Pharmacodynamic modeling of antibiotics on cystic fibrosis P. aeruginosa biofilms

抗生素对囊性纤维化铜绿假单胞菌生物膜的药效学模型

• 批准号: 8649011
• 负责人: Katherine Y. Yang
• 金额: $ 38.86万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-22 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8649011
• 关键词: Accounting; Acute; Acute Disease; Adult; Algorithms; Aminoglycosides; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antimicrobial Effect; Antimicrobial Resistance; Bacteria; Biomass; California; Cause of Death; Cells; Chronic; Clinical; Clinical Pharmacists; Collaborations; Collection; Combined Antibiotics; Cystic Fibrosis; Data; Denmark; Development; Disease; Dose; Drug Combinations; Drug Kinetics; Drug usage; Endocarditis; Evolution; Exhibits; Film; Genetic; Genus staphylococcus; Goals; Growth; Guidelines; Heterogeneity; Host Defense; Human; Imagery; Implant; In Vitro; Infection; International; Intravenous; Investigation; Lactams; Lead; Life; Liquid substance; Lung; Mediating; Meropenem; Metabolic; Microbial Biofilms; Modeling; Multi-Drug Resistance; Organism; Orthopedics; Outcome; Patients; Pharmacodynamics; Predisposition; Pseudomonas aeruginosa; Public Health; Regimen; Research; Research Methodology; Resistance; Respiratory Failure; Role; Sampling; San Francisco; Schedule; Serum; Simulate; Staging; Structure; System; Testing; Time; Tobramycin; Training; Translational Research; Treatment outcome; United States National Institutes of Health; Universities; Yang; antimicrobial; base; catheter related infection; clinical care; cystic fibrosis patients; design; drug development; effective therapy; experience; flexibility; improved; in vitro Model; in vivo; innovation; killings; mathematical model; multidisciplinary; novel strategies; pathogen; pharmacodynamic model; pharmacokinetic model; pressure; response; time use; translational study

DESCRIPTION (provided by applicant): Little is known regarding the pharmacokinetics (PK) and pharmacodynamics (PD) of antibiotics and biofilms yet bacterial biofilms account for over 80% of all important human infections, including cystic fibrosis (CF). The development of effective therapies to counter biofilm infections has been called one of the most pressing challenges in anti-bacterial drug development by the NIH. P. aeruginosa undergoes extensive genetic adaptation in the CF lung over time, allowing it to persist despite intense, repeated courses of antimicrobial treatment. Thus the current goal of antimicrobial therapy is to suppress infection and not cure. Guidelines for the treatment of P. aeruginosa airway infection are based upon PD analyses of bacteria grown in planktonic (e.g. liquid) culture which cannot be extrapolated to biofilms. Additionally, different classes of antibiotics are known to target differnt subpopulations within the biofilm. The long-term goal of this study is to identify the antibiotic combinations, doses, and schedules needed to eradicate P. aeruginosa biofilms in patients with CF through the application of PD on bacterial biofilms. Traditional PK/PD studies quantify antimicrobial effect based upon simple counts of "live" or "dead." The unique spatial and temporal approach to PD modeling proposed in this study will allow simultaneous visualization and quantification of the exposure response relationship of antibiotics on heterogeneous subpopulations within the biofilm in real-time and the associated effect on resistance evolution. The goal of Aim 1 is to optimize the design of an innovative dynamic in vitro biofilm PK/PD model that can simulate in vivo antibiotic concentration-time profiles on P. aeruginosa biofilms under continuous culture conditions. In Aim 2, this model will be used to determine the biofilm PD targets of meropenem and tobramycin, administered alone and in combination, on a unique collection of genetically identical P. aeruginosa isolates longitudinally-collected from CF patient over a period of 35 years thus allowing for comparisons in PD targets between isolates causing early vs. late disease and acute vs. chronic infection. In Aim 3, mathematical models describing the relationship between antibiotic activity and biofilm killing will be developed. We have assembled an international, multi-disciplinary research team with expertise in PK/PD, microbial biofilms, CF, and mathematical modeling. Results from this study will be used to investigate new antibiotic regimens for maximal bio- film killing. This translational study will provide an innovatve new framework for the investigation of antimicrobial PD that accounts for the genetic adaptations and phenotypic diversity observed in P. aeruginosa biofilms and will enable the discovery of alternative antimicrobial dosing strategies and drug combinations specifically targeting P. aeruginosa biofilms in CF with the ultimate goal of improving clinical care. Results of this study will have broad applications toward other biofilm-forming organisms (e.g., Staphyloccocus aureus) which are important causes of human infections such as endocarditis, orthopedic-implant infections, and catheter-related infections.

描述（由申请人提供）：关于抗生素和生物膜的药代动力学（PK）和药效动力学（PD），细菌生物膜占所有重要人类感染（包括囊性纤维化（CF））的80％以上。对抗生物膜感染的有效疗法的发展被称为NIH抗菌药物开发中最紧迫的挑战之一。随着时间的流逝，铜绿假单胞菌在CF肺中经历了广泛的遗传适应性，尽管强烈，重复的抗菌治疗方法，但仍可以持续存在。因此，抗菌治疗的当前目标是抑制感染而不是治愈。铜绿假单胞菌气道感染的指南基于对浮游生物（例如液体）培养物中生长的细菌的PD分析，该细菌无法外推到生物膜。另外，已知不同类别的抗生素靶向生物膜内的亚种不同。这项研究的长期目标是通过在细菌生物膜上应用PD来确定消除CF患者中铜绿假单胞菌生物膜所需的抗生素组合，剂量和时间表。传统的PK/PD研究基于“活”或“死”的简单计数来量化抗菌作用。本研究中提出的独特的空间和时间方法将允许同时可视化和定量抗生素对生物膜内异质亚浸润的暴露响应关系，以及对耐药性进化的相关作用。 AIM 1的目的是优化在连续培养条件下对铜绿假单胞菌生物膜上的体内抗生素浓度分布的设计创新动态生物膜PK/PD模型。在AIM 2中，该模型将用于确定单独和组合施用的MeropeNem和dobramycin的生物膜PD靶标，在独特的遗传相同的铜绿假单胞菌分离株集合中，纵向从CF患者那里纵向收集的CF患者纵向收集了35年的时间，从而在35年内允许在PD靶标之间进行比较。在AIM 3中，将开发描述抗生素活性与生物膜杀死之间关系的数学模型。我们组建了一个具有PK/PD，微生物生物膜，CF和数学建模的国际多学科研究团队。这项研究的结果将用于研究最大生物膜杀死的新抗生素方案。 This translational study will provide an innovatve new framework for the investigation of antimicrobial PD that accounts for the genetic adaptations and phenotypic diversity observed in P. aeruginosa biofilms and will enable the discovery of alternative antimicrobial dosing strategies and drug combinations specifically targeting P. aeruginosa biofilms in CF with the ultimate goal of improving clinical care.这项研究的结果将在其他形成生物膜的生物（例如金黄色葡萄球菌）上有广泛的应用，这些生物是人类感染的重要原因，例如心内膜炎，骨科 - 植入物感染和导管相关感染。