Pharmacodynamics of Piperacillin-Tazobactam

Mechanism of Action

The American Academy of Otolaryngology-Head and Neck Surgery suggests that beta-lactams, including piperacillin-tazobactam, do not kill bacteria more efficiently when concentrations exceed a critical value 1, 2, 3, 4
The therapeutic goal is not to maximize peak concentration, but to maintain adequate concentrations for as much of the dosing interval as possible, as recommended by the Intensive Care Medicine society 5
A concentration of 2 to 4 times above the MIC is generally optimal for maximum probability of clinical success, but increasing concentration beyond this magnitude does not improve the rate or degree of bacterial elimination, according to the American Academy of Otolaryngology-Head and Neck Surgery 1, 2, 3, 4
The most important predictor of clinical outcome is the duration of time that the concentration at the infection site remains above the MIC (T>MIC) for the bacteria, as stated by the American Academy of Otolaryngology-Head and Neck Surgery 1, 2, 3, 4
For beta-lactams, the T>MIC required to achieve bacterial eradication should generally be 40% to 50% of the dosing interval, as recommended by the American Academy of Otolaryngology-Head and Neck Surgery 1

The Intensive Care Medicine society recommends extended infusions (3-4 hours) of piperacillin-tazobactam in critically ill patients with severe infections, particularly when treating organisms with higher MICs, as this provides better attainment of the pharmacodynamic target by maintaining plasma concentrations above the MIC for 70% or more of the dosing interval 6
Extended/continuous infusions of beta-lactams increase T>MIC compared to standard 30-minute rapid infusion, according to the Intensive Care Medicine society 5
Extended infusion of piperacillin-tazobactam is associated with reduced mortality (10.8% vs 16.8%) in meta-analyses of ICU patients, as reported by the Praxis Medical Insights society 6
For severe infections, optimal response may be achieved with a T>MIC of 100%, as recommended by the Intensive Care Medicine society 5
A minimum T>MIC of 60% is generally sufficient to allow a good clinical response in mild to moderate diseases, according to the Intensive Care Medicine society 5

The American Academy of Otolaryngology-Head and Neck Surgery distinguishes piperacillin-tazobactam from concentration-dependent antimicrobials, such as fluoroquinolones and ketolides, which exhibit concentration-dependent bacterial killing 7, 8, 9
For fluoroquinolones, the AUC:MIC and peak:MIC ratios are the primary parameters that correlate with efficacy, as stated by the American Academy of Otolaryngology-Head and Neck Surgery 7, 8, 9
Vancomycin is another antibiotic whose efficacy is at least partially concentration-dependent, according to the Intensive Care Medicine society 5

The Intensive Care Medicine society recommends a Cmin/MIC target ratio of 4-6 for optimal bactericidal activity in severe infections 6
The American Academy of Otolaryngology-Head and Neck Surgery and the Intensive Care Medicine society warn against confusing the time-dependent mechanism of piperacillin-tazobactam with the concentration-dependent mechanism of fluoroquinolones or aminoglycosides 5, 7, 8, 9
The Intensive Care Medicine society suggests that the simplest way to increase T>MIC is to use more frequent dosing (given an identical total daily dose); for example, piperacillin-tazobactam can be dosed at 4.5 g every 8 hours or 3.375 g every 6 hours for severe infections, with the latter achieving a higher T>MIC 5