Impact of daptomycin dose exposure on biofilm embedded Enterococci resistance

达托霉素剂量暴露对生物膜嵌入肠球菌耐药性的影响

• 批准号: 8620019
• 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: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8620019
• 关键词: Ampicillin; Anti-Bacterial Agents; Antibiotic Therapy; Antibiotics; Bacterial Infections; Biocompatible Materials; Biological Preservation; Catheters; Characteristics; Clinical; Combined Antibiotics; Combined Modality Therapy; Complex; Daptomycin; Data; Development; Dose; Drug Combinations; Drug Exposure; Drug Kinetics; Enterococcus; Enterococcus faecium; Exposure to; Future; Goals; Healthcare; Heart Valves; Hospitals; Human; In Vitro; Infection; Knowledge; Lead; Left; Life; Measures; Mechanics; Medical; Medical Device; Metabolic; Microbial Biofilms; Morbidity - disease rate; Multi-Drug Resistance; Nosocomial Infections; Organism; Outcome; Patient Care; Patients; Pharmaceutical Preparations; Pharmacodynamics; Predisposition; Prevention; Production; Public Health; Publishing; Research; Resistance; Rifampin; Secondary to; Simulate; Staphylococcus aureus; Surface; Techniques; Testing; Therapeutic; Time; Treatment Failure; Vancomycin Resistance; Vancomycin resistant enterococcus; Venous; Work; antimicrobial; bactericide; base; beta-Lactams; clinically relevant; improved; infectious disease treatment; innovation; microbial; mortality; mutant; novel; pathogen; pharmacodynamic model; prevent; public health relevance; simulation; urinary; ventricular assist device

Summary Medical device infections (MDI) caused by vancomycin resistant Enterococcus (VRE) are associated with a high rate of treatment failure and increased mortality. Infections due to vancomycin-resistant Enterococcus faecium (VREF) are more problematic than any other species of enterococci since these organisms are associated with the highest rate of vancomycin resistance and are often multi-drug resistant making treatment more difficult due to the limited available antimicrobial options. MDI are one of the most difficult infections to treat because of the high association with biofilm producing pathogens, which represents a significant barrier for effective antibiotic therapy. Daptomycin, a novel lipopeptide antibiotic, rapidly penetrates biofilms and exerts bactericidal activity against metabolically active or arrested enterococci, including VREF. The daptomycin dose for VRE to optimize patient outcomes and prevent the emergence of resistance during MDI, however, is currently unknown. In addition, there is little to no information regarding the optimal daptomycin drug combination to treat VRE MDI. Therefore, there are two potential strategies to optimize daptomycin therapy for VRE MDI. One is daptomycin dose optimization and the other strategy is the use of combination therapy. The long-term goal is to optimize patient outcomes and preserve daptomycin therapy for VRE MDI infections through utilization of the ideal dose exposure to prevent daptomycin resistance in enterococci. The overall objective for this study is to define the dose-exposure breakpoint (pharmacokinetic/pharmacodynamic [PK/PD] breakpoint) for daptomycin resistance prevention in biofilm embedded VREF and the correlating breakpoint when daptomycin is combined with other antimicrobials. The central hypothesis is that higher daptomycin dose exposures alone or in antibiotic combination are needed against biofilm embedded VREF to prevent the emergence of resistance compared to dose exposures using planktonic VREF. The rationale behind the proposed research is that data on the daptomycin dose relationship with biofilm embedded enterococci 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 biofilm embedded molecularly defined and clinical strains of VREF to determine the optimal dose; and 2) Identify the optimal dose-exposure of daptomycin in combination with ampicillin or rifampin that is associated with the prevention of the development of VREF resistance. The proposed research is innovative because we will utilize an in vitro biofilm PK/PD model that simulates drug exposures in humans. This technique allows for frequent assessment of antibiotic activity as well as observation of changes in the organism susceptibility as it relates to specific drug exposures over time. The research proposed in this application is significant because it is expected to provide the knowledge needed to understand the resistance characteristics of biofilm embedded enterococci and their relationship to daptomycin dose exposure that will lead to dose optimization resulting in improved patient outcomes, and preservation of daptomycin as a viable therapeutic option for the treatment of enterococcal MDI.

概括 由万古霉素耐药肠球菌 (VRE) 引起的医疗器械感染 (MDI) 与 治疗失败率高，死亡率增加。耐万古霉素肠球菌引起的感染 屎肠球菌 (VREF) 比任何其他肠球菌种类都更成问题，因为这些生物体 与最高的万古霉素耐药率相关，并且通常具有多重耐药性 由于可用的抗菌药物选择有限，因此变得更加困难。 MDI 是最难治愈的感染之一 治疗，因为与产生生物膜的病原体高度相关，这是一个重要的障碍 以获得有效的抗生素治疗。达托霉素是一种新型脂肽抗生素，可快速渗透生物膜并 对代谢活跃或停滞的肠球菌（包括 VREF）发挥杀菌活性。这 用于 VRE 的达托霉素剂量可优化患者预后并防止 MDI 期间出现耐药性， 但目前尚不清楚。此外，关于最佳达托霉素的信息很少甚至没有。 治疗 VRE MDI 的药物组合。因此，有两种潜在的策略来优化达托霉素 VRE MDI 治疗。一种是达托霉素剂量优化，另一种策略是联合使用 治疗。长期目标是优化患者治疗效果并保留达托霉素治疗 VRE MDI 通过利用理想的剂量暴露来预防肠球菌对达托霉素的耐药性。这 本研究的总体目标是确定剂量暴露断点（药代动力学/药效学 [PK/PD] 断点）用于预防生物膜嵌入 VREF 中的达托霉素耐药性及其相关性 达托霉素与其他抗菌药物联合使用时出现断点。中心假设是更高 针对嵌入生物膜的 VREF，需要单独或联合使用达托霉素剂量暴露 与使用浮游 VREF 的剂量暴露相比，可以防止耐药性的出现。理由 拟议研究的背后是有关达托霉素剂量与嵌入的生物膜之间关系的数据 肠球菌将导致临床剂量优化、改善患者治疗结果、减少肠球菌的出现 耐药性，并保留达托霉素作为临床使用的可行抗生素。中心假设将是 通过追求两个具体目标进行测试：1) 确定达托霉素耐药性的剂量暴露断点 使用嵌入生物膜的分子定义和临床 VREF 菌株来确定最佳剂量；和 2) 确定达托霉素与氨苄西林或利福平联合用药的最佳暴露剂量 防止 VREF 电阻的发展。拟议的研究具有创新性，因为我们 将利用体外生物膜 PK/PD 模型来模拟人体药物暴露。该技术允许 经常评估抗生素活性并观察生物体敏感性的变化 与特定药物随时间的暴露有关。本申请中提出的研究意义重大，因为它 预计将提供了解嵌入生物膜的耐药特性所需的知识 肠球菌及其与达托霉素剂量暴露的关系将导致剂量优化 改善患者的治疗效果，并保留达托霉素作为治疗以下疾病的可行治疗选择 肠球菌 MDI。