Pharmacokinetics and pharmacodynamics of two multiple-dose piperacillin-tazobactam regimens

The pharmacokinetics and pharmacodynamics of two multiple-dose regimens of piperacillin-tazobactam (3.375 g every 6 h and 4.5 g every 8 h) were evaluated at steady state for 12 healthy adult volunteers, Inhibitory and bactericidal activities for the two regimens were determined with five American Type Culture Collection (ATCC) organisms (Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Bacteroides fragilis). The percentage of time that plasma concentrations remained above the MIC (T > MIC) for each organism and dosage regimen was calculated, Areas under the inhibitory (AUIC(0-24)) and bactericidal activity (AUBC(0-24)) curves were calculated,vith the trapezoidal rule by using the reciprocal of the inhibitory and bactericidal liters determined for each dosage regimen. In order to assess the validity of predicted measures of bactericidal (AUC(0-24)/MBC) and inhibitory (AUC(0-24)/MIC) activity to determine bacteriological response to beta-lactam antimicrobial agents, AUC(0-24)/MBC and AUC(0-24)/MIC values were compared with measured AUBC(0-24) and AUIC(0-24) values, Total body clearance values were equivalent for piperacillin (183.96 +/- 22.66 versus 181.72 +/- 19.54 ml/min/1.73 m(2), P > 0.05) and tazobactam (184.71 +/- 19.89 versus 184.87 +/- 18.35 ml/min/1.73 m(2), P > 0.05) following the administration of the 3.375-g-every-6-h and 4.5-g-every-8-h dosages, respectively. Comparison of area under the plasma concentration-time curve (AUC(0-24)) for piperacillin (967.74 +/- 135.56 mu g . h/ml versus 978.88 +/- 140.96 mu g . h/ml) and tazobactam (120.14 +/- 15.78 mu g . h/ml versus 120.01 +/- 16.22 mu g . h/ml) revealed no significant differences (P > 0.05) between the 3.375-g-every-6-h and 4.5-g-every-8-h regimens, respectively. Both regimens provided T > MIC values of > 60% for all organisms tested, Measured values of bactericidal (AUBC) and inhibitory (AUIC) activity were significantly different (P < 0.05) from predicted values (AUC(0-24)/MBC and AUC(0-24)/MIC) for all organisms studied with the exception of the bactericidal activity for P. aeruginosa and S. aureus, Additionally, ATCC organisms possessing the same MICs and MBCs exhibited great differences in measured AUBC(0-24) and AUIC(0-24) values, Reasons for this difference may be inherent differences in organism specific susceptibility.