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Generic Name: Piperacillin Sodium and Tazobactam Sodium
Class: Extended-spectrum Penicillins
Chemical Name: [2S - [2α,5α,6β(S*)]] - 6 - [[[[(4 - Ethyl - 2,3 - dioxo - 1 - piperazinyl)carbonyl]amino]phenylacetyl]amino] - 3,3 - dimethyl - 7 - oxo - 4 - thia - 1 - azabicyclo[3.2.0]heptane - 2 - carboxylic acid monosodium salt
Molecular Formula: C23H27N5O7S•Na
CAS Number: 59703-84-3

Introduction

Antibacterial; β-lactam antibiotic; fixed combination of piperacillin (an extended-spectrum penicillin) and tazobactam (a β-lactamase inhibitor).1 3 5 6 7 9 12 33 35

Uses for Zosyn

Gynecologic and Obstetric Infections

Treatment of postpartum endometritis or pelvic inflammatory disease (PID) caused by β-lactamase-producing Escherichia coli resistant to piperacillin but susceptible to piperacillin and tazobactam.1 21 33 34 35

Intra-abdominal Infections

Treatment of appendicitis (complicated by rupture or abscess) and peritonitis caused by β-lactamase-producing E. coli resistant to piperacillin but susceptible to piperacillin and tazobactam or caused by Bacteroides fragilis, B. ovatus, B. thetaiotaomicron, or B. vulgatus.1 12 13 14 33 35

Respiratory Tract Infections

Treatment of moderately severe community-acquired pneumonia (CAP) caused by β-lactamase-producing Haemophilus influenzae resistant to piperacillin but susceptible to piperacillin and tazobactam.1 33 35

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For empiric treatment of CAP in adults with risk factors for Pseudomonas aeruginosa, IDSA and ATS recommend a combination regimen that includes an antipneumococcal, antipseudomonal β-lactam (piperacillin and tazobactam, cefepime, imipenem, meropenem) and ciprofloxacin or levofloxacin; one of these β-lactams, an aminoglycoside, and azithromycin; or one of these β-lactams, an aminoglycoside, and an antipneumococcal fluoroquinolone.41 If Ps. aeruginosa has been identified by appropriate microbiologic testing, these experts recommend treatment with a regimen that includes an antipseudomonal β-lactam (cefepime, ceftazidime, aztreonam, imipenem, meropenem, piperacillin, ticarcillin) and ciprofloxacin, levofloxacin, or an aminoglycoside.41

Treatment of moderate to severe nosocomial pneumonia caused by β-lactamase-producing S. aureus resistant to piperacillin but susceptible to piperacillin and tazobactam or caused by Acinetobacter baumanii, H. influenzae, Klebsiella pneumoniae, or Ps. aeruginosa resistant to piperacillin but susceptible to piperacillin and tazobactam.1 33 34 35 For nosocomial pneumonia caused by Ps. aeruginosa, used in conjunction with an aminoglycoside or fluoroquinolone with antipseudomonal activity (e.g., ciprofloxacin, levofloxacin).1 33 34 35

For initial empiric treatment of hospital-acquired pneumonia, ventilator-associated pneumonia, or health-care associated pneumonia in adults who are severely ill or have late-onset disease or risk factors for multidrug-resistant bacteria, ATS, IDSA, and other clinicians recommend an antipseudomonal cephalosporin (cefepime, ceftazidime), antipseudomonal penicillin (piperacillin and tazobactam, ticarcillin and clavulanate), or an antipseudomonal carbapenem (imipenem, meropenem) used in conjunction with an aminoglycoside (amikacin, gentamicin, tobramycin) or antipseudomonal fluoroquinolone (ciprofloxacin, levofloxacin).34 42 In hospitals where oxacillin-resistant (methicillin-resistant) Staphylococcus is common or if there are risk factors for these strains, the initial regimen also should include vancomycin or linezolid.34 42

Septicemia

Treatment of septicemia caused by susceptible gram-negative bacteria. For initial empiric treatment of life-threatening sepsis, used in conjunction with vancomycin with or without an aminoglycoside.34

Skin and Skin Structure Infections

Treatment of uncomplicated and complicated skin and skin structure infections (including cellulitis, cutaneous abscess, ischemic/diabetic foot infections) caused by β-lactamase-producing Staphylococcus aureus resistant to piperacillin but susceptible to piperacillin and tazobactam.1 12 15 33 35

Urinary Tract Infections (UTIs)

Treatment of UTIs in hospitalized patients; used with or without an aminoglycoside.34

Zosyn Dosage and Administration

Administration

Administer by IV infusion.1 33 35

IV Administration

Piperacillin and tazobactam should not be admixed with other drugs (e.g., in a syringe or infusion bottle) and should not be added to blood products or albumin hydrolysates.1 33 35

If concomitant use of an aminoglycoside is indicated (e.g., for treatment of nosocomial pneumonia), piperacillin and tazobactam and the aminoglycoside should be administered separately.1 33 35

In certain situations when simultaneous coadministration of piperacillin and tazobactam and an aminoglycoside via Y-site infusion is considered necessary, this can be accomplished using only certain dosages of amikacin or gentamicin, only certain formulations of piperacillin and tazobactam (Zosyn) containing edetate disodium dihydrate (EDTA), and only certain acceptable diluents.1 33 35 (See Tables.) For Y-site coadministration, do not use any formulations of piperacillin and tazobactam other than those specified in the tables and do not use tobramycin or any aminoglycoside other than amikacin or gentamicin.1 33 35 Coadministration via Y-site infusion in any manner other than that specified in the tables may result in inactivation of the aminoglycoside.1 33 35

Based on amikacin dosage of 10–15 mg/kg daily given in 2 divided doses or gentamicin dosage of 3–5 mg/kg daily given in 3 divided doses; higher dosage or once-daily dosage has not been evaluated for Y-site compatibility.

