Additive effects of exogenous IL-12 supplementation and antibiotic treatment in infection prophylaxis

Abstract

The increasing clinical incidence and host risk of open fracture-associated infections, as well as the reduced effectiveness of conventional antibiotics to treat such infections, have driven the development of new therapies for the prophylaxis of open fracture-associated infections. We investigated percutaneous supplementation of a natural cytokine (i.e., interleukin 12p70 or IL-12) at an open fracture site to reduce open fracture-associated infections. We also determined the efficacy of the combination therapy of IL-12 and conventional antibiotic therapy in the prophylaxis of open fracture-associated infections. An open femur fracture infection model was produced by direct inoculation of a clinical isolate of Staphylococcus aureus after creating a femur fracture using rats. The animals were assigned to one of four groups: no drug administration, percutaneous supplementation of IL-12, intraperitoneal administration of the antibiotic ampicillin, or percutaneous IL-12 in combination with intraperitoneal ampicillin. Animals were euthanized at postoperative days 6, 10, 14, and 21. Percutaneous IL-12 led to a reduction in infection at postoperative days 6 and 10. For the first time, exogenous IL-12 was found to have additive effects in the prevention of infection when combined with conventional treatment (i.e., antibiotic therapy). Combination therapy of ampicillin and IL-12 substantially reduced the infection rate at postoperative day 6 and also decreased the time needed for complete inhibition of infection. Therefore, exogenous IL-12, providing a mechanism of protection independent of antibiotic resistance, complements the routine use of antibiotics.

Figure 1

Procedures in creating an open femur fracture and subsequent percutaneous IL-12 injection. (a) Creation of a femur fracture using a custom-designed setup; (b) exposure of the fracture; (c) bacterial inoculation; (d) intramedullary fixation of the fracture using a K-wire; and (e) percutaneous injection of IL-12. The arrow shows the fracture site.

Figure 2

Weight loss of rat groups. Data are an average of 4–6 rats.

Figure 3

Normalized intensity of MHC II on 1C7+ cells. The intensity of the control group was set at 100.

Figure 4

Systemic responses: (a) WBCs; (b) platelets; (c) neutrophils; (d) lymphocytes; and (e) monocytes. Shadowed areas indicate the reference levels.

Figure 4

Systemic responses: (a) WBCs; (b) platelets; (c) neutrophils; (d) lymphocytes; and (e) monocytes. Shadowed areas indicate the reference levels.