Ex vivo pharmacodynamic study of piperacillin alone and in combination with tazobactam, compared with ticarcillin plus clavulanic acid

Ten volunteers received piperacillin (4 g), piperacillin (4 g) plus tazobactam (0.5 g) (Tazocin), and ticarcillin (3 g) plus clavulanic acid (0.2 g) (Timentin) intravenously over 30 min in a cross-over blinded scheme. Blood samples were obtained 0.5 and 3 h after the end of infusion to measure by (high-pressure liquid chromatography) the concentration and bactericidal titers against 70 gram-negative bacilli. Serum time-kill curves were done against 35 strains to measure killing rates and area under the time-kill curve. Using the measure of serum bactericidal activity, ticarcillin-clavulanic acid and piperacillin-tazobactam were equally effective against Pseudomonas aeruginosa, Escherichia coli, Enterobacter cloacae, Serratia marcescens, and Bacteroides fragilis. Piperacillin-tazobactam was superior to ticarcillin-clavulanic acid against piperacillin-resistant Klebsiella pneumoniae (4 to 16 times) and S. marcescens (2 to 4 times). By using the area under the time-kill curve, piperacillin-tazobactam was equivalent to ticarcillin-clavulanic acid against piperacillin-susceptible strains; piperacillin-tazobactam was significantly more active than piperacillin against piperacillin-resistant strains and was more active than ticarcillin-clavulanic acid when the sample obtained 3 h after the end of infusion to volunteers was considered. Serum piperacillin concentrations (mean +/- standard error of the mean; in mg/liter) were 115 +/- 13 at 0.5 h and 7.4 +/- 1.4 at 3 h after the administration of piperacillin alone and 105.5 +/- 12.6 (0.5 h) and 7.7 +/- 1.6 after the administration of piperacillin-tazobactam. Serum tazobactam concentrations (in milligram per liter) were 13.1 +/- 1.4 at 0.5 h and 1.2 +/- 0.2 at 3 h. The piperacillin-tazobactam ratio was 8 +/- 0.3 at 0.5 h and 6.2 +/- 0.5 at 3 h. Piperacillin-tazobactam appears promising against beta-lactamase-producing gram-negative bacilli.