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


METHODS
Multiple-dose, open-label, randomized, crossover study.


METHODS
Clinical research center at Hartford Hospital.


METHODS
Twelve healthy volunteers.


METHODS
The two dosing regimens for piperacillin-tazobactam were administered intravenously in crossover design. Blood was sampled after the third dose.


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 (Cmax), area under the concentration-time curve (AUC0-tau), and total clearance of piperacillin differed significantly between the two study regimens, as did the Cmax, AUC0-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 microg/ml; a similar value for the piperacillin 3.0 g-tazobactam 0.375 g regimen was 16-32 microg/ml.


CONCLUSIONS
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.
Kim
Myo-Kyoung
MK
Department of Pharmacy Research, Hartford Hospital, Connecticut 06102, USA.
Capitano
Blair
B
Mattoes
Holly M
HM
Xuan
Dawei
D
Quintiliani
Richard
R
Nightingale
Charles H
CH
Nicolau
David P
DP
D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004359:Drug Therapy, Combination / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008826:Microbial Sensitivity Tests; D010397:Penicillanic Acid / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D010406:Penicillins / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D010878:Piperacillin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D000078142:Tazobactam; D065093:beta-Lactamase Inhibitors
D004791:Enzyme Inhibitors; D010406:Penicillins; D065093:beta-Lactamase Inhibitors; D010397:Penicillanic Acid; D000078142:Tazobactam; D010878:Piperacillin