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

基本信息

批准号：
8898002
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
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8898002
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 Health 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 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 multi-drug resistant pathogen mutant novel pathogen pharmacodynamic model prevent simulation urinary ventricular assist device

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：耐万古霉素肠球菌（VRE）引起的医疗器械感染（MDI）与高治疗失败率高和死亡率增加有关。由于这些生物体与万古霉素耐药性的最高速率相关，因此由于万古霉素抗性肠球菌（VREF）引起的感染比任何其他物种都更加问题，并且由于有限的可用可用抗菌抗菌抗菌抗菌抗药性，因此通常会耐多药的耐药性使治疗更加困难。由于与生物膜产生病原体的关联很高，MDI是治疗最困难的感染之一，这代表了有效的抗生素治疗的重要障碍。 Daptomycin是一种新型的脂肪肽抗生素，迅速穿透生物膜并施加杀菌活性，以针对包括VREF在内的代谢活性或捕获的肠球菌。目前尚不清楚VRO霉素的DAPTomycin剂量，以优化患者的结局并防止MDI期间的抗药性出现。此外，几乎没有关于最佳Daptomycin药物组合来治疗VRE MDI的信息。因此，有两种潜在的策略来优化Daptomycin治疗用于VRE MDI。一种是daptomycin剂量优化，另一种策略是使用联合疗法。长期的目标是通过利用理想剂量暴露以防止肠球菌中的daptomycin耐药性来优化患者的结局并保留Daptomycin治疗，以通过利用理想的剂量暴露于MDI感染。这项研究的总体目的是定义剂量暴露断裂点（药代动力学/药效动力学[PK/PD]断点），以预防嵌入生物膜的VREF中的daptomycin耐药性，并且当Daptomycin与其他抗菌剂合并时，相关的断点。中心假设是，与使用浮游板的剂量暴露相比，与嵌入的生物膜嵌入的VREF相比，需要较高的daptomycin剂量暴露或抗生素组合中的抗生素组合，以防止耐药的出现。拟议的研究背后的理由是，关于Daptomycin剂量关系与生物膜嵌入的肠球菌的数据将导致临床剂量优化，改善患者结果，降低的耐药性以及Daptomycin作为临床使用的可行抗生素。中央假设将通过追求两个具体目的来检验：1）使用嵌入的生物膜分子定义的生物膜抗性剂量的剂量暴露断裂点和VREF的临床菌株确定最佳剂量； 2）确定与预防VREF耐药性发育有关的氨苄青霉素与氨苄青霉素或利福平结合使用的最佳剂量暴露。拟议的研究具有创新性，因为我们将利用一种模拟人类药物暴露的体外生物膜PK/PD模型。该技术允许对抗生素活性进行频繁评估，并观察到与特定药物暴露有关的有机体易感性变化。该应用中提出的研究很重要，因为它有望提供所需的知识，以了解生物膜嵌入的肠球菌的抗性特征及其与Daptomycin剂量暴露的关系，这将导致剂量优化，从而改善患者的结果，并保留Daptomycin作为可行的肠球菌治疗肠球菌的可行治疗选择。