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（由适用提供）：由抗性霉素粪肠球菌（VREFM）引起的感染受到有限治疗方案的困扰，与可触及万古霉素敏感的菌株相比，死亡率增加有关。 Daptomycin（DAP），一种脂蛋白抗生素，其活性在VREFM菌株的最小抑制浓度（MIC）上具有优化区域的活性，具有对VREFM的潜在活性。但是，对DAP的耐药性在临床上发生，数据表明，对于防止DAP抗性出现的出现是必要的，目前必须高于当前批准的6 mg/kg/天的剂量。即使升高的DAP剂量也可能不足以防止耐药性，因为在两个不同的调节基因系统（LIAFSR和YYCFG）中具有突变的VREFM证明了单独使用DAP治疗的能力。这些突变经常在VREFM中具有DAP MIC的较高水平（3-4 µg/ml）。因此，必须进行新的涉及组合的治疗方案和保证研究。 β-内酰胺与DAP相结合。由于有限的体外数据证明了β-内酰胺可以增强对VREFM的DAP活性的能力。我们研究的总体目的是使用仅针对VREFM的DAP方案来定义DAP剂量暴露断点（药代动力学/药物动力学[PK/PD]断点），并具有已知的遗传变化，从而使它们具有DAP耐药性，然后评估Beta-Lactams的能力，从而对该突破点进行了积极影响。这些数据将提供有关最佳DAP暴露（剂量方案）与β-内酰胺的重要信息，以防止DAP耐药性并提供杀菌活性。长期目标是优化VREFM感染患者的结果，并将DAP作为对这些抗性病原体的可行药物，同时确定在DAP MIC升高时用于预防DAP抗性的最佳β-内酰胺。中心假设是，β-内酰胺可以通过降低VREFM DAP MIC来增加DAP AUC0-24/MIC的比率，从而提供改善的预防耐药性和杀菌活性。拟议的研究背后的理由是，有关DAP剂量关系与VREFM的数据及其如何受到β-LACTAM共治疗的影响将导致这些阴险感染患者的最佳治疗方案。中心假设将通过追求三个具体目的来测试：1）确定在临床剂量时可以实现AUC24H/MIC的断点，以克服VREFM中的DAP耐DIP耐DAP，易于耐DAP在体外PK/PD模型中抗DAP，2）与DAP ACTA-LADACT ACTIS AUC24H-LACT ACTOSITION一起进行，并启用了DAP AUC24H-HIC24H-lim MIC的活动。在体外PK/PD模型中的DAP耐药性，3）单独测试体外衍生的DAP AUC24H/MIC暴露，并与β-内酰胺与β-内酰胺合并为VRE-FAECIUM，以验证这些参数验证这些参数。在前两个目标下，将使用各种临床剂量的DAP和Beta-lactams来确定断点（和相应的DAP剂量）的实现的模拟心内膜植被（SEV）（SEV）（SEV）（SEV）（SEV）（SEVS）（SEVS）（SEVS（SEV）（SEVS（SEVS））的体外模型，使用良好的体外模型将在前两个目标中，使用前两个目标，将使用前两个目标来确定断点点（和相应的DAP剂量），使用各种临床剂量的体外模型，使用各种临床剂量的体外模型，使用各种临床剂量的体外模型，使用各种临床剂量的体外，使用各种临床剂量的体外模型，将使用各种DIP（和相应的DAP剂量）。拟议的研究具有创新性，因为我们将同时使用体外和体内PK/PD模型来确定最佳的β-LACTAM加上DAP组合方案针对VREFM，而VREFM尚未通过此类复杂的建模进行深入研究。这项研究之所以重要，是因为预计它将为了解最佳的DAP剂量策略提供知识的组成部分，并且是针对VREFM的最佳beta-lactam，并具有倾向于DAP抗性的VREFM。一旦获得了此类知识，改善患者的结果和将DAP保存为治疗VREFM感染的可行治疗选择将是最终结果。