The Demonstration and Significance of Synergism Between -Lactam Antibiotics

213

107

Clavulanic acid, Z-(2R,5R)-3-(β-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo-[3,2,0] heptane-2-carboxylic acid, has been shown to be an effective inhibitor of the β-lactamases of the Richmond types II, III, IV, and V. Inhibition is a time-dependent reaction and is irreversible. Clavulanic acid had poor antibacterial activity against Staphylococcus aureus, Enterobacteriaceae , and Pseudomonas aeruginosa , with minimal inhibitory levels greater than 25 μg/ml. It did inhibit the majority of Neisseria gonorrhoeae at 0.1 μg/ml and Haemophilus influenzae at 6.3 μg/ml. Clavulanic acid acted synergistically with penicillins and cephalosporins to inhibit β-lactamase-producing S. aureus and Enterobacteriaceae . Clavulanic acid combined with ampicillin inhibited β-lactamase-producing N. gonorrhoeae, H. influenzae, Escherichia coli, Salmonella typhi , and Shigella sonnei .

mentioning

confidence: 99%

Clavulanic Acid, a Novel Inhibitor of β-Lactamases

Neu

1978

213

107

“…Combinations of ampicillin and cloxacillin (1,7) and other selected pairs of #-lactam antibiotics (5,9,10,25) have been proven to be active in vitro and effective for the treatment of urinary tract infections caused by ampicillin-resistant strains. However, all penicillinase-producing strains are not susceptible to the synergistic action of ,8-lactam antibiotics, and the location of the genes for ,B-lactamase synthesis, either chromosomal or extrachromosomal, appears to control whether synergism occurs (16).…”

mentioning

confidence: 99%

R Factor-Mediated and Chromosomal Resistance to Ampicillin in Escherichia coli

Roupas¹,

Pitton²

1974

Sixty-four ampicillin-resistant strains of Escherichia coli were studied. Six characters were examined: (i) resistance to ampicillin, cephalothin, and carbenicillin, (ii) synergy between ampicillin and cloxacillin, (iii) level of,-lactamase activity after osmotic shock, (iv) transferability of ampicillin resistance, (v) immunological characterization of the enzyme, and (vi) determination of substrate profiles. One class of strains was found in which synthesis of ,B-lactamase is inferred to be plasmid mediated; these strains are highly resistant to ampicillin and carbenicillin, sensitive to cephalothin, do not show synergism between ampicillin and cloxacillin, and reveal a high enzymatic activity after osmotic shock. A second class is formed by strains for which ,-lactamase synthesis is inferred to be chromosomal; these strains present a low resistance level to ampicillin, are sensitive to carbenicillin and resistant to cephalothin, show a synergism between ampicillin and cloxacillin, and reveal a very low enzymatic activity after osmotic shock. These characters may be used to differentiate periplasmic and cell-bound /-lactamases.

“…DISCUSSION The hydrolysis of ,B-lactam antibiotics by ,8-lactamase enzymes elaborated by many strains of gram-negative bacilli can be competitively inhibited by certain f3-lactamase-resistant penicillins and cephalosporins (3,7,13,14,19). Combinations of such nonhydrolyzable substrate analogues and hydrolyzable penicillins and cephalosporins often exhibit synergistic antibacterial effects against these organisms (2,5,9,16,25). Rarely, stabilization of the hydrolyzable drug has been demonstrated directly in cultures exposed to such synergistic combinations (12).…”

mentioning

confidence: 99%

“…combinations~of p-lactam antibiotics exhibit synergistic antibacterial effects against various gram-negative bacilli (2,5,9,16,25). Most synergistic pairs of antibiotics consist of one member which is resistant to hydrolysis by the f-lactamase elaborated by the strain of organism being tested but exhibits a high affinity for the enzyme, and a second member which is susceptible to hydrolysis of the f3-lactamase but possesses a high degree of antibacterial activity against the organism (9).…”

mentioning

confidence: 99%

“…Most synergistic pairs of antibiotics consist of one member which is resistant to hydrolysis by the f-lactamase elaborated by the strain of organism being tested but exhibits a high affinity for the enzyme, and a second member which is susceptible to hydrolysis of the f3-lactamase but possesses a high degree of antibacterial activity against the organism (9). It is therefore usually assumed that such synergism depends upon inhibition of the enzyme by the #3-lactamaseresistant antibiotic (3,7,13,14,19) which protects the ,B-lactamase-sensitive drug from hydrolysis and allows it to kill the organism.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Mechanism of Synergistic Effects of β-Lactam Antibiotic Combinations on Gram-Negative Bacilli

Farrar

Newsome

1973

These studies were undertaken to elucidate further the mechanism of synergism of pairs of f3-lactam antibiotics on f3-lactamase-producing gram-negative bacilli. Three strains of gram-negative bacilli which elaborate ,B-lactamase enzymes with widely differing properties were employed. The antibacterial effects of ,B-lactam antibiotics, singly and in combination, on the three organisms investigated were exactly those which would have been predicted on the basis of the enzymological properties of the f-lactamases elaborated by these organisms. The findings thus support the hypothesis that the synergistic antibacterial effects of combinations of ,3-lactam antibiotics on these organisms were due to inhibition of the enzyme by one of the agents and killing of the organism by the other, which was protected from enzymatic hydrolysis, rather than the alternative possibility that the synergistic effects were due simply to the combined antibacterial actions of the two drugs.