Impact of daptomycin dose exposure on biofilm embedded Enterococci resistance

描述（由申请方提供）：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相关。由于万古霉素耐药屎肠球菌（VREF）引起的感染比任何其他肠球菌种属都更成问题，因为这些微生物与万古霉素耐药率最高相关，并且通常具有多重耐药性，由于可用的抗菌剂选择有限，治疗更加困难。MDI是最难治疗的感染之一，因为它与产生生物膜的病原体高度相关，这是有效抗生素治疗的重要障碍。达托霉素是一种新型脂肽类抗生素，可迅速穿透生物膜，对代谢活跃或停滞的肠球菌（包括VREF）发挥杀菌活性。然而，用于VRE以优化患者结局并防止MDI期间出现耐药性的达托霉素剂量目前尚不清楚。此外，几乎没有关于治疗VRE MDI的最佳达托霉素药物组合的信息。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，另一种是联合治疗。长期目标是优化患者结局，并通过利用理想剂量暴露来预防肠球菌中的达托霉素耐药性，保留VRE MDI感染的达托霉素治疗。本研究的总体目的是确定生物膜包埋VREF中达托霉素耐药性预防的剂量暴露断点（药代动力学/药效学[PK/PD]断点）以及达托霉素与其他抗菌剂联合给药时的相关断点。中心假设是，与使用非渗透性VREF的剂量暴露相比，需要更高的达托霉素单独或抗生素联合暴露来对抗生物膜包埋的VREF，以防止耐药性的出现。拟议研究背后的基本原理是，关于达托霉素与生物膜包埋肠球菌剂量关系的数据将导致临床剂量优化，改善患者结局，减少耐药性的出现，并保留达托霉素作为临床使用的可行抗生素。将通过追求两个特定目的来检验中心假设：1）使用生物膜包埋的分子定义和临床VREF菌株确定达托霉素耐药性的剂量暴露断点，以确定最佳剂量;和2）确定达托霉素与氨苄西林或利福平联合使用时预防VREF耐药性发生的最佳剂量暴露。拟议的研究是创新的，因为我们将利用体外生物膜PK/PD模型，模拟人体药物暴露。该技术允许频繁评估抗生素活性以及观察生物体敏感性的变化，因为它与特定药物暴露随时间的变化有关。本申请中提出的研究具有重要意义，因为预计将提供了解生物膜包埋肠球菌的耐药性特征及其与达托霉素剂量暴露的关系所需的知识，这将导致剂量优化，从而改善患者结局，并保留达托霉素作为治疗肠球菌MDI的可行治疗选择。

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.