Bacterial infections of implanted medical devices are a growing problem in health care today and have a significant impact on morbidity, mortality and health care costs. For example, approximately 1 million patients acquire a nosocomial implant infection in the US every year, and the financial impact of these infections is in the billions of dollars annually. A major challenge in treating bacterial implant infections is diagnosing them at an early stage. At present, the diagnosis of an infection associated with a medical device is made on the basis of clinical criteria, such as physical exam and microbial cultures, which is problematic because this methodology can only detect late stage infections that are challenging to treat. Medical device infections are therefore frequently undiagnosed and allowed to progress to an advanced stage, resulting in significant morbidity and mortality. Conversely, medical devices with sterile inflammation may be inappropriately removed, based on clinical judgment alone, incurring increased morbidity and healthcare costs. In this clinical environment, a technology that can specifically detect infected implanted devices at an early stage, and distinguish them from sterile inflammation has the potential to have a significant clinical and economic impact. The central objective of this proposal is to develop and rigorously evaluate a new family of PET imaging contrast agents that can image implant infections by targeting the maltodextrin transporter. We have termed these agents the 18F-MDPs as they are composed of 18F conjugated to maltodextrins. 18F-MDPs have high specificity and sensitivity for bacteria because they are internalized by bacteria as a food source via the maltodextrin transport pathway, but are not internalized by mammalian cells as mammalian cells lack maltodextrin transporters. The experiments in this proposal focus on developing a novel conjugate of maltodextrin for use in PET imaging of bacteria and determining its efficacy in imaging infected medical implants. The central hypothesis of this proposal is that: Conjugates of maltodextrins with 18F will detect bacterial infections of implanted medical devices in a highly specific and sensitive manner. The following Specific Aims are proposed:
Specific Aim 1 : Synthesis and metabolism of 18F-labeled maltohexaose, 18F-thiomaltose and 18F- deoxythiomaltose Specific Aim 2: Internalization and metabolism of 18F-labeled maltohexaose, 18F-thiomaltose and 18F-deoxythiomaltose by bacteria known to cause medical device infections Specific Aim 3: Comparative in vivo imaging of medical device infections in rats with 18F-MDPs
Medical device infections pose a major health issue resulting in significant cost, mortality and morbidity. Currently, out techniques available for the detection of infected medical devices are very limited. In this proposal, we will develop and test a novel family of imaging probes to detect medical device infections in humans.
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| Wang, Xiaojian; Borges, Clarissa A; Ning, Xinghai et al. (2018) A Trimethoprim Conjugate of Thiomaltose Has Enhanced Antibacterial Efficacy In Vivo. Bioconjug Chem 29:1729-1735 |
