Bacteriophage Therapy for Acute Fracture-Related Infections: An Effective Treatment When Compared With Antibiotics in a Canine Model.

Abstract

OBJECTIVES: To determine the effectiveness of bacteriophage therapy for the treatment of fracture related infections compared to antibiotic therapy in a preclinical canine model.Design:Preclinical controlled large-animal model study.Outcome and Measures Comparison:Clearance of bacteria based on CFU/g, callus formation based on radiographs and histomorphometry, callus maturity based on histomorphometry, and biofilm clearance based on semi-quantitative histomorphometry. METHODS: A canine model was used for this preclinical study examining bacteriophages specifically cultivated against Staphylococcus 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 S. 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 per 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. RESULTS: At 3 weeks, all dogs had confirmed infections. At 11 weeks, fractures that received bacteriophage therapy had statistically significant reductions in CFU/g when compared to those that did not receive bacteriophage. Fractures treated with bacteriophages had statistically significantly more robust callus formation on radiographs at 11 weeks, as well as, decreased biofilm formation and statistically significant increase in bone formation on histology/histomorphometry when compared to fractures that did not receive bacteriophages. CONCLUSIONS: Seven days of bacteriophage therapy was at least as good as 6 weeks of antibiotic therapy in terms of clearance of acute FRIs. It was superior in terms of reduction in CFU/g, better callus formation, and biofilm clearance.