Verification of a Novel Approach to Predicting Effects of Antibiotic Combinations: In Vitro Dynamic Model Study with Daptomycin and Gentamicin against Staphylococcus aureus

To explore whether susceptibility testing with antibiotic combinations at pharmacokinetically derived concentration ratios is predictive of the antimicrobial effect, a Staphylococcus aureus strain was exposed to daptomycin and gentamicin alone or in combination in multiple dosing experiments. The susceptibility of the S. aureus strain to daptomycin and gentamicin in combination was tested at concentration ratios equal to the ratios of 24 h areas under the concentration–time curve (AUC(24)s) of antibiotics simulated in an in vitro dynamic model in five-day treatments. The MICs of daptomycin and gentamicin decreased in the presence of each other; this led to an increase in the antibiotic AUC(24)/MIC ratios and the antibacterial effects. Effects of single and combined treatments were plotted against the AUC(24)/MIC ratios of daptomycin or gentamicin, and a significant sigmoid relationship was obtained. Similarly, when the effects of single and combined treatments were related to the total exposure of both drugs (the sum of AUC(24)/MIC ratios (∑AUC(24)/MIC)), a significant sigmoid relationship was obtained. These findings suggest that (1) the effects of antibiotic combinations can be predicted by AUC(24)/MICs using MICs of each antibacterial determined at pharmacokinetically derived concentration ratios; (2) ∑AUC(24)/MIC is a reliable predictor of the antibacterial effects of antibiotic combinations.