Impact of daptomycin dose exposure on biofilm embedded Enterococci resistance

描述(由申请人提供)：由万古霉素耐药肠球菌(VRE)引起的医疗器械感染(MDI)与高治疗失败率和增加死亡率有关。由万古霉素耐药屎肠球菌(VREF)引起的感染比任何其他种类的肠球菌更具问题，因为这些细菌与万古霉素耐药率最高有关，而且往往是多药耐药，由于可用的抗菌药选择有限，使得治疗更加困难。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抗生素，能迅速渗透生物膜，对包括Vref在内的代谢活跃或抑制的肠球菌具有杀菌活性。然而，目前尚不清楚VRE用于优化患者预后和防止MDI期间耐药出现的达托霉素剂量。此外，关于治疗VRE MDI的达托霉素最佳药物组合的信息很少，甚至没有。因此，有两种可能的策略来优化达托霉素对VRE MDI的治疗。一种是达托霉素的剂量优化，另一种是使用联合治疗。长期目标是通过利用理想的剂量暴露来预防肠球菌对达托霉素的耐药性，从而优化患者的预后并保留达托霉素治疗VRE MDI感染的方法。本研究的总体目标是确定生物膜包埋Vref中预防达托霉素耐药的剂量-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药联合使用时的相关断点。中心假设是，与使用浮游生物Vref的剂量暴露相比，针对生物膜嵌入的Vref需要更高剂量的达托霉素单独或与抗生素联合暴露，以防止耐药性的出现。这项拟议研究背后的理论基础是，关于达托霉素与生物膜嵌入肠球菌的剂量关系的数据将导致临床剂量优化，改善患者预后，减少耐药性的出现，并将达托霉素保留为临床上可行的抗生素。中心假设将通过追求两个具体目标来检验：1)使用嵌入分子定义的Vref临床菌株的生物膜来确定达托霉素耐药的剂量暴露断点，以确定最佳剂量；2)确定与预防Vref耐药有关的达托霉素与氨苄西林或利福平联合使用的最佳剂量暴露。这项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。这项技术允许经常评估抗生素活性，并观察随着时间的推移与特定药物暴露有关的有机体敏感性的变化。在本申请中提出的研究具有重要意义，因为它有望提供必要的知识，以了解生物被膜嵌入型肠球菌的耐药性特征及其与达托霉素剂量暴露的关系，从而导致剂量优化，从而改善患者的预后，并保留达托霉素作为治疗肠球菌MDI的可行治疗方案。

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.