Fibrinolytic and antibiotic treatment of prosthetic vascular graft infections in a novel rat model

Abstract

Objectives We developed a rat model of prosthetic vascular graft infection to assess, whether the fibrinolytic tissue plasminogen activator (tPA) could increase the efficacy of antibiotic therapy. Materials and methods Rats were implanted a polyethylene graft in the common carotid artery, pre-inoculated with approx. 6 log10 colony forming units (CFU) of methicillin resistant Staphylococcus aureus. Ten days after surgery, rats were randomized to either: 0.9% NaCl (n = 8), vancomycin (n = 8), vancomycin + tPA (n = 8), vancomycin + rifampicin (n = 18) or vancomycin + rifampicin + tPA (n = 18). Treatment duration was seven days. Approximately 36 hours after the end of treatment, the rats were euthanized, and grafts and organs were harvested for CFU enumeration. Results All animals in the control group had significantly higher CFU at the time of euthanization compared to bacterial load found on the grafts prior to inoculation (6.45 vs. 4.36 mean log10 CFU/mL, p = 0.0011), and both the procedure and infection were well tolerated. Vancomycin and rifampicin treatment were superior to monotherapy with vancomycin, as it lead to a marked decrease in median bacterial load on the grafts (3.50 vs. 6.56 log10 CFU/mL, p = 0.0016). The addition of tPA to vancomycin and rifampicin combination treatment did not show a further decrease in bacterial load (4.078 vs. 3.50 log10 CFU/mL, p = 0.26). The cure rate was 16% in the vancomycin + rifampicin group vs. 37.5% cure rate in the vancomycin + rifampicin + tPA group. Whilst interesting, this trend was not significant at our sample size (p = 0.24). Conclusion We developed the first functional model of an arterial prosthetic vascular graft infection in rats. Antibiotic combination therapy with vancomycin and rifampicin was superior to vancomycin monotherapy, and the addition of tPA did not significantly reduce bacterial load, nor significantly increase cure rate.

Efficacy of rifampicin combination therapy against MRSA prosthetic vascular graft infections in a rat model

“…The rat VGEI model used in this study has previously been described [ 17 ]. Briefly, pre-operatively the rats were given cefuroxime (50 mg/kg, B. Braun, Melsungen, Germany) and buprenorphine (0.05 mg/kg, “Temgesic”, Indivior, Slough, UK) subcutaneously and then anesthetized with isoflourane (Zoetis, Helsinki, Finland).…”

“…Differences in cure rate were assessed via Fisher’s exact test. Based on previous experiments in the same model, we assumed a 0% cure rate in animals treated with monotherapy of antibiotics and a >40% cure rate in animals treated with combination treatment of antibiotics + rifampicin [ 17 ]. Based on power calculations this resulted in a sample size of 13 rats pr.…”

“…We have previously shown a dramatic increase in therapeutic effect when combining vancomycin with rifampicin to treat early MRSA VGEI in a novel rat model [ 17 ]. This finding led us to hypothesize that combination of other antibiotics with rifampicin would also improve the antimicrobial efficacy against MRSA infections.…”