Compared to concentration dependent bactericidal antibiotics like aminoglycosides and fluoroquinolones, the antibacterial activity of β-lactam antibiotics are generally more time dependent. Unlike the former, when piperacillin-tazobactam concentrations exceed minimum inhibitory concentrations (MIC) of a pathogen by five folds, the exponential relationship between concentration and activity begins to level off. Otherwise, piperacillin-tazobactam bactericidal efficacy is shown to consist of a strong association with the duration of time the concentration exceeds minimum inhibitory concentrations (T). When the T in the serum equates to 60–70% of the frequency for drug administration (dosing interval), maximal activity is achieved against Gram-negative bacteria, while for Gram-positive bacteria it occurs at around 40–50%.
Within a 24-hour period in one clinical study, a T surpassing 60% was found for piperacillin-susceptible bacteria including Escherichia coli, Klebsiella pneumoniae and Staphylococcus aureus in two dosing regimes (4.5 g every 8 hours and 3.375 g every 8 hours).
The evidence for this was obtained through Monte Carlo experiments procured by a special program (OPTAMA), where for several different scenarios (e.g. hospital acquired infections, secondary peritonitis, skin or soft tissue infections), the probability of attaining those figures were in the ranges of 85–95% and 90–89% respectively for the two regimes. In addition, two similar dosing regimes (3.375 g and 4.5 g every 6 hours) both had lower chances of reaching the 90% T threshold compared to the 50% threshold against hospital acquired pneumonia pathogens.
The optimization of piperacillin-tazobactam drug efficiency has been covered by various studies, limiting the focus down to two types of infusions; continuous and intermittent. A comparison using the two administration methods under the same dosage regime of 13.5 g per day highlighted no major differences when treating complex intra-abdominal infections. Furthermore, a follow-up analysis of this trial deduced that both methods of administration lead to higher concentrations compared to the MIC of the pathogens that were used. Similar results are found in a study where a select number of β-lactam susceptible pathogens consisting of Enterococcus faecalis, Klebsiella pneumoniae and Citrobacter freundii were used to test a ~10 g every 24 hour dosing interval for continuous infusion.
Organisms with a piperacillin-tazobactam MIC values equal to 32 or less than 16 μg/mL lead to 50% T when extended-interval intermittent administrations under two different dosing intervals (8.1 g and 6.75 g every 12 hours) were used against them. The pharmacodynamic target attainments corresponding to pathogens with MIC values of 16 μg/mL are found to reach 92% when a more traditional 4 hour dosing regime is utilized to administer at irregular intervals. One study using the Monte Carlo simulation produced contradicting results to the previous studies, deducing that inadequate pharmacodynamic targets were achieved (T > 50%) for similar ESBL-producing bacteria, applying to both continuous and high dosage intermittent infusion.