In vitro synergistic activity between meropenem and other beta-lactams against methicillin-resistant Staphylococcus aureus

The in vitro activity of meropenem, a carbapenem antibiotic, combined with eight other β-lactams against methicillin-resistant Staphylococcus aureus (MRSA) was tested. The MICs of these antibiotics alone ranged from 12.5 to 1,600 μg/ml for the 25 clinical isolates of MRSA studied. All combinations with meropenem exhibited marked synergy as determined by the checkerboard method. The MICs in combinations of meropenem with other β-lactams were reduced to 1/4 - 1/64 those of the antibiotics alone. No antagonism was observed for any of the combinations of meropenem with other β-lactams. Synergism between meropenem and cefpiramide was the highest among the combinations tested, the geometric mean of the fractional inhibitory concentration index for this combination being 0.237. This combination also demonstrated strong bactericidal activity, the MBCs decreasing to 1/16 - 1/64 of those for the agents alone. In terms of the fractional inhibitory concentration index, this was the most effective combination against MRSA highly resistant to meropenem alone with synergism for 85 % (81/95) of the strains. In addition, synergism of imipenem with cephalosporins against MRSA was demonstrated. The affinity of meropenem and cefpiramide for MRSA penicillin-binding protein (PBP) 2′ was very low, and the combination of both antibiotics showed an additive increase in affinity for this protein, but not a synergistic increase. Thus, the mechanism of synergism did not seem to be related to affinity for PBP2′. It is possible that there is another factor besides PBP2′ which increases the resistance of MRSA and that the combinations inhibit the unknown factor.