Impact of daptomycin dose exposure on biofilm embedded Enterococci resistance

摘要 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，死亡率高。万古霉素耐药肠球菌致感染 粪肠球菌(Vref)比任何其他种类的肠球菌都更有问题，因为这些微生物 与万古霉素耐药率最高有关，并经常进行多药耐药治疗 由于现有的抗菌剂选择有限，因此更加困难。MDI是最难感染的疾病之一 治疗是因为与生物被膜产生的病原体高度相关，这是一个重要的障碍 进行有效的抗生素治疗。达托霉素是一种新型脂肽抗生素，可迅速渗透到生物膜和 对新陈代谢活跃或抑制的肠球菌，包括Vref，具有杀菌活性。这个 达托霉素剂量用于VRE以优化患者预后并防止MDI期间耐药的出现， 然而，目前还不清楚。此外，很少或根本没有关于最佳达托霉素的信息。 治疗VRE MDI的药物组合。因此，有两种可能的策略来优化达托霉素 VRE MDI的治疗。一种是达托霉素剂量优化，另一种是联合用药 心理治疗。长期目标是优化患者预后，并保留达托霉素治疗VRE MDI 通过利用理想剂量暴露预防肠球菌对达托霉素耐药感染。这个 这项研究的总体目标是定义剂量-暴露断点(药代动力学/药效学 Vref生物膜预防达托霉素耐药的[pk/pd]断点及其相关性 达托霉素与其他抗菌药联合使用时的断点。中心假设是更高的 需要单独或与抗生素联合应用达托霉素剂量，以对抗生物膜嵌入的Vref 与使用浮游生物VREF的剂量暴露相比，防止耐药性的出现。其基本原理是 这项拟议的研究背后是关于达托霉素与生物被膜之间剂量关系的数据 肠球菌将导致临床剂量优化，改善患者预后，减少出现 达托霉素作为临床使用的可行抗生素的耐药性和保存性。中心假设将是 通过追求两个特定目标进行测试：1)确定达托霉素耐药的剂量-暴露临界点 使用嵌入分子定义的Vref和临床菌株的生物膜来确定最佳剂量； 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 随着VREF抵抗的发展而发展。这项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。这项技术允许 经常评估抗生素的活性，并观察机体对抗生素敏感性的变化 与随时间推移的特定药物暴露有关。在本申请中提出的研究具有重要意义，因为它 可望提供所需的知识，以了解嵌入的生物膜的阻力特性 肠球菌及其与达托霉素剂量暴露的关系将导致剂量优化 改善患者预后，并保留达托霉素作为一种可行的治疗选择 肠球菌MDI。

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.