title: Activity of piperacillin/tazobactam in combination with amikacin, ciprofloxacin, and trovafloxacin against Pseudomonas aeruginosa by time-kill.
abstract: 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.
authors.affiliation: College of Pharmacy, The University of Texas at Austin, Austin, Texas, 78712, USA. burgessd@uthscsa.edu
authors.forename: D S
authors.initials: DS
authors.lastname: Burgess
authors.forename: R W
authors.initials: RW
authors.lastname: Hastings
mesh_terms: D000583:Amikacin / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000890:Anti-Infective Agents / Q000494:pharmacology*; D016009:Chi-Square Distribution; D002939:Ciprofloxacin / Q000494:pharmacology; D015169:Colony Count, Microbial; D004352:Drug Resistance, Microbial; D004357:Drug Synergism; D004359:Drug Therapy, Combination / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D024841:Fluoroquinolones; D006801:Humans; D009287:Naphthyridines / Q000494:pharmacology; D010397:Penicillanic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D010406:Penicillins / Q000494:pharmacology*; D010878:Piperacillin / Q000494:pharmacology; D011552:Pseudomonas Infections / Q000188:drug therapy*; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D000078142:Tazobactam
chemical_list: D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D004791:Enzyme Inhibitors; D024841:Fluoroquinolones; D009287:Naphthyridines; D010406:Penicillins; D002939:Ciprofloxacin; D000583:Amikacin; D010397:Penicillanic Acid; C080163:trovafloxacin; D000078142:Tazobactam; D010878:Piperacillin