Abstract
This study assesses the synergistic effect of the combination of cephalosporins and sulbactam with daptomycin against daptomycin-nonsusceptible, vancomycin-intermediate resistant Staphylococcus aureus (VISA) or heterogeneous vancomycin-intermediate S. aureus (h-VISA) isolates. The in vitro activity of daptomycin against daptomycin-nonsusceptible VISA/h-VISA isolates after adding cephalosporins with or without sulbactam was evaluated. The MIC of daptomycin against the VISA/h-VISA isolates was reduced after adding cephalosporins to daptomycin. Except for one VISA and two h-VISA isolates, the other VISA/h-VISA isolates became daptomycin-susceptible (MICs ≤ 1 mg/L). After adding sulbactam to each daptomycin/cephalosporin combination, the MIC of daptomycin against the VISA/h-VISA isolates decreased for 5 (33.3%), 6 (40.0%), 6 (40.0%), and 6 (40.0%) isolates with the cefazolin, cefmetazole, cefotaxime, and cefepime combinations, respectively. Synergism using the checkerboard method was noted in 100% of cefazolin and cefotaxime combinations and 87% and 80% of cefmetazole and cefepime combinations for all the VISA and h-VISA isolates. With the addition of sulbactam, synergism was noted in 100% of cefazolin, cefmetazole, and cefotaxime combinations and 93% of the cefepime combinations for all the VISA and h-VISA isolates. Almost all the FICs for the three-drug combinations were lower than those for the two-drug combinations. Using time-killing methods, a synergistic effect against five h-VISA isolates was observed. A synergistic effect of daptomycin, sulbactam, and each cephalosporin was observed for all VISA isolates. In conclusion, the activity of daptomycin against daptomycin-nonsusceptible VISA/h-VISA isolates can be enhanced by adding cephalosporins, and partially further promoted by sulbactam.
Highlights
Vancomycin belongs to the glycopeptide antibiotic class, and remains the drug of choice for severe methicillin-resistant Staphylococcus aureus (MRSA) infections [1,2]
The minimal inhibitory concentration (MIC) of daptomycin combined with a cephalosporin, or daptomycin combined with a cephalosporin and sulbactam, were determined by the microbroth dilution method as described above, modified from the Clinical and Laboratory Standards Institute (CLSI)’s recommendations [14,15]
All the vancomycin-intermediate resistant Staphylococcus aureus (VISA) and heterogeneous vancomycin-intermediate S. aureus (h-VISA) isolates were resistant to every cephalosporin, based on the MIC level
Summary
Vancomycin belongs to the glycopeptide antibiotic class, and remains the drug of choice for severe methicillin-resistant Staphylococcus aureus (MRSA) infections [1,2]. The appropriate antibiotics for VISA/h-VISA infections, which are associated with complicated clinical courses and treatment failures, are limited [5]. Some alternative antibiotics, such as daptomycin, may be therapeutic options [5]. A previous study [11] demonstrated that sulbactam can enhance the activity of beta-lactam antibiotics against MRSA. Based on the above results and the findings of our previous study [8], we hypothesize that this additional effect of cephalosporins or sulbactam in combination with daptomycin against VISA/h-VISA may occur. We assessed the synergistic effect of a combination of cephalosporins of all generations and sulbactam with daptomycin against daptomycin-nonsusceptible VISA/h-VISA isolates
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