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: 8322578
• 负责人: George Louis Drusano
• 金额: $ 68.78万
• 依托单位: UNIVERSITY OF FLORIDA
• 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 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8322578
• 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; 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）：革兰氏阴性细菌中的多药耐药性是ICU环境中感染患者的常见问题。与铜绿假单胞菌和杆菌属属。对于生物体而言，没有活跃的抗生素，这并不是一个罕见的事件，从本质上讲，我们将我们恢复到抗生素前时代。在某些药物中也定义了电阻，例如马达加斯加耶尔森氏菌的氨基糖苷耐药性。 Achaogen开发了几种新的氨基糖苷抗生素（Neoglycoside）。这些药物显着改善了对多种多种耐革兰氏阴性杆菌的活性，也改善了对甲氧西林金黄色葡萄球菌（MRSA）的活性。在不同的系列中，已经确定了针对铜绿假单胞菌和acinetobacter spp的有效活性的铅化合物。该提案的目的是在提案的范围内检查其中多达五个分子，对它们进行排序，对于至少两个分子，将它们逐步发展为新药应用。由于抗药性的增加及其引起肾毒性的潜力，氨基糖苷的使用量较低。这些新糖苷消除了与抗药性相关的大量问题。在特定的目标＃1中，我们将采用空心纤维感染模型来研究候选分子。我们可以确定会导致最佳细菌细胞杀死和抗性细菌亚群的抑制。这些目标将通过应用创新的大数学混合模型来确定。在特定的目标＃2中，我们将采用两种动物模型来验证这些暴露目标。由于鼠和人类的一半生活之间的差异，我们将采用一种新颖的方法来在所有动物模型中“人性化”药物管理。其中包括革兰氏阴性肺炎和小鼠大腿感染的鼠模型，作为皮肤/皮肤结构感染的替代物。后一种模型将在中性粒细胞减少和正常情况下运行。我们将在所有数据中应用另一个完全新颖的模型，以了解粒细胞杀死病原体。我们将验证SA＃1的暴露目标，并了解粒细胞撞击。在特定的目标＃3中，我们开发了一个完全新颖的体外系统，该系统具有人类近端肾小管上皮细胞（HPRTE细胞），可为任何模仿人类尿路特征的任何氨基/新糖苷生成浓度时间。通过随着时间的推移量化HPRTE细胞内部药物的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。暴露与效果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）。在特定的目标＃4中，我们将使用蒙特卡洛模拟的种群PK建模来识别最佳药物剂量。我们的目的是通过最佳剂量/治疗持续时间将至少2个分子带到NDA。在患有医院获得的感染的患者中，多耐药的生物已成为一个巨大的问题。我们打算优化新的氨基糖苷抗生素（新糖苷）的开发，以满足这一需求，并为诸如瘟疫，炭疽和病原体（例如Burkholderia Mallei和pseudomallei）等精选剂的治疗提供新产品。我们打算确定具有非常广泛的药物，以解决与许多此类病原体相关的感染问题。但是，因为铜绿假单胞菌和杆菌菌属属。在ICU环境中，在严重感染的患者中很难治疗，这是该提案的目的，目的是确定一种针对这些后一种病原体的极有效活性进行了专门优化的药物。