Resistance Suppression for P. Aeruginosa using Novel Combination Therapy Modeling

使用新型组合疗法模型抑制铜绿假单胞菌的耐药性

• 批准号: 7513833
• 负责人: George Louis Drusano
• 金额: $ 78.79万
• 依托单位: ORDWAY RESEARCH INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7513833
• 关键词: Accounting; Affect; Aminoglycosides; AmpC beta-lactamases; Animals; Anti-Infective Agents; Antibiotic Resistance; Antibiotics; Antimicrobial Effect; Area; Carbapenems; Categories; Cefepime; Cephalosporins; Clinical; Collection; Combination Chemotherapy; Combined Modality Therapy; Data; Development; Dose; Drug Combinations; Drug Kinetics; Drug resistance; Fiber; Fluoroquinolones; HIV; Human; In Vitro; Infection; Intensive Care Units; Knowledge; Laboratories; Lactams; Learning; Levaquin; Lung; Meropenem; Microbe; Modeling; Mono-S; Morbidity - disease rate; Multi-Drug Resistance; Mus; Mycobacterium tuberculosis; New Agents; Organism; Patients; Performance; Pharmaceutical Preparations; Pharmacodynamics; Pneumonia; Population; Probability; Process; Production; Protein Overexpression; Pseudomonas; Pseudomonas aeruginosa; Research Personnel; Resistance; Schedule; Sister; Site; Surface; System; Testing; Therapeutic; Therapeutic Agents; Time; Tobramycin; Translating; Treatment Protocols; Validation; Ventilator; Work; antimicrobial drug; base; data modeling; design; dosage; drug development; efflux pump; in vivo; innovation; killings; man; mathematical model; mortality; mouse model; mutant; novel; pathogen; prevent; prospective; research study; resistance mechanism; simulation

DESCRIPTION (provided by applicant): Pseudomonas aeruginosa is a major cause of morbidity and mortality in the ICU, particularly among patients with Ventilator-Associated Pneumonia. Many isolates are multi-drug resistant and some isolates are resistant to all currently extant anti-infective agents. There are currently no new antibiotics in clinical development (in man) with novel mechanisms of action against Pseudomonas. Given the cycle time associated with new drug development, it is likely that no antibiotics with new mechanisms of action for this pathogen will arise for 5 - 7 years. Thus, we must generate new knowledge about how best to suppress antibiotic resistance for this pathogen. This will help preserve our current drugs while we await new agents. Also, when agents with new mechanisms of action become available they can be developed in an optimal fashion for resistance suppression, both as monotherapy and in combination. In this application (Specific Aim #1), we hypothesize that we can identify optimal doses and schedules of administration for monotherapy for resistance suppression by studying this pathogen in our Hollow Fiber Infection Model (HFIM) and fitting a large mathematical model to the HFIM data to identify these doses and schedules. We further hypothesize that different resistance mechanisms will alter optimal doses and schedules. We propose to study isogenic mutants of the wild-type P. aeruginosa PAO-1 isolate, each containing a defined resistance mechanism. These findings will be bridged to man through use of Monte Carlo simulation (MCS). In Specific Aim #2, we propose to examine drugs in combination chemotherapy. We have developed a completely novel mathematical model that allows description of the impact of two drug combination chemotherapy on isolates of P. aeruginosa. This model is a mixture model and allows the fitting of the model to the concentration-time course of both agents as well as to fit the model to the disparate changes over time wrought by the combination of agents on the susceptible and less-susceptible populations of organisms present. Robust identification of the parameters of this system will allow calculation of optimal combination regimens for resistance suppression. Such regimens will be bridged to man through the use of MCS, as above. The HFIM is an in vitro system. In Specific Aim #3, we will also validate these optimal and non-optimal regimens in a neutropenic mouse pneumonia model, employing the same isolates studied in vitro in Aims #1 and #2. In examining this, we will use "humanized" dosing for the regimens, so that differences between mouse and human pharmacokinetics will not drive an improper inference. This will be done for both mono- and combination therapy. Prospective validation experiments will be designed and carried out. Results will be compared with the in vitro findings and also bridged to man. In so doing robust principles will be defined for drug regimens that will suppress amplification of resistant mutant populations. Pseudomonas aeruginosa is a pathogen of major importance in the Intensive Care Unit and is often resistant to many or even all of the drugs in our therapeutic armamentarium. As no agents with a unique mechanism of action active against Pseudomonas are expected for at least 7 years, it is imperative to learn how to use our currently available agents in a way that suppresses emergence of resistance and keeps these agents active for our patients. We plan to do this by 1) understanding the optimal way to dose Pseudomonas-active drugs in our hollow fiber infection model (HFIM) to suppress resistance and delineate the impact of different resistance mechanisms on this process 2) understand how to administer these drugs in combination in the HFIM to optimally suppress resistance emergence 3) validate the in vitro findings from the HFIM in a mouse model of Pseudomonas aeruginosa pneumonia.

