Antibacterial synergism between beta-lactam antibiotics: Results using clavulanic acid (BRL. 14151) with amoxycillin, carbenicillin or cephaloridine

Abstract

Bacterial resistance to β-lactam antibiotics is becoming increasingly important. This resistance is often mediated by the production of β-lactamase enzymes which destroy the antibiotics. Such resistance might be overcome firstly by developing antibiotics which are resistant to destruction by β-lactamase; secondly, by developing antibiotics of very high potency; thirdly, antibiotics could be developed which release antibacterially active moities on hydrolysis by β-lactamase. The fourth and perhaps one of the most promising approaches is to develop molecules which inactivate β-lactamases. Combinations of broadspectrum penicillins with isoxazole penicillins have been investigated but for various reasons were not successful in therapy. Recently clavulanic acid, a naturally occurring β-lactam molecule, has been investigated by the authors and other workers. Unlike isoxazole penicillins, clavulanic acid inhibits β-lactamase activity at low concentrations. The activity of ampicillin, cephaloridine or carbenicillin in combination with clavulanic acid against 215 bacterial isolates has been investigated. Concentrations as low as 1 mg/l of clavulanic acid regularly rendered ampicillin-resistant strains ofBacteroides fragilis, Haemophilus influenzae andStaphylococcus aureus sensitive to attainable blood concentrations of amoxycillin. 5 mg/l of clavulanic acid brought the majority of strains ofProteus mirabilis, all strains ofProteus vulgaris, most strains ofKlebsiella pneumoniae and a small proportion of ampicillin-resistant strains ofEscherichia coli into the therapeutic range of amoxycillin. Increasing the concentration of clavulanic acid to 10 mg/l rendered the majority of strains ofE. coli sensitive to amoxycillin. The combination did not show enhanced activity againstEnterobacter species,Serratia marcescens, and most strains ofProteus rettgeri andProteus morganii. There was no enhanced activity between carbenicillin and clavulanic acid against either carbenicillin-sensitive or carbenicillin-resistant strains ofPseudomonas aeruginosa. As would be expected the activity of amoxycillin was not enhanced against ampicillin-sensitive strains of various species or against inherently sensitive species. In a single, simple preliminary experimental mouse infection using intra-peritoneal inoculation ofKlebsiella pneumoniae, protection was suggested by a combination of amoxycillin with clavulanic acid given as two doses where as the individual drugs did not protect. It was concluded that the combined use of clavulanic acid with a broad-spectrum β-lactum antibiotic showed therapeutic potential and was deserving of further evaluation.