Abstract
The empirical combination of both a beta-lactam and glycopeptide to counter potential staphylococcal pathogens may improve the clinical outcomes for cases of Staphylococcus aureus bacteremia. We reported comparative in vitro studies of combination effects of different cephalosporins (i.e., cefazolin, cefmetazole, cefotaxime, and cefepime) combined with glycopeptides for 34 randomly selected methicillin-resistant S. aureus (MRSA) isolates by three methods, including the checkerboard, time-killing, and combination MIC measurement methods. Thirteen SCCmec type III isolates with a cefazolin MIC of ≥ 128 μg/mL were classified as the high-cefazolin MIC (HCM) group, whereas 13 SCCmec type IV and 8 SCCmec type V isolates were classified as the low-cefazolin MIC (LCM) group. With the checkerboard method, synergism was present for vancomycin-based combinations at 30.8–69.2 and 13.6–66.7%, as well as teicoplanin-based combinations of 38.5–84.6 and 0–47.6%, of the HCM and LCM isolates, respectively. No antagonism was noted. The in vitro inhibitory activity was evident even at a low concentration of 1/512x MIC of cephalosporin combined with sub-inhibitory concentrations (1/2x MIC) of a glycopeptide. With time-killing assays, synergism was noted at 1/2x or 1x susceptible breakpoint concentrations (SBCs) of a cephalosporin combined with 1/4 or 1/2 MIC of a glycopeptide. In the presence of 1/2 SBC of a cephalosporin, vancomycin or teicoplanin MICs decreased an average of 2.0- to 6.6- or 1.6- to 5.5-fold, respectively. With 8 μg/mL cephalosporin, the decline of glycopeptide MICs was most obvious in the presence of cefmetazole. In conclusion, cephalosporin-glycopeptide combinations at clinically achievable concentrations can exhibit in vitro synergistic antibacterial activity against clinical MRSA isolates. Such combinations require more clinical data to support their application for use in human MRSA infections.
Highlights
There has been increasing evidence supporting the poor efficacy of vancomycin in treating MRSA infections due to rising vancomycin MICs in clinical MRSA isolates, increasing from 0.25 to 2.0 μg/mL (Hawser et al, 2011; Chang et al, 2015; Niveditha and Sujatha, 2015)
We found in vitro inhibitory activity of the combinations of 1/2x MIC of vancomycin or teicoplanin and 1/2x MIC of a cephalosporin in all 13 HCM
Isolates belonged to SCCmec type III and did not harbor PVL, and they were closely related to hospital-acquired MRSA (HAMRSA) isolates (Sawanobori et al, 2015)
Summary
There has been increasing evidence supporting the poor efficacy of vancomycin in treating MRSA infections due to rising vancomycin MICs in clinical MRSA isolates, increasing from 0.25 to 2.0 μg/mL (Hawser et al, 2011; Chang et al, 2015; Niveditha and Sujatha, 2015). An in vitro pharmacodynamic study of vancomycin alone, cefazolin alone or in combination against MRSA was recently reported (Hagihara et al, 2012). The synergism of cefepime or cefpirome combined with vancomycin or teicoplanin against MRSA isolates has been explored (Carricajo et al, 2001; Lozniewski et al, 2001; Toyokawa et al., 2003). We conducted a comparative in vitro study of the combination of any of four generation cephalosporins with either vancomycin or teicoplanin against MRSA isolates by three laboratory methods to elucidate the variation in the antibacterial activity of different cephalosporin-glycopeptide (C-G) combinations. PCR amplification of PVL genes, i.e., lukF-PV and lukS-PV, was performed as previously described (Montanaro et al, 2016). The M-PCR assay used primers for mec (mecI-F, mecI-R, IS1272-F, and mecR1-R) and ccr (ccrAB-α2, ccrAB-α3, ccrAB-α4, and ccrAB-β2) complexes
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