Pharmacokinetic and pharmacodynamic evaluation of two dosing regimens for piperacillin-tazobactam

Study Objective. To compare the pharmacokinetic and pharmacodynamic profiles of two dosing regimens for piperacillin-tazobactam against commonly encountered pathogens. The regimens compared were piperacillin 4.0 g-tazobactam 0.5 g administered every 8 hours, and piperacillin 3.0 g-tazobactam 0.375 g administered every 6 hours. Design. Multiple-dose, open-label, randomized, crossover study. Setting. Clinical research center at Hartford Hospital. Subjects. Twelve healthy volunteers. Intervention. The two dosing regimens for piperacillin-tazobactam were administered intravenously in crossover design. Blood was sampled after the third dose. Measurements and Main Results. Drug concentrations were determined by a validated high-performance liquid chromatography assay. The percentage of time above minimum inhibitory concentration (%T>MIC) for piperacillin was calculated for a range of MIC values. The maximum concentration (C-max), area under the concentration-time curve (AUC(0-tau)), and total clearance of piperacillin differed significantly between the two study regimens, as did the C-max AUC(0-tau), volume of distribution, and total clearance of tazobactam (p<0.05). The piperacillin 4.0 g-tazobactam 0.5 g regimen provided 40-50% T>MIC for MIC values 8-16 mug/ml; a similar value for the piperacillin 3.0 g-tazobactam 0.375 g regimen was 16-32 mug/ml. Conclusion. Although statistically significant differences in the pharmacodynamic profile were noted for the regimens, both provide adequate T>MIC against commonly encountered pathogens considered susceptible to piperacillin-tazobactam. However, for treatment of Pseudomonas aeruginosa infection, combination therapy or higher-dosage regimens (e.g., piperacillin 3.0 g-tazobactam 0.375 g every 4 hours, piperacillin 4.0 g-tazobactam 0.5 g every 6 hours, or continuous-infusion piperacillin 12 g-tazobactam 1.5 g/day) may be a prudent option when full MIC data are unavailable.