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A puzzling case report of a septicaemic post-surgical staphylococcal knee arthritis which did not respond to long-term courses of associated rifampicin and teicoplanin or vancomycin, despite apparently favourable in vitro susceptibility assays, but which rapidly resolved after i.v. followed by oral administration of linezolid is presented, and discussed in the context of the most recent literature evidence. The lack of response to a 14-d-long course of glycopeptides does not find explanation from the in vitro minimum inhibitory concentrations (MIC90) of involved organisms, which showed full susceptibility of Staphylococcus aureus to vancomycin and teicoplanin, and sensitivity of an accompanying Staphylococcus epidermidis isolated from blood cultures to vancomycin and rifampicin, with borderline ‘intermediate’ values found for teicoplanin. Since neither bone involvement nor abscess formation was of concern, effective glycopeptide and rifampicin penetration into infectious tissue should have been assured. From a clinical viewpoint, the introduction of a 2-week i.v. linezolid followed by 1 further week of oral linezolid led to complete clinical and microbiological cure, and an unexpected functional success.