Arthroplasty is a life enhancing surgery, however a significant number of prosthetic joints fail due to biofilm related bacterial infections; mainly S. aureus. Currently available prosthetic joint infection (PJI) treatments are traumatic, costly, and have high failure rates with significant morbidity and mortality. Cheaper and less traumatic therapeutic options with better success rates are needed. Ticagrelor, an anti-platelet drug used for treatment of atherosclerosis, has previously been known to inhibit S. aureus biofilm formation and bacterial dissemination to surrounding tissues in a pre-colonised subcutaneous disc infection animal model.
We used in-vitro experiments followed by a pre-clinical animal study to test therapeutic efficacy of ticagrelor ± cephazolin for treatment of S. aureus PJI. Mice were randomised into five groups (n=8/group): (i) sterile implants; (ii) infected implants + PBS; (iii) infected implants + cephazolin; (iv) infected implants + ticagrelor and; (v) infected implants + ticagrelor and cephazolin. S. aureus biofilm formation was induced on knee implant of mice by contaminating the cut end protruding into the joint space. Ticagrelor (3mg/kg loading dose followed by 1.5mg/kg twice daily) was administered through oral gavage from day 4 to day 7 post-surgery, while cephazolin (2.5mg/kg) was given intravenously on day 7. On day 14 post-surgery, mice were euthanised, and implants and surrounding tissues were collected for microbiological quantification and histological analysis.
Ticagrelor ± cephazolin showed in-vitro antimicrobial and antibiofilm activities against S. aureus and down regulated biofilm related genes, fib and icaD. Ticagrelor ± cephazolin significantly reduced bacterial concentration on the implants in comparison to PBS treated control (log10cfu/ml, 3.2 versus 0.8 and 3.2 versus 1.6) (p<0.05). In addition, ticagrelor reduced bacterial dissemination into surrounding tissues (log10cfu/ml, 7.1 versus 3.6) (p<0.05). These results were supported by peri-prosthetic tissue histology. Our results suggest that ticagrelor may be a good drug candidate for development of an adjuvant therapy for biofilm related S. aureus PJI.