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 efficacy of ticarcillin-clavulanic acid was compared with the efficacies of standard antistaphylococcal agents (flucloxacillin, oxacillin, nafcillin, and vancomycin) and ticarcillin in an experimental model of Staphylococcus aureus endocarditis. Therapy was either initiated soon (8 h) after infection, when numbers of bacteria in aortic valve vegetations were relatively low (approximately 6 to 8 log1o CFU/g), or delayed until 24 h after infection, when the vegetations usually contained >9 loglo CFU/g. Doses of the antibiotic were selected to produce peak concentrations in rat serum similar to those achievable in humans after administration of parenteral therapeutic doses. Ticarcillin-clavulanic acid was more effective overall than ticarcillin alone against endocarditis caused by ,I-lactamase-producing strains of S. aureus, illustrating the P-lactamase-inhibitory activity of clavulanic acid in vivo. Ticarcillin-clavulanic acid was as effective as the standard antistaphylococcal ,-lactam agents flucloxacillin, oxacillin, and nafcillin in these infections, whereas vancomycin was generally less active. These results illustrate the clinical potential of ticarcillin-clavulanic acid in the prophylaxis or therapy of severe staphylococcal infections.Staphylococcus aureus remains a major pathogen, and 80% to greater than 90% of clinical isolates of S. aureus are 3-lactamase producers (10, 17). Clavulanic acid is a potent inhibitor of a wide range of bacterial 3-lactamases, including those produced by S. aureus (22). The combination of ticarcillin and clavulanic acid has been shown to extend the spectrum of ticarcillin to include P-lactamase-producing strains both in vitro (29) and in vivo (2, 21, 29), and successful treatment of clinical staphylococcal infections with ticarcillin-clavulanic acid has been reported (9, 15).Experimental Staphylococcus endocarditis represents one of the more severe of the available animal models of staphylococcal infections. It is considered to be a discriminative model closely resembling the human infection in pathology and mortality (10,25) and is a stringent test of antibiotic efficacy, especially when therapy is delayed until the endocarditis is particularly well established.The combination of clavulanic acid with amoxicillin has been shown to be effective in rats against early endocarditis in which the vegetations contained approximately 6 to 8 log1o CFU of S. aureus per g (3, 5) and against late S. aureus endocarditis in which bacterial counts were 9 to 10 log1o CFU/g (5). The activity of a combination of clavulanic acid with ticarcillin against S. aureus endocarditis in rabbits has been reported elsewhere (7,24). Accordingly, the efficacy of ticarcillin-clavulanic acid in rats against early and late endocarditis caused by four ,-lactamase-producing, methicillin-susceptible strains of S. aureus has been assessed. The activity of the combination was compared with that of ticarcillin alone and with the activities of agents commonly employed in the treatment of staphylococcal infections...

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The efficacy of amoxycillin/clavulanic acid was compared with that of flucloxacillin, vancomycin and amoxycillin in an experimental model of Staphylococcus aureus endocarditis. Doses of the antibiotics were selected to produce peak concentrations in rat serum similar to those achievable in man after administration of parenteral therapeutic doses. Amoxycillin clavulanic acid was more effective than amoxycillin alone against endocarditis caused by beta-lactamase producing strains of Staph. aureus, illustrating the beta-lactamase inhibitory activity of clavulanic acid in vivo. Amoxycillin/clavulanic acid was as effective as flucloxacillin in these infections whereas vancomycin was generally less active. These results illustrate the clinical potential of amoxycillin/clavulanic acid in the prophylaxis, or in the therapy of severe staphylococcal infections.