Bactericidal activity of daptomycin versus vancomycin in the presence of human albumin against vancomycin-susceptible but tolerant methicillin-resistant Staphylococcus aureus (MRSA) with daptomycin minimum inhibitory concentrations of 1–2 μg/mL

Abstract

This study explored the influence of vancomycin tolerance and protein binding on the bactericidal activity of vancomycin versus daptomycin (protein binding 36.9% vs. 91.7%, respectively) against four vancomycin-tolerant methicillin-resistant Staphylococcus aureus (MRSA) [minimum inhibitory concentration/minimum bactericidal concentration (MIC/MBC) = 0.5/16, 1/32, 2/32 and 1/32 μg/mL for vancomycin and 1/1, 1/2, 2/2 and 2/4 μg/mL for daptomycin]. Killing curves were performed with vancomycin/daptomycin concentrations equal to serum peak concentrations ( C max) (65.70/98.60 μg/mL) and trough concentrations ( C min) (7.90/9.13 μg/mL) in the presence and absence of a physiological human albumin concentration (4 g/dL), controlled with curves with the theoretical free drug fraction of vancomycin/daptomycin C max (41.45/8.18 μg/mL) and C min (4.98/0.76 μg/mL). Vancomycin C max and C min concentrations, regardless of the media, showed a bacteriostatic profile not reaching a reduction of 99% or 99.9% of the initial inocula during the 24-h experimental time period. Daptomycin antibacterial profiles significantly differed when testing C max and C min. C max was rapidly bactericidal (≤4 h) with >5 log 10 reduction in the initial inocula for all strains, regardless of the presence or not of albumin or the use of concentrations similar to free C max. C min exhibited similar final colony counts at 0 h and 24 h in curves with albumin, but with >3 log colony-forming units (CFU)/mL reduction at ≤4 h for strains with an MIC of 1 μg/mL and ca. 2 log CFU/mL reduction at ≤6 h for strains with an MIC of 2 μg/mL. This activity was significantly higher than the activity of the free C min fraction. The results of this study reinforce the idea that pharmacodynamics using concentrations calculated using reported protein binding are unreliable. Daptomycin exhibited rapid antibacterial activity against vancomycin-tolerant MRSA isolates even against those with high daptomycin MICs in the presence of physiological albumin concentrations.