Predicting the antistaphylococcal effects of daptomycin-rifampicin combinations in an in vitro dynamic model

To predict the effects of combined use of antibiotics on their pharmacodynamics, the susceptibility of Staphylococcus aureus to daptomycin-rifampicin combinations was tested at concentration ratios equal to the ratios of daptomycin and rifampicin 24-h areas under the concentration-time curve (AUC₂₄s) simulated in an in vitro dynamic model. In combination with rifampicin, daptomycin MICs decreased 2- to 31-fold, whereas rifampicin MICs were similar with or without daptomycin. The enhanced susceptibility of S. aureus to daptomycin combined with rifampicin resulted in both an increase of the actual AUC₂₄/MIC ratios and also more pronounced antibacterial effects compared with single treatments. The areas between the control growth and time-kill curves (ABBCs) determined in combined and single daptomycin treatments were plotted against AUC₂₄/MIC on the same graph (r² 0.90). These findings suggest that the effects of daptomycin-rifampicin combinations can be predicted by AUC₂₄/MICs of daptomycin using its MIC determined at pharmacokinetically derived daptomycin-to-rifampicin concentration ratios.