Antagonistic effect of rifampin on the efficacy of high-dose levofloxacin in staphylococcal experimental foreign-body infection

Abstract

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.

FIG. 1.

Time-kill curves for strain in the log phase obtained with subinhibitory and clinically available concentrations (μg/ml) (A) and in the stationary phase obtained with the trough and peak concentrations (B) in TCF of rats treated with levofloxacin (LVX) alone and in combination with rifampin (RIF). Note that the levofloxacin concentrations used in the log-phase studies were lower than those used in the stationary-phase studies. In the stationary-phase studies, the trough concentrations of levofloxacin were equivalent to the subinhibitory ones in the log phase, whereas two peak concentrations of levofloxacin are represented as being equivalent to the peak levels of both dosages. The antagonistic effect obtained with the combination of levofloxacin and rifampin in the log phase was observed with levofloxacin at concentrations of 1 and 4 μg/ml (LVX 1 and LVX 4, respectively), whereas the combination of levofloxacin at 12 μg/ml (LVX 12) and rifampin in the stationary phase decreased the efficacy of levofloxacin at 12 μg/ml alone by more than 1 log CFU/ml. Errors bars indicate standard deviations; in some cases, the bars are smaller than the symbols and so cannot be seen.

FIG. 2.

Between-group comparisons of the decreases in bacterial counts from TCF (mean log CFU/ml) at the end of 7 days and 14 days of therapy. The n values represent the number of TCF samples and not the number of animals for each group. Note that the number of samples used for the two groups treated with levofloxacin at 100 mg/kg/day and levofloxacin at 100 mg/kg/day plus rifampin for the studies with 7 days of therapy was larger than that for the remaining therapeutic groups because the animals were maintained for a longer period. Differences in efficacy between the two therapeutic groups were maintained over time, although the number of samples included in the study with 14 days of therapy was less than that in the study with 7 days of therapy. Errors bars indicate standard deviations. Abbreviations and symbols: 7d, 7 days of therapy; 14d, 14 days of therapy; LVX, levofloxacin; RIF, rifampin; CTRL, control; *, P < 0.05 versus the results for the control; **, P < 0.05 versus the results for the groups treated with levofloxacin at 50 mg/kg/day (LVX 50) plus rifampin and levofloxacin at 100 mg/kg/day (LVX 100) plus rifampin and P < 0.03 versus the results for the groups treated with levofloxacin at 50 mg/kg/day and the controls.