The increasing number of implant-associated infections and of multiresistant pathogens is a major problem in the daily routine. In the field of osteomyelitis, it is difficult to manage a valid clinical study because of multiple influencing factors. Therefore, models of osteomyelitis with a simulation of the pathophysiology to evaluate treatment options for implant-associated infections are necessary. The aim of this study is to develop a standardized and reproducible osteomyelitis model in-vivo to improve treatment options. This study analyses the influence of a post-infectious implant exchange one week after infection and the infection progress afterward in combination with a systemic versus a local antibiotic treatment in-vivo. Therefore, the implant exchange, the exchange to a local drug-delivery system with gentamicin, and the implant removal are examined. Furthermore, the influence of an additional systemic antibiotic therapy is evaluated. An in-vivo model concerning the implant exchange is established that analyzes clinic, radiologic, microbiologic, histologic, and immunohistochemical diagnostics to obtain detailed evaluation and clinical reproducibility. Our study shows a clear advantage of the combined local and systemic antibiotic treatment in contrast to the implant removal and to a non-combined antibiotic therapy. Group genta/syst. showed the lowest infection rate with a percentage of 62.5% concerning microbiologic analysis, which is in accordance with the immunohistochemical, cytochemical, histologic, and radiologic analysis. Our in-vivo rat model has shown valid and reproducible results, which will lead to further investigations regarding treatment options and influencing factors concerning the therapy of osteomyelitis and implant-associated infections.