Since
levofloxacin at high doses was more active than
levofloxacin at conventional doses and was the best
therapy alone in a rat model of staphylococcal
foreign-body infection, in this study we tested how these differences affect the activities of their respective combinations with
rifampin in vitro and in vivo. In vitro studies were performed in the log and stationary phases. By using this model,
rifampin at 25 mg/kg of
body weight/12 h,
levofloxacin at 100 mg/kg/day,
levofloxacin at 100 mg/kg/day plus
rifampin,
levofloxacin at 50 mg/kg/day,
levofloxacin at 50 mg/kg/day plus
rifampin, or a control treatment was administered for 7 days; and
therapy with for
levofloxacin at 100 mg/kg/day alone and
rifampin alone was prolonged to 14 days. We screened for the appearance of resistant strains. Killing curves in the log phase showed a clear antagonism with
levofloxacin at concentrations >or=2x MIC and
rifampin and tended to occur in the stationary phase. At the end of 7 days of
therapy,
levofloxacin at 100 mg/kg/day was the best treatment and decreased the bacterial counts from
tissue cage fluid (P < 0.05 compared with the results for groups except those receiving
rifampin alone). At the end of 14 days of
therapy with
levofloxacin at 100 mg/kg/day,
levofloxacin at 100 mg/kg/day plus
rifampin, and the control treatment, the bacterial counts on the coverslips were 2.24 (P < 0.05 compared with the results with the combined
therapy), 3.36, and 5.4 log CFU/ml, respectively. No
rifampin or
levofloxacin resistance was detected in any group except that receiving
rifampin alone. In conclusion, high-dose
levofloxacin was the best treatment and no resistant strains appeared; the addition of
rifampin showed an antagonistic effect. The efficacy of the
rifampin-
levofloxacin combination is not significantly improved by the dosage of
levofloxacin.