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

Abstract

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 with the trapezoidal rule by using the reciprocal of the inhibitory and bactericidal titers 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 ␤-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-gevery-8-h dosages, respectively. Comparison of area under the plasma concentration-time curve (AUC 0-24 ) for piperacillin (967.74 ؎ 135.56 g ⅐ h/ml versus 978.88 ؎ 140.96 g ⅐ h/ml) and tazobactam (120.14 ؎ 15.78 g ⅐ h/ml versus 120.01 ؎ 16.22 g ⅐ 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.

Scaling beta‐lactam antimicrobial pharmacokinetics from early life to old age

“…A flowchart of study selection for each drug is provided in Figure . A total of 2082 articles were identified and screened, with 130 studies included in the final analysis . Some studies provided PK parameters for two drugs (e.g.…”

Steady-state pharmacokinetics and pharmacodynamics of piperacillin/tazobactam administered by prolonged infusion in hospitalised patients

“…Several studies have been published describing the pharmacokinetics of PIP/TAZ when administered by intermittent and continuous infusions in healthy volunteers and select patient populations [24][25][26][27][28][29][30][31]. However, the pharmacokinetics of this drug combination administered by prolonged infusion has not been described previously.…”

Pharmacodynamic Modeling of β-lactam Antibiotics for the Empiric Treatment of Secondary Peritonitis: A Report from the OPTAMA Program

“…Estimates of fraction unbound for imipenem-cilastatin and meropenem were taken from the package insert and were 0.8-0.95 and 0.85-0.98, respectively [16,17]. Mean Ϯ standard deviation of CL and Vd of piperacillin/tazobactam (11.0 Ϯ 1.4 L/h and 12.0 Ϯ 1.8 L) were obtained from a two-way randomized crossover study in 12 healthy volunteers [18]. Mean fraction unbound estimates for piperacillin/tazobactam were 0.65-0.75 [19].…”