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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, with mean peak plasma concentrations of approximately 134, 242, and 298 μg/mL for the 2.25 g, 3.375 g, and 4.5 g ZOSYN (piperacillin/tazobactam) doses, respectively. The corresponding mean peak plasma concentrations of tazobactam were 15, 24, and 34 μg/mL, respectively.

Following a 30-minute I.V. infusion of 3.375 g ZOSYN every 6 hours, steady-state plasma concentrations of piperacillin and tazobactam were similar to those attained after the first dose. In like manner, steady-state plasma concentrations were not different from those attained after the first dose when 2.25 g or 4.5 g doses of ZOSYN were administered via 30-minute infusions every 6 hours. Steady-state plasma concentrations after 30-minute infusions every 6 hours are provided in Table 1.

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.

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

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.

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 (piperacillin and tazobactam for injection, USP). (See DOSAGE AND ADMINISTRATION section for specific recommendations for the treatment of patients with renal insufficiency.)

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 section.

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/ Tazobactam Dosea No. of Evaluable Subjects Plasma Concentrations** (μg/mL) AUC** (μg•hr/mL)
30 min 1 hr 2 hr 3 hr 4 hr 6 hr AUC0-6
2.25 g 8 134(14) 57(14) 17.1(23) 5.2(32) 2.5(35) 0.9(14)b 131 (14)
3.375 g 6 242(12) 106(8) 34.6(20) 11.5(19) 5.1(22) 1.0(10) 242 (10)
4.5 g 8 298(14) 141(19) 46.6(28) 16.4(29) 6.9(29) 1.4(30) 322 (16)
2.25 g 8 14.8(14) 7.2(22) 2.6(30) 1.1(35) 0.7(6)c < 0.5 16.0 (21)
3.375 g 6 24.2(14) 10.7(7) 4.0(18) 1.4(21) 0.7(16)b < 0.5 25.0 (8)
4.5 g 8 33.8(15) 17.3(16) 6.8(24) 2.8(25) 1.3(30) < 0.5 39.8 (15)
** Numbers in parentheses are coefficients of variation (CV%).
a Piperacillin and tazobactam were given in combination.
b N = 4
c N = 3


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 distribution volume is 0.243 (0.011) L/kg and is independent of age.


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 β-lactamase inhibitor of the 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 β-lactamases at tazobactam concentrations achieved with the recommended dosage regimen.

Piperacillin/tazobactam has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

Aerobic and facultative gram-positive microorganisms

Staphylococcus aureus (excluding methicillin and oxacillin-resistant isolates)

Aerobic and facultative gram-negative microorganisms

Acinetobacter baumanii
Escherichia coli

Haemophilus influenzae
(excluding β-lactamase negative, ampicillin-resistant isolates)
Klebsiella pneumoniae

Pseudomonas aeruginosa
(given in combination with an aminoglycoside to which the isolate is susceptible)

Gram-negative anaerobes

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% of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for piperacillin/tazobactam. However, the safety and effectiveness of piperacillin/tazobactam in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials.

Aerobic and facultative gram-positive microorganisms

Enterococcus faecalis (ampicillin or penicillin-susceptible isolates only)
Staphylococcus epidermidis
(excluding methicillin and oxacillin-resistant isolates)
Streptococcus agalactiae

Streptococcus pneumoniae
† (penicillin-susceptible isolates only)
Streptococcus pyogenes

Viridans group streptococci†

Aerobic and facultative gram-negative microorganisms

Citrobacter koseri
Moraxella catarrhalis

Morganella morganii

Neisseria gonorrhoeae

Proteus mirabilis

Proteus vulgaris

Serratia marcescens

Providencia stuartii

Providencia rettgeri

Salmonella enterica

Gram-positive anaerobes

Clostridium perfringens

Gram-negative anaerobes

Bacteroides distasonis
Prevotella melaninogenica

† These are not β-lactamase producing bacteria and, therefore, are susceptible to piperacillin alone.

