Bacterial persistence
Our focus is to use innovative molecular imaging technologies to optimize clinical care in complicated bone infections. Bone infections, particularly those involving prosthetic joints and other implants are devastating complication with rising incidence. Staphylococcus aureus is a major human pathogen causing various clinical syndromes, including implant-associated orthopedic infections. Current treatments for S. aureus implant-associated infection have not been optimized owing to lack of data on bacterial dynamics and antibiotic pharmacokinetics at the site of infection.
One example is the pharmacokinetics of rifampin, a well-known drug that targets S. aureus in implant-associated infection. Previous findings from pre-clinical animal models as well as clinical imaging studies in human patients, revealed rifampin concentrations in infected bone are lower than previously thought. Importantly, the currently used rifampin dose results in inadequate drug concentrations in bone. High-dose rifampin, however, can shorten the duration of therapy without increasing treatment failure rate. Moreover, high-dose rifampin can mitigate development of bacterial resistance and selection of mutations in bacterial genes related to persistence. We now decipher the mechanisms responsible for bacterial persistence and re-emergence of virulence under changing antibiotic pressure.
Pathogen-Specific Imaging
Diagnosis and monitoring of bone infections is key for rapid and precise treatment to achieve cure. While, Gram-positive bacteria cause most bone infections, Gram-negative bone infection may be devastating in vulnerable patients, such as diabetic foot ulcers and in patients undergoing orthopedic surgery with implants. Treatment often requires surgery to remove infected bone and/or implant and is likely to result in serious disabilities (e.g., limb amputation). Antibiotic treatment is often sub-optimal due to limited drug penetration into bone and bacterial biofilm. However, when bone is not involved (e.g., superficial skin and soft tissue infection), antibiotic treatment is likely to be efficient and surgery may be avoided. Current diagnostics (e.g., CT, MRI) lack sufficient sensitivity and specificity to detect bone infection. Establishing a novel bacterial-specific PET-based imaging method will facilitate a rapid method for not only a more specific way to diagnose infections (e.g., live bacteria versus sterile-inflammation or post-operative changes) but also a more-specific method to monitor treatment.
2-Deoxy-2-[18F]fluoro-d-sorbitol (18F-FDS) is a pathogen-specific PET tracer that detects Enterobacterales via a conserved sorbitol-specific pathway. We have recently developed a novel mouse model for Gram negative implant-associated spine infection. Using this murine model, we found that 18F-FDS is sensitive and specific for Gram negative bone infection. We are now advancing to translate this modality to clinical use.
Sex-differences in bone infection
Host-drug-pathogen interactions are highly sex-specific. Male patients with implant-associated infections have worse outcomes than females and male mice with S. aureus orthopedic implant infections have a higher bacterial burden then females. The basis for this increased risk is not well understood. While behavioral differences, such as personal hygiene, occupation, and sport’s activities, may explain some of these differences, genetic and physiological factors, such as the inflammatory response, play a major role. Important sex-differences are also observed in drug metabolism. Elucidating male versus female host-determinants, drug concentration in situ and resulting pathogen dynamics, will facilitate the development of novel sex-specific treatment strategies to enhance antibiotic efficacy and reduce recurrence.