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 ≥30% (bacteriostatic) and ≥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%). Conclusion: 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.