Table 1. Y-site Compatibility for Zosyn (with EDTA) in Single-dose Vials and Bulk Vials133

Aminoglycoside

Zosyn Dosage (g)

Zosyn Diluent (mL)

Aminoglycoside Concentration Range (mg/mL)

Acceptable Diluents

Amikacin

2.25, 3.375, 4.5

50, 100, 150

1.75–7.5

0.9% sodium chloride injection or 5% dextrose injection

Gentamicin

2.25, 3.375, 4.5

100, 150

0.7–3.32

0.9% sodium chloride injection

Based on amikacin dosage of 10–15 mg/kg daily given in 2 divided doses or gentamicin dosage of 3–5 mg/kg daily given in 3 divided doses; higher dosage or once-daily dosage has not been evaluated for Y-site compatibility.

Frozen Zosyn injections in Galaxy containers that contain 3.375 g/50 mL are not compatible with gentamicin and should not be used for Y-site coadministration with gentamicin.

Table 2. Y-site Compatibility for Zosyn (with EDTA) Frozen Injections in Galaxy Containers 35

Aminoglycoside

Zosyn Dosage (g)

Aminoglycoside Concentration Range (mg/mL)

Acceptable Diluents

Amikacin

2.25, 3.375, 4.5

1.75–7.5

0.9% sodium chloride injection or 5% dextrose injection

Gentamicin

2.25 or 4.5

0.7–3.32

0.9% sodium chloride injection

Reconstitution and Dilution

Reconstitute Zosyn single-dose vials containing 2 g of piperacillin and 0.25 g of tazobactam, 3 g of piperacillin and 0.375 g of tazobactam, or 4 g of piperacillin and 0.5 g of tazobactam by adding 10, 15, or 20 mL, respectively, of 0.9% sodium chloride injection, sterile water for injection, 5% dextrose injection, bacteriostatic water for injection (with parabens or benzyl alcohol), or bacteriostatic sodium chloride injection (with parabens or benzyl alcohol).1 Shake thoroughly until contents are dissolved.1 Reconstituted solutions should be diluted further to the desired volume (usually 50–150 mL) with 0.9% sodium chloride injection, sterile water for injection (maximum recommended volume is 50 mL), 5% dextrose injection, or 6% dextrose in 0.9% sodium chloride.1 33 Lactated Ringer's injection is compatible with and can be used to dilute reconstituted solutions of Zosyn (with EDTA), but cannot be used to dilute piperacillin and tazobactam preparations that do not contain EDTA.1 33

ADD-Vantage vials containing Zosyn should be diluted according to the manufacturer’s labeling.1

Reconstitute Zosyn pharmacy bulk vials containing 36 g of piperacillin and 4.5 g of tazobactam by adding 152 mL of a compatible IV solution (see Solution Compatibility under Stability) to provide a solution containing 200 mg/mL of piperacillin and 25 mg/mL of tazobactam.33 Pharmacy bulk vials of the drug are not intended for direct IV infusion; prior to administration, solutions reconstituted in the pharmacy bulk vial must be further diluted with a compatible IV solution.33

Thaw the commercially available injection (frozen) of Zosyn in Galaxy containers at room temperature (20–25°C) or in a refrigerator (2–8°C); do not force thaw by immersion in a water bath or by exposure to microwave radiation.35 A precipitate may have formed in the frozen injection, but should dissolve with little or no agitation after reaching room temperature.35 Discard thawed injection if an insoluble precipitate is present or if container seals or outlet ports are not intact.35 Additives should not be introduced into the injection.35 The injections should not be used in series connections with other plastic containers, since such use could result in air embolism from residual air being drawn from the primary container before administration of fluid from the secondary container is complete.35

Rate of Administration

Administer by IV infusion over 30 minutes.1 33 35

Dosage

Available as a fixed combination of piperacillin sodium and tazobactam sodium in an 8:1 ratio; dosage usually expressed in terms of the total of the piperacillin and tazobactam content of the fixed combination (i.e., grams of Zosyn).1 33 35 Potency of both piperacillin sodium and tazobactam sodium are expressed in terms of the bases.1 33 35

Pediatric Patients

Intra-abdominal Infections
Appendicitis and/or Peritonitis
IV

Children 2 months to <9 months of age: 80 mg/kg of piperacillin and 10 mg/kg of tazobactam every 8 hours.1 33 35

IV

Children ≥9 months of age weighing ≤40 kg: 100 mg/kg of piperacillin and 12.5 mg/kg of tazobactam every 8 hours.1 33 35

IV

Children weighing >40 kg: 3.375 g (3 g of piperacillin and 0.375 g of tazobactam) every 6 hours.1 33 35

Adults

Gynecologic and Obstetric Infections
IV

3.375 g (3 g of piperacillin and 0.375 g of tazobactam) every 6 hours for 7–10 days.1 33 35

