Pharmacodynamic Profiling of Piperacillin in the Presence of Tazobactam in Patients through the Use of Population Pharmacokinetic Models and Monte Carlo Simulation

Abstract

The primary objectives of this analysis were to determine which pharmacokinetic model most accurately describes the elimination pathways for piperacillin in the presence of tazobactam through population pharmacokinetic modeling and to characterize its pharmacodynamic profile. Once the optimal pharmacokinetic model was identified, Monte Carlo simulation of 10,000 subjects with ADAPT II was performed to estimate the probability of attaining a target free-piperacillin concentration greater than the MIC for 50% of the dosing interval for 3.375 g every 6 h or every 4 h given as a 0.5-h infusion at each MIC between 0.25 and 32 g/ml.In the population pharmacokinetic analysis, measurements of bias and precision, observed-predicted plots, and r 2 values were highly acceptable for all three models and all three models were appropriate candidates for the Monte Carlo simulation evaluation. Visual comparison of the distribution of the piperacillin concentrations at the pharmacodynamic endpoint-h 3 concentrations of a 6-h dosing interval-between the simulated populations and raw data revealed that the linear model was most reflective of the raw data at the pharmacodynamic endpoint, and the linear model was therefore selected for the target attainment analysis. In the target attainment analysis, administration of 3 g of piperacillin every 6 h resulted in a robust target attainment rate that exceeded 95% for MICs of <8 mg/liter. The 4-h piperacillin administration interval had a superior pharmacodynamic profile and provided target attainment rates exceeding 95% for MICs of <16 mg/liter. This study indicates that piperacillin-tazobactam should have utility for empirical therapy of hospital-onset infections.Antimicrobial pharmacodynamics is a term used to describe the relationship between drug exposure and antimicrobial activity. In recent years there have been tremendous strides in understanding the relationship between the pharmacodynamics of beta-lactams and treatment outcomes. Beta-lactams, in contrast to aminoglycosides and fluoroquinolones, exhibit little concentration-dependent bacterial killing (7-9, 14, 24, 25, 29, 30). This phenomenon was observed in early Staphylococcus aureus time-kill curve studies, which demonstrated that the rate of bacterial killing was not improved by increasing the concentration of penicillin (19). For beta-lactams, the time during which the free (unbound) serum drug concentration exceeds the MIC of the drug for the organism (T Ͼ MIC) appears to be the best predictor of outcomes (7-9, 24, 25). The serum free-beta-lactam concentration does not have to remain above the MIC for the entire dosing interval, and the fraction of the dosing interval during which it is required to remain above the MIC for the maximal antimicrobial effect varies for the different types of beta-lactams (7-9). Although the T Ͼ MIC varies for different drug-bacteria combinations, satisfactory outcomes (near-maximal bactericidal effect) are achieved when the free (unbound)-antibiotic concentration remains above the MIC for t...

Three Decades of β-Lactamase Inhibitors

“…This substrate stability may be due, in part, to piperacillin's lower affinity for and lower turnover (k cat s) by these enzymes and also piperacillin's greater affinity for bacterial PBPs (234). We also propose that the pharmacokinetics and pharmacodynamics of the 3.375-g and 4.5-g formulations lead to extended periods of time when free drug concentrations (Ͼ100 g/ml piperacillin in serum) are greater than the MIC for Ն50% of the dosing interval for many nosocomial pathogens (242). It is likely that the high serum concentrations combined with the superior activity of piperacillin and the relatively "better" inhibitory activity of tazobactam versus clavulanate or sulbactam is enough to inhibit a majority of ␤-lactamases in a complex ␤-lactamase background (class A and C ␤-lactamases) (328).…”

Pharmacokinetics and Pharmacodynamics of Aerosolized Antibacterial Agents in Chronically Infected Cystic Fibrosis Patients

“…The MIC that was covered for 50% of the dosing interval by either regimen was evaluated; a PK/PD analysis of drug effects has not been performed. In the non-CF population, the target was met by administration of 3 g piperacillin every 6 h for hypothetical isolates with a numerical MIC of Յ8 mg/liter, while administration every 4 h resulted in a more robust target attainment and covered hypothetical isolates with numerical MICs of Ն16 mg/liter (226), which corresponds to the resistance breakpoint set by the EUCAST. A piperacillin dose of 3 g every 4 h achieved robust target attainment in CF patients for hypothetical isolates with MICs of Յ12 mg/liter (227).…”

“…Time above the MIC is the relevant parameter for these ␤-lactams. The PK/PD of piperacillin has been studied in hospitalized non-CF patients and in CF patients (226,227). A PK/PD target of 50% TϾMIC was set for both patient populations, who were dosed with two different regimens.…”

Use of pharmacodynamic principles to inform β‐lactam dosing: “S” does not always mean success

“…First, it produces a lower peak concentration of the drug.'' 24 Because the bacterial kill rate for these agents is not concentration-dependent, this does not present a major disadvantage. 3,4,[28][29][30] Second, the drug concentrations remain in excess of the MIC for a longer period of time.…”

“…However, as demonstrated in the aforementioned TZP MCS studies, increasing the TZP dose from 3.375 grams to 4.5 grams every 6 hours had a minimal impact on the PTA profile. 24,25 To increase fT >MIC by 1 . 26 Control patients received alternative empiric therapy (in doses appropriate for renal function as recommended by the manufacturer) within 24 hours of the first positive blood culture result to which the isolate was found to be susceptible using current CLSI susceptibility breakpoints.…”