There have been postmarketing reports of overdose with piperacillin/tazobactam. The majority of those events experienced, including nausea, vomiting, and diarrhea, have also been reported with the usual recommended dosages. Patients may experience neuromuscular excitability or convulsions if higher than recommended doses are given intravenously (particularly in the presence of renal failure).
Treatment should be supportive and symptomatic according the patient's clinical presentation. Excessive serum concentrations of either piperacillin or tazobactam may be reduced by hemodialysis. Following a single 3.375 g dose of piperacillin/tazobactam, the percentage of the piperacillin and tazobactam dose removed by hemodialysis was approximately 31% and 39%, respectively.
The pharmacodynamic parameter for piperacillin/tazobactam that is most predictive of clinical and microbiological efficacy is time above MIC.
The mean and coefficients of variation (CV%) for the pharmacokinetic parameters of piperacillin and tazobactam after multiple intravenous doses are summarized in Table 6.
Table 6: Mean (CV%) Piperacillin and Tazobactam PK Parameters
| Piperacillin | ||||||
| Piperacillin/ Tazobactam Dosea | Cmax mcg/mL | AUCb mcg•h/mL | CL mL/min | VL | T½h | CLR mL/min |
| 2.25 g | 134 | 131 (14) | 257 | 17.4 | 0.79 | -- |
| 3.375 g | 242 | 242 (10) | 207 | 15.1 | 0.84 | 140 |
| 4.5 g | 298 | 322 (16) | 210 | 15.4 | 0.84 | -- |
| Tazobactam | ||||||
| Piperacillin/ Tazobactam Dosea | Cmax mcg/mL | AUCb mcg•h/mL | CL mL/min | VL | T½ | CLR% mL/min |
| 2.25 g | 15 | 16.0 (21) | 258 | 17.0 | 0.77 | -- |
| 3.375 g | 24 | 25.0 (8) | 251 | 14.8 | 0.68 | 166 |
| 4.5 g | 34 | 39.8 (15) | 206 | 14.7 | 0.82 | -- |
| a Piperacillin and tazobactam were given in combination, infused over 30 minutes. b Numbers in parentheses are coefficients of variation (CV%). | ||||||
Peak plasma concentrations of piperacillin and tazobactam are attained immediately after completion of an intravenous infusion of Tazocin. Piperacillin plasma concentrations, following a 30-minute infusion of Tazocin, were similar to those attained when equivalent doses of piperacillin were administered alone. Steady-state plasma concentrations of piperacillin and tazobactam were similar to those attained after the first dose due to the short half-lives of piperacillin and tazobactam.
DistributionBoth 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 and tazobactam are widely distributed into tissues and body fluids including intestinal mucosa, gallbladder, lung, female reproductive tissues (uterus, ovary, and fallopian tube), interstitial fluid, and bile. Mean tissue concentrations are generally 50% to 100% of those in plasma. Distribution of piperacillin and tazobactam into cerebrospinal fluid is low in subjects with non-inflamed meninges, as with other penicillins (see Table 7).
Table 7: Piperacillin/Tazobactam Concentrations in Selected Tissues and Fluids after Single 4 g/0.5 g 30-min IV Infusion of Tazocin
| Tissue or Fluid | Na | Sampling periodb (h) | Mean PIP Concentration Range (mg/L) | Tissue:Plasma Range | Tazo Concentration Range (mg/L) | Tazo Tissue:Plasma Range |
| Skin | 35 | 0.5 - 4.5 | 34.8 - 94.2 | 0.60 - 1.1 | 4.0 - 7.7 | 0.49 - 0.93 |
| Fatty Tissue | 37 | 0.5 - 4.5 | 4.0 - 10.1 | 0.097 - 0.115 | 0.7 - 1.5 | 0.10 - 0.13 |
| Muscle | 36 | 0.5 - 4.5 | 9.4 - 23.3 | 0.29 - 0.18 | 1.4 - 2.7 | 0.18 - 0.30 |
| Proximal Intestinal Mucosa | 7 | 1.5 - 2.5 | 31.4 | 0.55 | 10.3 | 1.15 |
| Distal Intestinal Mucosa | 7 | 1.5 - 2.5 | 31.2 | 0.59 | 14.5 | 2.1 |
| Appendix | 22 | 0.5 - 2.5 | 26.5 - 64.1 | 0.43 - 0.53 | 9.1 - 18.6 | 0.80 - 1.35 |
| a Each subject provided a single sample. b Time from the start of the infusion |
Piperacillin is metabolized to a minor microbiologically active desethyl metabolite. Tazobactam is metabolized to a single metabolite that lacks pharmacological and antibacterial activities.
ExcretionFollowing single or multiple Tazocin doses to healthy subjects, the plasma half-life of piperacillin and of tazobactam ranged from 0.7 to 1.2 hours and was unaffected by dose or duration of infusion.
Both piperacillin and tazobactam are eliminated via the kidney by glomerular filtration and tubular secretion. Piperacillin is excreted rapidly as unchanged drug with 68% of the administered dose excreted in the urine. Tazobactam and its metabolite are eliminated primarily by renal excretion with 80% of the administered dose excreted as unchanged drug and the remainder as the single metabolite. Piperacillin, tazobactam and desethyl piperacillin are also secreted into the bile.
