Pharmacokinetics and pharmacodynamics of piperacillin/tazobactam when administered by continuous infusion and intermittent dosing

• Published in: Clinical therapeutics Vol. 24; no. 7; pp. 1090 - 1104
• Main Authors: Burgess, David S., Waldrep, Travis
• Format: Journal Article Conference Proceeding
• Language: English
• Published: Belle Mead, NJ Elsevier Inc 01.07.2002; Excerpta Medica; Elsevier Limited
• Subjects: Adult; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimicrobial agents; Biological and medical sciences; Catheters; Clinical isolates; Clinical trials; continuous infusion; Cross-Over Studies; Drug Administration Schedule; Drug Therapy, Combination - administration & dosage; Drug Therapy, Combination - pharmacokinetics; Drug Therapy, Combination - pharmacology; Female; Humans; Infusions, Intravenous; Klebsiella pneumoniae; Klebsiella pneumoniae - drug effects; Klebsiella pneumoniae - isolation & purification; Male; Medical sciences; Microbial Sensitivity Tests; Minimum inhibitory concentration; Penicillanic Acid - administration & dosage; Penicillanic Acid - analogs & derivatives; Penicillanic Acid - pharmacokinetics; Penicillanic Acid - pharmacology; Penicillins - administration & dosage; Penicillins - pharmacokinetics; Penicillins - pharmacology; Pharmacodynamics; Pharmacokinetics; Pharmacology. Drug treatments; Piperacillin; Piperacillin - administration & dosage; Piperacillin - pharmacokinetics; Piperacillin - pharmacology; piperacillin/tazobactam; Pseudomonas aeruginosa - drug effects; Pseudomonas aeruginosa - isolation & purification; Tazobactam; pharmacokinetics; piperacillin/tazobactam; pharmacodynamics; continuous infusion; Pseudomonadales; Biological fluid; Intravenous administration; β-Lactamase; Penicillin derivatives; Efficiency; Piperacillin; Bacteria; Pseudomonadaceae; Pseudomonas aeruginosa; Serum; Dose; Enterobacteriaceae; Human; Drug combination; Enzyme; β-Lactams; Enzyme inhibitor; Normal; In vitro; Antibiotic; Bolus injection; Tazobactam; Minimum inhibitory concentration; Hydrolases; Intermittent injection; Antibacterial agent; Pharmacokinetics; Comparative study; Klebsiella pneumoniae
• ISSN: 0149-2918; 1879-114X
• DOI: 10.1016/S0149-2918(02)80021-2

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 μg/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 ≥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 K pneumoniae ( P ≤ 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 ≥ 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.