Pharmacokinetic-Pharmacodynamics of Antimicrobials in Resistant Infections

描述(申请人提供)：多重耐药(MDR)细菌，即耐甲氧西林金黄色葡萄球菌(MRSA)和产超广谱β-内酰胺酶(ESBL)的肠杆菌科细菌，已成为日益严峻的治疗挑战。万古霉素和碳青霉烯类是这些耐多药细菌引起的严重感染的主要治疗策略。近二十年来，出现了对这些抗生素敏感性降低的病例，而且这些报告的频率在世界范围内继续增加，无论是在医院还是在门诊。尽管在筛查和检测方面取得了重大进展，但由于市面上销售的抗生素的剂量信息不够理想，以及新抗生素的供应不足，儿童患者的多药耐药感染的治疗方法受到了特别的挑战。分析用于多药耐药感染的抗生素的儿科药代动力学-药效学(PK-PD)图谱将优化剂量，从而最大化治疗效果并将毒副作用降至最低。这项以患者为导向的研究职业发展(K-23)建议的目的是培养候选人成为临床转化药物疗法(CTP)独立研究员所需的知识和能力，CTP是一个术语，包括候选人对进行基础生命科学研究的兴趣，该研究有可能改善由MDR细菌引起的严重感染的儿科患者的健康结果。候选人是加州大学圣地亚哥分校(UCSD)斯卡格斯药学和药学学院的药剂师教员，并居住在米勒儿童医院和长滩纪念医疗中心。在Victor Nizet博士(加州大学圣迭戈分校儿科教授和儿科药理与药物发现科主任)和Edmund Capparelli博士(加州大学圣迭戈分校临床药剂学教授和NICHD儿科药理研究部主任)的大力指导下，候选人将使用合作儿童医院之前和预期收集的样本进行PK-PD分析。这项为期5年的职业发展计划的优势在于，它结合了教学和实验室培训、负责任的研究、有指导的研究和专业网络。她将获得临床研究高级研究硕士学位。她的长期职业目标是促进MDR感染患者安全和适当地使用抗菌药物，并通过研究加强我们对MDR感染的了解和管理策略。全球范围内多药耐药(MDR)细菌之间新出现的耐药性已成为日益严峻的治疗挑战。伴随这一挑战的是儿童中存在的微小药理学数据以及具有新作用机制的新抗菌剂的有限可获得性。该项目的目标是检查用于MDR感染的抗生素的儿科药代动力学-药效学概况，以便优化给药，并传播这些临床适用的数据，因为它可能导致对儿童的新的给药建议。

DESCRIPTION (provided by applicant): Multidrug resistant (MDR) bacteria, namely methicillin-resistant Staphylococcus aureus (MRSA) and extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae, have become an increasing therapeutic challenge. Vancomycin and carbapenems are the primary treatment strategy for serious infections caused by these MDR bacteria. In the recent two decades, cases of reduced susceptibility to these antibiotics have emerged, and the frequency of these reports continues to increase worldwide, in both the hospital and outpatient settings. Despite significant advances in screening and detection, treatment approaches for MDR infections in pediatric patients are specifically challenged due to suboptimal dosing information for marketed antibiotics and the unavailability of new antibiotics. Analyzing the pediatric pharmacokinetic- pharmacodynamics (PK-PD) profile of antibiotics useful in MDR infections will optimize dosing, thereby maximizing therapeutic effects and minimizing toxicities. The purpose of this Mentored Patient-Oriented Research Career Development (K-23) proposal is to develop the knowledge and aptitude necessary for the candidate to become an independent researcher in clinical translational pharmacotherapy (CTP), a term encompassing the candidate's interest in conducting basic life sciences research that has the potential to improve health outcomes of pediatric patients with serious infections caused by MDR bacteria. The candidate is a pharmacist faculty member at the University of California, San Diego (UCSD) Skaggs School of Pharmacy and Pharmaceutical Sciences and in-residence at Miller Children's Hospital & Long Beach Memorial Medical Center. Under the robust mentorship of Dr. Victor Nizet (Professor of Pediatrics and Chief of the Division of Pediatric Pharmacology & Drug Discovery at UCSD) for support in overall career planning, and Dr. Edmund Capparelli (Clinical Professor of Pharmacy and Director of the NICHD Pediatric Pharmacology Research Unit at UCSD) for training in PK-PD modeling, the candidate will conduct PK-PD analyses using previously and prospectively collected samples within collaborating children's hospitals. The strength of this 5-year career development plan is that it incorporates didactic and laboratory training, responsible conduct of research, mentored research and professional networking. She will obtain a Masters of Advanced Studies in Clinical Research. Her long-term career goal is to promote safe and appropriate use of antimicrobial medications among patients with MDR infections, and through research, to enhance our understanding of, and management strategies for, MDR infections. The worldwide emerging resistance among multidrug resistant (MDR) bacteria has become an increasing therapeutic challenge. Coupled to this challenge is the minute pharmacologic data that exist in children and limited availability of new antimicrobial agents with novel mechanisms of action. This project's objectives are to examine the pediatric pharmacokinetic-pharmacodynamic profiles of antibiotics useful in MDR infections in order to optimize dosing, and to disseminate these clinically applicable data since it may lead to new dosing recommendations in children.