Vancomycin (VAN) Combinations with Β-Lactams (BLs) against Methicillin-Resistant Staphylococcus aureus (MRSA), Heterogeneous Intermediate-Level Resistance to Vancomycin (hVISA) and Vancomycin-Intermediate Staphylococcus aureus (VISA)

Abstract

Background Staphylococcus aureus (S. aureus), especially Methicillin-resistant S. aureus (MRSA) remains a major cause of serious infection and is associated with increased morbidity and mortality. Vancomycin (VAN) has been the mainstay of therapy for MRSA infections. However, decades of selective pressure have led to increasing concerns regarding the efficacy of VAN against MRSA. In vitro data suggest the potential for potent synergy between several Β-lactams (BLs) and VAN. The objective of this study is to further explore the synergistic effect between BLs and VAN against MRSA strains with varying susceptibility to VAN.MethodsFifty randomly selected clinical MRSA strains from the Anti-Infective Research Laboratory library with varying susceptibility to VAN were evaluated for VAN alone and VAN in combination with Cefazolin (CFZ), Cefepime (FEP), Ceftaroline (CPT), and Nafcillin (NAF) minimum inhibitory concentration (MIC) by microdilution in duplicate. The potential for synergy was assessed by 24 hours time-kills (TK). Synergy was defined as >2 log10 CFU/mL difference between combination and the most active single agent at 24 hours.ResultsBLs reduced VAN MIC values against all strains (4–16 fold reduction). In TK studies against MRSA, all BLs demonstrated a similar extent of killing at 24 hours and showed synergy with VAN against all strains. Each combination was superior to any single agent alone, and each was bactericidal (3.42 ± 0.26 log10 CFU/cm2 reduction, P < 0.001 for all comparisons). All single agent exposures demonstrated no activity at 24 hours.Phenotype (Number of Strains)VAN MIC Range (µg/mL)VAN MIC Range with CFZVAN MIC Range with FEPVAN MIC Range with CPTVAN MIC Range with NAFMRSA (15)0.5 – 20.0625 – 0.250.0625 – 10.0625 – 0.250.125 – 0.5hVISA (20)0.5 – 20.125 – 0.50.0625 – 0.50.0625 – 0.50.125 – 1VISA (15)4 (all)0.0625 – 0.50.5 – 20.0625 – 0.250.125 – 1ConclusionThe combination of VAN and BLs significantly improved antibacterial activity against MRSA, hVISA, and VISA compared with any agent alone, supporting the potential use of Vancomycin/BL combination therapy in infections caused by MRSA. Further clinical research is warranted to investigate the synergistic activity of vancomycin against these Staphylococcus strains.Disclosures M. J. Rybak, Allergen: Scientific Advisor, Consulting fee