A Pharmacologic Approach to Prevent Daptomycin Resistance in VRE

 描述（由申请方提供）：与万古霉素敏感菌株相比，万古霉素耐药屎肠球菌（VREfm）引起的感染受到有限治疗选择的困扰，并与死亡率增加相关。达托霉素（DAP）是一种脂肽抗生素，其活性取决于VREfm菌株最小抑制浓度（MIC）上的优化浓度曲线下面积（AUC），对VREfm具有强效活性。然而，在临床上会出现对DAP的耐药性，数据表明，必须使用高于目前批准的6 mg/kg/天剂量才能防止出现DAP耐药性。甚至升高的DAP剂量也可能不足以预防耐药性，因为在两种不同的调节基因系统（liaFSR和yycFG）中具有突变的VREfm证明了抵抗单独使用DAP治疗的能力。这些突变在具有较高“敏感”水平（3-4 µg/ml）DAP MIC的VREfm中很常见。因此，新的治疗方案，包括组合是必要的，值得研究。β-内酰胺类药物与DAP联合使用是值得关注的;因为有限的体外数据已证明β-内酰胺类药物能够增强DAP对VREfm的活性。我们研究的总体目的是确定单独使用DAP方案对抗VREfm的DAP剂量暴露断点（药代动力学/药效学[PK/PD]断点），已知遗传变化使其倾向于DAP耐药，然后评价β-内酰胺类药物对该断点产生积极影响的能力。这些数据将提供关于最佳DAP暴露（给药方案）与β-内酰胺类药物联合预防DAP耐药性并提供杀菌活性的重要信息。长期目标是优化VREfm感染患者的结局，并保留DAP作为对抗这些耐药病原体的可行药物，同时确定当DAP MIC升高时用于预防DAP耐药的最佳β-内酰胺组合。中心假设是β-内酰胺将通过降低VREfm DAP MIC来增加DAP AUC 0 -24/MIC比，从而提供更好的耐药性预防和杀菌活性。拟议研究背后的基本原理是，关于DAP与VREfm剂量关系以及β-内酰胺联合治疗对其影响的数据将为这些隐性感染患者提供最佳治疗方案。将通过追求三个具体目标来检验中心假设：1）确定AUC 24 h/MIC断点是否可在临床剂量下实现以克服体外PK/PD模型中具有DAP抗性倾向的VREfm中的DAP抗性，2）评价几种关键β-内酰胺以优化DAP AUC 24 h/MIC暴露并恢复体外PK/PD模型中针对具有DAP抗性倾向的VREfm的DAP活性，和3）在良好建立的动物心内膜炎模型中测试单独和与β-内酰胺组合的VRE-屎肠菌的体外衍生DAP AUC 24 h/MIC暴露，以验证这些参数。在前两个目标下，将使用成熟的模拟心内膜赘生物（SEV）体外模型（之前针对兔心内膜炎模型进行了验证），使用不同临床剂量的DAP和β-内酰胺确定折点（和相应的DAP剂量）。拟议的研究是创新的，因为我们将使用体外和体内PK/PD模型来确定针对VREfm的最佳β-内酰胺加DAP联合方案，这些方案尚未通过复杂的建模进行深入研究。该研究是重要的，因为它预计将提供完整的知识，以了解最佳的DAP给药策略和最好的β-内酰胺对VREfm的协同作用与DAP耐药性的倾向。一旦获得这些知识，改善患者结局并保留DAP作为治疗VREfm感染的可行治疗选择将是最终结果。

 DESCRIPTION (provided by applicant): Infections caused by vancomycin-resistant Enterococcus faecium (VREfm) are plagued by limited treatment options and are associated with increased mortality compared to vancomycin-susceptible strains. Daptomycin (DAP), a lipopeptide antibiotic with activity contingent upon an optimized area under the concentration curve (AUC) over the minimum inhibitory concentration (MIC) of the VREfm strain, possesses potent activity against VREfm. However, resistance to DAP occurs clinically, and data demonstrate that doses above the currently approved 6 mg/kg/day are necessary to prevent DAP resistance emergence. Even elevated DAP doses may not be sufficient to prevent resistance, as VREfm with mutations in two different regulatory gene systems (liaFSR and yycFG) demonstrate the ability to resist treatment with DAP alone. These mutations are frequent among VREfm with DAP MICs in the higher levels of "susceptible" (3-4 µg/ml). As such, novel therapeutic regimens involving combinations are necessary and warrant study. Beta-lactams are of interest in combination with DAP; as limited in vitro data have demonstrated the ability of beta-lactams to enhance DAP activity against VREfm. The overall objective of our study is to define the DAP dose exposure breakpoint (pharmacokinetic/pharmacodynamic [PK/PD] breakpoint) with DAP regimens alone against VREfm with known genetic changes giving them proclivity for DAP resistance and then evaluate the ability of beta-lactams to positively affect that breakpoint. These data will provide important information on the optimal DAP exposure (dosing regimens) in combination with beta-lactams to prevent DAP resistance and provide bactericidal activity. The long-term goal is to optimize VREfm infection patient outcomes and preserve DAP as a viable agent against these resistant pathogens while determining the optimal beta-lactam to use in combination for DAP resistance prevention when the DAP MIC is elevated. The central hypothesis is that beta-lactams will increase the DAP AUC0-24/MIC ratio by lowering the VREfm DAP MIC and thus provide improved resistance prevention and bactericidal activity. The rationale behind the proposed research is that data on the DAP dose relationship with VREfm and how it is affected by beta-lactam co-therapy will lead to optimal treatment regimens for patients with these insidious infections. The central hypothesis will be tested by pursuing three Specific Aims: 1) Determine if an AUC24h/MIC breakpoint is achievable at clinical dosages to overcome DAP resistance in VREfm with predisposition for DAP resistance in an in vitro PK/PD model, 2) Evaluate several key beta-lactams to optimize DAP AUC24h/MIC exposure and restore DAP activity against VREfm with predisposition for DAP resistance in an in vitro PK/PD model, and 3) test the in vitro derived DAP AUC24h/MIC exposures alone and in combination with a beta-lactam for VRE-faecium in a well-established animal endocarditis model to validate these parameters. Under the first two aims, a well-established in vitro model of simulated endocardial vegetations (SEVs) (previously validated against a rabbit endocarditis model) will be used to determine breakpoints (and corresponding DAP doses) using various clinical doses of DAP and beta-lactams. The proposed research is innovative because we will use both in vitro and in vivo PK/PD models to determine optimal beta-lactam plus DAP combination regimens against VREfm that have yet to be studied in-depth with complex modeling such as this. The research is significant because it is expected to provide knowledge integral to understanding optimal DAP dosing strategies and the best beta-lactam for synergy against VREfm with proclivity for DAP resistance. Once such knowledge is available, improved patient outcomes and the preservation of DAP as a viable therapeutic option in the treatment of VREfm infections will be the ultimate result.