countries; men; novel; novel therapeutics; pathogen; pharmacodynamic model; pharmacokinetic model; pre-clinical; resistant strain; sex; spatiotemporal; standard care

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.

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 164,000 例腹泻死亡归因于志贺氏菌（占总数的 12.5%） 腹泻死亡），对中低收入国家（LMIC）造成不成比例的影响。对中低收入国家的影响是 最近对全球肠道多中心研究 (GEMS) 的重新分析表明，志贺氏菌已 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 (MSM) 社区中的志贺氏菌病例证实，其影响不仅限于 中低收入国家。展望未来，志贺氏菌病新疗法的开发还存在重大差距。长期来看 拟议工作的目标是建立一个严格的临床前框架，可用于确定 重新利用治疗志贺氏菌病的机会或新的化学实体。 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抗隐孢子虫功效的重要性。药代动力学/ 通过体外和体内表征抗隐孢子虫药物的药效（PK/PD）关系 隐孢子虫病的体内模型。我们对该提案的中心假设是，体外的类似方法 体内模型可用于建立药物暴露与体内疗效之间的关系 志贺氏菌病治疗。然而，虽然目前尚无治疗隐孢子虫病的“金标准” 在人类中，有一系列已批准的抗菌药物对人类志贺氏菌病具有不同的临床疗效。 为了实现我们的假设，我们已经开始开发志贺氏菌感染的体外和体内模型 它可用于表征抗志贺氏菌疗法的功效。令人兴奋的初步数据来自 这些模型表明它们可用于识别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功效在不同人群中有所不同。 诊所。我们建议通过以下三项来评估抗菌药物的 PK/PD 关系 具体目标： (1) 通过一组体外模型来表征抗菌药物的抗志贺氏菌功效。 (2) 研究抗菌药物治疗志贺氏菌病的体内疗效和药代动力学。 (3) 识别 抗菌体外功效、药代动力学和体内功效之间的关联。 总而言之，这些研究将帮助我们更好地了解志贺氏菌病的当前治疗方法和 将提供一系列方法来确定新的治疗方案。此外，工作结果将提供 为传染病药物发现提供基本支持，特别是在肠道感染领域。