Susceptibility Testing Methods

As is recommended with all antimicrobials, the results of in vitro susceptibility tests, when available, should be provided to the physician as periodic reports, which describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial.

Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of piperacillin and tazobactam powders.1,2 MIC values should be determined using serial dilutions of piperacillin combined with a fixed concentration of 4 μg/mL tazobactam. The MIC values obtained should be interpreted according to criteria provided in Table 2.

Diffusion Technique: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure1,3 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 100 μg of piperacillin and 10 μg of tazobactam to test the susceptibility of microorganisms to piperacillin/tazobactam. The disk diffusion interpreted criteria are provided in Table 2.

Anaerobic Techniques

For anaerobic bacteria, the susceptibility to piperacillin/tazobactam can be determined by the reference agar dilution method.4


Pathogen Susceptibility Test Result Interpretive Criteria
Minimal Inhibitory Concentration (MIC in μg/mL) Disk Diffusion (Zone Diameterinmm)
Enterobacteriaceae and Acinetobacter baumanii ≤ 16 32 - 64 ≥ 128 ≥ 21 18 - 20 ≤ 17
Haemophilus influenzaea ≤ 1 - ≥ 2 - - -
Pseudomonas aeruginosa ≤ 64 - ≥ 128 ≥ 18 - ≤ 17
Staphylococcus aureus ≤ 8 - ≥ 16 ≥ 18 - ≤ 17
Bacteroides fragilis group ≤ 32 64 ≥ 128 - - -
a These interpretive criteria for Haemophilus influenzae are applicable only to tests performed using Haemophilus Test Medium inoculated with a direct colony suspension and incubated at 35°C in ambient air for 20 to 24 hours.

A report of S (“Susceptible”) indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentration usually achievable. A report of I (“Intermediate”) indicates that the results should be considered equivocal, and if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone, which prevents small, uncontrolled technical factors from causing major discrepancies in interpretation. A report of R (“Resistant”) indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentration usually achievable; other therapy should be considered.

Quality Control

Standardized susceptibility test procedures require the use of quality control microorganisms to control the technical aspects of the test procedures.1,2,3,4 Standard piperacillin/tazobactam powder should provide the following ranges of values noted in Table 3. Quality control microorganisms are specific strains of microorganisms with intrinsic biological properties relating to resistance mechanisms and their genetic expression within the microorganism; the specific strains used for microbiological quality control are not clinically significant.


QC Strain Acceptable Quality Control Ranges
Minimum Inhibitory Concentration Range (MIC in μg/mL) Disk Diffusion Zone Diameter Ranges in mm
Escherichia coli ATCC 25922 1 - 4 24 - 30
Escherichia coli ATCC 35218 0.5 - 2 24 - 30
Pseudomonas aeruginosa ATCC 27853 1 - 8 25 - 33
Haemophilus influenzaea ATCC 49247 0.06 - 0.5 33-38
Staphylococcus aureus ATCC 29213 0.25 - 2 -
Staphylococcus aureus ATCC 25923 - 27 - 36
Bacteroides fragilis ATCC 25285 0.12 - 0.5 -
Bacteroides thetaiotaomicron ATCC 29741 4 - 16 -
a This quality control range for Haemophilus influenzae is applicable only to tests performed using Haemophilus Test Medium inoculated with a direct colony suspension and incubated at 35°C in ambient air for 20 to 24 hours.


1. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; 21st Informational Supplement. CLSI document M100-S21. CLSI, 940 West Valley Rd., Suite 1400, Wayne, PA 19087, 2011

2. CLSI. Methods for Dilution Antimicrobial Susceptibility Test for Bacteria that Grow Aerobically; Approved Standard – 8th ed. CLSI document M07-A8, 2009.

3. CLSI. Performance Standards for Antimicrobial Disk Susceptibility Test; Approved Standard – 10th ed.CLSI document M02-A10, 2009.

4. CLSI. Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard – 7th ed. CLSI document M11-A7, 2007.

Last reviewed on RxList: 10/13/2011
This monograph has been modified to include the generic and brand name in many instances.


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