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•NaC₁₀H₁₁N₄NaO₅S
CAS Number: 157044-21-8
Brands: Zosyn

Medically reviewed by Drugs.com. Last updated on Sep 2, 2019.

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Introduction

Antibacterial; β-lactam antibiotic; fixed combination of piperacillin (an extended-spectrum penicillin) and tazobactam (a β-lactamase inhibitor).^{1 3 5 6 12 28 43 46 60}

Uses for Piperacillin/Tazobactam

Gynecologic and Obstetric Infections

Treatment of postpartum endometritis or pelvic inflammatory disease (PID) caused by susceptible β-lactamase-producing Escherichia coli.^{1 21 197}

Not included in CDC recommendations for treatment of PID;³⁴⁴ if a penicillin used for empiric treatment of PID, CDC and others recommend a parenteral regimen that includes the fixed combination of ampicillin and sulbactam (ampicillin/sulbactam) in conjunction with doxycycline.^{344 345}

Intra-abdominal Infections

Treatment of appendicitis (complicated by rupture or abscess) and peritonitis caused by susceptible β-lactamase-producing E. coli, Bacteroides fragilis, B. ovatus, B. thetaiotaomicron, or B. vulgatus.^{1 12 13 14 43 197}

Has been used for treatment of various intra-abdominal infections;^{43 708} recommended as one of several options for initial empiric treatment of high-risk or severe community-acquired extrabiliary intra-abdominal infections (e.g., in patients with advanced age, immunocompromise, severe physiologic disturbance), community-acquired biliary tract infections (e.g., acute cholecystitis), and complicated healthcare-associated intra-abdominal infections.⁷⁰⁸

Respiratory Tract Infections

Treatment of moderately severe community-acquired pneumonia (CAP) caused by susceptible β-lactamase-producing Haemophilus influenzae.¹ Also used for treatment of CAP caused by susceptible Enterobacteriaceae† or anaerobic bacteria†.⁵¹²

Recommended as one of several options for empiric treatment of CAP in hospitalized patients requiring treatment in an intensive care unit (ICU).⁵¹² If Pseudomonas aeruginosa known or suspected to be involved, use in conjunction with a fluoroquinolone with antipseudomonal activity (ciprofloxacin, levofloxacin) with or without an aminoglycoside or in conjunction with an aminoglycoside and azithromycin.⁵¹² Factors that increase risk of Ps. aeruginosa infection in CAP patients include severe CAP requiring treatment in an ICU, structural lung disease (e.g., bronchiectasis), repeated COPD exacerbations, alcoholism, chronic corticosteroid therapy, and frequent anti-infective therapy.⁵¹²

Treatment of moderate to severe nosocomial pneumonia caused by susceptible β-lactamase-producing Staphylococcus aureus or susceptible Acinetobacter baumannii, H. influenzae, Klebsiella pneumoniae, or Ps. aeruginosa.^{1 197} If Ps. aeruginosa involved, use in conjunction with an aminoglycoside or a fluoroquinolone with antipseudomonal activity (e.g., ciprofloxacin, levofloxacin) recommended.^{1 197 315}

One of several options recommended for initial empiric treatment of hospital-acquired pneumonia (HAP) not associated with mechanical ventilation and initial empiric treatment of ventilator-associated pneumonia (VAP).³¹⁵

In patients with HAP not at high risk of mortality, can consider use of piperacillin/tazobactam alone (monotherapy) for initial empiric treatment if no factors are present that increase likelihood of methicillin-resistant S. aureus (MRSA; also known as oxacillin-resistant S. aureus or ORSA);³¹⁵ use in conjunction with an antibacterial active against MRSA (vancomycin, linezolid) recommended if such factors are present or if patient is at high risk of mortality or has received IV anti-infectives during prior 90 days.³¹⁵

In patients with clinically suspected VAP, can consider use of piperacillin/tazobactam alone (monotherapy) for initial empiric treatment in patients not at increased risk for MRSA;³¹⁵ in those with factors that increase risk of MRSA or multidrug-resistant gram-negative bacteria, use in conjunction with an anti-infective active against MRSA (vancomycin, linezolid) plus an antipseudomonal fluoroquinolone (ciprofloxacin, levofloxacin), aminoglycoside (amikacin, gentamicin, tobramycin), or polymyxin B recommended.³¹⁵

Septicemia

Treatment of septicemia†.^{39 40 41 43 197} Recommended as one of several options for initial empiric treatment of sepsis and bacteremia.^{39 42 43 197}

