Next-generation combination dosing strategies to combat resistant Acinetobacter baumannii

项目总结/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”是世界上三大最严重的人类健康威胁之一。加剧这一点是一个 对A.鲍曼不动杆菌会导致严重的 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（β-内酰胺类抗生素的成员）耐药（CR）A。鲍曼不动杆菌感染 美国卫生保健系统每年3.89亿美元。为.对大多数或所有抗生素耐药的鲍曼不动杆菌 单药治疗在美国和世界范围内迅速增加，单药治疗显然不再是 可行的因此，临床医生被迫使用经验性的、非优化的组合，这些组合可能失败， 甚至更多的耐药性，新的剂量策略的发展，使用抗生素在有效的 组合是关键。该项目将产生有前途的联合给药方案，以打击多药- 耐药（MDR）和泛耐药（PDR）A.鲍曼不动杆菌。我们的初步数据显示， 碳青霉烯与氨基糖苷类抗生素对MDR A非常有效。鲍曼不动杆菌。合理 优化治疗，该项目将提供关于β-内酰胺类抗生素与 它们在A.鲍曼不动杆菌（Aim 1，阶段1）。这将确定细菌的最佳组合， 靶向受体应该被β-内酰胺抗生素结合和灭活，并将大大提高最佳的 β-内酰胺治疗。在目标1的第2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的创新的两种和三种药物组合给药策略的预防。 鲍曼不动杆菌。这些体外模型可以模拟抗生素浓度-时间曲线，其反映了体外模型中的那些。 患者待测试的组合方案包括同时和顺序给药正常和 短程氨基糖苷类药物治疗。新的广谱β-内酰胺酶抑制剂对 显著提高A.将对鲍曼不动杆菌进行评估。在目标2中， 将评估β-内酰胺类药物与靶受体结合的能力，并应用转录组学和基因组学方法 使用来自目标1的细菌样品阐明耐药性预防的机制基础。下一篇：In Aim 3、靶受体结合、药物浓度、细菌杀灭、耐药预防和耐药方面的数据 机制将用于开发新的基于机制的模型。合理运用这些模型， 优化更好地靶向MDR和PDR A的两种和三种药物组合给药策略。鲍曼不动杆菌。在 目的4，这些方案将通过动态体外和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具有良好的发展前景， 针对MDR和PDR A的稳健的组合给药策略。用于未来临床试验的鲍曼不动杆菌。

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.