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.

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Bacterial killing and the development of reduced vancomycin susceptibility during continuous-infusion vancomycin (CIV) therapy were dependent on the area under the concentration-time curve over 24 h divided by the MIC (ƒAUC 24 /MIC), with values of >240 (equivalent total serum AUC 24 /MICs of >480) being bactericidal and suppressing emerging resistance in methicillin-resistant Staphylococcus aureus (MRSA). Also, vancomycin therapy was less likely to be bactericidal and 4.4 times more likely to lead to reduced vancomycin susceptibility in health care-associated MRSA than in community-associated MRSA.