Optimization of Neoglycoside Antibiotics for Nosocomial Pathogens and Select Agen

新糖苷类抗生素治疗院内病原体的优化及药物选择

• 批准号: 7989055
• 负责人: George Louis Drusano
• 金额: $ 87.5万
• 依托单位: ORDWAY RESEARCH INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7989055
• 关键词: Accounting; Acinetobacter; Address; Aerosols; Amikacin; Aminoglycoside Antibiotics; Aminoglycoside resistance; Aminoglycosides; Animal Model; Anthrax disease; Anti-Infective Agents; Antibiotic Therapy; Antibiotics; Apoptosis; Bacillus (bacterium); Bacillus anthracis; Bacteria; Bacterial Infections; Bacterial Pneumonia; Bacterial Proteins; Biological Assay; Biological Models; Biological Warfare; Bioterrorism; Burkholderia; Burkholderia mallei; Burkholderia pseudomallei; Cells; Clinical; Colorado; Daptomycin; Data; Development; Dose; Dose Fractionation; Dose-Limiting; Drug Administration Schedule; Drug Exposure; Drug Kinetics; Enterobacteriaceae; Environment; Enzymes; Epithelial Cells; Event; Exposure to; Fiber; Frequencies; Generations; Gentamicins; Government; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Gram-Positive Bacteria; Half-Life; Hospitals; Human; In Vitro; Infection; Kidney; Klebsiella pneumonia bacterium; Learning; Linezolid; Madagascar; Methods; Microbe; Modeling; Multi-Drug Resistance; Mus; Necrosis; Nephrotoxic; Nosocomial Infections; Organism; Parents; Patients; Penetration; Performance; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Phase II Clinical Trials; Phase III Clinical Trials; Plague; Pneumonia; Population; Predisposition; Prevention; Probability; Protein Biosynthesis; Pseudomonas aeruginosa; Reaction; Regimen; Relative (related person); Research Institute; Resistance; Resources; Running; Schedule; Series; Serum; Site; Skin; Staging; Structure; System; Systemic infection; Test Result; Therapeutic; Thigh structure; Time; Tobramycin; Toxic effect; Treatment outcome; Tubular formation; Urinary tract; Yersinia pestis; bacterial resistance; base; cell killing; dosage; drug candidate; drug discovery; drug efficacy; granulocyte; improved; in vivo; indexing; innovation; interest; killings; lead series; mathematical model; methicillin resistant Staphylococcus aureus; mouse model; nephrotoxicity; next generation; novel; pathogen; prevent; simulation; therapy duration; tigecycline; treatment duration

DESCRIPTION (provided by applicant): Multi-drug resistance in Gram-negative bacteria is a common problem in infected patients in the ICU environment. With Pseudomonas aeruginosa and Acinetobacter spp. it is not an uncommon event for there to be no antibiotics active for the organism, essentially returning us to the pre-antibiotic era. Resistance has also been defined in Select Agents, such as aminoglycoside resistance in Yersinia pestis in Madagascar. Achaogen has developed several series of new aminoglycoside antibiotics (neoglycosides). These agents have markedly improved activity against a wide variety of multi-resistant Gram-negative bacilli and also against Methicillin-Resistant Staphylococcus aureus (MRSA). In a different series, lead compounds have been identified with potent activity against Pseudomonas aeruginosa and Acinetobacter spp. It is the intent of this proposal to examine up to five of these molecules over the span of the proposal, rank order them and, for at least two of the molecules, to progress them into New Drug Applications. Aminoglycosides have become less used because of increasing resistance and their potential to cause nephrotoxicity. These neoglycosides obviate a great deal of the problems associated with resistance. In Specific Aim #1, we will employ our hollow fiber infection model to study candidate molecules. We can identify exposure targets that will result in optimal bacterial cell kill and suppression of resistant bacterial subpopulations. These targets will be identified through application of innovative large mathematical mixture models. In Specific Aim # 2, we will employ two animal models to validate these exposure targets. Because of the difference between murine and human half lives, we will employ a novel method of "humanizing" the drug administration in all animal models. These include a murine model of Gram-negative pneumonia and mouse thigh infection as a surrogate for skin/skin structure infection. This latter model will be run in both neutropenic and normal conditions. We will apply another completely novel model to all data, to understand pathogen kill by granulocytes. We will validate exposure targets from SA #1 with an understanding of the granulocyte impact. In Specific Aim #3, we developed a completely novel in vitro system with human proximal renal tubular epithelial cells (hPRTE cells) allowing generation of a concentration-time profile for any amino/neoglycoside that mimics the human urinary tract profile. By quantifying the amount of drug inside hPRTE cells over time and observing for apoptosis or necrosis, we can derive a relationship between drug exposure, duration and nephrotoxic event occurrence. Relationships between exposure and both effect and toxicity allows exploration of doses and durations to optimize these relationships simultaneously (maximal effect/ minimal toxicity). In Specific Aim # 4, we will employ population PK modeling with Monte Carlo simulation to identify optimal drug doses. Our aim is to bring at least 2 molecules to NDA with optimal doses/durations of therapy. Multi-resistant organisms have become a huge problem in patients with hospital-acquired infections. We intend to optimize the development of new aminoglycoside antibiotics (neoglycosides) to address this need and also to provide new products for the therapy of Select Agents, such as Plague, Anthrax and pathogens such as Burkholderia mallei and pseudomallei. We intend to identify an agent with very broad spectrum to address the infection problems associated with many of these pathogens. However, because Pseudomonas aeruginosa and Acinetobacter spp. are especially resistant and, hence, difficult to treat in seriously infected patients in the ICU setting, it is an aim of this proposal to identify an agent that is specifically optimized for extremely potent activity against these latter pathogens.