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 susceptible β-lactamase-producing S. aureus.^{1 12 15} Recommended as a possible option for empiric monotherapy of complicated skin and skin structure infections that could be polymicrobial and unlikely to involve MRSA;¹⁹⁷ do not use alone in infections that may be caused by MRSA.¹⁹⁷

Although fixed combination of amoxicillin and clavulanate (amoxicillin/clavulanate) usually drug of choice, piperacillin/tazobactam suggested as an alternative for treatment of infected human or animal (e.g., dog, cat, reptile) bite wounds† when a parenteral anti-infective used.^{292 543} Purulent bite wounds usually are polymicrobial and broad-spectrum anti-infective coverage recommended;^{292 543} nonpurulent infected bite wounds usually caused by staphylococci and streptococci, but can be polymicrobial.⁵⁴³

Possible option for empiric treatment of severe cellulitis or treatment of clostridial myonecrosis† (gas gangrene);⁵⁴³ used in conjunction with vancomycin.⁵⁴³

Possible option for empiric treatment of necrotizing fasciitis†;⁵⁴³ used in conjunction with vancomycin or linezolid.⁵⁴³

Urinary Tract Infections (UTIs)

Treatment of UTIs† in hospitalized patients;^{43 197} used with or without an aminoglycoside.^{43 197}

Empiric Therapy in Febrile Neutropenic Patients

Has been used alone (monotherapy) or in conjunction with other anti-infectives (e.g., aminoglycosides) for empiric anti-infective therapy in febrile neutropenic patients†.^{43 197 359 787}

Recommended as one of several options for initial outpatient management of febrile neutropenia in adults receiving treatment for malignancy.⁷⁸⁷

Perioperative Prophylaxis

Has been used for perioperative prophylaxis† to decrease postoperative infections in patients undergoing various urologic procedures (e.g., prostate biopsy),^{48 374} gastroduodenal procedures (e.g., pancreatic duodenectomy),^{47 374} or liver transplantation.^{49 374} Not generally recommended for perioperative prophylaxis.^{43 360}

Piperacillin/Tazobactam Dosage and Administration

Administration

Administer by IV infusion.^{1 35 36 37 38 45}

Usually administered by intermittent IV infusion;^{35 36 37 38 43 45} has been administered by continuous IV infusion†.^{25 43 49 56 58}

Do not give by rapid IV injection.²⁵

IV Infusion

For solution compatibility information, see Compatibility under Stability.

Do not admix with other drugs (e.g., in a syringe or infusion bottle);^{1 35 36 37 38 45} do not add to blood products or albumin hydrolysates.^{1 35 36 37 38 45}

If concomitant use of an aminoglycoside indicated (e.g., treatment of nosocomial pneumonia), reconstitute, dilute, and administer piperacillin/tazobactam and the aminoglycoside separately.^{1 35 36 37 38 45} (See Concomitant Use with Aminoglycosides under Dosage and Administration.)

Piperacillin/tazobactam (Zosyn) and generic preparations of piperacillin/tazobactam commercially available in US are not identical.^{1 35 36 37 38} Zosyn is formulated with edetate disodium dihydrate (EDTA) and sodium citrate;¹ generic preparations do not contain EDTA or sodium citrate.^{35 36 37 38} EDTA acts as a metal chelating agent and sodium citrate acts as a buffer to inhibit certain aspects of chemical degradation and particulate formation following reconstitution with commonly used diluents or storage of solutions of the drug.⁴⁴

Lactated Ringer’s injection is compatible for coadministration via Y-site infusion only with solutions prepared using piperacillin/sodium (Zosyn) formulated with EDTA;¹ lactated Ringer's injection is incompatible with and cannot be used for Y-site infusion with solutions prepared using piperacillin/tazobactam (generic) that do not contain EDTA.^{1 35 37 38}

Reconstitution and Dilution

Single-dose vials of piperacillin/tazobactam (Zosyn, generic): Reconstitute vials containing 2.25 g (2 g of piperacillin and 0.25 g of tazobactam), 3.375 g (3 g of piperacillin and 0.375 g of tazobactam), or 4.5 g (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 35 37 38} Swirl until contents are dissolved.^{1 35 37 38} Further dilute reconstituted solutions to 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% dextran in sodium chloride.^{1 35 37 38}

Single-dose ADD-Vantage vials of piperacillin/tazobactam (generic): Reconstitute and dilute in ADD-Vantage system according to the manufacturer’s labeling.⁴⁵

Pharmacy bulk piperacillin/tazobactam (Zosyn, generic): Reconstitute vials or bottles containing 40.5 g (36 g of piperacillin and 4.5 g of tazobactam) by adding 152 mL of a compatible IV solution (see Compatibility under Stability) to provide a solution containing 200 mg/mL of piperacillin and 25 mg/mL of tazobactam.^{1 36} Not intended for direct IV infusion;^{1 36} solutions reconstituted in pharmacy bulk vials or bottles must be further diluted with a compatible IV solution prior to administration.^{1 36}

