Pseudomonal infections have a high rate of morbidity and mortality, thus combination therapy is often recommended. We compared the activity of piperacillin/tazobactam in combination with amikacin, ciprofloxacin, or trovafloxacin at different concentrations against P. aeruginosa using time-kill methodology. MICs were determined for 4 clinical isolates of P. aeruginosa. Time-kill studies were conducted over 24 h. Each drug was tested alone and in combination using the following concentrations: 2 and 1/4, 1/4 and 2, and 1/4 and 1/4xMIC of piperacillin/tazobactam and amikacin, ciprofloxacin, or trovafloxacin. Combinations were classified as synergistic, indifferent, or antagonistic. Synergy was defined as > or = 2-log(10) decrease in CFU/mL at 24 h with the combination when compared to the most active single agent and the number of surviving organisms for the antimicrobial combination was > or =2-log(10) less than the initial inoculum. The MICs for piperacillin/tazobactam, amikacin, ciprofloxacin, and trovafloxacin, ranged from 4/4-512/4, 0.5-4, 0.125-4, and 0.5-8 microg/mL, respectively. Fifty eight percent of the combinations using concentrations of 1/4xMIC of piperacillin/tazobactam and 2xMIC of amikacin, ciprofloxacin, and trovafloxacin or 2xMIC of piperacillin/tazobactam and 1/4xMIC of amikacin, ciprofloxacin, and trovafloxacin were synergistic. Although no differences existed in synergistic activity between the two combinations, the 1/4 and 2xMIC maintained colony counts below the limit of quantification for 24 h for a significantly greater percentage of isolates than the 2 and 1/4xMIC combinations (75 and 25%, respectively; p = 0.04). Overall, synergy was most frequently (42%) noted with the piperacillin/tazobactam and amikacin combinations followed by 33 and 8% of the piperacillin/tazobactam and trovafloxacin and ciprofloxacin combinations. No combination demonstrated antagonism. Further more extensive studies are necessary to determine clinical significance.