July 30, 2016
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Mechanism Of Action

ZOSYN is an antibacterial drug [see Microbiology].


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/ Tazobactam Dose* Cmax mcg/mL AUC† mcg•h/mL CL mL/min V L 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 --
Piperacillin/ Tazobactam Dose* Cmax mcg/mL AUC† mcg•h/mL CL mL/min V L T½h 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 --
* Piperacillin and tazobactam were given in combination, infused over 30 minutes.
†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 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 7).

Table 7: Piperacillin/Tazobactam Concentrations in Selected Tissues and Fluids after Single 4 g/0.5 g 30-min IV Infus ion of ZOSYN

Tissue or Fluid N* Sampling period†(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
* Each subject provided a single sample.
†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.


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 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].

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.


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.


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 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].


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

Spectrum of Activity

Piperacillin/tazobactam has been shown to be active against most isolates of the following microorganisms both in vitro and in clinical infections [see INDICATIONS AND USAGE].

Gram-positive Bacteria

Staphylococcus aureus (methicillin susceptible isolates only)

Gram-negative Bacteria

Acinetobacter baumannii
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)

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% 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.

Gram-positive Bacteria

Enterococcus faecalis (ampicillin or penicillin-susceptible isolates only)
Staphylococcus epidermidis
(methicillin susceptible isolates only)
Streptococcus agalactiae2

Streptococcus pneumoniae2
(penicillin-susceptible isolates only)
Streptococcus pyogenes2

Viridans group streptococci2

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

2These 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 8.

Diffusion Technique

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method1,3 and requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 100 mcg of piperacillin and 10 mcg of tazobactam to test the susceptibility of microorganisms to piperacillin/tazobactam. The disk diffusion interpreted criteria are provided in Table 8.

Anaerobic Techniques

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

Table 8: Susceptibility Interpretive Criteria for Piperacillin/Tazobactam

Pathogen Susceptibility Test Re ult Interpretive Criteria
Minimal Inhibitory
(MIC in mcg/mL)
Dis k Diffus ion
(Zone Diameter in mm)
S I R S   I R
Enterobacteriaceae ≤ 16 32 - 64 ≥ 128 ≥ 21 18 - 20 ≤ 17
Acinetobacter baumannii ≤ 16 32 - 64 ≥ 128 ≥ 21 18 - 20 ≤ 17
Haemophilus influenzae* ≤ 1 - ≥ 2 ≥ 21 - -
Pseudomonas aeruginosa ≤ 16 32 - 64 ≥ 128 ≥ 21 15 -20 ≤ 14
Bacteroides fragilis group ≤ 32 64 ≥ 128 - - -
Note: Susceptibility of staphylococci to piperacillin/tazobactam may be deduced from testing only penicillin and either cefoxitin or oxacillin.
* 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 at the infection site necessary to inhibit growth of the pathogen. 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 even if the antimicrobial compound in the blood reaches the concentration usually achievable at the infection site; other therapy should be considered.

Quality Control

Standardized susceptibility test procedures require the use of quality controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test procedures. Standard piperacillin/tazobactam powder should provide the following ranges of values noted in Table 9. Quality control bacteria are specific strains of bacteria 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.

Table 9: Acceptable Quality Control Ranges for Piperacillin/Tazobactam to Be Used in Validation of Susceptibility Test

QC Strain Acceptable Quality Control Ranges
Minimum Inhibitory
Concentration Range (MIC in
Disk Diffus ion Zone Diameter Ranges
in mm
Escherichia coli ATCC 25922 1 - 4 0 3 I 4 2
Escherichia coli ATCC 35218 2 - .5 0. 0 3 - 4 2
Pseudomonas aeruginosa ATCC 27853 1 - 8 3 3 - 5 2
Haemophilus influenzae* ATCC 49247 0.06 - 0.5 8 3 - 3 3
Staphylococcus aureus ATCC 29213 0.25 - 2 -
Staphylococcus aureus ATCC 25923 - 6 3 - 7 2
Bacteroides fragilis† ATCC 25285 0.12 - 0.5 -
Bacteroides thetaiotaomicron†ATCC 29741 4 - 16
Clostridium difficile† ATCC 700057 4 - 16 -
Eubacterium lentum† ATCC 43055 4 - 16
* 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.
† The quality control ranges for Bacteroides fragilis and Bacteroides thetaiotaomicron are applicable only to tests performed using the agar dilution method.

Last reviewed on RxList: 6/8/2015
This monograph has been modified to include the generic and brand name in many instances.

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