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‐τ ), and total clearance of piperacillin differed significantly between the two study regimens, as did the C max , AUC 0‐τ , 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 μg/ml; a similar value for the piperacillin 3.0 g‐tazobactam 0.375 g regimen was 16–32 μg/ml. Conclusion. Although statistically significant differences in the pharmaco‐dynamic 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.