Predicting effects of antibiotic combinations using MICs determined at pharmacokinetically derived concentration ratios: in vitro model studies with linezolid- and rifampicin-exposed Staphylococcus aureus

Abstract

To predict the effects of combined use of antibiotics on their pharmacodynamics, the susceptibility of Staphylococcus aureus to linezolid–rifampicin combinations was tested at concentration ratios equal to the ratios of 24-area under the concentration–time curve (AUC₂₄) simulated in an in vitro dynamic model. The linezolid MICs in combination with rifampicin decreased 8- to 67-fold. The rifampicin MICs were similar with or without linezolid. The enhanced activity of linezolid combined with rifampicin increased the AUC₂₄/MIC ratios and provided more pronounced antibacterial effects compared with single treatments. The areas between the control growth and time-kill curves (ABBCs) determined in combined and single treatments with linezolid were plotted against AUC₂₄/MIC on the same graph (r² 0.94). These findings suggest that the effects of linezolid–rifampicin combinations can be predicted by AUC₂₄/MICs of linezolid using its MIC determined at pharmacokinetically derived linezolid-to-rifampicin concentration ratios.

Keywords:

• Linezolid
• Rifampicin
• Staphylococcus aureus
• Pharmacodynamics
• In vitro dynamic model