Intra-abdominal Infections
IV

3.375 g (3 g of piperacillin and 0.375 g of tazobactam) every 6 hours for 7–10 days.1 33 35

Respiratory Tract Infections
IV

3.375 g (3 g of piperacillin and 0.375 g of tazobactam) every 6 hours for 7–10 days.1 33 35

Nosocomial Pneumonia
IV

4.5 g (4 g of piperacillin and 0.5 g of tazobactam) every 6 hours for 7–14 days; used in conjunction with an aminoglycoside.1 33 35

The aminoglycoside should be continued for the duration of treatment in patients in whom Ps. aeruginosa is isolated; if nosocomial pneumonia is not caused by Ps. aeruginosa, the aminoglycoside may be discontinued at the discretion of the clinician, taking into account severity of the infection and the patient’s clinical and bacteriologic progress.1 33 35

Skin and Skin Structure Infections
IV

3.375 g (3 g of piperacillin and 0.375 g of tazobactam) every 6 hours for 7–10 days.1 33 35

Special Populations

Hepatic Impairment

No dosage adjustment required in patients with hepatic impairment.1 3 12 33 35

Serum half-lives of piperacillin and tazobactam are prolonged in patients with hepatic cirrhosis;1 3 33 35 not considered clinically important.1 3 12 33 35

Renal Impairment

Dosage adjustment recommended in adults with Clcr ≤40 mL/minute and in adults undergoing hemodialysis or CAPD.1 7 12 33 35 No dosage recommendations for pediatric patients with renal impairment.1 33 35

In adults with nosocomial pneumonia and renal impairment who are receiving concomitant aminoglycoside therapy, dosage of the aminoglycoside should be adjusted according to the recommendations for that drug.1 33 35

Table 3. Dosage for Adults with Renal Impairment13335

Clcr (mL/min)

Daily Dosage (Except Nosocomial Pneumonia)

Daily Dosage (Nosocomial Pneumonia)

20–40

2.25 g every 6 hours

3.375 g every 6 hours

<20

2.25 g every 8 hours

2.25 g every 6 hours

Hemodialysis Patients

2.25 g every 12 hours; also give 0.75 g after each hemodialysis session

2.25 g every 8 hours; also give 0.75 g after each hemodialysis session

CAPD Patients

2.25 g every 12 hours

2.25 g every 8 hours

Cautions for Zosyn

Contraindications

  • Hypersensitivity to any penicillin, cephalosporin, or β-lactamase inhibitor.1 33 35

Warnings/Precautions

Warnings

Clostridium difficile-associated Diarrhea and Colitis (CDAD)

Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridium difficile.1 33 35 36 37 38 39 40 C. difficile-associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) has been reported with nearly all anti-infectives, including piperacillin and tazobactam, and may range in severity from mild diarrhea to fatal colitis.1 33 35 36 37 38 39 40 Hyper toxin-producing strains of C. difficile are associated with increased morbidity and mortality since they may be refractory to anti-infectives and colectomy may be required.1 33 35

Consider CDAD if diarrhea develops during or after therapy and manage accordingly.1 33 35 36 37 38 39 40 Careful medical history is necessary since CDAD has been reported to occur as late as 2 months or longer after anti-infective therapy is discontinued.1 33 35 36 37 38 39 40

If CDAD is suspected or confirmed, piperacillin and tazobactam may need to be discontinued.1 33 35 36 37 38 39 40 Some mild cases may respond to discontinuance alone.36 37 38 39 40 Manage moderate to severe cases with fluid, electrolyte, and protein supplementation, anti-infective therapy active against C. difficile (e.g., oral metronidazole or vancomycin), and surgical evaluation when clinically indicated.1 33 35 36 37 38 39 40

Sensitivity Reactions

Hypersensitivity Reactions

Serious and occasionally fatal hypersensitivity reactions, including anaphylaxis, reported with penicillins.1 33 35

Prior to initiation of therapy, make careful inquiry regarding previous hypersensitivity reactions to penicillins, cephalosporins, or other drugs.1 33 35 Partial cross-allergenicity occurs among penicillins and other β-lactam antibiotics including cephalosporins and cephamycins.1 33 35

If a severe hypersensitivity reaction occurs, discontinue immediately and institute appropriate therapy as indicated (e.g., epinephrine, corticosteroids, maintenance of an adequate airway and oxygen).1 33 35

General Precautions

Selection and Use of Anti-infectives

To reduce development of drug-resistant bacteria and maintain effectiveness of piperacillin and tazobactam and other antibacterials, use only for treatment of infections proven or strongly suspected to be caused by susceptible bacteria.1 33 35

When selecting or modifying anti-infective therapy, use results of culture and in vitro susceptibility testing.1 33 35 In the absence of such data, consider local epidemiology and susceptibility patterns when selecting anti-infectives for empiric therapy.1 33 35

Hematologic Effects

Bleeding manifestation reported with some β-lactam antibiotics, including piperacillin.1 33 35 These reactions have sometimes been associated with abnormal coagulation tests (e.g., clotting time, platelet aggregation, PT) and are most likely to occur in patients with renal failure.1 33 35

Periodically evaluate hematologic function, especially with prolonged treatment (i.e., ≥21 days).1 33 35

If bleeding manifestations occur, discontinue piperacillin and tazobactam and institute appropriate measures.1 33 35

Nervous System Effects

Neuromuscular excitability or seizures reported with some penicillins when higher than recommended dosage used (especially in patients with renal failure).1 33 35

Sodium Content and Electrolyte Imbalance

Fixed-combination of piperacillin and tazobactam contains 2.79 mEq (64 mg) of sodium per g of piperacillin.1 33 (See Geriatric Use under Cautions.)

