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Clinical Pharmacy Specialist, Infectious Diseases, Seton Family of Hospitals, University Medical Center at Brackenridge, Austin, TX
Clinical Pharmacist, Infectious Diseases, St. Francis Hospital, Beech Grove, IN
Clinical Pharmacist, Infectious Diseases, Clarian Health Partners, Inc., Methodist Hospital, Indianapolis, IN
Infectious Diseases Physician, Infectious Diseases of Indiana, Indianapolis
Professor of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, Purdue University, Indianapolis and West Lafayette, IN
Associate Professor of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, Purdue University, Indianapolis and West Lafayette
Reprints: Dr. Kays, Purdue University School of Pharmacy and Pharmaceutical Sciences, Department of Pharmacy Practice, W7555 Myers Building, WHS, 1001 W. Tenth St., Indianapolis, IN 46202, fax 317/613-2316, mkays{at}iupui.edu
BACKGROUND: Prolonging the infusion of a β-lactam antibiotic enhances the time in which unbound drug concentrations remain above the minimum inhibitory concentration (fT>MIC).
OBJECTIVE: To compare the pharmacodynamics of several dosing regimens of piperacillin/tazobactam administered by intermittent and prolonged infusion using pharmacokinetic data from hospitalized patients.
METHODS: Steady-state pharmacokinetic data were obtained from 13 patients who received piperacillin/tazobactam 4.5 g every 8 hours, infused over 4 hours. Monte Carlo simulations (10,000 pts.) were performed to calculate pharmacodynamic exposures at 50% fT>MIC for 4 intermittent-infusion regimens (3.375 g every 4 and 6 h, 4.5 g every 6 and 8 h) and 4 prolonged-infusion regimens (2.25 g, 3.375 g, 4.5 g, and 6.75 g every 8 h [4-h infusion]) of piperacillin/tazobactam using pharmacokinetic data for piperacillin. Cumulative fraction of response (CFR) was calculated using MIC data for 6 gram-negative pathogens (Meropenem Yearly Susceptibility Test Information Collection, 2004–2007), and probability of target attainment (PTA) was calculated at MICs ranging from 1 µg/mL to 64 µg/mL.
RESULTS: The CFR for 3.375 g every 4 hours (intermittent infusion)
and 3.375–4.5 g every 8 hours (prolonged infusion) greater than or equal
to 90.3% for Escherichia coli, Serratia marcescens, and
Citrobacter spp. Increasing the prolonged-infusion dose to 6.75 g
improved the CFR to greater than 90% for Enterobacter spp. For every
regimen evaluated, the CFR was less than 90% for Klebsiella
pneumoniae and Pseudomonas aeruginosa. At an MIC of 16 µg/mL,
PTA was greater than 90% for one intermittent-infusion regimen (3.375 g every
4 h) and 3 prolonged-infusion regimens (
3.375 g every 8 h), but no regimen
achieved a PTA greater than 90% at an MIC of 64 µg/mL.
CONCLUSIONS: At doses greater than or equal to 3.375 g every 8 hours, 4-hour infusions of piperacillin/tazobactam achieved excellent target attainment with lower daily doses compared with standard regimens at MICs less than or equal to 16 µg/mL.
Key Words: Monte Carlo, pharmacodynamics, piperacillin, prolonged infusion, tazobactam
Published Online, October 6, 2009. www.theannals.com, DOI 10.1345/aph.1M304
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  J. C Rotschafer and M. Ullman Comparative Pharmacodynamics of Intermittent and Prolonged Infusions of Piperacillin/Tazobactam Using Monte Carlo Simulation and Steady-State Pharmacokinetic Data from Hospitalized Patients Ann. Pharmacother., November 1, 2009; 43(11): 1887 - 1889. [Abstract] [Full Text] [PDF]
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