F-18 fluorodeoxysorbitol for detecting response of bacterial infection to treatment

F-18 氟脱氧山梨醇用于检测细菌感染对治疗的反应

基本信息

批准号：
10372094
负责人：
CHIN K NG
金额：
$ 23.45万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-16 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10372094
关键词：
Antibiotic Resistance Antibiotics Bacteria Bacterial Antibiotic Resistance Bacterial Infections Bacterial Pneumonia Bioluminescence Biopsy Carbapenems Categories Ceftriaxone Chemistry Clinic Clinical Clinical Trials Communicable Diseases Development Diagnosis Discipline of Nuclear Medicine Disease Progression Double-Blind Method Drug Kinetics Drug resistance Early treatment Escherichia coli Future Genetic Materials Goals Gram-Negative Bacteria Health Hospitals Human Image Imaging Device Imaging Techniques Imaging technology Infection Inflammation Klebsiella Klebsiella pneumoniae Knowledge Label Leukocytes Location Lung Lung infections Magnetic Resonance Imaging Methods Microbe Modeling Monitor Morbidity - disease rate Multi-Drug Resistance Mus Outcome Oxyquinoline Patient imaging Patients Persons Pharmaceutical Preparations Pharmacotherapy Physicians Positron-Emission Tomography Pre-Clinical Model Prediction of Response to Therapy Public Health Publishing Reporting Research Research Proposals Rodent Sensitivity and Specificity Signal Transduction Site Source Specialist Speed Sterility Stress Techniques Testing Thigh structure Time Treatment Cost Treatment Efficacy Treatment outcome Triage Work X-Ray Computed Tomography accurate diagnosis antibiotic resistant infections antimicrobial base carbapenem resistance cellular imaging clinically relevant diagnostic platform dosage drug development drug-sensitive effective therapy emerging pathogen evidence base fluorodeoxyglucose imaging agent improved innovation interest microbial mortality mouse model non-invasive imaging novel novel therapeutics pathogen pre-clinical resistant Klebsiella pneumoniae resistant strain response symposium tool treatment planning treatment response whole body imaging

项目摘要

Project summary (Abstract): Bacterial infections cause significant mortality and morbidity worldwide despite the availability of antibiotics. Antibiotic resistance is one of the most urgent threats to the public's health. Klebsiella microbes are gram- negative bacteria that have the inherent adaptive ability to resist treatment and also pass along genetic material that facilitates drug resistance in other bacteria. Klebsiella pneumoniae (Kp) infection has created a tremendous clinical problem for many hospitals worldwide. As of today, none of the current convention methods can provide early specific diagnosis and rapid monitoring of infections in the clinic. Consequently, treatment is often delayed or indefinite. The long-term goal is to develop a novel pathogen-specific and non-invasive whole-body imaging technique to guide patient management, monitor treatment efficacy, and speed drug development. The objective of this proposal is to validate F-18 fluorodeoxysorbitol (FDS) as an imaging tool for monitoring treatment efficacy and identifying drug resistant Kp from drug sensitive Kp. The central hypothesis is that FDS is a promising PET imaging agent with simple chemistry, optimal pharmacokinetics, and high specificity and sensitivity for predicting treatment response to bacterial infection. The rationale underlying this proposal is that its completion will contribute to accurate diagnosis for guiding effective treatment. The central hypothesis will be tested by pursuing two specific aims: 1) Identify the optimal imaging time of FDS for 2 drug-resistant and 2 drug- sensitive Kp strains in a clinically relevant preclinical mouse model of lung infection, 2) Determine the ability of FDS PET imaging to differentiate treatment response between drug-resistant Kp strains and drug-sensitive ones in mice of lung infection. We will pursue these aims by using novel and more clinically relevant Kp mouse models of lung infection and a double-blinded strategy to mimic actual clinical patient situation. The proposed studies are significant and innovative because FDS PET imaging can be validated to be a useful tool to triage drug options by predicting early treatment response to bacterial infection and thus avoiding the misuse and overuse of antibiotics. The results will have an important positive impact immediately in that they will establish an imaging technique for better understanding of bacterial infection, guiding patient management, and assisting drug development because they lay the groundwork to develop a suite of techniques for better treatment of Kp drug-resistant infections.

项目概要（摘要）：尽管有抗生素可用，但细菌感染在世界范围内仍造成严重的死亡率和发病率。抗生素耐药性是对公众健康最紧迫的威胁之一。克雷伯氏菌是革兰氏菌阴性细菌具有固有的适应能力，可以抵抗治疗并传递遗传物质促进其他细菌的耐药性。肺炎克雷伯菌 (Kp) 感染造成了巨大的全球许多医院的临床问题。截至目前，现有的约定方法都无法提供临床感染的早期特异性诊断和快速监测。因此，治疗常常被延误或无限期。长期目标是开发一种新型病原体特异性和非侵入性全身成像指导患者管理、监测治疗效果和加速药物开发的技术。该提案的目的是验证 F-18 氟脱氧山梨醇 (FDS) 作为监测成像工具治疗效果并从药物敏感 Kp 中识别耐药 Kp。中心假设是FDS 是一种有前途的 PET 显像剂，具有简单的化学性质、最佳的药代动力学和高特异性预测对细菌感染的治疗反应的敏感性。该提案的基本原理是其完成将有助于准确诊断，指导有效治疗。中心假设将是通过追求两个特定目标进行测试：1）确定 2 种耐药和 2 种耐药的 FDS 的最佳成像时间临床相关的临床前小鼠肺部感染模型中的敏感 Kp 菌株，2) 确定 FDS PET 成像可区分耐药 Kp 菌株和药物敏感菌株之间的治疗反应在肺部感染的小鼠中。我们将通过使用新颖且更具临床相关性的 Kp 小鼠模型来实现这些目标肺部感染的情况和模仿实际临床患者情况的双盲策略。拟议的研究具有重要意义和创新性，因为 FDS PET 成像可以被验证为一种有用的方法。通过预测对细菌感染的早期治疗反应来分类药物选择的工具，从而避免滥用和过度使用抗生素。结果将立即产生重要的积极影响，因为它们将建立成像技术，以更好地了解细菌感染，指导患者管理，以及协助药物开发，因为他们为开发一套更好的技术奠定了基础治疗Kp耐药感染。