Pharmacokinetic/pharmacodynamic modeling to predict in vivo effectiveness of various dosing regimens of piperacillin/tazobactam and piperacillin monotherapy against gram-negative pulmonary isolates from patients managed in intensive care units in 2002.
OBJECTIVE
This study compared the pharmacokinetic/pharmacodynamic (PK/PD) properties of piperacillin/tazobactam (PTZ) combination treatment with those of piperacillin (PIP) monotherapy against clinical gram-negative pulmonary isolates from US patients treated in intensive care units.


METHODS
Computer modeling was used to integrate national in vitro microbiologic data from 2002 with pharmacokinetic data from published studies in healthy volunteers. PTZ (3.375 g q4h, 3.375 g q6h, 4.5 g q6h, and 4.5 g q8h) and PIP (3 g q4h, 3 g q6h, 4 g q6h, and 4 g q8h) were modeled using Monte Carlo simulations. The cumulative fraction of response (CFR) was determined for percentage of time that the free serum concentration remained above the MIC of >or=30% (bacteriostatic) and >or=50% (bactericidal). Because simulated comparisons with an artificially derived sample size were used, statistical methods were not applied.


RESULTS
Overall, 2584 gram-negative pulmonary isolates were evaluated, including Enterobacteriaceae (n = 1430), Pseudomonas aeruginosa (n = 799), Acinetobacter baumannii (n = 179), and "other" (n = 176). The percents susceptible with PTZ and PIP were as follows: Enterobacteriaceae, 86% and 66%, respectively; P aeruginosa, 89% and 84%; and A baumannii, 47% and 34%. CFR rates with PTZ were numerically higher than those with PIP against Enterobacteriaceae (ranges, 86%-89% and 66%-73%, respectively) and A baumannii (47%-53% and 33%-42%), but not against P aeruginosa (79%-84% and 75%-81%).


CONCLUSIONS
Results from PK/PD models with Monte Carlo simulation suggested that susceptibility differences among these selected gram-negative isolates collected in 2002 may be of sufficient magnitude to result in notable PK/PD differences between PTZ and PIP.
Frei
Christopher R
CR
Center for the Advancement of Research and Education in Infectious Diseases, The University of Texas at Austin College of Pharmacy and Pharmacotherapy Research and Education Center, Austin, Texas, USA. freic@uthscsa.edu
Burgess
David S
DS
D040981:Acinetobacter baumannii / Q000187:drug effects / Q000201:enzymology / Q000302:isolation & purification; D000890:Anti-Infective Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D001426:Bacterial Proteins / Q000378:metabolism; D004359:Drug Therapy, Combination; D004755:Enterobacteriaceae / Q000187:drug effects / Q000201:enzymology / Q000302:isolation & purification; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology; D006207:Half-Life; D006801:Humans; D007362:Intensive Care Units; D008171:Lung Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D009010:Monte Carlo Method; D010343:Patient Admission; D010397:Penicillanic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D010878:Piperacillin / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000201:enzymology / Q000302:isolation & purification; D000078142:Tazobactam; D014481:United States; D001618:beta-Lactamases / Q000378:metabolism
D000890:Anti-Infective Agents; D001426:Bacterial Proteins; D010397:Penicillanic Acid; D001618:beta-Lactamases; D000078142:Tazobactam; D010878:Piperacillin