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）引起的医疗装置感染（MDI）与 高治疗失败率和死亡率增加。由于抗性霉素肠球菌引起的感染 粪便（VREF）比其他任何种类的肠球菌更有问题，因为这些生物是 与万古霉素耐药性的最高速度相关，并且通常是多药的耐药性治疗 由于可用的抗菌选择有限，因此更加困难。 MDI是最困难的感染之一 由于与生物膜产生病原体的相关性很高，因此治疗代表了重要的障碍 用于有效的抗生素疗法。 Daptomycin是一种新型的脂蛋白抗生素，迅速穿透生物膜和 针对包括VREF在内的代谢活性或停滞的肠球菌发挥杀菌活性。这 daptomycin剂量为VRE，以优化患者预后并防止MDI期间的抗药性出现 但是，目前未知。另外，关于最佳Daptomycin的信息很少 药物组合以治疗VRE MDI。因此，有两种优化daptomycin的潜在策略 VRE MDI的治疗。一种是daptomycin剂量优化，另一个策略是使用组合 治疗。长期目标是优化患者的预后并保留Daptomycin疗法的VRE MDI 通过利用理想剂量暴露以防止肠球菌耐药性的感染。这 这项研究的总体目标是定义剂量暴露断裂点（药代动力学/药效学 [PK/PD]断点）用于预防生物膜嵌入VREF和相关性的Daptomycin耐药性 当daptomycin与其他抗菌素结合时，断点。中心假设是更高 daptomycin剂量单独暴露或抗生素组合需要嵌入生物膜的VREF到 与使用浮游生物VREF接触剂量相比，防止抗药性的出现。理由 拟议的研究背后是关于二霉素剂量关系与生物膜嵌入的数据的数据 肠球菌将导致临床剂量优化，改善患者结局，减少的出现 耐药性并保存DAPTOMYCIN作为临床用途的可行抗生素。中心假设将是 通过追求两个具体目的测试：1）确定Daptomycin抗性的剂量暴露断裂点 使用生物膜嵌入的分子定义和VREF的临床菌株来确定最佳剂量；和2） 确定daptomycin与氨苄青霉素或利福平相关的最佳剂量暴露 随着预防VREF抵抗的发展。拟议的研究具有创新性，因为我们 将利用模拟人类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生物体敏感性的变化 随着时间的流逝，特定的药物暴露有关。在本应用程序中提出的研究很重要，因为它 预计将提供了解嵌入生物膜的抗性特征所需的知识 肠球菌及其与Daptomycin剂量暴露的关系，这将导致优化剂量，从而导致 改善了患者的结局，并保存daptomycin作为治疗的可行治疗选择 肠球菌MDI。