Bacteriophage Therapy for Acute Fracture-Related Infections: An Effective Treatment When Compared to Antibiotics In A Canine Model.

Abstract

Acute fracture-related infections are challenging problems, affecting up to 20% of orthopaedic trauma patients. High recurrence rates, secondary surgeries, and rehospitalizations lead to increased healthcare costs and are major burdens to patients. Bacteriophage therapy offers a potential alternative treatment option to address these challenges. In previous studies, it has been shown to be effective against biofilm and bacterial clearance on orthopaedic implants, however, their effects on fracture healing are poorly understood. The aim of this study was to determine if bacteriophages are as good as antibiotic therapy for the treatment of fracture related infection. A canine model was used for this preclinical study examining bacteriophages specifically cultivated against S. aureus (OJ1). Based on sample size calculations and ethical care and use of animals, bilateral 1 cm ulnar defects (n=32; 16 dogs) were created and stabilized using plate and screw fixation. Implants were incubated in a suspension of biofilm-producing Staphylococcus aureus (OJ1). After 3 weeks, bone samples from fracture sites were cultured and surgical sites underwent irrigation and debridement (I&D) with retention of hardware, followed by 1 of 4 treatments (n=8/group): no additional treatment, 6 weeks of parenteral antibiotics, 7 days of bacteriophage therapy, or combination antibiotic/bacteriophage therapy. At 11 weeks, dogs were humanely euthanatized and bacterial load, callus formation, and histomorphometry for callus maturity and biofilm formation were assessed using quantitative microbial bone cultures, radiography and semi-quantitative histomorphometry. At 3 weeks, all surgical sites/ulnae had confirmed infections . At 11 weeks, fractures that received bacteriophage therapy (542 ± 204 CFU/g) had statistically significantly less CFU/g when compared to those (45,065 ± 4,409 CFU/g) that did not receive bacteriophage (p=0.033). Fractures treated with bacteriophages had statistically significantly (p<0.0001) more robust callus formation on radiographs at 11 weeks (77.7% ± 9% vs 52.5% ± 14%), as well as decreased biofilm formation (median = 1 vs 2; p=0.049) and statistically significant (p=0.035) increase in bone formation on histology/histomorphometry when compared to fractures that did not receive bacteriophages (20.7 ± 6 vs 15.7 ± 7). Seven days of bacteriophage therapy was at least as good as 6 weeks of antibiotic therapy in terms of clearance of acute fracture-related infections. It was superior in terms of reduction in CFU/g, better callus formation, and biofilm clearance.