Chemical formula: C₂₃H₂₇N₅O₇S Molecular mass: 517.555 g/mol PubChem compound: 43672
Piperacillin, a broad-spectrum, semisynthetic penicillin exerts bactericidal activity by inhibition of both septum and cell-wall synthesis.
The time above the minimum inhibitory concentration (T>MIC) is considered to be the major pharmacodynamic determinant of efficacy for piperacillin.
The two main mechanisms of resistance to piperacillin/tazobactam are:
Additionally, alterations in bacterial membrane permeability, as well as expression of multi-drug efflux pumps, may cause or contribute to bacterial resistance to piperacillin/tazobactam, especially in Gram-negative bacteria.
EUCAST Clinical MIC Breakpoints for Piperacillin/Tazobactam (2009-12-02, v1). For Susceptibility Testing Purposes, the Concentration of Tazobactam is fixed at 4 mg/l
| Pathogen | Species-related breakpoints (S≤/R>) |
|---|---|
| Enterobacteriaceae | 8/16 |
| Pseudomonas | 16/16 |
| Gram-negative and Gram-positive anaerobes | 8/16 |
| Non-species related breakpoints | 4/16 |
The susceptibility of streptococci is inferred from the penicillin susceptibility.
The susceptibility of staphylococci is inferred from the oxacillin susceptibility.
The prevalence of acquired resistance may vary geographically and with time for selected species, and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.
The peak piperacillin and tazobactam concentrations after 4 g/0.5 g administered over 30 minutes by intravenous infusion are 298 μg/ml and 34 μg/ml respectively.
Both piperacillin and tazobactam are approximately 30% bound to plasma proteins. The protein binding of either piperacillin or tazobactam is unaffected by the presence of the other compound. Protein binding of the tazobactam metabolite is negligible.
Piperacillin/tazobactam is widely distributed in tissues and body fluids including intestinal mucosa, gallbladder, lung, bile, and bone. Mean tissue concentrations are generally 50 to 100% of those in plasma. Distribution into cerebrospinal fluid is low in subjects with non-inflamed meninges, as with other penicillins.
Piperacillin is metabolised to a minor microbiologically active desethyl metabolite.
Piperacillin is eliminated via the kidney by glomerular filtration and tubular secretion.
Piperacillin is excreted rapidly as unchanged substance, with 68% of the administered dose appearing in the urine. Piperacillin, tazobactam, and desethyl piperacillin are also secreted into the bile.
Following single or multiple doses of piperacillin/tazobactam to healthy subjects, the plasma half-life of piperacillin and tazobactam ranged from 0.7 to 1.2 hours and was unaffected by dose or duration of infusion.
The elimination half-lives of both piperacillin and tazobactam are increased with decreasing renal clearance.
There are no significant changes in piperacillin pharmacokinetics due to tazobactam. Piperacillin appears to slightly reduce the clearance of tazobactam.
The half-life of piperacillin increases by approximately 25%, respectively, in patients with hepatic cirrhosis compared to healthy subjects.
The half-life of piperacillin increases with decreasing creatinine clearance. The increase in half-life is two-fold for piperacillin, respectively, at creatinine clearance below 20 ml/min compared to patients with normal renal function.
Haemodialysis removes 30% to 50% of piperacillin/tazobactam, with an additional 5% of the tazobactam dose removed as the tazobactam metabolite. Peritoneal dialysis removes approximately 6% and 21% of the piperacillin and tazobactam doses, respectively, with up to 18% of the tazobactam dose removed as the tazobactam metabolite.
In a population PK analysis, estimated clearance for 9 month-old to 12 year-old patients was comparable to adults, with a population mean (SE) value of 5.64 (0.34) ml/min/kg. The piperacillin clearance estimate is 80% of this value for paediatric patients 2-9 months of age. The population mean (SE) for piperacillin volume of distribution is 0.243 (0.011) l/kg and is independent of age.
The mean half-life for piperacillin were 32%, respectively, in the elderly compared with younger subjects. This difference may be due to age-related changes in creatinine clearance.
No difference in piperacillin or tazobactam pharmacokinetics was observed between Asian (n=9) and Caucasian (n=9) healthy volunteers who received single 4 g/0.5 g doses.
Preclinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity and genotoxicity. Carcinogenicity studies have not been conducted with piperacillin/tazobactam.
A fertility and general reproduction study in rats using intraperitoneal administration of tazobactam or the combination piperacillin/tazobactam reported a decrease in litter size and an increase in fetuses with ossification delays and variations of ribs, concurrent with maternal toxicity. Fertility of the F1 generation and embryonic development of F2 generation were not impaired.
Teratogenicity studies using intravenous administration of tazobactam or the combination piperacillin/tazobactam in mice and rats resulted in slight reductions in rat fetal weights at maternally toxic doses but did not show teratogenic effects.
Peri/postnatal development was impaired (reduced pup weights, increase in stillbirths, increase in pup mortality) concurrent with maternal toxicity after intraperitoneal administration of tazobactam or the combination piperacillin/tazobactam in the rat.
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