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

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• 作者：Martha Torrico^a ; Lorenzo Aguilar^a ; ^{laguilar@med.ucm.es} ; David Sevillano^a ; Marí ; a-José ; Gimé ; nez^a ; Luis Alou^a ; Natalia Gonzá ; lez^a ; Fabio Cafini^a ; Roy Cleeland^b ; José ; Prieto^a
• 关键词：Protein binding ; Bactericidal activity ; Vancomycin tolerance
• 刊名：International Journal of Antimicrobial Agents
• 出版年：2011
• 出版时间：April 2011
• 年：2011
• 卷：37
• 期：4
• 页码：332-338
• 全文大小：208 K

文摘

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 24 h 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 Ca²⁺. 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 log₁₀ reductions in initial inocula] against all strains. Vancomycin produced an E_max of 2.3 log₁₀ reductions at 8 h against the VSSA and reductions ≤1.8 log₁₀ for the other strains in the 8–24 h 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.