Penetration of amoxycillin, ticarcillin and clavulanic acid into lymph after intravenous infusion in rabbits to simulate human serum pharmacokinetics.

The distribution of amoxycillin, ticarcillin and clavulanic acid into lymph collected from the right lymphatic duct of rabbits was examined after intravenous administration. The compounds were administered to simulate, in the plasma of rabbits, the concentrations of amoxycillin, ticarcillin and clavulanic acid measured in human serum after the administration of either an iv bolus dose of amoxycillin 1.0 g plus clavulanic acid 200 mg, ticarcillin 3.0 g plus clavulanic acid 200 mg, or an iv infusion of amoxycillin 2.0 g plus clavulanic acid 200 mg or ticarcillin 3.0 g plus clavulanic acid 200 mg given over 30 min. Lymph concentrations of the compounds reached a peak rapidly after the simulation of a bolus dose (0-1 h) and the concentration-versus-time profiles in plasma and lymph were generally similar after 45 min. Following simulation of an iv infusion, peak concentrations of amoxycillin and clavulanic acid in lymph were reached at approximately the same time as for the bolus simulation, but that of ticarcillin occurred slightly later. The elimination half-lives of the compounds were similar in plasma and lymph. The percentage penetration values were high (greater than 80%) irrespective of the concentration-versus-time curve simulated. The penetration of clavulanic acid was compatible with that of the coadministered penicillin agent and was similar when given with either amoxycillin or ticarcillin.

Simulation of human serum pharmacokinetics of ticarcillin-clavulanic acid and ceftazidime in rabbits, and efficacy against experimental Klebsiella pneumoniae meningitis.

The penetration into cerebrospinal fluid (CSF) and efficacy of ticarcillin-clavulanic acid, ticarcillin alone, and ceftazidime were compared in rabbits with experimentally induced Klebsiella pneumoniae meningitis. The compounds were administered to simulate in rabbit plasma the concentration-versus-time curves observed in humans after 30-min infusions of Timentin (3 g of ticarcillin plus 100 mg of clavulanic acid), ticarcillin (3 g), and ceftazidime (2 g). Single- and multiple-dosing schedules were used. The penetrations of clavulanic acid into CSF (expressed as [area under the concentration-time curve for CSF/area under the curve for plasma] x 100) after the two dosing schedules were 28 and 24.5%, similar to that for ceftazidime (21%; multiple-dosing only) and greater than those for ticarcillin (8.4 and 9.3%). Ticarcillin was ineffective in reducing viable counts in CSF but, in the presence of clavulanic acid, reduced bacterial numbers by approximately 99% at 4 h after a single dose and by 99.99% at 12 h after three doses given at 4-h intervals. Two doses of ceftazidime given 8 h apart were more effective than the three doses of ticarcillin-clavulanic acid, in keeping with the in vitro activities of these compounds against the infecting organism. These results illustrate the ability of clavulanic acid to penetrate the blood-CSF barrier such that concentrations of the inhibitor in CSF potentiate the activity of ticarcillin against the ticarcillin-resistant, beta-lactamase-producing strain of K. pneumoniae.

Temocillin efficacy in experimental Klebsiella pneumoniae meningitis after infusion into rabbit plasma to simulate antibiotic concentrations in human serum.

An infusion system was developed to simulate in the plasma of rabbits the concentrations of temocillin in human serum measured after administration of a 2-g intravenous bolus dose. The efficacy of therapy with this infusion against experimental Klebsiella pneumoniae meningitis was compared with that of a conventional bolus dose to the animals. The marked difference between the elimination half-life (t1/2) of temocillin in rabbit plasma and human serum (0.3 and 5 h, respectively) was reflected in concentrations in cerebrospinal fluid (CSF). The mean peak concentration after infusion occurred 3.5 h later than after bolus dosing, and levels were more prolonged (t1/2 in CSF was 6.3 h compared with 0.83 h following the bolus dose). After infusion, the mean viable count in CSF decreased by 4 log10 CFU/ml, whereas the bolus dose was ineffective because of the rapid fall to subinhibitory concentrations. These results suggest that the infusion system used is valuable for experimental studies with antibacterial agents whose elimination kinetics differ markedly between animals and humans.

Pharmacokinetics and distribution of ticarcillin-clavulanic acid (Timentin) in experimental animals.

The pharmacokinetics and distribution of ticarcillin and clavulanic acid were studied in rats and rabbits after intravenous coadministration of the compounds. The elimination half-lives for ticarcillin and clavulanic acid were similar in both rats (ticarcillin, 0.22 h; clavulanic acid, 0.24 h) and rabbits (ticarcillin, 0.38 h; clavulanic acid, 0.31 h). Both compounds distributed widely throughout rat tissues, and the patterns of distribution were similar to those observed for other beta-lactams. Values for penetration into rat pleural, peritoneal, and subcutaneous fluids calculated from the equation (AUCfluid/AUCserum) X 100, where AUC is the area under the concentration-time curve, were between 83 and 93% for ticarcillin and 86 and 103% for clavulanic acid. Values for penetration into tissue cages in rabbits were 139% +/- 45% for ticarcillin and 109% +/- 22% for clavulanic acid. The penetration of clavulanic acid into rabbit cerebrospinal fluid was higher (P less than 0.05) (4.0% +/- 0.61%) than that of ticarcillin (1.3% +/- 0.53%). Overall, the results show that ticarcillin and clavulanic acid distribute readily throughout body tissues and fluids and predict that the penicillin and beta-lactamase inhibitor would be present together at sites of infection.