Consider sodium content when used in patients requiring restricted salt intake.1 33 35

Determine electrolyte concentrations periodically in patients with low potassium reserves; consider possibility of hypokalemia in those with potentially low potassium reserves who are receiving cytotoxic therapy or diuretics.1 33 35

Cystic Fibrosis Patients

Possibility of increased incidence of fever and rash.1 33 35

Laboratory Monitoring

Periodically assess organ system functions, including renal, hepatic, and hematopoietic, during prolonged therapy.2 Monitoring hematopoietic function is especially important when duration is ≥21 days (see Hematologic Effects under Cautions).1 33 35

Specific Populations

Pregnancy

Category B.1 33 35

Lactation

Piperacillin distributed into milk; not known whether tazobactam is distributed into milk.1 33 35 Use with caution.1 33 35

Pediatric Use

Use for treatment of appendicitis and/or peritonitis in pediatric patients ≥2 months of age is supported by evidence from well-controlled studies and pharmacokinetic studies in adults and pediatric patients.1 33 35

Safety and efficacy not established in pediatric patients <2 months of age.1 33 35

Geriatric Use

Piperacillin and tazobactam contains sodium (see Sodium Content and Electrolyte Imbalance under Cautions).1 33 35 Patients receiving the usual IV dosage will receive 768 or 1024 mg (33.5 or 44.6 mEq) of sodium daily.1 33 Geriatric patients may respond to salt loading with blunted natriuresis;1 33 35 this may be clinically important with regard to such diseases as congestive heart failure.1 33 35

Select dosage with caution (usually starting at low end of dosage range) because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1 33 35

Substantially eliminated by kidneys; risk of toxicity may be greater in patients with impaired renal function.1 33 35 Assess renal function periodically since geriatric patients are more likely to have renal impairment.1 33 35

No dosage adjustments except those related to renal function.1 33 35 (See Renal Impairment under Dosage and Administration.)

Hepatic Impairment

Serum half-lives of piperacillin and tazobactam are prolonged in patients with hepatic cirrhosis;1 3 33 35 not considered clinically important.1 3 12 33 35

No dosage adjustment required in patients with hepatic impairment.1 3 12 33 35

Renal Impairment

Dosage adjustments recommended in adults with Clcr ≤40 mL/minute and in those undergoing hemodialysis or CAPD.1 33 35 No dosage recommendations in pediatric patients with impaired renal function.1 33 35 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Adults: GI effects (diarrhea, constipation, nausea); headache; insomnia; fever; dermatologic reactions (rash, pruritus).1 33 35

Pediatric patients with severe intra-abdominal infections (including appendicitis and/or peritonitis): Diarrhea, fever, vomiting, local reaction, abscess, sepsis, abdominal pain, infection, bloody diarrhea, pharyngitis, constipation, increased AST.1 33 35

Interactions for Zosyn

Specific Drugs and Laboratory Tests

Drug or Test

Interaction

Comments

Aminoglycosides

Substantial inactivation of aminoglycosides can occur if combined with piperacillin in vitro1 33 35

Amikacin and gentamicin: Compatible in vitro with formulations of piperacillin and tazobactam (Zosyn) containing EDTA and can be used for simultaneous Y-site administration under specific conditions1 33 35 (see Administration under Dosage and Administration)

Tobramycin: Not compatible in vitro with piperacillin and tazobactam, including formulations of Zosyn containing EDTA1 33 35

Studies using piperacillin indicate clinically important decreases in aminoglycoside concentrations if the drugs are administered concomitantly in patients with end-stage renal disease (ESRD) requiring hemodialysis; effect may vary depending on the specific aminoglycoside1 33 35

Tobramycin: Sequential administration of Zosyn and tobramycin in patients with normal or mild to moderate renal impairment does not appear to significantly affect tobramycin pharmacokinetics, but tobramycin concentrations may be significantly altered in those with ESRD requiring hemodialysis 1 33 35

Monitor aminoglycoside concentrations1 33 35

If simultaneous coadministration of piperacillin and tazobactam and an aminoglycoside via Y-site infusion is considered necessary, use only certain dosages of amikacin or gentamicin, only certain formulations of piperacillin and tazobactam (Zosyn) containing EDTA, and only certain acceptable diluents1 33 35 (see Administration under Dosage and Administration)

Anticoagulants (oral anticoagulant, heparin)

Monitor coagulation parameters more frequently if used concomitantly with high doses of heparin, oral anticoagulants, or other drugs that affect blood coagulation or thrombocyte function1 33 35

Methotrexate

Possible decreased renal clearance of methotrexate and increased risk of methotrexate adverse effects1 33 35

Determine serum methotrexate concentrations and monitor for signs and symptoms of methotrexate toxicity1 33 35

Neuromuscular blocking agents (vecuronium)

Prolonged neuromuscular blockade reported when vecuronium used with piperacillin; could also occur with piperacillin and tazobactam1 33 35

Because of similar mechanism of action, possibility of prolonged neuromuscular blockade with piperacillin and other nondepolarizing muscle relaxants1 33 35

