Experimental study on the efficacy of combinations of glycopeptides and β-lactams against Staphylococcus aureus with reduced susceptibility to glycopeptides

Objectives: The combination of glycopeptides and beta-lactams has been proposed as an alternative therapy against infections due to Staphylococcus aureus with reduced susceptibility to glycopeptides, though its role is still controversial. Our aim was to evaluate the efficacy (decrease in bacterial concentration after 24 h therapy) of these combinations both in vitro and in vivo. Methods: Four strains of S. aureus with different glycopeptide susceptibility (MICs of vancomycin from 1 to 8 mg/L) were used. In vitro experiments were performed by means of time-kill curves while we used the mouse peritonitis model for in vivo evaluation. Results: Combinations of glycopeptides and beta-lactams showed synergy in in vitro time-kill curves against the four staphylococcal strains, the highest efficacy being detected against the glycopeptide-intermediate S. aureus (GISA) strain (MIC = 8 mg/L) (Delta log 24 h = -3.19 cfu/mL for vancomycin at 1/2 x MIC and oxacillinat 1/64 x MIC versus -0.56 cfu/mL for vancomycin alone at 1/2 x MIC). On the other hand, no significant increase in efficacy was observed in vivo in the experimental model. The efficacy of the combinations decreased in correlation to the decreasing susceptibility of the strains to glycopeptides, showing only residual activity against the GISA strain (Delta log 24 h = -1.42 cfu/mL for vancomycin and cloxacillin versus -1.22 cfu/mL for vancomycin). Conclusions: In the in vivo setting we were unable to demonstrate the synergism between glycopeptides and beta-lactams observed in vitro; nor did combinations show antagonism against any of the strains. Though the usefulness of these combinations cannot be totally ruled out in highly specific clinical conditions, it seems unlikely that they will provide a serious therapeutic alternative in most hGISA and GISA infections in the coming years.