Pharmacokinetic-Pharmacodynamics of Antimicrobials in Resistant Infections

描述（由申请人提供）：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）肠杆菌科，已成为日益增加的治疗挑战。万古霉素和碳青霉烯类是这些MDR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，并且在医院和门诊环境中，这些报告的频率在全球范围内继续增加。尽管在筛查和检测方面取得了重大进展，但由于市售抗生素的剂量信息不佳以及新抗生素的不可用，儿科患者MDR感染的治疗方法受到了特别的挑战。分析可用于MDR感染的抗生素的儿科药代动力学-药效学（PK-PD）特征将优化给药，从而最大化治疗效果并最小化毒性。该指导以患者为导向的研究职业发展（K-23）提案的目的是培养候选人成为临床转化药物治疗（CTP）独立研究员所需的知识和能力，该术语涵盖候选人对进行基础生命科学研究的兴趣，该研究有可能改善患有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居住。在维克托·尼泽特博士的大力指导下（儿科学教授和儿科药理学和药物发现在加州大学圣地亚哥分校的部门主任）的支持，在整体职业规划，和博士埃德蒙卡帕雷利（药学临床教授和加州大学圣地亚哥分校NICHD儿科药理学研究中心主任）进行PK-PD建模培训，候选人将使用合作儿童医院内以前和前瞻性收集的样本进行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MDR感染患者安全和适当使用抗菌药物，并通过研究，提高我们对MDR感染的理解和管理策略。世界范围内出现的多药耐药（MDR）细菌的耐药性已成为日益增长的治疗挑战。与这一挑战相结合的是存在于儿童中的微小药理学数据和具有新作用机制的新抗菌药物的有限可用性。该项目的目的是研究用于MDR感染的抗生素的儿科药代动力学-药效学特征，以优化剂量，并传播这些临床适用的数据，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.