Given the inconsistent clinical findings, our goal was to characterize the pharmacodynamics (PDs) of prolonged-infusion piperacillin-tazobactam (TZP) in an in vitro pharmacodynamic model of Pseudomonas aeruginosa. Specifically, the study was designed to investigate the influence of MIC on the activity of prolonged-infusion TZP using pharmacokinetics (PKs) consistent with a non-critically ill patient population. There was no benefit with prolonged- compared with standard-infusion TZP against isolates with susceptible MICs of 8 or 16 mg/L. However, prolonged-infusion TZP produced more than two times the final bacterial kill against less susceptible isolates with an intermediate MIC of 32 mg/L. The PDs of TZP were well described by a sigmoid Emax model (r(2) = 0.84) where %ƒT>MIC thresholds of 27 and 75% were associated with bacteriostatic and bactericidal effects, respectively. However, the well-established PD relationship with %ƒT>MIC was not observed with prolonged-infusion TZP. In conclusion, this study characterizes the targeted benefits of prolong-infusion TZP based on pathogen MIC, and supports the assertion that the benefits are selective and most likely observed in patients with less susceptible pathogens or altered PKs.