Next-generation combination dosing strategies to combat resistant Acinetobacter baumannii

项目摘要/摘要 由于缺乏有效的抗生素，鲍曼不动杆菌是最危险的六种细菌之一。 “超级细菌”导致世界上三大最严重的人类健康威胁之一。雪上加霜的是 对鲍曼不动杆菌有效的新抗生素的数量急剧减少，这可能会导致严重的 血液、呼吸道、伤口和其他感染具有非常高的发病率和高达80%的死亡率。 碳青霉烯类(β-内酰胺类抗生素)耐药鲍曼不动杆菌感染导致 美国医疗体系每年3.89亿美元。作为鲍曼不动杆菌对大多数或所有抗生素耐药的菌株 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 可行。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 对于更多的耐药性，使用抗生素有效的新的剂量策略的发展 组合是至关重要的。该项目将产生有前景的联合剂量方案，以对抗多药- 抗(MDR)和抗大熊猫(PDR)鲍曼不动杆菌。我们的初步数据显示，结合一个 碳青霉烯类抗生素联合氨基糖苷类抗生素对耐多药鲍曼不动杆菌有很好的抗药性。理性地 优化治疗，该项目将提供第一个关于β-内酰胺类抗生素与 它们的细菌靶标受体在鲍曼不动杆菌中(目标1，阶段1)。这将确定细菌的最佳组合 应被β-内酰胺类抗生素结合并失活的靶向受体，将大大改善最佳 β-内酰胺疗法。在AIM 1的第二阶段，体外感染模型将评估细菌的杀灭和耐药性。 预防MDR和PDR A的创新的两药和三药联合给药策略。 鲍曼尼。这些体外模型可以模拟抗生素的浓度-时间曲线，反映出 病人。接受试验的联合方案包括同时和顺序给药，正常剂量和 短程氨基糖苷类药物。新型广谱β-内酰胺酶抑制剂的抗肿瘤作用 将评估显著提高鲍曼不动杆菌中β-内酰胺类抗生素的活性。在目标2中，动力学 将评估β-内酰胺类药物与靶受体结合的情况，并应用转录和基因组学方法 利用Aim 1中的细菌样本，阐明了预防耐药性的机制基础。 3、靶受体结合、药物浓度、细菌杀灭、耐药性预防和耐药性的数据 将利用机制来开发新的基于机制的模式。合理地应用这些模型将 优化两种和三种药物联合给药策略，更好地针对MDR和PDR鲍曼不动杆菌。在……里面 目的4，这些方案将通过动态的体外和小鼠肺炎模型进行前瞻性验证 免疫系统完整或受损的免疫系统。该项目具有开发高效、高效、可持续发展的前景 针对MDR和PDR鲍曼不动杆菌的强有力的联合剂量策略，用于在未来的临床试验中进行测试。

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.