PHARMACODYNAMICS OF PIPERACILLIN ALONE AND IN COMBINATION WITH TAZOBACTAM AGAINST PIPERACILLIN-RESISTANT AND PIPERACILLIN-SUSCEPTIBLE ORGANISMS IN AN IN-VITRO MODEL OF INFECTION

The pharmacodynamics of dosage regimens of piperacillin alone or in co mbination with tazobactam against piperacillin-resistant or -susceptib le bacteria were studied in an in vitro model of infection. Experiment s were conducted by using a fixed daily exposure of 12 g of piperacill in, given as 3 g alone or in combination with tazobactam at 0.375 g ev ery 6 h, or the same total dose of the combination given as 4 g of pip eracillin plus 0.5 g of tazobactam every 8 h. The addition of tazobact am to piperacillin, irrespective of the dosing interval, did not alter the killing of piperacillin-susceptible organisms (Escherichia coli J 53 and Pseudomonas aeruginosa ATCC 27853). In contrast, experiments wi th an isogenic TEM-3-containing transconjugant of E. coli J53 (E. coli J53.2-TEM-3) that was resistant to piperacillin (MIC, 128 mu g/ml) sh owed that the addition of tazobactam resulted in bacterial killing sim ilar to that observed with the wild-type strain. Although tazobactam c oncentrations fell to less than 4 mg/liter (the concentration associat ed 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 observe d when the same total 24-h dose of piperacillin-tazobactam was fractio nated into dosing intervals of every 6 or 8 h. Investigations with Sta phylococcus aureus 7176 (piperacillin MIC, 128 mu g/ml) showed that th e 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.