Probenecid

Prolonged piperacillin and tazobactam half-lives1 33 35

Tests for Aspergillus

Possible false-positive results in Platelia Aspergillus EIA test1 33 35

Use caution when interpreting such tests and confirm diagnosis of Aspergillus infection using other diagnostic methods1 33 35

Tests for glucose

Possible false-positive reactions in urine glucose tests using copper reduction (e.g., Clinitest)1 33 35

Use glucose tests based on enzymatic glucose oxidase reactions (e.g., Diastix, Tes-Tape)1 33 35

Vancomycin

No evidence of pharmacokinetic interaction1 33 35

Zosyn Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations attained immediately after completion of IV infusion.1 33 35

Piperacillin plasma concentrations with the fixed-combination of piperacillin and tazobactam are similar to those attained with equivalent doses of piperacillin administered alone.1 33 35

Distribution

Extent

Both piperacillin and tazobactam widely distributed into tissues and body fluids, including intestinal mucosa, gallbladder, lung, female reproductive tissues (uterus, ovary, fallopian tube), interstitial fluid, and bile.1 33 35

Only low concentrations of piperacillin and tazobactam distributed into CSF.1 33 35

Both piperacillin and tazobactam cross the placenta.1 33 35 Piperacillin is distributed into milk; not known whether tazobactam is distributed into milk.1 33 35

Plasma Protein Binding

Both piperacillin and tazobactam approximately 30% bound to plasma proteins.1 33 35

Elimination

Metabolism

Piperacillin metabolized to a minor microbiologically active desethyl metabolite.1 33 35 Tazobactam metabolized to a single metabolite that lacks pharmacologic and antibacterial activity.1 33 35

Elimination Route

Piperacillin, tazobactam, and their metabolites eliminated principally in urine by glomerular filtration and active tubular secretion; also excreted in bile.1 33 35

68% of piperacillin dose eliminated unchanged in urine; 80% of tazobactam dose eliminated unchanged drug in urine.1 33 35

Half-life

Plasma half-live of piperacillin and of tazobactam range from 0.7–1.2 hours.1 33 35

Special Populations

Patients with cirrhosis: Half-life of piperacillin and tazobactam increased by approximately 25 and 18%, respectively, compared with patients with normal hepatic function.1 33 35

Patients with renal impairment: Half-lives of piperacillin and tazobactam increase with decreasing Clcr.1 33 35 In those with Clcr <20 mL/minute, half-life of piperacillin is 2 times higher and half-life of tazobactam is 4 times higher compared with patients with normal renal function.1 33 35

Pediatric patients: Clearance of piperacillin and tazobactam in children 9 months to 12 years of age is comparable to that reported in adults.1 33 35 Piperacillin clearance in children 2–9 months of age is estimated to be 80% of that value;1 33 35 clearance is slower in patients <2 months of age compared to older children.1 33 35

Stability

Storage

Parenteral

Powder for Injection

20–25°C.1 33

Reconstituted single-dose vials should be used immediately after reconstitution; any unused injection should be discarded after 24 hours if stored at 20–25°C or after 48 hours if refrigerated at 2–8°C.1

ADD-Vantage vials prepared using 0.9% sodium chloride or 5% dextrose are stable for 24 hours at room temperature; these reconstituted solutions should not be refrigerated or frozen.1

Reconstituted bulk vials should be discarded after 24 hours if stored at 20–25°C or after 48 hours if refrigerated at 2–8°C.33 Do not freeze.33

Injection (Frozen)

-20° C or lower.35 Thawed solutions of the commercial frozen injection are stable for 24 hours at room temperature (20–25°C) or 14 days at 2–8°C.35

Do not refreeze after thawing.35

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Solution Compatibility

If sterile water for injection is used for dilution, the maximum recommended volume is 50 mL.1 33

Lactated Ringer’s injection is compatible with Zosyn (with EDTA), but is incompatible with and should not be used to reconstitute or dilute piperacillin and tazobactam preparations that do not contain EDTA.1 33

Chemically unstable in solutions containing only sodium bicarbonate and solutions that alter pH.1 33 35

Compatible

Dextran 6% in sodium chloride 0.9%1 33

Dextrose 5%1 33 35

Sodium chloride 0.9%1 33 35

Ringer’s injection, lactated (compatible only with Zosyn containing EDTA)1 33

Drug Compatibility

Y-site CompatibilityHID

Compatible

Amikacin (compatible only with Zosyn containing EDTA)1 33 35

Aminophylline

Aztreonam

Bivalirudin

Bleomycin sulfate

Bumetanide

Buprenorphine HCl

Butorphanol tartrate

Calcium gluconate

Carboplatin

Carmustine

Cefepime HCl

Cimetidine HCl

Clindamycin phosphate

Co-trimoxazole

Cyclophosphamide

Cytarabine

Dexamethasone sodium phosphate

Dexmedetomidine HCl

Diphenhydramine HCl

Docetaxel

Dopamine HCl

Enalaprilat

Etoposide

Etoposide phosphate

Fenoldopam mesylate

Floxuridine

Fluconazole

Fludarabine phosphate

Fluorouracil

Furosemide

Gentamicin (compatible only with Zosyn containing EDTA)1 33 35

Gallium nitrate

Granisetron HCl

Heparin sodium

Hetastarch in lactated electrolyte injection (Hextend)

