In vitro synergistic effects of double and triple combinations of beta-lactams, vancomycin, and netilmicin against methicillin-resistant Staphylococcus aureus strains

Several studies have previously reported synergistic effects between vancom ycin and a given beta -lactam or a given aminoglycoside against methicillin -resistant Staphylococcus aureus (MRSA) strains. The aim of our study was t o exhaustively compare the effects of different combinations of a beta -lac tam, vancomycin, and/or an aminoglycoside against 32 clinical MRSA strains with different aminoglycoside susceptibility patterns. The effects of 26 di fferent beta -lactam-vancomycin and 8 different aminoglycoside-vancomycin c ombinations were first studied using a disk diffusion screening method. The best interactions with vancomycin were observed with either imipenem, cefa zolin, or netilmicin, By checkerboard studies, imipenem-vancomycin and cefa zolin-vancomycin each provided a synergistic bacteriostatic effect against 22 strains; the mean fractional inhibitory concentration (FIC) indexes were 0.35 and 0.46 for imipenem-vancomycin and cefazolin-vancomycin, respective ly. The vancomycin-netilmicin combination provided an indifferent effect ag ainst all of the 32 strains tested; the mean of FIC index was 1.096. The me an concentrations of imipenem, cefazolin, netilmicin, and vancomycin at whi ch FIC indexes were calculated were clinically achievable. Killing experime nts were then performed using imipenem, cefazolin, netilmicin, and vancomyc in at one-half of the MIG, alone and in different combinations, against 10 strains. The vancomycin-netilmicin regimen was rarely bactericidal, even ag ainst strains susceptible to netilmicin. The imipenem-vancomycin and cefazo lin-vancomycin combinations were strongly bactericidal against six and five strains, respectively. The addition of netilmicin markedly enhanced the ki lling activity of the combination of cefazolin or imipenem plus vancomycin, but only for the MRSA strains against which the beta -lactam-vancomycin co mbinations had no bactericidal effect. It is noteworthy that the latter str ains were both susceptible to netilmicin and heterogeneously resistant to m ethicillin.