PHARMACOKINETICS AND PHARMACODYNAMICS OF 2 MULTIPLE-DOSE PIPERACILLIN-TAZOBACTAM REGIMENS

The pharmacokinetics and pharmacodynamics of two multiple-dose regimen s of piperacillin-tazobactam (3.375 g every 6 h and 4.5 g every 8 h) w ere evaluated at steady state for 12 healthy adult volunteers, Inhibit ory and bactericidal activities for the two regimens were determined w ith five American Type Culture Collection (ATCC) organisms (Escherichi a coli, Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeru ginosa, 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 th e trapezoidal rule by using the reciprocal of the inhibitory and bacte ricidal 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 resp onse 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) value s, Total body clearance values were equivalent for piperacillin (183.9 6 +/- 22.66 versus 181.72 +/- 19.54 ml/min/1.73 m(2), P > 0.05) and ta zobactam (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 plasm a concentration-time curve (AUC(0-24)) for piperacillin (967.74 +/- 13 5.56 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) rev ealed 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 bactericida l activity for P. aeruginosa and S. aureus, Additionally, ATCC organis ms possessing the same MICs and MBCs exhibited great differences in me asured AUBC(0-24) and AUIC(0-24) values, Reasons for this difference m ay be inherent differences in organism specific susceptibility.