12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
ZOSYN is an antibacterial drug [see Microbiology (12.4)].
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 9.
|Cmax : maximum observed concentration, AUC: Area under the curve, CL=clearance, CLR= Renal clearance|
V=volume of distribution, T1/2 = elimination half-life
|Piperacillin/Tazobactam Dose*||Cmax (mcg/mL)||AUC† (mcg∙h/mL)||CL (mL/min)||V|
|2.25 g||134||131 ||257||17.4||0.79||--|
|3.375 g||242||242 ||207||15.1||0.84||140|
|4.5 g||298||322 ||210||15.4||0.84||--|
|Piperacillin/Tazobactam Dose*||Cmax (mcg/mL)||AUC† (mcg∙h/mL)||CL (mL/min)||V|
|T1/2 (h)||CLR (mL/min)|
|2.25 g||15||16.0 ||258||17.0||0.77||--|
|3.375 g||24||25.0 ||251||14.8||0.68||166|
|4.5 g||34||39.8 ||206||14.7||0.82||--|
Peak plasma concentrations of piperacillin and tazobactam are attained immediately after completion of an intravenous infusion of ZOSYN. Piperacillin plasma concentrations, following a 30-minute infusion of ZOSYN, 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.
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 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 10).
|Tissue or Fluid||N*||Sampling period†|
|Mean PIP Concentration Range|
|Tissue:Plasma Range||Tazo Concentration Range|
|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|
Piperacillin is metabolized to a minor microbiologically active desethyl metabolite. Tazobactam is metabolized to a single metabolite that lacks pharmacological and antibacterial activities.
Following single or multiple ZOSYN 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.
After the administration of single doses of piperacillin/tazobactam to subjects with renal impairment, the half-life of piperacillin and of tazobactam increases with decreasing creatinine clearance. At creatinine clearance below 20 mL/min, the increase in half-life is twofold for piperacillin and fourfold for tazobactam compared to subjects with normal renal function. Dosage adjustments for ZOSYN are recommended when creatinine clearance is below 40 mL/min in patients receiving the usual recommended daily dose of ZOSYN. See Dosage and Administration (2) for specific recommendations for the treatment of patients with renal -impairment.
Hemodialysis removes 30% to 40% of a piperacillin/tazobactam dose 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 16% of the tazobactam dose removed as the tazobactam metabolite. For dosage recommendations for patients undergoing hemodialysis [see Dosage and Administration (2)].
The half-life of piperacillin and of tazobactam increases by approximately 25% and 18%, respectively, in patients with hepatic cirrhosis compared to healthy subjects. However, this difference does not warrant dosage adjustment of ZOSYN due to hepatic cirrhosis.
Piperacillin and tazobactam pharmacokinetics were studied in pediatric patients 2 months of age and older. The clearance of both compounds is slower in the younger patients compared to older children and adults.
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 pediatric patients 2 – 9 months old. In patients younger than 2 months of age, clearance of piperacillin is slower compared to older children; however, it is not adequately characterized for dosing recommendations. The population mean (SE) for piperacillin volume of distribution is 0.243 (0.011) L/kg and is independent of age.
The impact of age on the pharmacokinetics of piperacillin and tazobactam was evaluated in healthy male subjects, aged 18 – 35 years (n=6) and aged 65 to 80 years (n=12). Mean half-life for piperacilln and tazobactam was 32% and 55% higher, respectively, in the elderly compared to the younger subjects. This difference may be due to age-related changes in creatinine clearance.
The potential for pharmacokinetic drug interactions between ZOSYN and aminoglycosides, probenecid, vancomycin, heparin, vecuronium, and methotrexate has been evaluated [see Drug Interactions (7)].
Mechanism of Action
Piperacillin sodium exerts bactericidal activity by inhibiting septum formation and cell wall synthesis of susceptible bacteria. In vitro, piperacillin is active against a variety of gram-positive and gram-negative aerobic and anaerobic bacteria. Tazobactam sodium has little clinically relevant in vitro activity against bacteria due to its reduced affinity to penicillin-binding proteins. It is, however, a beta-lactamase inhibitor of the Molecular class A enzymes, including Richmond-Sykes class III (Bush class 2b & 2b') penicillinases and cephalosporinases. It varies in its ability to inhibit class II and IV (2a & 4) penicillinases. Tazobactam does not induce chromosomally-mediated beta-lactamases at tazobactam concentrations achieved with the recommended dosage regimen.
ZOSYN has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage (1)]:
Staphylococcus aureus (methicillin susceptible isolates only)
Haemophilus influenzae (excluding beta-lactamase negative, ampicillin-resistant isolates)
Pseudomonas aeruginosa (given in combination with an aminoglycoside to which the isolate is susceptible)
Bacteroides fragilis group (B. fragilis, B. ovatus, B. thetaiotaomicron, and B. vulgatus)
The following in vitro data are available, but their clinical significance is unknown.
At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for piperacillin/tazobactam against isolates of similar genus or organism group.
However, the efficacy of ZOSYN in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials.
Enterococcus faecalis (ampicillin or penicillin-susceptible isolates only)
Staphylococcus epidermidis (methicillin susceptible isolates only)
- These are not beta-lactamase producing bacteria and, therefore, are susceptible to piperacillin alone.