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: L Mizen, G Woodnutt, I Kernutt, E J Catherall
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 33 Issue 5 Pg. 693-9 (May 1989) ISSN: 0066-4804 [Print] United States
• PMID: 2665641 (Publication Type: Journal Article)

Chemical References

• Clavulanic Acids
• Penicillins
• Ceftazidime
• Ticarcillin

Topics

• Animals
• Ceftazidime (administration & dosage, pharmacokinetics, therapeutic use)
• Clavulanic Acids (administration & dosage, pharmacokinetics, therapeutic use)
• Humans
• Klebsiella pneumoniae
• Male
• Meningitis (drug therapy, microbiology)
• Microbial Sensitivity Tests
• Penicillins (pharmacokinetics)
• Rabbits
• Ticarcillin (administration & dosage, pharmacokinetics, therapeutic use)
• Time Factors