Comparative pharmacodynamics of intermittent and prolonged infusions of piperacillin/tazobactam using Monte Carlo simulations and steady-state pharmacokinetic data from hospitalized patients.
BACKGROUND
Prolonging the infusion of a beta-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 microg/mL to 64 microg/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 microg/mL, PTA was greater than 90% for one intermittent-infusion regimen (3.375 g every 4 h) and 3 prolonged-infusion regimens (> or = 3.375 g every 8 h), but no regimen achieved a PTA greater than 90% at an MIC of 64 microg/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 microg/mL.
Shea
Katherine M
KM
Infectious Diseases, Seton Family of Hospitals, University Medical Center at Brackenridge, Austin, TX, USA.
Cheatham
S Christian
SC
Smith
David W
DW
Wack
Matthew F
MF
Sowinski
Kevin M
KM
Kays
Michael B
MB
D000328:Adult; D000368:Aged; D004334:Drug Administration Schedule; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy / Q000378:metabolism / Q000382:microbiology; D006760:Hospitalization; D006801:Humans; D007262:Infusions, Intravenous; D008826:Microbial Sensitivity Tests / Q000379:methods; D008875:Middle Aged; D009010:Monte Carlo Method; D010397:Penicillanic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D010878:Piperacillin / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D000078142:Tazobactam
D010397:Penicillanic Acid; D000078142:Tazobactam; D010878:Piperacillin