描述（由申请人提供）：革兰氏阴性菌的多重耐药性是 ICU 环境中感染患者的常见问题。含有铜绿假单胞菌和不动杆菌属。没有对生物体有活性的抗生素并不罕见，这实际上使我们回到了前抗生素时代。 Select Agents 中也定义了耐药性，例如马达加斯加鼠疫耶尔森氏菌的氨基糖苷类耐药性。 Achaogen 开发了多个系列的新型氨基糖苷类抗生素（新糖苷类）。这些药物显着提高了针对多种多重耐药革兰氏阴性杆菌以及耐甲氧西林金黄色葡萄球菌 (MRSA) 的活性。在不同的系列中，先导化合物已被鉴定出对铜绿假单胞菌和不动杆菌属具有有效的活性。该提案的目的是在提案范围内检查最多五个这样的分子，对它们进行排序，并且对于至少其中两个分子，将它们推进到新药申请中。由于耐药性增加及其可能引起肾毒性，氨基糖苷类药物已越来越少使用。这些新糖苷类药物消除了许多与耐药性相关的问题。在具体目标#1中，我们将采用中空纤维感染模型来研究候选分子。我们可以确定暴露目标，从而实现最佳的细菌细胞杀死和抑制耐药细菌亚群。这些目标将通过应用创新的大型数学混合模型来确定。在具体目标#2 中，我们将采用两种动物模型来验证这些暴露目标。由于小鼠和人类半衰期的差异，我们将在所有动物模型中采用一种“人性化”给药的新方法。其中包括革兰氏阴性肺炎的鼠模型和作为皮肤/皮肤结构感染替代物的小鼠大腿感染模型。后一种模型将在中性粒细胞减少和正常条件下运行。我们将对所有数据应用另一个全新的模型，以了解粒细胞杀死病原体的作用。我们将通过了解粒细胞影响来验证 SA #1 的暴露目标。在具体目标#3中，我们开发了一种全新的体外系统，采用人近端肾小管上皮细胞（hPRTE细胞），可以生成模拟人尿路特征的任何氨基/新糖苷的浓度-时间特征。通过随着时间的推移量化 hPRTE 细胞内的药物量并观察细胞凋亡或坏死，我们可以得出药物暴露、持续时间和肾毒性事件发生之间的关系。暴露与效应和毒性之间的关系允许探索剂量和持续时间以同时优化这些关系（最大效应/最小毒性）。在具体目标 4 中，我们将采用群体 PK 模型和蒙特卡罗模拟来确定最佳药物剂量。我们的目标是通过最佳剂量/治疗持续时间将至少 2 个分子纳入 NDA。多重耐药微生物已成为医院获得性感染患者的一个大问题。我们打算优化新型氨基糖苷类抗生素（新糖苷类）的开发，以满足这一需求，并为治疗鼠疫、炭疽等特定病原体以及鼻疽伯克霍尔德菌和伪鼻疽等病原体提供新产品。我们打算找到一种具有非常广谱的药剂来解决与许多这些病原体相关的感染问题。然而，因为铜绿假单胞菌和不动杆菌属。由于这些病原体特别具有抵抗力，因此很难在 ICU 环境中治疗严重感染的患者，因此本提案的目的是确定一种针对后一种病原体具有极强活性的专门优化药物。