Pharmacokinetics and pharmacodynamics of piperacillin/tazobactam when administered by continuous infusion and intermittent dosing.
BACKGROUND
Although intermittent bolus dosing is currently the standard of practice for many antimicrobial agents, beta-lactams exhibit time-dependent bacterial killing. Maximizing the time above the minimum inhibitory concentration (MIC) for a pathogen is the best pharmacodynamic predictor of efficacy. Use of a continuous infusion has been advocated for maximizing the time above the MIC compared with intermittent bolus dosing.


OBJECTIVE
This study compared the pharmacokinetics and pharmacodynamics of piperacillin/tazobactam when administered as an intermittent bolus versus a continuous infusion against clinical isolates of Pseudomonas aeruginosa and Klebsiella pneumoniae.


METHODS
Healthy volunteers were randomly assigned to receive piperacillin 3 g/ tazobactam 0.375 g q6h for 24 hours, piperacillin 6 g/tazobactam 0.75 g continuous infusion over 24 hours, and piperacillin 12 g/tazobactam 1.5 g continuous infusion over 24 hours. Five clinical isolates each of P aeruginosa and K pneumoniae were used for pharmacodynamic analyses.


RESULTS
Eleven healthy subjects (7 men, 4 women; mean +/- SD age, 28 +/- 4.7 years) were enrolled. Mean steady-state serum concentrations of piperacillin were 16.0 +/- 5.0 and 37.2 +/- 6.8 microg/mL with piperacillin 6 and 12 g, respectively. Piperacillin/tazobactam 13.5 g continuous infusion (piperacillin 12 g/tazobactam 1.5 g) was significantly more likely to produce a serum inhibitory titer > or = 1:2 against P aeruginosa at 24 hours than either the 6.75 g continuous infusion (piperacillin 6 g/tazobactam 0.75 g) or 3.375 g q6h (piperacillin 3 g/ tazobactam 0.375 g). There were no statistical differences against K pneumoniae between regimens. The median area under the inhibitory activity-time curve (AUIC) for the 13.5 g continuous infusion was higher than that for 3.375 g q6h and the 6.75 g continuous infusion against both P aeruginosa and Kpneumoniae (P < or = 0.007, 13.5 g continuous infusion and 3.375 g q6h vs 6.75 g continuous infusion against K pneumoniae). The percentage of subjects with an AUIC > or = 125 was higher with both 3.375 g q6h and the 13.5 g continuous infusion than with the 6.75 g continuous infusion against P aeruginosa and K pneumoniae (both, P < 0.001 vs 6.75 g continuous infusion against K pneumoniae).


CONCLUSIONS
Piperacillin 12 g/tazobactam 1.5 g continuous infusion consistently resulted in serum concentrations above the breakpoint for Enterobacteriaceae and many of the susceptible strains of P aeruginosa in this study in 11 healthy subjects. Randomized controlled clinical trials are warranted to determine the appropriate dose of piperacillin/tazobactam.
Burgess
David S
DS
College of Pharmacy, University of Texas at Austin, USA. burgessd@uthscsa.edu
Waldrep
Travis
T
D000328:Adult; D018592:Cross-Over Studies; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007711:Klebsiella pneumoniae / Q000187:drug effects / Q000302:isolation & purification; D008297:Male; D008826:Microbial Sensitivity Tests; D010397:Penicillanic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D010406:Penicillins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D010878:Piperacillin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000302:isolation & purification; D000078142:Tazobactam
D010406:Penicillins; D010397:Penicillanic Acid; D000078142:Tazobactam; D010878:Piperacillin