title: Simulation of human serum pharmacokinetics of ticarcillin-clavulanic acid and ceftazidime in rabbits, and efficacy against experimental Klebsiella pneumoniae meningitis.
abstract: 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.
authors.affiliation: Beecham Pharmaceuticals Research Division, Chemotherapeutic Research Centre, Betchworth, Surrey, England.
authors.forename: L
authors.initials: L
authors.lastname: Mizen
authors.forename: G
authors.initials: G
authors.lastname: Woodnutt
authors.forename: I
authors.initials: I
authors.lastname: Kernutt
authors.forename: E J
authors.initials: EJ
authors.lastname: Catherall
mesh_terms: D000818:Animals; D002442:Ceftazidime / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002969:Clavulanic Acids / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D007711:Klebsiella pneumoniae; D008297:Male; D008581:Meningitis / Q000188:drug therapy* / Q000382:microbiology; D008826:Microbial Sensitivity Tests; D010406:Penicillins / Q000493:pharmacokinetics*; D011817:Rabbits; D013982:Ticarcillin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013997:Time Factors
chemical_list: D002969:Clavulanic Acids; D010406:Penicillins; D002442:Ceftazidime; D013982:Ticarcillin