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

项目摘要（Abstract）： 尽管抗生素的可用性，细菌感染在世界范围内引起显著的死亡率和发病率。 抗生素耐药性是对公众健康最紧迫的威胁之一。克雷伯菌属微生物是革兰- 阴性细菌，具有抵抗治疗的固有适应能力，并且还传递沿着遗传物质 促进其他细菌的耐药性。肺炎克雷伯氏菌（Kp）感染造成了巨大的 世界各地许多医院的临床问题。到目前为止，没有一个现行的公约方法可以提供 早期特异性诊断和快速监测临床感染。因此，治疗往往被推迟 或不确定。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、监测治疗效果和加速药物开发的技术。 本提案的目的是验证F-18氟脱氧山梨醇（FDS）作为监测的成像工具 治疗效果和从药物敏感Kp中鉴别药物抗性Kp。核心假设是， 是一种有前途的PET成像剂，具有简单的化学性质、最佳的药代动力学和高特异性， 用于预测对细菌感染的治疗反应的灵敏度。这项建议的基本理由是， 它的完成将有助于准确诊断以指导有效治疗。核心假设是 通过追求两个特定目标进行测试：1）确定FDS对于2种耐药和2种耐药的最佳成像时间， 在临床相关的临床前小鼠肺部感染模型中测定敏感Kp菌株的能力，2）测定 FDS PET成像用于区分耐药Kp菌株和药物敏感菌株之间的治疗反应 肺部感染的小鼠。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 肺部感染和双盲策略来模拟实际的临床患者情况。 所提出的研究是重要的和创新的，因为FDS PET成像可以被验证是有用的， 通过预测对细菌感染的早期治疗反应，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， 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 Kp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.