Next-generation combination dosing strategies to combat resistant Acinetobacter baumannii

对抗耐药鲍曼不动杆菌的下一代组合给药策略

• 批准号: 10053289
• 负责人: Jurgen Bernd Bulitta
• 金额: $ 67.41万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-11-08 至 2022-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10053289
• 关键词: Acinetobacter baumannii; Affinity; Aminoglycoside Antibiotics; Aminoglycoside resistance; Aminoglycosides; Antibiotic Resistance; Antibiotics; Aztreonam; Bacteria; Binding; Binding Proteins; Biological Assay; Blood Circulation; Carbapenems; Ceftazidime; Cessation of life; Clinical Trials; Combined Antibiotics; Combined Modality Therapy; Dangerousness; Data; Dose; Drug Combinations; Fiber; Future; Genomic approach; Genomics; Goals; Health; Healthcare Systems; Human; Immune system; In Vitro; Infection; Kinetics; Lead; Membrane; Methyltransferase; Modeling; Molecular; Monobactams; Morbidity - disease rate; Multi-Drug Resistance; Mus; Nosocomial Infections; Patients; Penetration; Penicillin-Binding Proteins; Pharmaceutical Preparations; Pharmacology; Prevention; Pseudomonas aeruginosa; Regimen; Resistance; Resistance development; Respiratory System; Ribosomal RNA; Sampling; Scheme; Site; Superbug; System; Testing; Time; United States; World Health Organization; base; beta-Lactamase; beta-Lactams; carbapenem resistance; clinical development; clinically relevant; combat; combat wound; cost; design; dosage; global health; improved; in vitro Model; inhibitor/antagonist; innovation; insight; member; mortality; next generation; novel; pneumonia model; prevent; prospective; receptor; receptor binding; resistance mechanism; synergism; transcriptomics; treatment optimization; wound

Project Summary/Abstract Due to a lack of effective antibiotics, Acinetobacter baumannii is one of the six most dangerous bacterial “superbugs” that cause one of the world’s three most serious human health threats. Exacerbating this is a dramatic decline in the number of new antibiotics effective against A. baumannii, which can cause serious bloodstream, respiratory tract, wound, and other infections with very high morbidity and up to 80% mortality. Carbapenem (a member of the β-lactam class of antibiotics)-resistant (CR) A. baumannii infections cost the U.S. health-care system $389 million per year. As A. baumannii isolates resistant to most or all antibiotics in monotherapy are rapidly increasing in the United States and worldwide, monotherapy is clearly no longer viable. With clinicians therefore being forced to use empiric, non-optimized combinations that may fail and lead to even more resistance, the development of novel dosing strategies that use antibiotics in efficacious combinations is critical. This project will yield promising combination dosing schemes to combat multidrug- resistant (MDR) and pandrug-resistant (PDR) A. baumannii. Our preliminary data show that combining a carbapenem with an aminoglycoside antibiotic is highly effective against MDR A. baumannii. To rationally optimize therapies, this project will provide the first systematic data on the binding of β-lactam antibiotics to their bacterial target receptors in A. baumannii (Aim 1, stage 1). This will identify the optimal sets of bacterial target receptors that should be bound and inactivated by β-lactam antibiotics and will greatly improve optimal β-lactam therapies. In stage 2 of Aim 1, in vitro infection models will assess bacterial killing and resistance prevention for innovative two- and three-drug combination dosing strategies against MDR and PDR A. baumannii. These in vitro models can simulate antibiotic concentration-time profiles that mirror those in patients. Combination regimens to be tested include simultaneous and sequential dosing with normal and short-course aminoglycoside therapy. The ability of novel broad-spectrum β-lactamase inhibitors to significantly enhance the activity of β-lactam antibiotics in A. baumannii will be assessed. In Aim 2, the kinetics of target receptor binding by β-lactams will be evaluated, and transcriptomic and genomic approaches applied to elucidate the mechanistic basis for resistance prevention, using bacterial samples from Aim 1. Next, in Aim 3, data on target receptor binding, drug concentrations, bacterial killing, resistance prevention, and resistance mechanisms will be used to develop new mechanism-based models. Applying these models will rationally optimize two- and three-drug combination dosing strategies that better target MDR and PDR A. baumannii. In Aim 4, these regimens will be validated prospectively via dynamic in vitro and murine pneumonia models with an intact or compromised immune system. This project holds excellent promise for developing efficacious and robust combination dosing strategies against MDR and PDR A. baumannii for testing in future clinical trials.

项目概要/摘要 由于缺乏有效的抗生素，鲍曼不动杆菌是六种最危险的细菌之一 “超级细菌”造成世界上三大最严重的人类健康威胁之一。加剧这种情况的是 对鲍曼不动杆菌有效的新型抗生素数量急剧下降，这可能会导致严重的后果 血液、呼吸道、伤口和其他感染，发病率非常高，死亡率高达 80%。 碳青霉烯类（β-内酰胺类抗生素的一员）耐药 (CR) 鲍曼不动杆菌感染导致 美国医疗保健系统每年 3.89 亿美元。由于鲍曼不动杆菌分离株对大多数或所有抗生素具有耐药性 单一疗法在美国和世界范围内迅速增加，单一疗法显然不再有效 可行的。因此，临床医生被迫使用经验性的、非优化的组合，这些组合可能会失败并导致 为了抵抗更多的耐药性，开发新的剂量策略，使用有效的抗生素 组合至关重要。该项目将产生有前景的联合给药方案，以对抗多种药物 耐药（MDR）和全耐药（PDR）鲍曼不动杆菌。我们的初步数据表明，结合 碳青霉烯与氨基糖苷类抗生素对多重耐药鲍曼不动杆菌非常有效。理性地 优化疗法，该项目将提供第一个关于 β-内酰胺抗生素与 鲍曼不动杆菌中的细菌靶受体（目标 1，第 1 阶段）。这将确定最佳的细菌组 应该被β-内酰胺抗生素结合和灭活的目标受体，将大大提高最佳效果 β-内酰胺疗法。在目标 1 的第二阶段，体外感染模型将评估细菌杀灭和耐药性 针对 MDR 和 PDR A 的创新型两药和三药组合给药策略的预防。 鲍曼氏菌。这些体外模型可以模拟抗生素浓度-时间曲线，反映了抗生素浓度-时间曲线。 患者。待测试的组合方案包括与正常和连续给药同时和顺序给药。 短期氨基糖甙类药物治疗。新型广谱β-内酰胺酶抑制剂的能力 将评估鲍曼不动杆菌中β-内酰胺抗生素活性的显着增强。在目标 2 中，动力学 将评估 β-内酰胺与靶受体结合的情况，并应用转录组学和基因组学方法 使用目标 1 中的细菌样本阐明预防耐药性的机制基础。接下来，在目标中 3、靶标受体结合、药物浓度、细菌杀灭、耐药预防、耐药性等数据 机制将用于开发新的基于机制的模型。合理地应用这些模型 优化两种和三种药物组合给药策略，更好地针对 MDR 和 PDR 鲍曼不动杆菌。在 目标 4，这些方案将通过动态体外和小鼠肺炎模型进行前瞻性验证 完整或受损的免疫系统。该项目对于开发有效和 针对 MDR 和 PDR 鲍曼不动杆菌的强有力的组合剂量策略，用于在未来的临床试验中进行测试。