Hydrocortisone sodium phosphate

Hydrocortisone sodium succinate

Hydromorphone HCl

Ifosfamide

Lansoprazole

Leucovorin calcium

Linezolid

Lorazepam

Magnesium sulfate

Mannitol

Meperidine HCl

Mesna

Methotrexate sodium

Methylprednisolone sodium succinate

Metoclopramide HCl

Metronidazole

Milrinone lactate

Morphine sulfate

Ondansetron HCl

Potassium chloride

Ranitidine HCl

Remifentanil HCl

Sargramostim

Sodium bicarbonate

Thiotepa

Vinblastine sulfate

Vincristine sulfate

Zidovudine

Incompatible

Acyclovir sodium

Amiodarone HCl

Amphotericin B

Amphotericin B cholesteryl sulfate complex

Azithromycin

Chlorpromazine HCl

Cisplatin

Dacarbazine

Daunorubicin HCl

Dobutamine HCl

Doxorubicin HCl

Doxorubicin HCl liposome injection

Doxycycline hyclate

Drotrecogin alfa (activated)

Droperidol

Famotidine

Ganciclovir sodium

Gemcitabine HCl

Haloperidol lactate

Hydroxyzine HCl

Idarubicin HCl

Mitomycin

Mitoxantrone HCl

Nalbuphine HCl

Prochlorperazine edisylate

Promethazine HCl

Streptozocin

Variable

Vancomycin HCl

Actions and Spectrum

  • Fixed combination of piperacillin sodium (an extended-spectrum penicillin) and tazobactam sodium (a β-lactamase inhibitor).1 3 5 6 7 9 12 33 35

  • Piperacillin and tazobactam commercially available in the US (Zosyn) is formulated with EDTA and sodium citrate 1 33 35 44 to decrease certain aspects of chemical degradation and particulate formation and to facilitate coadministration with certain aminoglycosides.44 (See Dosage and Administration.)

  • Tazobactam synergistically expands piperacillin’s spectrum of activity against β-lactamase-producing bacteria by irreversibly and completely inhibiting β-lactamase.1 2 4 5 6 7 8 10 12 33 35

  • Usually bactericidal.1 33 35

  • Like other β-lactam antibiotics, antibacterial activity results from inhibition of bacterial cell wall synthesis.1 33 35

  • Spectrum of activity includes many gram-positive and -negative aerobes and some anaerobes.1 2 4 5 6 9 10 11 15 18 19 20 21 22 33 35 Inactive against mycobacteria, Mycoplasma, Rickettsia, fungi, and viruses.a

  • Gram-positive aerobes: Active in vitro and in clinical infections against S. aureus.1 33 35 Also active in vitro against S. epidermidis, Streptococcus pneumoniae (penicillin-susceptible strains only), S. agalactiae (group B streptococci), S. pyogenes (group A β-hemolytic streptococci), viridans streptococci, and Enterococcus faecalis (penicillin- or ampicillin-resistant strains only).1 33 35 Oxacillin-resistant (methicillin-resistant) staphylococci are resistant.1 33 35

  • Gram-negative aerobes: Active in vitro and in clinical infections against Acinetobacter baumanii, Escherichia coli, Haemophilus influenzae (except β-lactamase-negative, ampicillin-resistant strains; BLNAR), Klebsiella pneumoniae, and Pseudomonas aeruginosa.1 33 35 Also active in vitro against Citrobacter koseri, Moraxella catarrhalis, Morganella morganii, Neisseria gonorrhoeae, Proteus mirabilis, P. vulgaris, Serratia marcescens, Providencia, and Salmonella enterica.1 33 35 Pseudomonas resistant to piperacillin generally also are resistant to piperacillin and tazobactam.5 10 11 12

  • Anaerobes: Active in vitro and in clinical infections against Bacteroides fragilis, B. ovatus, B. thetaiotaomicron, and B. vulgatus.1 33 35 Also active in vitro against B. distasonis and Prevotella melaninogenica.1 33 35

Advice to Patients

  • Advise patients that antibacterials (including piperacillin and tazobactam) should only be used to treat bacterial infections and not used to treat viral infections (e.g., the common cold).1 33 35

  • Importance of completing full course of therapy, even if feeling better after a few days.1 33 35

  • Advise patients that skipping doses or not completing the full course of therapy may decrease effectiveness and increase the likelihood that bacteria will develop resistance and will not be treatable with piperacillin and tazobactam or other antibacterials in the future.1 33 35

  • Advise patients that diarrhea is a common problem caused by anti-infectives and usually ends when the drug is discontinued.1 33 35 Importance of contacting a clinician if watery and bloody stools (with or without stomach cramps and fever) occur during or as late as 2 months or longer after the last dose.1 33 35

  • Importance of discontinuing therapy and informing clinician if an allergic reaction occurs.a

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1

  • Importance of women informing clinician if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Piperacillin Sodium and Tazobactam Sodium

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV infusion

2 g (of piperacillin) and 0.25 g (of tazobactam) (labeled as a combined total potency of 2.25 g)

Zosyn

Wyeth

Zosyn ADD-Vantage

Wyeth

3 g (of piperacillin) and 0.375 g (of tazobactam) (labeled as a combined total potency of 3.375 g)

Zosyn

Wyeth

Zosyn ADD-Vantage

Wyeth

4 g (of piperacillin) and 0.5 g (of tazobactam) (labeled as a combined total potency of 4.5 g)

