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The efficacies of the quinolones ciprofloxacin and pefloxacin alone and in combination with rifampin were compared with those of vancomycin alone and in combination with rifampin in a rat model of chronic osteomyelitis caused by methicillin-resistant Staphylococcus aureus. Neither the quinolones nor vancomycin alone was effective in reducing titers of organisms in bone after therapy, while rifampin alone was effective. All combination regimens with rifampin were more effective than the regimen with rifampin alone was, although these differences did not achieve statistical significance. Rifampin-resistant isolates were detected rarely. Quinolone-rifampin combination regimens may offer a nonparenteral option for the treatment of chronic osteomyelitis caused by methicillin-resistant S. aureus.