1539. Dalbavancin, Vancomycin, and Daptomycin Alone and in Combination with Cefazolin Against Vancomycin Intermediate-Resistant (VISA) and Daptomycin Non-Susceptible (DNS) Staphylococcus aureus

Abstract

BackgroundGlycopeptides and lipopeptides, more specifically vancomycin (VAN) and daptomycin (DAP) have been principally utilized in treating MRSA infections. Due to continued use, MRSA strains have developed resistance to these antibiotics including vancomycin intermediate susceptible Staphylococcus aureus (VISA) and daptomycin non-susceptible strains (DNS). Lipoglycopeptides; notably dalbavancin (DAL), have been employed due to their ease of administration and enhanced activity against highly resistant S. aureus. As previously demonstrated, the use of β-lactams, specifically cefazolin (CFZ) in combination with anti-MRSA drug therapy has been effective in eradicating S. aureus complicated by increased resistance. The objective of this study was to evaluate the activity of DAL, VAN, and DAP, alone and in combination with CFZ in a pharmacokinetic/pharmacodynamic (PK/PD) model.MethodsThe well-characterized DNS-VISA strain, D712, was evaluated in eight different regimens in duplicate via a one-compartment 7-day PK/PD model. The experimental regimens were as follows: D712 growth control, DAL 1500 mg given on day 1, VAN 2 g given every 12 hours, DAP 10 mg/kg once-daily, CFZ 2 g given every 8 hours and DAL, DAP, and VAN in combination with CFZ.ResultsThe combinations of DAL+CFZ, VAN+CFZ, and DAP+CFZ demonstrated a significant log10 CFU/mL reduction (more than 5 log 10 CFU/mL and up to detection limit), compared with each drug used as monotherapy (P < 0.001). Neither DAP nor VAN demonstrated sustained bactericidal activity, (represented by a >3-log10 CFU/mL reduction from baseline) and resulted in significant regrowth, when administered alone. However, the DAP +CFZ, and VAN+CFZ combination models demonstrated bactericidal activity at 4 hours and 24 hours, respectively. While DAL alone did demonstrate bactericidal activity, the DAL+CFZ combination was more rapidly bactericidal, achieving a > 3-log reduction from baseline in 8 hours vs. 48 hours (P < 0.05).ConclusionThe combination of DAL, VAN, or DAP with CFZ demonstrated significantly improved activity against this multiple drug-resistant S. aureus strain. Further research is warranted, both in vivo and in vitro, to explore the synergistic capabilities of anti-MRSA drug therapy in combination with β-lactams.Disclosures All authors: No reported disclosures.