A novel model of experimental foreign body infection was developed in rats: four perforated Teflon tissue cages per animal were implanted subcutaneously and 3 to 4 weeks later were infected with 0.5 x 10(5) to 2 x 10(5) CFU of methicillin-resistant Staphylococcus aureus. After 2 weeks, the number of CFU in the cage fluid was determined [day 1 mean, (7.25 +/- 0.79) log10 CFU/ml], and treatment with vancomycin (50 mg/kg twice a day [BID]), fleroxacin (50 mg/kg BID), or fifampin (25 mg/kg BID), alone and in combination, was initiated for a duration of 6 days. Concentrations of antibiotics in cage fluids were in the range of those encountered in clinical conditions. Eighteen hours after the last injection (day 7), the number of CFU in the cage fluid was determined and the difference between day 1 and day 7 values was calculated. Rifampin, alone and in combination with fleroxacin or vancomycin, was the most effective regimen in reducing the bacterial counts in the tissue cage fluids [(1.87 +/- 1.44, 2.18 +/- 1.02, and 2.55 +/- 1.09 log10) CFU/ml, P less than 0.001, respectively]. After treatment, cage fluids and cages were analyzed for resistant bacteria. Resistance to rifampin occurred in 15 of 19 cages in animals treated with rifampin alone and in 4 of 25 in animals treated with rifampin plus vancomycin. We detected no development of resistance to rifampin in animals treated with rifampin plus fleroxacin or to fleroxacin in animals treated with this antimicrobial agent. In conclusion, regimens including rifampin alone or in combination with vancomycin or fleroxacin were an effective treatment of foreign body infection due to methicillin-resistant S. aureus in reducing bacteria counts, but rifampin monotherapy was compromised by significant emergence of resistance. The combined therapy of fleroxacin with rifampin prevent development of resistance to rifampin.