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 Bacteroidesfragilis. Piperacillin-tazobactam was superior to ticarcillin-clavulanic acid against piperacillin-resistant Kiebsiella 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 milligrams 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 ,3-lactamase-producing gram-negative bacilli.Infections by gram-negative organisms are still a major cause of morbidity in patients with cancer, especially when they are neutropenic (19). Treatment of these infections often consists of the administration of a broad-spectrum ,-lactam antibiotic in combination with an aminoglycoside, although the use of monotherapy with a broad-spectrum cephalosporin or imipenem has been advocated. The increasing incidence of gram-negative bacilli with broad-spectrum ,3-lactamases has caused the empiric use of monotherapy to be questioned. One way to overcome this problem is use of the combination of a broad-spectrum penicillin with an effective ,-lactamase inhibitor. Piperacillin is a broadspectrum penicillin which has a high level of in vitro activity against members of the family Enterobacteriaceae and Pseudomonas aeruginosa. Tazobactam is an effective inhibitor of various types of 3-lactamases, especially the penicillinase type of Staphylococcus aureus, the TEM types, and the cephalosporinase of Bacteroides fragilis (2,3,(8)(9)(10)14). In particular, tazobactam is a better inhibitor of the chromosomal cephalosporinases of members of the family Enterobactenaceae (Enterobacter,...