Effect of human albumin physiological concentrations on the in vitro bactericidal activity of daptomycin vs. vancomycin Cmax concentrations against Gram-positive isolates exhibiting the main resistance phenotypes

Abstract number: 1733_1555

Cafini F., Aguilar L., González N., Giménez M., Torrico M., Alou L., Sevillano D., Vallejo P., Prieto J.

Objectives: To study the effect of the presence of physiological concentrations of human albumin on the Time needed to obtain bactericidal activity (≥3 log₁₀ – 99.9% – initial inocula reduction) by concentrations similar to the Cmax obtained in serum after i.v. 4 mg/kg of daptomycin and 1g vancomycin, against quinolone-susceptible (QS) and -resistant (QR) S. pneumoniae (SP), methicillin-susceptible (MS), -resistant (MR), and heterogeneous vancomycin-intermediate (hVI) S. aureus (SA), and vancomycin-susceptible (VS) and -resistant (VR) E. faecium (E).

Methods: Killing curves were performed with final inocula of approx. 10⁷ cfu/mL, and a final concentration of daptomycin or vancomycin of 56 mg/mL and 25.5 mg/mL, respectively in different media: a) Mueller-Hinton broth with 5% lysed horse blood for S. pneumoniae or without blood supplement for S. aureus and E. faecium (Cmax-MH), and b) MH broth with 4 g/dl human albumin (Cmax-HAlb). In parallel, killing curves with daptomycin or vancomycin concentrations (4.7 and 16.1 mg/mL, respectively) corresponding to free-drug Cmax were performed in Mueller-Hinton broth.

Results: MICs of daptomycin and vancomycin and Time (h) to obtain bactericidal activity are shown in the Table.

Conclusions: Daptomycin Cmax, despite its high protein binding, exhibited rapid bactericidal activity (time ≤ 2 h) against all strains tested regardless resistance phenotype, that is delayed in the presence of human albumin. In contrast, vancomycin Cmax exhibited slow bactericidal activity (obtained generally at 24 h) against SP, MSSA and MRSA, but never against hVI, VSE and VRE. Theoretical extrapolation of active drug from total drug by using the protein binding rate seems a non accurate method to study antibacterial activity considering the implications of protein binding.