Piperacillin irreversibly binds to the enzyme
penicillin-binding proteins, inhibiting the biosynthesis of bacterial cell walls. Moreover, this leads to the release of
autolysins that break down the bacteria's cell wall. Some
β-lactamase enzymes also consist of residue at their active site, enabling them to hydrolyze the β-lactam ring found within these antibiotics. The inclusion of a β-lactamase inhibitor does not always increase drug efficacy. Some bacteria may produce certain types of β-lactamase such as AmpC, which are intrinsically resistant to tazobactam.
Mechanisms of resistance A major mechanism of resistance against piperacillin-tazobactam is Gram-negative bacteria producing β-lactamases. Other currently known mechanisms include mutations in the active site of penicillin-binding proteins, changes in membrane efflux, or bacteria permeability. Furthermore, mutations in penicillin-binding proteins cause fluctuations in piperacillin affinity, whereas
Streptococcus pneumoniae (PBP-2b) autolytic response is significantly reduced due to decreased affinity with piperacillin. Although membrane permeability changes are less common as a mechanism of resistance, studies investigating
Klebsiella pneumoniae have reported a correlation between decreased permeability of piperacillin and increased SHV-1 β-lactamase production.
Pharmacokinetics Piperacillin is generally available in their stable form as crystallized potassium or sodium salt, quickly losing bactericidal activity upon dissolution due to their short half-lives. Measured by
creatinine clearance (CrCl), patients with less than 30 mL/min of clearance had significantly reduced levels of piperacillin/tazobactam excretion, measuring down to 35% of the initial dosage, while the area under the curve (AUC) for piperacillin increased by about three folds for those with less than 20 mL/min. A reduced dosage or alteration in the interval of administration is recommended for patients lying under 40 mL/min of CrCl, depending on the severity of dysfunction. Renal is the main pathway for drug elimination for both tazobactam and piperacillin in the body. While there are other non-renal means of drug elimination like
hepatobiliary excretion, they occur less frequently. Tazobactam renal elimination may be significantly reduced through piperacillin interaction, dropping from 63.7% to 56.8% of the administered dose over a 24-hour period. Piperacillin may be actively diffused through filtration into the biliary tract during renal clearing, indicated by a generally higher concentration of piperacillin than tazobactam in the bile. The metabolites that make up the remaining percentage in the excreted urine are composed of M1 (inactive) and N-desethyl-piperacillin (active), formed from the division of β-lactam rings of both tazobactam and piperacillin respectively. Due to the hydrophilic nature of piperacillin-tazobactam, a volume distribution of ~15 L amounting to various sites (tissues) is desired, as hydrophilic compounds are not able to pass through plasma membranes as easily as hydrophobic compounds.
Pharmacodynamics 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>MIC). When the T>MIC 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%. 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>MIC 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. 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. One study using the Monte Carlo simulation produced contradicting results to the previous studies, deducing that inadequate pharmacodynamic targets were achieved (T>MIC > 50%) for similar ESBL-producing bacteria, applying to both continuous and high dosage intermittent infusion. ==Chemistry==