Pharmacodynamic and response surface analysis of linezolid or vancomycin combined with meropenem against Staphylococcus aureus

Abstract

Purpose: To systematically assess the impact of pharmacodynamic interactions when adding either linezolid or vancomycin to meropenem on the antibacterial activity against methicillin-susceptible Staphylococcus aureus (MSSA). These regimens are frequently used in empiric therapy when risk factors for MRSA are present, but MSSA will often turn out as pathogen. Methods: Checkerboard and time-kill curve studies were performed against three strains of MSSA covering clinically relevant concentrations of all antibiotics. We newly elaborated a response surface analysis (RSA) to quantify the extent of the pharmacodynamic interactions. Results: The most prominent result was that linezolid fully antagonised the rapid (4-6 h) bactericidal effect of meropenem against MSSA to bacteriostasis at clinically relevant concentrations of both drugs. This interaction was invisible in the conventional checkerboard analysis (insensitive turbidity threshold). RSA quantified a 1.5-3.2 log10-fold higher bacterial load compared to expected additivity for linezolid and meropenem. Vancomycin and meropenem interacted partly synergistic (subinhibitory) or additive (inhibitory combinations) being bactericidal after 24 h. Conclusions: Standard doses of linezolid and meropenem will provide inhibitory concentrations and thus pharmacodynamic antagonism throughout the whole dosing interval for MSSA. Further data is required to assess the clinical significance of this interaction.