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

Abstract

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)

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

“…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.…”

Evaluation of piperacillin-tazobactam in experimental meningitis caused by a beta-lactamase-producing strain of K1-positive Escherichia coli

“…An alternative approach for the treatment of meningitis due to such organisms is the use of a penicillin derivative combined with an agent that inhibits the 1-lactamase elaborated by the infecting organism. Limited data on cerebrospinal fluid (CSF) penetration and efficacy of such combinations in experimental animals and humans are available (3,5,9,14,24,28). Using a well-standardized rabbit model, we studied the pharmacokinetics and therapeutic efficacy of a novel P-lactamase inhibitor, tazobactam (CL 298,741; formerly YTR 830), combined with piperacillin, a broad-spectrum acylureido-penicillin, in experimental meningitis due to a ,-lactamase-producing strain of Escherichia coli.…”

In vitro susceptibilities of feline and canine Escherichia coli and Pseudomonas spp. isolates to ticarcillin and ticarcillin–clavulanic acid

“…The therapeutic success of T/C depends on in vitro bacterial susceptibility, as well as in vivo host factors and drug pharmacokinetics . In a study on rats and rabbits, ticarcillin and clavulanic acid were both found to penetrate non‐inflamed liver, kidney, lung, bone marrow and pleural/peritoneal fluid to different concentrations . As penicillin derivatives are hydrophilic, weak acids that penetrate well into inflamed tissues, but not across non‐inflamed natural body barriers, the use of T/C could be considered for susceptible upper and lower urinary tract infections, hepatitis/cholangiohepatitis, osteomyelitis, pneumonia, sepsis and peritonitis in dogs and cats.…”