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, ,-lactamase-producing strain of K. pneumoniae.In the presence of clavulanic acid the antibacterial spectrum of ticarcillin is extended to include ticarcillin-resistant, P-lactamase-producing strains of members of the family Enterobacteriaceae, Pseudomonas aeruginosa, Bacteroides spp., Haemophilus influenzae, and staphylococci (6,8,20). For clavulanic acid to inhibit ,B-lactamases produced in vivo and allow ticarcillin to exert its bactericidal effect, both compounds should display similar distribution characteristics. This has been demonstrated both in animals (4, 5, 24) and in humans (1,3,22). In the study reported here, the penetration into cerebrospinal fluid (CSF) and the efficacy of ticarcillin-clavulanic acid were investigated in a rabbit model of meningitis (18) in which the infecting organism was a strain of Klebsiella pneumoniae.To compensate for the more rapid elimination of ticarcillin (elimination half-life, 0.4 to 0.6 h), clavulanic acid (0.3 to 0.6 h), and ceftazidime (0.75 to 0.88 h) from serum in the rabbit (16, 21, 23; unpublished data) than from serum in humans (half-life, 1.1 ± 0.5, 1.0 + 0.06, and 1.8 ± 0.21, respectively) (7, 9), the antibiotics were administered to infected rabbits by using a procedure designed to simulate in rabbit plasma the concentration-versus-time curves observed in human serum after therapeutic doses. The efficacy of ticarcillinclavulanic acid was compared with results for ticarcillin alone and with those for ceftazidime, a broad-spectrum cephalosporin considered useful for the treatment of gramnegative-bacilliary m...

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 (t4/2) 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 (tl/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 log1o 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.The study of the distribution and antibacterial activity of new antibiotics in experimental animal models is important in providing a basis for investigative studies in humans, but the pharmacokinetics of ,-lactam antibiotics may differ greatly between humans and animals (6, 9, 11, 18). This is exemplified by temocillin, a 6-oa-methoxy penicillin which has high and prolonged concentrations in human serum and has an elimination half-life (t1/2) of about 5 h (5, 7, 16) but which, like many other P-lactam antibiotics, is rapidly eliminated from the blood of most laboratory animals, with t1/2 values of between 10 and 30 min (3).In addition to its distinctive pharmacokinetics in humans and its metabolic stability in the body, temocillin shows good activity against gram-negative bacteria and is stable to many bacterial P-lactamases (16 (1,2,8).To compensate for the interspecies differences in pharmacokinetics and to evaluate the influence of the prolonged half-life of temocillin on therapy, a technique was designed that involved the intravenous infusion of a continuously diluted solution to modify the elimination kinetics of temocillin in rabbits. In the studies described here, the penetration and efficacy of temocillin were examined in rabbits with experimental K. pneumoniae meningitis after infusion to simulate in rabbit plasma the concentration-versus-time curve observed for temocillin in human serum following an intravenous bolus dose of 2 g. The results were compared * Corresponding author.with those obtained after normal bolus administration of temocillin to rabbits. MATERIALS AND METHODSTest organism. K. pneumoniae ESH, a clinical isolate from a urinary tract infection, was used to induce meningitis in the rabbits. This strain was ampicillin resistant, producing the chromosomally mediated, Richmond and Sykes Class IV, broad-spectrum P-lactamase typical of K. pneumoniae. The MICs and MBCs of temocillin against K. pneumoniae ESH were determ...

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 j3-lactams. Values for penetration into rat pleural, peritoneal, and subcutaneous fluids calculated from the equation (AUCfljd/AUC,.rum) 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 < 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 ,-lactamase inhibitor would be present together at sites of infection.Ticarcillin is active against a broad range of gram-positive and -negative bacteria, including Pseudomonas aeruginosa. It shows moderate stability in the presence of the Richmond class I ,-lactamases but is inactivated by most other ,Blactamases encountered in clinical isolates. In the presence of the ,B-lactamase inhibitor clavulanic acid, however, the spectrum of activity is extended to include many bacterial strains resistant to ticarcillin alone (5,7,15).In the treatment of infections, the inhibitor should display distribution characteristics similar to ticarcillin to achieve effective concentrations of both compounds at infected sites. In the experiments described here, the pharmacokinetics and distribution properties of ticarcillin and clavulanic acid were characterized after intravenous coadministration of the two compounds to rats and rabbits. The doses administered in the experiments were calculated on the basis of dose/ surface area (11) to be comparable with a recommended dose of ticarcillin-clavulanic acid for humans (3 g of ticarcillin with 100 mg of clavulanic acid; 3.1 g of Timentin [Beecham Pharmaceuticals, Worthing, England] The blood samples removed from the rats at 5, 45, and 90 min and from the rabbits at 10 and 60 min were used for determination of the binding of ticarcillin and clavulanic acid to serum proteins. Portions of the samples were kept for bioassay, and the remaining volumes of sera were centrifuged through a Centrifree micropartition system (Amicon, Gloucestershire, England)

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.