Activity of simulated serum concentrations of daptomycin versus vancomycin during the first 24h of treatment in the presence of physiological albumin concentrations against vancomycin-susceptible, -tolerant or -intermediate-resistant Staphylococcus aureus

Abstract

In order to determine whether reduced susceptibility or tolerance to vancomycin in Staphylococcus aureus influences the activity of daptomycin by simulating serum concentrations in the first 24h of treatment in the presence of physiological concentrations of human albumin, a computerised pharmacodynamic simulation was performed using Mueller-Hinton broth with 4 g/dL human albumin concentrations. For daptomycin, the media was adjusted to physiological ionised calcium concentrations by adding 100 μg/mL Ca(2+). Protein binding was measured. Six S. aureus isolates were used, comprising one vancomycin-susceptible S. aureus (VSSA), three vancomycin-tolerant strains, one heteroresistant vancomycin-intermediate S. aureus (hVISA) and one homogeneous vancomycin-intermediate S. aureus (VISA). Minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) of daptomycin increased eight times when determined in the presence of albumin (MIC(ALB) and MBC(ALB), respectively). Measured protein binding was 86.6% (C(max)) and 86.5% (C(min)) for daptomycin and 51.6% (C(max)) and 42.2% (C(min)) for vancomycin. Similar values were obtained for fAUC/MIC (where fAUC is the area under the concentration-time curve obtained with extrapolated concentrations using the highest protein binding rate experimentally obtained) and AUC/MIC(ALB) for each antibiotic. Daptomycin showed early (≤ 6 h) bactericidal activity [maximal effect (E(max)) >4 log(10) reductions in initial inocula] against all strains. Vancomycin produced an E(max) of 2.3 log(10) reductions at 8h against the VSSA and reductions ≤1.8 log(10) for the other strains in the 8-24h period. Pharmacodynamic parameters were fAUC/MBC from 8.0 to 15.6 (vancomycin) and from 56.0 to 111.6 (daptomycin) for tolerant strains, and fAUC/MIC of 126.8 and 63.3 for vancomycin and 222.6 and 113.2 for daptomycin against hVISA and VISA strains, respectively. Against the study strains (vancomycin-susceptible, -tolerant, heteroresistant or intermediate), daptomycin, in contrast to vancomycin, exhibited early bactericidal activity despite its high protein binding.