Theoretical and experimental strudy of the population and evolutionary dynamics o

描述（由申请人提供）：耐药菌感染或在治疗过程中产生耐药性是抗生素治疗失败的主要原因。但这种遗传耐药性不仅是治疗失败的原因；患者长期患病或死于细菌感染，这些细菌对用于治疗的抗生素完全敏感。拟议研究的目标是制定和评估抗生素治疗方案，以有效地快速清除细菌感染，同时最大限度地减少治疗过程中产生耐药性的可能性。为了实现这些目标，我们将构建和分析数学和计算机模拟模型的特性，这些模型将抗生素和细菌的药效学以及抗生素治疗的药代动力学与感染宿主中细菌的种群和进化动力学结合起来。利用体外培养的对甲氧西林敏感和耐药的金黄色葡萄球菌（MSSA和MSRA）和大肠杆菌，我们将估计这些模型的参数，评估其构建背后假设的有效性，并测试我们对其特性分析所产生的预测（假设）。基于这些实验结果，我们将对这些模型进行修正，使其更加准确，并提出单药和多药治疗方案，以提高其在清除细菌感染和防止耐药性进化方面的疗效。在这些调查中，特别值得关注的是细菌和宿主介导的过程，这些过程使遗传易感细菌对抗生素难以耐受。这些非遗传抗性机制包括非生长细菌的亚群（持久性）、感染群体的物理结构（生物膜）、感染密度和细菌的生理状态（潜伏期）。

DESCRIPTION (provided by applicant): Infections with resistant bacteria or resistance evolving during the course of treatment are major reasons antibiotic treatment fails. But this inherited resistance is not only reason treatment fails; patients remain ill for extensive periods or die due to infections with bacteria that are and remain fully susceptible to the antibiotics used for treatment. The goals of the proposed studies are to develop and evaluate antibiotic treatment protocols that are effective in rapidly clearing bacterial infections and, at the same time, minimize the likelihood of resistance evolving during the course of treatment. To achieve these goals, we will construct and analyze the properties of mathematical and computer simulation models that combine the pharmacodynamics of antibiotics and bacteria and the pharmacokinetics of the antibiotic treatment, with the population and evolutionary dynamics of bacteria in infected hosts. Using methicillin sensitive and resistant Staphylococcus aureus (MSSA and MSRA) and E. coli in invitro culture, we will estimate the parameters of these models and evaluate the validity of the assumptions behind their construction and test the predictions (hypotheses) generated from our analysis of their properties. Based on the results of these experiments, we will modify these models to make them more accurate and proposed the single and multi- drug treatment protocols to increase their efficacy in clearing bacterial infections and preventing the evolution of resistance. Of particular concern in these investigations are bacteria- and host-mediated processes that make genetically susceptible bacteria refractory to antibiotics. Included among these mechanisms of non-inherited resistance are subpopulations of non-growing bacteria (persistence) the physical structure of the infecting population (biofilms), the density of the infection, and physiological state of the bacteria (latent stages). PUBLIC HEALTH RELEVANCE: A theoretical and experimental study will be performed to improve the efficacy of antibiotic treatment and prevent the evolution of resistance. To achieve this end, we will use mathematical models, computer simulations and experiments with Staphylococcus aureus and E.coli. Particular consideration will be given to methicillin resistant S. aureus infections (MRSA).