Single-dose (frozen) premixed injections of piperacillin/tazobactam in dextrose (Zosyn in Galaxy containers): Thaw at room temperature (20–25°C) or in a refrigerator (2–8°C);¹ do not thaw by immersion in a water bath or by exposure to microwave radiation.¹ A precipitate may have formed in the frozen injection, but should dissolve with little or no agitation after reaching room temperature.¹ Discard thawed injection if an insoluble precipitate is present or if container seals or outlet ports are not intact.¹ Do not introduce additives into the injection.¹ Do not use in series connections with other plastic containers;¹ 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.¹

Rate of Administration

Administer by IV infusion over 30 minutes.^{1 25 35 36 37 38 43}

Has been administered by IV infusion over 3–4 hours†^{24 25 43 54 55 57 58} and by continuous IV infusion†.^{25 43 49 56 58} Some clinicians suggest 4-hour intermittent IV infusions or continuous IV infusion may be beneficial in certain clinical situations (e.g., critically ill patients, pathogen with high piperacillin/tazobactam MIC);^{25 43 52 53 54 58} some evidence that lengthening infusion duration may maximize pharmacokinetic/pharmacodynamic properties of the drug.^{24 43 54 55 57 58 59}

Concomitant Use with Aminoglycosides

Because piperacillin/tazobactam and aminoglycosides are physically and/or chemically incompatible in vitro,^{1 35 36 37 38 45 83 236} reconstitute, dilute, and administer the drugs separately if concomitant use indicated (e.g., treatment of nosocomial pneumonia).^{1 35 36 37 38 45}

In certain situations when coadministration of piperacillin/tazobactam and an aminoglycoside via Y-site infusion considered necessary, use only certain dosages of amikacin or gentamicin and only certain acceptable diluents.^{1 35 36 37 38 44 45} (See Tables 1 and 2.) For Y-site coadministration, do not use tobramycin or any aminoglycoside other than amikacin or gentamicin.^{1 35 36 37 38 45} Coadministration via Y-site infusion in any manner other than that specified in the tables may result in inactivation of the aminoglycoside.^{1 35 36 37 38 45}

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.

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 premixed 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.

Dosage

Available as fixed combination of piperacillin sodium and tazobactam sodium (piperacillin/tazobactam);^{1 35 36 37 38 45} potency of each drug expressed in terms of the base.^{1 35 36 37 45 38} Contains 8:1 ratio of piperacillin to tazobactam.^{1 35 36 37 38 45}

Dosage of piperacillin/tazobactam usually expressed as the total (sum) of the dosage of each of the 2 components (i.e., dosage of piperacillin plus dosage of tazobactam).^{1 35 36 37 38 43 45 315 543 708} However, dosage for pediatric patients often expressed in terms of piperacillin component.^{24 25 292 543 708}

Pediatric Patients

General Neonatal Dosage†

IV

Neonates ≤28 days of age†: AAP recommends dosage based on postmenstrual age (i.e., gestational age plus chronologic age).²⁹² AAP recommends 100 mg/kg (of piperacillin) every 8 hours in those with postmenstrual age ≤30 weeks and 80 mg/kg (of piperacillin) every 6 hours in those with postmenstrual age >30 weeks.²⁹²

Neonates weighing <1 kg†: Some clinicians recommend 100 mg/kg (of piperacillin) every 12 hours in those ≤14 days of age and 100 mg/kg (of piperacillin) every 8 hours in those 15–28 days of age.²⁴

Neonates weighing ≥1 kg†: Some clinicians recommend 100 mg/kg (of piperacillin) every 12 hours in those ≤7 days of age and 100 mg/kg (of piperacillin) every 8 hours in those 8–28 days of age.²⁴

Severe infections in neonates and infants <2 months of age†: Some clinicians recommend 80 mg/kg (of piperacillin) every 6 hours;²⁴ others recommend 80 mg/kg (of piperacillin) every 4 hours.²⁴ Some suggest shortening dosing interval to every 6 hours and prolonging duration of IV infusion to 4 hours to maximize pharmacokinetic/pharmacodynamic properties of the drug.²⁴

General Pediatric Dosage

IV

Pediatric patients beyond neonatal period: AAP recommends 240–300 mg/kg (of piperacillin) daily in 3 or 4 divided doses.²⁹² These experts state 400–600 mg/kg (of piperacillin) daily in 6 divided doses may be appropriate in some patients with cystic fibrosis.²⁹²

