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The pharmacodynamics of dosage regimens of piperacillin alone or in combination with tazobactam against piperacillin-resistant or -susceptible bacteria were studied in an in vitro model of infection. Experiments were conducted by using a fixed daily exposure of 12 g of piperacillin, given as 3 g alone or in combination with tazobactam at 0.375 g every 6 h, or the same total dose of the combination given as 4 g of piperacillin plus 0.5 g of tazobactam every 8 h. The addition of tazobactam to piperacillin, irrespective of the dosing interval, did not alter the killing of piperacillin-susceptible organisms (Escherichia coli J53 and Pseudomonas aeruginosa ATCC 27853). In contrast, experiments with an isogenic TEM-3-containing transconjugant of E. coli J53 (E. coli J53.2-TEM-3) that was resistant to piperacillin (MIC, 128 μg/ml) showed that the addition of tazobactam resulted in bacterial killing similar to that observed with the wild-type strain. Although tazobactam concentrations fell to less than 4 mg/liter (the concentration associated with a reduction in the piperacillin MIC from 128 to 2 mg/liter) 2 to 3 h after a dose, a similar degree of bacterial killing was observed when the same total 24-h dose of piperacillin-tazobactam was fractionated into dosing intervals of every 6 or 8 h. Investigations with Staphylococcus aureus 7176 (piperacillin MIC, 128 μg/ml) showed that the addition of tazobactam, again irrespective of dosing interval, also resulted in net bacterial killing which was not seen with piperacillin alone. These data support the use of extended dosing intervals (every 8 h) of piperacillin-tazobactam in the treatment of infections caused by piperacillin-resistant bacteria.