Pharmacokinetic-pharmacodynamic modelling of the in vitro antiinfective effect of piperacillin-tazobactam combinations.
OBJECTIVE
The aim of the study was to investigate the in vitro antiinfective effect of piperacillin-tazobactam (PIP-TZB) combinations on Escherichia coli in simulations of free concentration time profiles of both drugs, similar to those obtained in human tissue after i.v. bolus administrations.


METHODS
An in vitro dilution model was used to expose E. coli ATCC 35218 (beta-lactamase producer) to various piperacillin-tazobactam concentration profiles obtained after i.v. bolus multiple dose, using different dose ratio combinations (1:4, 1:8, 1:16) and dosing regimens, ranging from once-a-day to 4 times a day. The antimicrobial effect was evaluated by determination of the number of bacteria over time. The concentration of PIP in the model was determined by HPLC.


RESULTS
A modified Emax model was used to describe the pharmacodynamic effect. The model was linked with the piperacillin concentrations determined experimentally to provide a pharmacokinetic-pharmacodynamic (PK-PD) model. The EC50 for piperacillin alone averaged 5.66 +/- 0.29 micrograms/ml. The EC50 for all doses of piperacillin combined with 0.5 g of tazobactam were dose-dependent and averaged 1.70 +/- 0.56, 3.95 +/- 1.02, and 6.14 +/- 1.24 micrograms/ml for PIP 2, 4, and 8 g, respectively. By increasing the dose of TZB in combination with a fixed dose of PIP, a decreased EC50 was observed.


CONCLUSIONS
The PK-PD model allowed a detailed evaluation of the dosing regimens investigated. The results suggested that for these combinations, 3 times a day administration is as effective as 4 times a day. Pharmacodynamic activity of the combinations can be prolonged by sufficiently high inhibitor concentrations.
Dalla Costa
T
T
Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Nolting
A
A
Rand
K
K
Derendorf
H
H
D003114:Colony-Forming Units Assay; D003198:Computer Simulation; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects; D006801:Humans; D008954:Models, Biological; D010397:Penicillanic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D010406:Penicillins / Q000493:pharmacokinetics* / Q000494:pharmacology; D010878:Piperacillin / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000078142:Tazobactam; D065093:beta-Lactamase Inhibitors
D004791:Enzyme Inhibitors; D010406:Penicillins; D065093:beta-Lactamase Inhibitors; D010397:Penicillanic Acid; D000078142:Tazobactam; D010878:Piperacillin