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.