): 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.
This research proposal is directly relevant to public health and would advance the capability of infectious disease specialists to detect early response to treatment for patients with bacterial infection. This proposal to further validate F-18 fluorodeoxysorbitol (FDS) as a potential PET imaging agent for gram-negative bacteria by understanding its ability to triage drug options could potentially allow clinicians to quickly change the treatment plan, thereby minimizing patient stress, improving survival, and reducing treatment costs.
