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ZOSYN®Clinical Pharmacology (piperacillin, tazobactam)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

ZOSYN is an antibacterial drug [see Microbiology (12.4)].

12.2 Pharmacodynamics

The pharmacodynamic parameter for piperacillin/tazobactam that is most predictive of clinical and microbiological efficacy is time above MIC.

12.3 Pharmacokinetics

The mean and coefficients of variation (CV%) for the pharmacokinetic parameters of piperacillin and tazobactam after multiple intravenous doses are summarized in Table 7.

Table 7: Mean (CV%) Piperacillin and Tazobactam PK Parameters
Cmax : maximum observed concentration, AUC: Area under the curve, CL=clearance, CLR= Renal clearance
V=volume of distribution, T1/2 = elimination half-life
*
Piperacillin and tazobactam were given in combination, infused over 30 minutes.
Numbers in []parentheses are coefficients of variation [CV%].
Piperacillin
Piperacillin/Tazobactam Dose*Cmax (mcg/mL)AUC (mcg∙h/mL)CL (mL/min)V
(L)
T1/2
(h)
CLR (mL/min)
2.25 g134131 [14]25717.40.79--
3.375 g242242 [10]20715.10.84140
4.5 g298322 [16]21015.40.84--
Tazobactam
Piperacillin/Tazobactam Dose*Cmax (mcg/mL)AUC (mcg∙h/mL)CL (mL/min)V
(L)
T1/2 (h)CLR (mL/min)
2.25 g1516.0 [21]25817.00.77--
3.375 g2425.0 [8]25114.80.68166
4.5 g3439.8 [15]20614.70.82--

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.

Distribution

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 8).

Table 8: Piperacillin/Tazobactam Concentrations in Selected Tissues and Fluids after Single 4 g/0.5 g 30-min IV Infusion of ZOSYN
Tissue or FluidN*Sampling period
(h)
Mean PIP Concentration Range
(mg/L)
Tissue:Plasma RangeTazo Concentration Range
(mg/L)
Tazo Tissue:Plasma Range
*
Each subject provided a single sample.
Time from the start of the infusion
Skin350.5 – 4.534.8 – 94.20.60 – 1.14.0 – 7.70.49 – 0.93
Fatty Tissue370.5 – 4.54.0 – 10.10.097 – 0.1150.7 – 1.50.10 – 0.13
Muscle360.5 – 4.59.4 – 23.30.29 – 0.181.4 – 2.70.18 – 0.30
Proximal Intestinal Mucosa71.5 – 2.531.40.5510.31.15
Distal Intestinal Mucosa71.5 – 2.531.20.5914.52.1
Appendix220.5 – 2.526.5 – 64.10.43 – 0.539.1 – 18.60.80 – 1.35

Metabolism

Piperacillin is metabolized to a minor microbiologically active desethyl metabolite. Tazobactam is metabolized to a single metabolite that lacks pharmacological and antibacterial activities.

Excretion

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.

Specific Populations

Renal Impairment

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)].

Hepatic Impairment

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.

Pediatrics

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.

Geriatrics

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.

Race

The effect of race on piperacillin and tazobactam was evaluated in healthy male volunteers. No difference in piperacillin or tazobactam pharmacokinetics was observed between Asian (n=9) and Caucasian (n=9) healthy volunteers who received single 4/0.5 g doses.

Drug Interactions

The potential for pharmacokinetic drug interactions between ZOSYN and aminoglycosides, probenecid, vancomycin, heparin, vecuronium, and methotrexate has been evaluated [see Drug Interactions (7)].

12.4 Microbiology

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.

Antimicrobial Activity

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)]:

Aerobic bacteria

Gram-positive bacteria

Staphylococcus aureus (methicillin susceptible isolates only)

Gram-negative bacteria

Acinetobacter baumannii
Escherichia coli
Haemophilus influenzae
(excluding beta-lactamase negative, ampicillin-resistant isolates)
Klebsiella pneumoniae
Pseudomonas aeruginosa
(given in combination with an aminoglycoside to which the isolate is susceptible)

Anaerobic bacteria

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.

Aerobic bacteria

Gram-positive bacteria

Enterococcus faecalis (ampicillin or penicillin-susceptible isolates only)
Staphylococcus epidermidis (methicillin susceptible isolates only)

Streptococcus agalactiae4
Streptococcus pneumoniae4 (penicillin-susceptible isolates only)
Streptococcus pyogenes4
Viridans group streptococci4

Gram-negative bacteria

Citrobacter koseri
Moraxella catarrhalis
Morganella morganii
Neisseria gonorrhoeae
Proteus mirabilis
Proteus vulgaris
Serratia marcescens
Providencia stuartii
Providencia rettgeri
Salmonella enterica

Anaerobic bacteria

Clostridium perfringens
Bacteroides distasonis
Prevotella melaninogenica


4
These are not beta-lactamase producing bacteria and, therefore, are susceptible to piperacillin alone.

Susceptibility Testing

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

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