Zosyn

Wyeth

Zosyn ADD-Vantage

Wyeth

36 g (of piperacillin) and 4.5 g (of tazobactam) (labeled as a combined total potency of 40.5 g) pharmacy bulk package

Zosyn

Wyeth

Piperacillin Sodium and Tazobactam Sodium in Dextrose

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection (frozen), for IV infusion

40 mg (of piperacillin) per mL (2 g) and 5 mg (of tazobactam) per mL (0.25 g) (labeled as a combined total potency of 2.25 g) in 2% Dextrose

Zosyn Iso-osmotic in Dextrose Injection (Galaxy [Baxter])

Wyeth

40 mg (of piperacillin) per mL (4 g) and 5 mg (of tazobactam) per mL (0.5 g) (labeled as a combined total potency of 4.5 g) in 2% Dextrose

Zosyn Iso-osmotic in Dextrose Injection (Galaxy [Baxter])

Wyeth

60 mg of (of piperacillin) per mL (3 g) and 7.5 mg (of tazobactam) per mL (0.375 g) (labeled as a combined total potency of 3.375 g) in 0.7% Dextrose

Zosyn Iso-osmotic in Dextrose Injection (Galaxy [Baxter])

Wyeth

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Zosyn 3-0.375GM Solution (WYETH PHARMACEUTICAL): 1/$28.99 or 3/$79.97

Zosyn 4-0.5GM Solution (WYETH PHARMACEUTICAL): 1/$252.28 or 3/$734.91

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions April 1, 2009. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Wyeth. Zosyn (piperacillin sodium and tazobactam sodium) for injection prescribing information. Philadelphia, PA; 2007 Nov.

2. Lederle. Zosyn (piperacillin sodium/tazobactam sodium) product monograph. Pearl River, NY; 1993 Nov.

3. Sörgel F, Kinzig M. The chemistry, pharmacokinetics and tissue distribution of piperacillin/tazobactam. J Antimicrob Chemother. 1993; 31(Suppl A):39-60. [PubMed 8383655]

4. Livermore DM. Determinants of the activity of β-lactamase inhibitor combinations. J Antimicrob Chemother. 1993; 31(Suppl A):9-21. [PubMed 8449836]

5. Acar JF, Goldstein FW, Kitzis MD. Susceptibility survey of piperacillin alone and in the presence of tazobactam. J Antimicrob Chemother. 1993; 31(Suppl A):23-8. [PubMed 8383653]

6. Kuck NA, Jacobus NV, Petersen PJ et al. Comparative in vitro and in vivo activities of piperacillin combined with the β-lactamase inhibitors tazobactam, clavulanic acid, and sulbactam. Antimicrob Agents Chemother. 1989; 33:1964-9. [PubMed 2558615]

7. Johnson CA, Halstenson CE, Kelloway JS et al. Single-dose pharmacokinetics of piperacillin and tazobactam in patients with renal disease. Clin Pharmacol Ther. 1992; 51:32-41. [IDIS 291165] [PubMed 1310077]

8. Piddock LJV, Jin YF, Turner HL. Activity of 13 β-lactam agents combined with BRL 42715 against β-lactamase producing gram-negative bacteria compared to combinations with clavulanic acid, tazobactam and sulbactam. J Antimicrob Chemother. 1993; 31:89-103. [PubMed 8383105]

9. Williams JD. Interactions between antibiotics and beta-lactamase inhibitors. Infect Med. 1993; 10(Suppl A):15-21.

10. Fuchs PC, Barry AL. In vitro activity of piperacillin/tazobactam: a review. Infect Med. 1993; 10(Suppl A):22-7.

11. Eliopoulos GM, Klimm K, Ferraro MJ et al. Comparative in vitro activity of piperacillin combined with the beta-lactamase inhibitor tazobactam (YTF 830). Diagn Microbiol Infect Dis. 1989; 12:481-8. [PubMed 2560420]

12. Bryson HM, Brogden RN. Piperacillin/tazobactam: a review of its antibacterial activity, pharmacokinetic properties and therapeutic potential. Drugs. 1994; 47:506-35. [PubMed 7514977]

13. Niinikoski J, Havia T, Alhava E et al. Piperacillin/tazobactam versus imipenem/cilastatin in the treatment of intra-abdominal infections. Surg Gynecol Obstet. 1993; 176:255-61. [IDIS 310569] [PubMed 8382381]

14. Brismar B, Malmborg AS, Tunevall G et al. Piperacillin-tazobactam versus imipenem-cilastatin for treatment of intra-abdominal infections. Antimicrob Agents Chemother. 1992; 36:2766-73. [IDIS 306782] [PubMed 1336347]

15. Tan JS, Wishnow RM, Talan DA et al. Treatment of hospitalized patients with complicated skin and skin structure infections: double-blind, randomized, multicenter study of piperacillin-tazobactam versus ticarcillin-clavulanate. Antimicrob Agents Chemother. 1993; 37:1580-6. [IDIS 318763] [PubMed 8215266]

16. Mouton Y, Leroy O, Beuscart C et al. Efficacy, safety and tolerance of parenteral piperacillin/tazobactam in the treatment of patients with lower respiratory tract infections. J Antimicrob Chemother. 1993; 31(Suppl A):87-95. [PubMed 8383658]

