Pharmacokinetic-Pharmacodynamics of Antimicrobials in Resistant Infections

描述（由申请人提供）：耐多药（MDR）细菌，即耐甲氧西林金黄色葡萄球菌（MRSA）和广谱β -内酰胺酶（ESBL）产生肠杆菌科，已经成为越来越大的治疗挑战。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。在最近二十年中，出现了对这些抗生素敏感性降低的病例，并且在世界范围内，在医院和门诊环境中，这些报告的频率继续增加。尽管在筛查和检测方面取得了重大进展，但由于市场上抗生素的剂量信息不理想以及新抗生素的不可获得，儿科患者耐多药感染的治疗方法尤其受到挑战。分析耐多药耐多药感染抗生素的儿科药代动力学-药效学（PK-PD）概况将优化剂量，从而最大化治疗效果并最小化毒性。这项以患者为导向的指导研究职业发展（K-23）提案的目的是培养候选人成为临床转化药物治疗（CTP）领域独立研究人员所需的知识和能力，CTP是一个涵盖候选人对进行基础生命科学研究的兴趣的术语，该研究有可能改善由耐多药细菌引起的严重感染的儿科患者的健康结果。该候选人是加州大学圣地亚哥分校（UCSD）斯卡格斯药学和药物科学学院的药剂师教员，并在米勒儿童医院和长滩纪念医疗中心实习。在Victor Nizet博士（儿科教授，UCSD儿科药理学和药物发现部门主任）的大力指导下，支持整体职业规划，以及Edmund Capparelli博士（临床药学教授，UCSD NICHD儿科药理学研究部门主任）的PK-PD建模培训下，候选人将使用以前和未来在合作儿童医院收集的样本进行PK-PD分析。这个5年职业发展计划的优势在于它包含了教学和实验室培训、负责任的研究行为、指导研究和专业网络。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耐多药感染患者安全、适当地使用抗菌药物，并通过研究提高我们对耐多药感染的理解和管理策略。世界范围内出现的耐多药细菌（MDR）耐药性已成为日益严峻的治疗挑战。与这一挑战相结合的是，儿童中存在的药理学数据很少，而且具有新的作用机制的新型抗菌药物的可用性有限。该项目的目的是检查耐多药感染抗生素的儿科药代动力学-药效学概况，以优化剂量，并传播这些临床应用数据，因为它可能导致儿童的新剂量建议。

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.