Title

Pharmacokinetics/pharmacodynamics of beta-lactams alone and in combination with beta-lactamase inhibitors against beta-lactamase-inducible Pseudomonas aeruginosa

Date of Completion

January 2003

Keywords

Health Sciences, Pharmacology|Biology, Animal Physiology|Health Sciences, Pharmacy

Degree

Ph.D.

Abstract

The pharmacokinetics and antimicrobial efficacies of β-lactams alone and in combination with β-lactamase inhibitors were investigated applying a rabbit tissue cage model against a strain of AmpC β-lactamase inducible Pseudomonas aeruginosa (PSA246). Two sterilized golf wiffle balls were surgically implanted in the rabbit dorsal cervical area. After 4 weeks, wiffle balls were filled with tissue cage fluid (TCF), in which 2-ml of 10 6 CFU/ml of the test isolate were inoculated. To achieve the same T > MIC as in humans, 400 mg/kg of the β-lactams alone and in combination with the inhibitors were administrated b.i.d. via subcutaneous injection. The dose regimens were as follows: piperacillin alone, the combination of piperacillin (4-g)-tazobactam (0.5-g), ticarcillin alone, the combination of ticarcillin (3-g)-clavulanate (0.1-g), and the combination of ticarcillin (3-g) - clavulanate (0.3-g). The pharmacokinetics of the drugs in serum and TCF were evaluated, there were no impact of tazobactam and clavulanate on the absorption, tissue penetration and elimination of piperacillin and ticarcillin. Tazobactam significantly enhanced the antimicrobial activity of piperacillin against the strain of AmpC β-lactamase inducible P. aeruginosa . No AmpC induction by tazobactam was observed in vitro and in vivo. The antibacterial activity of ticarcillin was synergised by clavulanate at low dose, but clavulanate at high dose had no impact on ticarcillin. AmpC induction by high dose clavulanate was observed in rabbit TCF, which was confirmed by the in vitro induction study. The results of the present study indicate that bacterial resistance could be developed due to AmpC in vivo induction by clavulanate. Consequently, to ensure the successful therapy for P. aeruginosa infected patients, the combination of piperacillin and tazobactam should be used, instead of the combination of ticarcillin and clavulanate. ^