Correlation of vancomycin and daptomycin susceptibility in Staphylococcus aureus in reference to accessory gene regulator (agr) polymorphism and function

Objectives: Recently, an association between the accessory gene regulator (agr) in Staphylococcus aureus and the development of vancomycin resistance secondary to suboptimal exposure has been demonstrated. We investigated the relationship of vancomycin with and without gentamicin or rifampicin, and daptomycin in the development of resistance in agr groups I and II. Methods: S. aureus belonging to agr groups I and II was exposed to varying concentrations of vancomycin and daptomycin simulating an fAUC/MIC of 14-460 and 30-239, respectively, in an in vitro pharmacodynamic model. Results: Vancomycin regimens resulting in fAUC/MIC of 16.1-107.0 resulted in resistance in agr I and agr II knockout strains, whereas regimens resulting in fAUC/MIC of 16.1 resulted in emergence of resistance in agr I- and agr II-positive strains. Overall, agr-null strains demonstrated a higher likelihood of resistance and a greater change in vancomycin susceptibility. The addition of gentamicin and rifampicin to vancomycin at these same exposures prevented the emergence of resistance. At extremely low daptomycin exposures of fAUC/MIC of 22-66, an increase in MIC of 2-3-fold up to a maximum of 0.75 mg/L was observed. However, this was independent of agr group and/or function and still within the susceptible range of daptomycin. Conclusions: The combination of vancomycin with either rifampicin or gentamicin prevented the emergence of vancomycin resistance in agr I and II S. aureus isolates. Changes in daptomycin susceptibility were independent of agr group and function. The association between agr and vancomycin resistance in S. aureus requires further investigation.