A Folate-Targeted PET Radiotracer to Guide Antibiotic Therapy in Vertebral Discitis-Osteomyelitis
Abstract
Investigators: This proposal represents the joint efforts of Dr. David Wilson M.D., Ph.D. (University of California, San Francisco) and Dr. Sanjay Jain M.D. (Johns Hopkins). Dr. Wilson is the chief of neuroradiology at the San Francisco VA Medical Center and is motivated to study spinal infection based on challenging diagnostic cases seen in clinical practice. Dr. Jain is an Infectious Diseases physician whose practice involves many difficult-to-diagnose infections, and whose lab has developed several new imaging methods to study bacteria. Hypothesis: The central hypothesis of this proposal is that imaging methods targeting bacteria-specific metabolic pathways will allow highly accurate diagnosis of active infections. This strategy has been used for decades in designing powerful antibiotics. For example, penicillin and vancomycin block important pathways in cell-wall synthesis (human cells don’t have cell walls). We believe that imaging methods based on this concept will allow easy distinction between “them” and “us,” allowing better diagnosis and treatment of infections. Motivation: The diagnosis of bacterial infections can be difficult in clinical practice. This is primarily because symptoms caused by other issues (viral infection, inflammatory disorders, etc.) are often similar to those caused by bacterial infections. One result is that infected patients suffer if they are not properly diagnosed and treated with antibiotics. Another concern is over-treatment; many patients are administered antibiotics who do not need them. Many antibiotics have side effects that would ideally be avoided. Furthermore, overuse of antibiotics contributes to the global problem of antibiotic resistance. This proposal aims to both combat this dangerous trend and improve the care of individual patients by improving the diagnosis of bacterial infections. Summary of Proposal: Many methods to diagnose infection rely on imaging. These methods include computed tomography (CT) and magnetic resonance imaging (MRI) that provide structural information on bones, muscles, etc. but are frequently inadequate to diagnose active infections. In this proposal, we develop a method to detect infection based on bacterial metabolism. This technique uses positron emission tomography (PET), an imaging technique commonly used for the diagnosis of cancer. While most PET scanning uses a molecule similar to glucose to identify “hot” tissues with increased metabolism, we will use a molecule that only bacteria use namely para-aminobenzoic acid (PABA). One of the reasons why PABA has been used in sunscreen is that it is nontoxic and not metabolized by human tissues. In contrast, bacteria need PABA to make folic acid (vitamin B9) and accumulate it very rapidly. Motivated by this difference, we developed the first synthesis of “hot” PABA labeled by the radionucleus carbon-11 and showed that it can detect infection in mice. In this proposal, we further study carbon-11 PABA imaging in spinal infection, and describe how it can be used to help guide early antibiotic treatment. We will show not only that carbon-11 PABA could provide information on the type of organism present, but also could quickly tell doctors whether a bacterial infection is responding to therapy. Impact: Since carbon-11 PABA was synthesized and tested for the first time in the Wilson and Jain laboratories only recently, the main focus of this 3-year award is better understanding how the method will work in complex clinical scenarios. Therefore, the focus of this proposal is on evaluating carbon-11 PABA in advanced animal (rat) models. However, there are no barriers preventing translation to humans in the near-term. The impact of a new technology to better diagnose acute bacterial infections would be high for both military and civilian populations. Relevance to Topic Area: In developing bacteria-specific methods for imaging infection, we will address antimicrobial resi
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810641
Entities
People
- David M Wilson
Organizations
- United States Army
- University of California, San Francisco