Antibacterial activity of ticarcillin in the presence of clavulanate potassium.

The antibacterial effects produced by ticarcillin disodium plus clavulanate potassium, a combination of the broad-spectrum penicillin ticarcillin, and the beta-lactamase inhibitor clavulanic acid as the potassium salt, have been measured in vitro and in experimental infection studies. The presence of clavulanic acid resulted in a significant enhancement of the activity of ticarcillin against a wide range of beta-lactamase-producing bacteria. These included ticarcillin-resistant strains of Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, P. vulgaris, Yersinia enterocolitica, and the anaerobe Bacteroides fragilis. In addition, beta-lactamase-producing isolates of Hemophilus influenzae, Branhamella catarrhalis, Neisseria gonorrhoeae, and Staphylococcus aureus were susceptible to ticarcillin and clavulanate. Clavulanic acid did not influence the activity of ticarcillin against ticarcillin-susceptible bacteria. The bactericidal effects of the antibiotic combination were measured in an in vitro kinetic model in which the drug concentrations were varied to simulate those measured in humans after intravenous dosing with ticarcillin (3.0 g) and clavulanate potassium (100 mg clavulanic acid). In these tests, ticarcillin plus clavulanic acid had pronounced bactericidal activity against ticarcillin-resistant bacteria. The protection of ticarcillin by clavulanic acid from inactivation by bacterial beta-lactamases in vivo was demonstrated in experimental infection models in which the efficacy of the ticarcillin plus clavulanic acid combination against infections caused by beta-lactamase-producing bacteria was correlated with the presence of effective concentrations of both antibiotic and inhibitor at the site of infection.

Bactericidal effects of amoxycillin/clavulanic acid against Legionella pneumophila.

The antibacterial activities of amoxycillin, clavulanic acid and the combination of both agents against Legionella spp. were compared in serial-dilution tests, time-kill curve studies and in turbidimetric studies in a continuous recording biophotometer. Both beta-lactam compounds showed high levels of activity against L. pneumophila in serial dilution tests, clavulanic acid (MIC 0.1-0.25 mg/l) being two-fold more active than amoxycillin. The combination of amoxycillin and clavulanic acid was more effective than either of the constituents and was two to four times more active than erythromycin. Clavulanic acid was shown to reduce the extent of inactivation of amoxycillin by L. pneumophila and amoxycillin/clavulanic acid was rapidly bactericidal against the organism in tests in which amoxycillin was ineffective. Microscopical examination showed distinctive morphological effects produced by amoxycillin and by clavulanic acid and synergy between the compounds could be attributed to beta-lactamase inhibition, or by binding to different penicillin binding proteins, or both. These results warrant further studies in vitro and in vivo to elaborate the bactericidal effects demonstrated by amoxycillin and clavulanic acid against Legionella spp.

Bactericidal effects of amoxycillin/clavulanic acid and ticarcillin/clavulanic acid in in-vitro kinetic models.

The bactericidal effects of amoxycillin and ticarcillin in the presence of clavulanic acid against beta-lactamase-producing bacteria were investigated in in-vitro kinetic models. Amoxycillin/clavulanic acid was rapidly bactericidal as a simulated intravenous 1.2 g bolus dose, against a strain of Klebsiella pneumoniae highly resistant to amoxycillin. Similarly, ticarcillin/clavulanic acid at concentrations similar to those achieved with a 30 min iv infusion of ticarcillin/clavulanic acid (5.0 g/200 mg) produced bactericidal effects against a ticarcillin-resistant strain of Pseudomonas aeruginosa. Addition of gentamicin to the system resulted in a further enhancement of activity.

Bactericidal effects of amoxycillin/clavulanic acid against intracellular Legionella pneumophila in tissue culture studies.

The bactericidal effects of amoxycillin, clavulanic acid and amoxycillin plus clavulanic acid were determined against Legionella pneumophila growing intracellularly in MRC-5 human fetal lung fibroblast cells. The strain of L. pneumophila was shown to be growing within the cells by transmission electron microscopy and this was confirmed by the results of bactericidal tests in which gentamicin was shown to be ineffective in preventing growth of the organism in the tissue culture system. Amoxycillin failed to prevent infection of the cell monolayers and had no effect on the growth of intracellular L. pneumophila. Transmission electron microscopy showed the presence of large numbers of bacteria of normal morphology within the fibroblasts. In contrast, clavulanic acid and amoxycillin/clavulanic acid protected the cell sheets from the effects of infection with L. pneumophila and reduced the numbers of intracellular bacteria to the same extent as erythromycin. Also, bacteria of abnormal morphology were observed within fibroblast cells of the cultures treated with clavulanic acid and the combination. These data demonstrate the penetration of clavulanic acid, when used alone or in the presence of amoxycillin, into cells infected with L. pneumophila and the resulting bactericidal activity of the agents against intracellular bacteria.