Novel PET Probe for Imaging-Based Differentiation of Foreign-Body-Associated Bacterial Infection from Sterile Inflammation.

Introduction: There has been a significant rise in surgical procedures involving implantation of prosthetic devices with a consequent increase in the number of associated infections. The incidence of infection in orthopedic trauma patients is high, depending upon type of injury, location, and severity of trauma. Other surgical procedures like implantation of cardiac devices, instrumented spinal fusions, and vascular grafts can also be associated with serious microbial infections. However, after invasive surgical procedures, it can be difficult to differentiate between inflammation and infection, which is needed to define ideal treatment. Diagnosis of bacterial infection can be challenging, especially in the early stage and deep-seated infections. Thus, there is a clinical need for reliable, sensitive, and specific noninvasive imaging to identify bacterial infection and differentiate it from inflammation. Herein, we developed a novel small molecule-based PET imaging probe, [⁶⁸Ga]Ga-BP, and evaluated it in foreign body methicillin-resistant Staphylococcus aureus (MRSA) osteomyelitis, in comparison with inflamed and normal rat models and also compared results to those with [⁶⁸Ga]Ga-Citrate and [¹⁸F]FDG.

Methods: Synthesis of [⁶⁸Ga]Ga-BP was carried out with >98% radiochemical purity with a final pH of 6.0-6.5 before injection. MRSA foreign body osteomyelitis was generated in Wistar rats, with uninfected instrumented animals used for comparison. At day 7 post-surgery, the diet of the rats was switched from normal chow diet to an iron-deficient diet and deionized water for the ensuing 7 days. On day 14 post-surgery, the rats fasted for 6 h before administration of [⁶⁸Ga]Ga-BP. On the day of imaging, [⁶⁸Ga]Ga-BP (35.11±3.59 MBq, n = 5), [⁶⁸Ga]Ga-citrate (26.32±7.99 MBq, n = 4) and [¹⁸F]FDG (40.35±2.97MBq, n = 4) were injected into the tail vein of normal, MRSA and instrumented non-infected groups of Wistar rats with foreign body. After administration of the radiotracers, all animals underwent a 10 min static PET scan at 15, 30, 60, and 120 min post-injection (p.i) followed by 7 min CT scan using Siemens Inveon PET/CT scanner. Acquired images were analyzed using MIM 7.2.7 software. After final imaging, animals were euthanized, and vital organs/tissues and infected tibia harvested for ex vivo biodistribution. The extent of infection in terms of CFU/g was calculated from harvested vital organs and infected tibiae.

Results: The MRSA infected foreign body osteomyelitis model had ~1.3E+07 CFU MRSA/g (mean) in infected tibia with no bacteria isolated from the liver, kidney, urine, or blood. Imaging showed >10-fold higher uptake in infected tibiae than contralateral tibiae at 120 min post injection (Figure 1A-B). The higher uptake of [⁶⁸Ga]Ga-BP in infected tibiae appeared as early as 15 min p.i. and increased over time. In addition, [⁶⁸Ga]Ga-BP differentiated between the inflammation and bacterial infection (Figure 1C-D). Comparing uptake of [⁶⁸Ga]Ga-BP, in normal, instrumented uninfected; and infected tibiae, there was a significant difference in uptake of [⁶⁸Ga]Ga-BP between instrumented uninfected and infected tibiae. Comparison of [⁶⁸Ga]Ga-BP with [⁶⁸Ga]Ga-citrate and [¹⁸F]FDG showed superiority of [⁶⁸Ga]Ga-BP in identifying the site of bacterial infection.

Conclusions: The developed novel PET probe, [⁶⁸Ga]Ga-BP, showed superior imaging capability to identify MRSA-infected tibiae as compared to [⁶⁸Ga]Ga-citrate or [¹⁸F]FDG, offering potential clinical and commercial value in diagnosing the bacterial infection and differentiating it from sterile inflammation. Acknowledgment: We thank the Division of Nuclear Medicine at Mayo Clinic, National Center for Advancing Translational Sciences of NIH grants UL1TR002494/UL1TR002377, and Minnesota Partnership for Biotechnology and Medical Genomics Translational Product Development Fund for funding this study. There is a pending patent application on this technology.

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