18. Meyer KS, Urban C, Eagan JA et al. Nosocomial outbreak of Klebsiella infection resistant to late-generation cephalosporins. Ann Intern Med. 1993; 119:353-8. [IDIS 319318] [PubMed 8135915]

19. Mehtar S, Drabu YJ, Blakemore PH. The in-vitro activity of piperacillin/tazobactam, ciprofloxacin, ceftazidime and imipenem against multiple resistant gram-negative bacteria. J Antimicrob Chemother. 1990; 25:915-9. [PubMed 2164513]

20. Van der Auwera P, Duchateau V, Lambert C et al. Ex vivo pharmacodynamic study of piperacillin alone and in combination with tazobactam, compared with ticarcillin plus clavulanic acid. Antimicrob Agents Chemother. 1993; 37:1860-8. [IDIS 319428] [PubMed 8239597]

21. Sweet RL, Roy S, Faro S et al. Piperacillin and tazobactam versus clindamycin and gentamicin in the treatment of hospitalized women with pelvic infection. Obstet Gynecol. 1994; 83:280-6. [IDIS 324592] [PubMed 8290195]

22. Collins LA, Wennersten CB, Ferraro MJ et al. Comparative activities of piperacillin and tazobactam against clinical isolates of Legionella spp. Antimicrob Agents Chemother. 1994; 38:144-6. [IDIS 324742] [PubMed 8141570]

23. Reviewers’ comments (personal observations) on ticarcillin disodium and clavulanate potassium.

26. Teasley DC, Gerding DN, Olson MM et al. Prospective randomized trial of metronidazole versus vancomycin for Clostridium difficile-associated diarrhea and colitis. Lancet. 1983; 2:1043-6. [IDIS 178007] [PubMed 6138597]

27. Caputo GM, Weitekamp MR. The treatment of Clostridium difficile colitis. JAMA. 1993; 269:2088. [IDIS 313397] [PubMed 8468761]

28. Spera RV. The treatment of Clostridium difficile colitis. JAMA. 1993; 269:2088.

29. Ettlin R, Hoigne R, Bruppacher R et al. Atopy and adverse drug reactions. Int Arch Aller Appl Immunol. 1981; 66(Suppl 1):93-5.

30. Lederle Laboratories, Pearl River, NY: Personal communication.

31. Shlaes DM, Norden C. Piperacillin/tazobactam (P/T) compared to ticarcillin/clavulanate (T/C) in community-acquired bacterial lower respiratory tract infection. Proceedings of ICAAC New Orleans 1993. Poster No. 646.

32. Anon. A reminder: piperacillin/tazobactam is not for pseudomonas. Med Lett Drugs Ther. 1994; 36:110. [PubMed 7968784]

33. Wyeth. Zosyn (piperacillin sodium and tazobactam sodium) pharmacy bulk package prescribing information. Philadelphia, PA; 2007 Nov.

34. Anon. Choice of antibacterial drugs. Treat Guidel Med Lett. 2007; 5:33-50.

35. Wyeth. Zosyn (piperacillin sodium and tazobactam sodium) injection in Galaxy containers (PL 2040 plastic) prescribing information. Philadelphia, PA; 2007 Nov.

36. Johnson S, Gerding DN. Clostridium difficile-associated diarrhea. Clin Infect Dis. 1998; 26:1027-36. [IDIS 407733] [PubMed 9597221]

37. Gerding DN, Johnson S, Peterson LR et al for the Society for Healthcare Epidemiology of American. Position paper on Clostridium difficile-associated diarrhea and colitis. Infect Control Hosp Epidemiol. 1995; 16:459-77. [PubMed 7594392]

38. Fekety R for the American College of Gastroenterology Practice Parameters Committee. Guidelines for the diagnosis and management of Clostridium difficile-associated diarrhea and colitis. Am J Gastroenterol. 1997; 92:739-50 (IDIS 386628) [IDIS 386628] [PubMed 9149180]

39. American Society of Health-System Pharmacists Commission on Therapeutics. ASHP therapeutic position statement on the preferential use of metronidazole for the treatment of Clostridium difficile-associated disease. Am J Health-Syst Pharm. 1998; 55:1407-11. [IDIS 407213] [PubMed 9659970]

40. Wilcox MH. Treatment of Clostridium difficile infection. J Antimicrob Chemother. 1998; 41(Suppl C):41-6. [IDIS 407246] [PubMed 9630373]

41. Mandell LA, Wunderink RG, Anzueto A et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007; 44 Suppl 2:S27-72. [PubMed 17278083]

42. American Thoracic Society and the Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005; 171:388-416. [PubMed 15699079]

43. Kucers A, Crowe S, Grayson ML et al, eds. The use of antibiotics. A clinical review of antibacterial, antifungal, and antiviral drugs. 5th ed. Jordan Hill, Oxford: Butterworth-Heinemann; 1997:145-80,220-6.

44. Desai NR, Shah SM, Cohen J et al. Zosyn (piperacillin/tazobactam) reformulation: Expanded compatibility and coadministration with lactated Ringer's solutions and selected aminoglycosides. Ther Clin Risk Manag. 2008; 4:303-14. [PubMed 18728835]

a. AHFS Drug Information 2004. McEvoy GK, ed. Extended-spectrum Penicillins General Statement. American Society of Health-System Pharmacists; 2004:341-9.

HID. Trissel LA. Handbook on injectable drugs. 14th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2007:1359-66.

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