Impact of Daptomycin Dose Exposure on Enterococci and Characterization of Resista

达托霉素剂量暴露对肠球菌的影响和耐药性的表征

• 批准号: 8029807
• 负责人: Michael Joseph Rybak
• 金额: $ 19万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8029807
• 关键词: Accounting; Animals; Antibiotics; Area; Bacteremia; Bacterial Infections; Bacteriophages; Basic Science; Biological Preservation; Cell Membrane Proteins; Cell Wall; Cell membrane; Characteristics; Clinical; Clinical Sciences; Daptomycin; Data; Dose; Drug Kinetics; Drug resistance; Endocarditis; Enterococcus; FDA approved; Gene Cluster; Gene Expression; Genes; Genus staphylococcus; Goals; In Vitro; Infection; Knowledge; Lead; Linezolid; Membrane Potentials; Membrane Proteins; Minimum Inhibitory Concentration measurement; Modeling; Morbidity - disease rate; Multi-Drug Resistance; Mutation; Organism; Outcome; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phospholipids; Plasma; Predisposition; Protein C; Public Health; Reporting; Research; Resistance; Shock; Simulate; Staphylococcus aureus; Testing; Therapeutic; Time; Vancomycin Resistance; Vancomycin resistant enterococcus; Work; bactericide; fluidity; improved; in vitro Model; in vivo; infectious disease treatment; innovation; insight; killings; mortality; mutant; novel; pharmacodynamic model; pressure; prevent; resistance mechanism; resistant strain

DESCRIPTION (provided by applicant): Infections caused by vancomycin resistant Enterococcus (VRE) are associated with limited treatment options and increased mortality. Daptomycin, a novel lipopeptide antibiotic, has activity against VRE. The daptomycin dose for VRE to optimize patient outcomes and prevent the emergence of resistance, however, is currently unknown. The long-term goal is to optimize outcomes and preserve daptomycin therapy for VRE infections through utilization of the ideal dose exposure and determination of phenotypic and genotypic changes associated with daptomycin resistance in enterococci. The overall objective of this study is to define the dose exposure breakpoint (pharmacokinetic/pharmacodynamic [PK/PD] breakpoint) for daptomycin and the correlating dose and determine if known phenotypic and genotypic changes associated with daptomycin resistance in S. aureus are also found in enterococci. The central hypothesis is that higher daptomycin doses will provide greater bactericidal activity and prevent the emergence of resistance. Additionally, phenotypic and genetic changes found in daptomycin resistant enterococci maybe different than those found in S. aureus. The rationale behind the proposed research is that data on the daptomycin dose relationship with enterococci and insights into the mechanisms of resistance will lead to clinical dose optimization, improved patient outcomes, reduced emergence of resistance, and preservation of daptomycin as a viable antibiotic for clinical use. The central hypothesis will be tested by pursuing two Specific Aims: 1) Determine the dose exposure breakpoints for daptomycin resistance using molecularly defined and clinical strains of VRE to determine the optimal dose; and 2) Identify phenotypic and genetic changes associated with the cytoplasmic membrane and the cell wall of daptomycin resistant enterococci derived from in vitro PK/PD models. Under the first aim, a well established in vitro model of simulated endocardial vegetations (previously validated against an animal endocarditis model) will be used to determine the breakpoints (and corresponding doses) utilizing various clinical doses of daptomycin. The daptomycin resistant strains developed in this model with daptomycin exposure will then be examined for changes in the cell wall, cytoplasmic membrane, gene sequences and gene expression. The proposed research is innovative because we will utilize an in vitro PK/PD model, which both simulates drug pressure under clinical conditions and allows for frequent assessment of changes in the organism, to derive the daptomycin resistant mutants to be studied. The research proposed in this application is significant because it is expected to provide the knowledge needed to understand the resistance characteristics of enterococci and their relationship to daptomycin dose exposure that will lead to dose optimization and improved patient outcomes. Once such knowledge is available, improved patient outcomes and the preservation of daptomycin as a viable therapeutic option for the treatment of enterococcal infections will result. PUBLIC HEALTH RELEVANCE: Narrative Preservation of available antibiotics to treat multidrug resistant bacterial infections is vital to public health. Vancomycin resistant enterococcal infections are associated with increased mortality and treatment options are limited. The overall goal of this project is to determine the optimal dose of daptomycin for enterococcal infections and increase current knowledge of the mechanisms of resistance, which will allow better understanding and treatment of this infectious disease.

描述（由申请人提供）：由耐万古霉素肠球菌（VRE）引起的感染与有限的治疗选择和增加的死亡率相关。达托霉素是一种新型脂肽抗生素，具有抗 VRE 活性。然而，目前尚不清楚用于 VRE 的达托霉素剂量可优化患者预后并防止耐药性的出现。长期目标是通过利用理想剂量暴露和确定与肠球菌达托霉素耐药性相关的表型和基因型变化，优化结果并保留达托霉素治疗 VRE 感染的疗法。本研究的总体目标是确定达托霉素的剂量暴露断点（药代动力学/药效学 [PK/PD] 断点）和相关剂量，并确定与金黄色葡萄球菌达托霉素耐药性相关的已知表型和基因型变化是否也存在于金黄色葡萄球菌中。肠球菌。中心假设是较高的达托霉素剂量将提供更强的杀菌活性并防止耐药性的出现。此外，达托霉素耐药肠球菌中发现的表型和遗传变化可能与金黄色葡萄球菌中发现的不同。拟议研究背后的基本原理是，有关达托霉素与肠球菌剂量关系的数据以及对耐药机制的深入了解将导致临床剂量优化，改善患者结果，减少耐药性的出现，并保留达托霉素作为临床使用的可行抗生素。将通过追求两个具体目标来检验中心假设：1) 使用 VRE 的分子定义和临床菌株确定达托霉素耐药性的剂量暴露断点，以确定最佳剂量； 2) 鉴定与来自体外 PK/PD 模型的达托霉素耐药肠球菌的细胞质膜和细胞壁相关的表型和遗传变化。在第一个目标下，将使用一个完善的模拟心内膜赘生物体外模型（之前针对动物心内膜炎模型进行验证）来确定利用不同临床剂量的达托霉素的断点（和相应剂量）。然后将检查在接触达托霉素的该模型中开发的达托霉素抗性菌株的细胞壁、细胞质膜、基因序列和基因表达的变化。拟议的研究具有创新性，因为我们将利用体外 PK/PD 模型，该模型既可以模拟临床条件下的药物压力，又可以频繁评估生物体的变化，从而衍生出待研究的达托霉素耐药突变体。本申请中提出的研究意义重大，因为它有望提供了解肠球菌耐药特性及其与达托霉素剂量暴露之间关系所需的知识，从而实现剂量优化和改善患者预后。一旦掌握了这些知识，就会改善患者的治疗效果，并保留达托霉素作为治疗肠球菌感染的可行治疗选择。 公共卫生相关性：叙述 保留可用的抗生素来治疗多重耐药细菌感染对于公共卫生至关重要。万古霉素耐药肠球菌感染与死亡率增加相关，且治疗选择有限。该项目的总体目标是确定达托霉素治疗肠球菌感染的最佳剂量，并增加目前对耐药机制的了解，这将有助于更好地了解和治疗这种传染病。