THE EFFECT OF TAZOBACTAM ON THE PHARMACOKINETICS AND THE ANTIBACTERIAL ACTIVITY OF PIPERACILLIN IN DOGS

Tazobactam (Tazosyn(R)) is a novel beta-lactamase inhibitor belonging to a class of penicillanic acid sulfones. Tazobactam was developed to be used in combination with piperacillin against beta-lactamase produc ing microorganisms. The current study was conducted to determine the e ffect of tazobactam on the pharmacokinetics and the antibacterial acti vity of piperacillin in dogs. Three groups of animals consisting of th ree beagle dogs per group were used for the study. The animals were ad ministered a single I.V. dose of tazobactam (40 mg/kg), piperacillin ( 320 mg/kg) or the combination in a ratio of 1:8 (tazobactam: piperacil lin). Blood samples were drawn at different time intervals. The serum bactericidal titers (SBT) were determined against a plasmid-mediated b eta-lactamase producing strain of Eschericia coli (LSU-80-8). Serum co ncentrations of both compounds were determined by high performance liq uid chromatography. The mean serum bactericidal titers of the combinat ion was 1:16 against this piperacillin resistant strain of E. coli, 2 h after dosing as compared to less than 1:2 when piperacillin was give n alone at the same dose. This indicates that serum concentrations gre ater than 187 mu g/ml of piperacillin (SBT < 1:2) were required to kil l 99.9% of the piperacillin resistant E. coli inoculum (10(6) CFU/ml) when piperacillin was given alone. However, when piperacillin was admi nistered in combination with tazobactam, concentrations as low as 7 mu g/ml of piperacillin and 2 mu g/ml of tazobactam were sufficient to e xhibit the same bactericidal activity. These results indicate an in-vi vo synergistic effect of tazobactam on the piperacillin activity at th is dosing ratio which lasted for approximately 5 h after dosing. The c oadministration of tazobactam did not appear to affect the pharmacokin etic parameters of piperacillin. However, the elimination of tazobacta m was significantly inhibited when coadministered with piperacillin, r esulting in a reduction of the clearance (3.5 vs. 7.5 ml/min per kg) a nd prolongation of the half-life (43 vs. 31 min). (C) 1997 Elsevier Sc ience B.V.