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.

总结 由万古霉素耐药肠球菌（VRE）引起的医疗器械感染（MDI）与 治疗失败率高和死亡率增加。万古霉素耐药肠球菌感染 屎肠球菌（VREF）比任何其他肠球菌物种都更有问题，因为这些生物体 与万古霉素耐药率最高相关，并且通常是多药耐药， 由于可用的抗菌剂选择有限，因此更加困难。MDI是最难治疗的感染之一。 治疗，因为与生物膜产生病原体的高度关联，这代表了一个重要的障碍 有效的抗生素治疗。达托霉素是一种新型脂肽类抗生素，能迅速穿透生物膜， 对代谢活跃或停滞的肠球菌（包括VREF）发挥杀菌活性。的 VRE的达托霉素剂量，以优化患者结局并防止MDI期间出现耐药性， 但目前尚不清楚。此外，几乎没有关于最佳达托霉素的信息 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 治疗VRE MDI。一种是达托霉素剂量优化，另一种是联合用药 疗法长期目标是优化患者结局并保留VRE MDI的达托霉素治疗 通过使用理想剂量暴露预防肠球菌的达托霉素耐药性，的 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）用于生物膜包埋的VREF中的达托霉素耐药性预防以及相关的 当达托霉素与其他抗菌剂组合时，核心假设是， 需要单独或与抗生素组合的达托霉素剂量暴露来对抗生物膜包埋的VREF， 与使用双稳态VREF的剂量暴露相比，可防止电阻的出现。的理由 在拟议的研究背后， 肠球菌将导致临床剂量优化，改善患者结局，减少 耐药性和保存达托霉素作为临床应用的可行抗生素。核心假设是 通过追求两个特定目的进行测试：1）确定达托霉素耐药性的剂量暴露折点 使用生物膜包埋的VREF的分子定义和临床菌株来确定最佳剂量;以及2） 确定达托霉素与氨苄西林或利福平联合用药的最佳剂量暴露， 防止VREF电阻的发展。这项研究是创新的，因为我们 将利用模拟人体药物暴露的体外生物膜PK/PD模型。该技术允许 经常评估抗生素活性以及观察微生物敏感性的变化， 与特定的药物暴露有关本申请中提出的研究具有重要意义，因为它 预计将提供所需的知识，以了解生物膜嵌入的阻力特性 肠球菌及其与达托霉素剂量暴露的关系，这将导致剂量优化， 改善患者预后，并保留达托霉素作为治疗 肠球菌MDI。