描述（由申请人提供）：铜绿假单胞菌是 ICU 发病和死亡的主要原因，尤其是呼吸机相关肺炎患者。许多分离株具有多重耐药性，一些分离株对所有现有的抗感染药物具有耐药性。目前尚无针对假单胞菌具有新作用机制的新抗生素（用于人体）处于临床开发阶段。考虑到新药开发的周期时间，5 - 7 年内可能不会出现针对这种病原体具有新作用机制的抗生素。因此，我们必须产生关于如何最好地抑制这种病原体的抗生素耐药性的新知识。这将有助于在我们等待新药物的同时保留我们现有的药物。此外，当具有新作用机制的药物问世时，它们可以以最佳方式开发以抑制耐药性，无论是单一疗法还是联合疗法。在此应用中（具体目标#1），我们假设我们可以通过在中空纤维感染模型 (HFIM) 中研究这种病原体并将大型数学模型与 HFIM 数据拟合来确定用于抑制耐药性的单一疗法的最佳剂量和给药方案以确定这些剂量和时间表。我们进一步假设不同的耐药机制将改变最佳剂量和时间表。我们建议研究野生型铜绿假单胞菌 PAO-1 分离株的同基因突变体，每个突变体都含有明确的抗性机制。这些发现将通过使用蒙特卡罗模拟（MCS）与人类联系起来。在具体目标#2 中，我们建议检查联合化疗中的药物。我们开发了一种全新的数学模型，可以描述两种药物联合化疗对铜绿假单胞菌分离株的影响。该模型是一个混合模型，允许模型拟合两种药物的浓度-时间过程，以及使模型拟合药物组合对易感人群和不易感人群随时间的不同变化。存在的生物体。该系统参数的稳健识别将允许计算用于抑制耐药性的最佳组合方案。如上所述，此类治疗方案将通过使用 MCS 应用于人类。 HFIM 是一个体外系统。在具体目标#3 中，我们还将在中性粒细胞减少性小鼠肺炎模型中验证这些最佳和非最佳方案，采用与目标#1 和#2 中体外研究的相同分离株。在对此进行研究时，我们将在治疗方案中使用“人性化”剂量，以便小鼠和人类药代动力学之间的差异不会导致不正确的推论。这将针对单一疗法和联合疗法进行。将设计并进行前瞻性验证实验。结果将与体外研究结果进行比较，并与人体进行比较。在此过程中，将为抑制耐药突变体群体扩增的药物治疗方案定义强有力的原则。铜绿假单胞菌是重症监护病房中非常重要的病原体，通常对我们治疗设备中的许多甚至全部药物具有耐药性。由于预计至少 7 年内不会有针对假单胞菌具有独特作用机制的药物，因此必须了解如何使用我们现有的药物来抑制耐药性的出现并使这些药物对我们的患者保持活性。我们计划通过 1) 了解在中空纤维感染模型 (HFIM) 中给予假单胞菌活性药物的最佳方式来抑制耐药性并描述不同耐药机制对此过程的影响 2) 了解如何在中空纤维感染模型中施用这些药物HFIM 中的组合，以最佳地抑制耐药性的出现 3) 在铜绿假单胞菌肺炎小鼠模型中验证 HFIM 的体外研究结果。