In vitro effects of beta-lactams combined with beta-lactamase inhibitors against methicillin-resistant Staphylococcus aureus

Abstract

The effects of combinations of 13-lactams with two P-lactamase inhibitors, sulbactam and clavulanic acid, were determined in vitro against 22 clinical isolates of methicillin-resistant Staphylococcus aureus. Combinations of cefpirome, cefotaxime, and cefazolin with sulbactam (10 ,ug/ml) showed synergistic effects against more than 70% of the strains. Combinations of methicillin and penicillin G with sulbactam also showed synergistic effects against 50 and 68% of the strains, respectively, while cefotiam, moxalactam, flomoxef, and cefmetazole in combination with sulbactam showed such effects against only 40% or fewer. Clavulanic acid was synergistic only when combined with penicillin G, the effect probably being due to the 1-lactamase inhibition by the inhibitor. Sulbactam did not improve the antimicrobial activities of the 1-lactams against methicillinsusceptible S. aureus strains. At 42°C the MICs of cefotaxime, methicillin, and flomoxef alone were markedly decreased from the values at 35°C, and no synergy between these P-lactams and sulbactam appeared. The resistance to penicillin G was not inhibited by incubation at 42°C, and combinations of penicillin G with sulbactam and clavulanic acid showed synergy. The amounts of 13-lactamase produced were not related to the decreases in the MICs of the I-lactams, except for penicillin G combined with sulbactam. Clavulanic acid showed slightly stronger ,3-lactamase-inhibiting activity than sulbactam did. These results suggest that the synergy between sulbactam and the 13-lactams, except for penicillin G, may not be due to 13-lactamase inhibition but to suppression of the methicillin-resistant S. aureus-specific resistance based on other factors.Recently, reports have been made on the isolation of and infections with methicillin-resistant Staphylococcus aureus (MRSA) (1,5,9,25,26). The resistance of these strains is associated with the presence of a low-affinity penicillinbinding protein, PBP 2' (23) or PBP 2a (10), and the protein has been suggested to be inducible by ,-lactams (7, 18, 22). The role of ,B-lactamase in the resistance has also been examined with the ,B-lactamase inhibitors clavulanic acid (17, 18) and sulbactam (3,8), and it has been reported that staphylococcal P-lactamase may be the cause of decreased antimicrobial activities of drugs such as penicillin G and cefazolin, which are relatively susceptible to 1-lactamase hydrolysis (4, 15). There has also been a report that drug inactivation by penicillinase is the main possible mechanism of resistance to cefazolin, cephaloridine, and cephalothin in S. aureus (14).To determine the role of ,-lactamase in the resistance to more antimicrobial agents, we determined the effects of combinations of nine 3-lactams with the two 3-lactamase inhibitors in vitro against clinically isolated MRSA strains. The ,B-lactams examined were cefpirome (20) and flomoxef (21), which have strong antimicrobial activities against S. aureus as well as gram-negative bacteria; five other cephalosporins (cefotaxime, moxalactam, cefmetazo...

Multiple mechanisms of methicillin resistance and improved methods for detection in clinical isolates of Staphylococcus aureus

“…We determined the clavulanic acid MIC for several strains and found that it varied considerably, from about 8 ,ug/ml (in the laboratory susceptible strains) to as high as 64 p,g/ml or more (for strains CDC 6 [36] and BM 72, for which the methicillin MICs, 4 and 8 ptg/ml, respectively, were also the highest). It appears, therefore, that 4 ,ug of clavulanate per ml may lower the methicillin MIC for some strains through synergistic antibacterial action, similar to the case noted for sulbactam (16) and confirming the findings of Sierra-Madero and colleagues (30).…”

Activity of cefpirome combined with beta-lactamase inhibitors and affinity for the penicillin-binding proteins of methicillin-resistantStaphylococcus aureus

“…The variation between inhibitors is presumably due to differences in potency for the 13-1actamase. Contrary to previous reports, synergy was reproducibly observed for some strains with clavulanic acid (11). For cefpirome and methicillin the reduction in MIC was not sufficient to alter the MIC50 or MIC90, although for the individual strains the observed synergy was a greater than four-fold reduction in the MIC of cefpirome.…”

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

“…Recently, synergistic activity of combinations of fosfomycin with fi-lactams (10,(29)(30)(31)(32) and sulbactam with 13-1aetams (33) has been demonstrated, and for this reason we tested the activity of combinations of meropenem with these antibiotics. The synergism between meropenem and cefpiramide was the greatest among the tested combinations, and this combination also showed effective bactericidal activity against MRSA.…”