The prophylactic and therapeutic activities of teicoplanin were evaluated in two different experimental models of foreign body infections caused by methicillin-resistant Staphylococcus aureus (MRSA). In a guinea pig model of prophylaxis, subcutaneously implanted tissue cages were infected at a > 90% rate by 10(2) CFU of MRSA in control animals. A single dose of 30 mg of teicoplanin per kg of body weight administered intraperitoneally 6 h before bacterial challenge was as effective as vancomycin in preventing experimental infection in tissue cages injected with either 10(2), 10(3), or 10(4) CFU of MRSA. In a rat model evaluating the therapy of chronic tissue cage infection caused by MRSA, the efficacy of a 7-day high-dose (30 mg/kg once daily) regimen of teicoplanin was compared with that of vancomycin (50 mg/kg twice daily). Whereas high levels of teicoplanin were found in tissue cage fluid, continuously exceeding its MBC for MRSA by 8- to 16-fold, no significant reduction in the viable counts of MRSA occurred during therapy. In contrast, either vancomycin alone or a combined regimen of high-dose teicoplanin plus rifampin (25 mg/kg twice daily) could significantly decrease the viable counts in tissue cage fluids. Whereas the bacteria recovered from tissue cage fluids during therapy showed no evidence of teicoplanin resistance, they failed to be killed even by high levels of this antimicrobial agent. The altered susceptibility of in vivo growing bacteria to teicoplanin killing might in part explain the defective activity of this antimicrobial agent when used as monotherapy against chronic S. aureus infections. These data may indicate the need for a combined regimen of teicoplanin with other agents such as rifampin to optimize the therapy of severe staphylococcal infections.