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In the case of severe defects, the biological substrate, including the bones or dentin, is essential. While aseptic loosening of the components of a prosthesis, commonly occurring at an advanced age, is the most common cause of total failure and is also a manifestation of periprosthetic infection, the least frequently observed, but often the most devastating, cause of late prosthetic failure is infection at the implantation sites. Whereas aseptic loosening is a complex process of biological failure dependent upon both genotypic and phenotypic considerations, infection at the implantation sites results from dissemination of an infecting agent from distant sources, usually from the respiratory tract, from areas of impaired host resistance or from contact with contaminated material. The majority of infections are treated empirically, and the combined application of antibacterial agents in combination with bone grafts and/or membranes is currently the most common treatment. Empirical antibacterial therapy usually results in a limited success, which is defined as a reasonable expectation of clinical and radiographical success with the applied treatment modalities. Early intervention and radical excision of infected implants and infected bone are very important for the prognosis of successful outcomes. The number of reported clinical failures is not an adequate measure of the efficacy of the treatment protocols, which are dependent upon many factors, including host immune resistance and environmental factors. Evidence based criteria need to be applied in the follow-up of cases with severe infectious complications. In the case of periprosthetic infection, such evidence based criteria should always include at least resection of the infected components and/or implantation of the new prosthesis in a clean surgery and application of appropriate principles for debridement and application of antibacterial substances. 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