INTRODUCTION: Prosthetic Joint infections (PJI) remain a devastaing problem in orthopaedic surgery. Treatment of PJI requires reoperation, long-term IV antibiotics and in many cases is not successful, with high rates of reinfection. Recent work has demonstrated that a subset of immune cells, myeloid derived suppressor cells (MDSC) may play a role in blunting the host immune response during Staphylococcus aureus PJI. These same cells have been found in tumor states where they have been shown to be downregulated using the phosphodiesterase 5 inhibitor (PDE5-I) sildenafil. We endeavored to examine whether sildenafil administration leads to decreased bacterial burden in vivo in an established mouse model of PJI.
METHODS: Two experiments were carried out. In each experiment, mice were divided into a treatment gorup and infected control (n=12 in each group). A 0.8 mm titanium implant was inserted into the right femurs in a retrograde fashion and the joint space was innoculated wiht bioluminescent S. aureus (1 x 103 colony forming units [CFUs]). The treatment group received daily intraperitoneal injections of sildenafil (20mg/kg in 100 µL) for 28 days, while the second infected control gorup received 100 µL daily saline injections. In vivo bioluminescent imaging was used to monitor bacterial burden for 28 days. Mice were sacrificed at post-operative day (POD) 28, and implant and tissue were harvested for CFU enumeration. On the second occasion, bacterial burden was monitored for 21 days via in vivo imaging, right knee joints were X-rayed, and right hind limbs were fixed in formalin for future histological analysis.
RESULTS: Sildenafil treated mice showed significantly lower bacterial burden based on bioluminescent signal from POD7-POD28 (p < 0.05). Mean CFUs from implants were lower for the sildenafil group vs infected controls, with CFUs enumerated from 8% (1/12) of sildenafil treatment implants versus 50% (6/12) of infected controls (p < 0.5). Tissue CFUs were lower in sildenafil treated mice compared to infected control mice, however this was not statistically significant.
CONCLUSION: This study demonstrated in a validated in vivo model of PJI that daily sildenafil significantly decreases bacterial burden and rate of implant infection compared to controls. Further study is needed to describe the mechanism of action, verify possible immune modulatory and vasodilatory effects, and explore other related PDE inhibitors. These preliminary findings suggest that sildenafil may have a role in treating PJI.