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

项目摘要(摘要)： 尽管有抗生素可用，但细菌感染在世界范围内造成了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- 具有抵抗治疗并传递遗传物质的固有适应能力的阴性细菌 这促进了其他细菌的抗药性。肺炎克雷伯氏菌(Kp)感染已造成巨大的 这是全球许多医院面临的临床问题。到今天为止，当前的约定方法都不能提供 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。 或者是无限期的。长期目标是开发一种新的病原体特异性和非侵入性全身成像 指导患者管理、监测治疗效果和加快药物开发的技术。 这项建议的目的是验证F-18氟脱氧山梨醇(FDS)作为监测的成像工具 治疗效果及耐药株与敏感株的鉴别。中心假设是FDS 是一种化学简单、药代动力学最佳、高特异性和高选择性的PET显像剂。 预测细菌感染治疗反应的敏感性。这项建议背后的理由是 它的完成将有助于准确诊断，指导有效的治疗。中心假设将是 通过追求两个具体目标进行测试：1)确定2种耐药药物和2种药物的FDS最佳成像时间 临床相关的临床前小鼠肺部感染模型中敏感的KP菌株，2)决定 FDS PET显像鉴别耐药株与敏感株的治疗反应 在肺部感染的小鼠中。我们将通过使用新的和更临床相关的KP小鼠模型来实现这些目标 肺部感染的风险和模拟临床患者实际情况的双盲策略。 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 通过预测细菌感染的早期治疗反应来对药物选择进行分类的工具，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，指导患者治疗，以及 帮助药物开发，因为他们为开发一套更好的技术奠定了基础 金葡菌耐药感染的治疗。

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.