A Pharmacologic Approach to Prevent Daptomycin Resistance in VRE

预防 VRE 达托霉素耐药的药理学方法

• 批准号: 9193057
• 负责人: Michael Joseph Rybak
• 金额: $ 38.5万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-10 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9193057
• 关键词: Achievement; Adverse effects; Advocate; Affect; Ampicillin; Animals; Antibiotics; Area; Bacteremia; Bacteria; Binding; Biological Preservation; Calcium; Cell Membrane Alteration; Cell Wall; Cell division; Cell membrane; Cell surface; Charge; Clinical; Clinical Data; Combined Modality Therapy; Complex; Daptomycin; Data; Dose; Drug Costs; Drug Kinetics; Drug resistance; Endocarditis; Enterococcus; Enterococcus faecalis; Enterococcus faecium; Exhibits; Future; Genes; Genetic; Genetic Predisposition to Disease; Genetic study; Goals; Homeostasis; Hospitals; In Vitro; Infection; Knowledge; Laboratories; Life; Mediating; Minimum Inhibitory Concentration measurement; Modeling; Mutation; Oryctolagus cuniculus; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phospholipid Metabolism; Predisposition; Prevention; Publishing; Regimen; Regulator Genes; Reporting; Research; Research Proposals; Resistance; Resistance development; Staphylococcus aureus; Surface; System; Testing; Therapeutic; Thick; Time; Treatment Protocols; Vancomycin; Vancomycin resistant enterococcus; Work; bactericide; base; beta-Lactams; biological adaptation to stress; cell envelope; dosage; improved; in vitro Model; in vitro testing; in vivo; innovation; interest; mortality; multi-drug resistant pathogen; novel therapeutics; pathogen; pharmacodynamic model; prevent; public health relevance; response; success; synergism

 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.

 描述（由申请人提供）：由耐万古霉素屎肠球菌（VREfm）引起的感染受到有限的治疗选择的困扰，并且与万古霉素敏感菌株（DAP）相比，其死亡率增加，达托霉素是一种脂肽抗生素，其活性取决于其活性。 VREfm 菌株的浓度曲线下面积 (AUC) 超过最低抑制浓度 (MIC)，具有有效的抗病毒活性然而，临床上出现了对 DAP 的耐药性，数据表明，超过目前批准的 6 毫克/公斤/天的剂量对于预防 DAP 耐药性的出现是必要的，因为 VREfm 存在突变，因此即使提高 DAP 剂量也可能不足以预防耐药性。两种不同的调控基因系统（liaFSR 和 yycFG）表现出抵抗单独使用 DAP 治疗的能力。这些突变在 DAP MIC 处于较高“易感”水平的 VREfm 中很常见（3-4）。因此，涉及组合的新治疗方案是必要的，并且需要对 β-内酰胺与 DAP 的组合进行研究；因为有限的体外数据已证明 β-内酰胺能够增强 DAP 对抗 VREfm 的活性。我们研究的总体目标是确定 DAP 剂量暴露断点（药代动力学/药效 [PK/PD] 断点），仅使用 DAP 方案对抗 VREfm，已知基因变化使他们倾向于DAP 耐药性，然后评估 β-内酰胺对该断点产生积极影响的能力。这些数据将提供有关与 β-内酰胺结合使用的最佳 DAP 暴露（给药方案）的重要信息，以防止 DAP 耐药性并提供杀菌活性。优化 VREfm 感染患者的治疗效果，并保留 DAP 作为抵抗这些耐药病原体的可行药物，同时确定当 DAP MIC 升高时组合用于预防 DAP 耐药的最佳 β-内酰胺。中心假设是，β-内酰胺将通过降低 VREfm DAP MIC 来增加 DAP AUC0-24/MIC 比率，从而改善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 剂量与 VREfm 和 VREfm 之间关系的数据。 β-内酰胺联合治疗对它的影响将如何为患有这些隐匿感染的患者提供最佳的治疗方案，将通过追求三个具体目标来检验中心假设：1)。确定临床剂量是否可以实现 AUC24h/MIC 断点，以克服 VREfm 中的 DAP 耐药性，并在体外 PK/PD 模型中具有 DAP 耐药性，2) 评估几种关键的 β-内酰胺，以优化 DAP AUC24h/MIC 暴露并恢复 DAP在体外 PK/PD 模型中针对具有 DAP 耐药倾向的 VREfm 活性，以及​​ 3) 测试体外衍生的 DAP在完善的动物心内膜炎模型中单独使用 AUC24h/MIC 暴露以及与 β-内酰胺联合用于 VRE-faecium，以验证这些参数。在前两个目标下，建立了完善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）将用于使用各种临床剂量的 DAP 和 β-内酰胺来确定断点（以及相应的 DAP 剂量）。拟议的研究具有创新性，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 组合方案，该方案尚未通过此类复杂模型进行深入研究。提供完整的知识，以了解最佳 DAP 剂量策略和最佳 β-内酰胺，以协同对抗具有 DAP 耐药倾向的 VREfm。 VREfm 感染将是最终结果。