Severe infections in children: Some clinicians suggest 80 mg/kg (of piperacillin) every 6–8 hours in those 2–9 months of age and 100 mg/kg (of piperacillin) every 6–8 hours in those >9 months of age.²⁴

Intra-abdominal Infections

Appendicitis and/or Peritonitis

IV

Children 2–9 months of age: 80 mg/kg (of piperacillin) and 10 mg/kg (of tazobactam) every 8 hours.¹

Children ≥9 months of age weighing ≤40 kg with normal renal function: 100 mg/kg (of piperacillin) and 12.5 mg/kg (of tazobactam) every 8 hours.¹

Children weighing >40 kg with normal renal function: 3.375 g (3 g of piperacillin and 0.375 g of tazobactam) every 6 hours.¹

Complicated Intra-abdominal Infections

IV

Pediatric patients: Some clinicians recommend 200–300 mg/kg (of piperacillin) daily in divided doses every 6–8 hours.⁷⁰⁸

Some clinicians state usual duration of treatment is 4–7 days (unless difficult to achieve adequate source control);⁷⁰⁸ longer duration not associated with improved outcomes.⁷⁰⁸

Skin and Skin Structure Infections

Necrotizing Infections of Skin, Fascia, and Muscle†

IV

Pediatric patients: Some clinicians recommend 60–75 mg/kg (of piperacillin) every 6 hours in conjunction with vancomycin.⁵⁴³

Adults

General Adult Dosage

IV

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

Gynecologic and Obstetric Infections

Postpartum Endometritis or PID

IV

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

Intra-abdominal Infections

Appendicitis and/or Peritonitis

IV

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

Complicated Intra-abdominal Infections

IV

Some clinicians recommend 3.375 g (3 g of piperacillin and 0.375 g of tazobactam) every 6 hours.⁷⁰⁸ If Ps. aeruginosa identified, these clinicians recommend 3.375 g (3 g of piperacillin and 0.375 g of tazobactam) every 4 hours or 4.5 g (4 g of piperacillin and 0.5 g of tazobactam) every 6 hours.⁷⁰⁸

Some clinicians state usual duration of treatment is 4–7 days (unless difficult to achieve adequate source control);⁷⁰⁸ longer duration not associated with improved outcomes.⁷⁰⁸

Respiratory Tract Infections

Community-acquired Pneumonia

IV

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

Nosocomial Pneumonia

IV

Initial empiric treatment of nosocomial pneumonia: Manufacturer recommends 4.5 g (4 g of piperacillin and 0.5 g of tazobactam) every 6 hours for 7–14 days;¹ used in conjunction with an aminoglycoside.¹ If Ps. aeruginosa identified, continue concomitant aminoglycoside for full duration of treatment.¹

Initial empiric treatment of HAP or VAP: Some clinicians recommend 4.5 g (4 g of piperacillin and 0.5 g of tazobactam) every 6 hours used alone or in conjunction with other anti-infectives (see Respiratory Tract Infections under Uses).³¹⁵ These experts state usual duration of treatment is 7 days;³¹⁵ a longer or shorter duration may be indicated depending on clinical response.³¹⁵

Skin and Skin Structure Infections

Uncomplicated and Complicated Infections

IV

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

Incisional Surgical Site Infections†

IV

Some clinicians recommended 3.375 g (3 g of piperacillin and 0.375 g of tazobactam) every 6 hours or 4.5 g (4 g of piperacillin and 0.5 g of tazobactam) every 8 hours.⁵⁴³

Infected Human or Animal Bite Wounds†

IV

Some clinicians recommend 3.375 g (3 g of piperacillin and 0.375 g of tazobactam) every 6–8 hours.⁵⁴³

Necrotizing Infections of Skin, Fascia, and Muscle†

IV

Some clinicians recommend 3.375 g (3 g of piperacillin and 0.375 g of tazobactam) every 6–8 hours in conjunction with vancomycin.⁵⁴³

Prescribing Limits

Pediatric Patients

IV

Maximum 16 g (of piperacillin) daily;^{24 292} AAP states a maximum of 24 g (of piperacillin) daily may be appropriate in some cystic fibrosis patients.²⁹²

Adults

IV

Maximum 3.375 g (3 g of piperacillin and 0.375 g of tazobactam) every 4 hours⁷⁰⁸ or 4.5 g (4 g of piperacillin and 0.5 g of tazobactam) every 6 hours.⁴³

Maximum 18 g (16 g of piperacillin and 2 g of tazobactam) daily recommended by manufacturer.¹

Special Populations

Hepatic Impairment

Dosage adjustments not needed.^{1 3 12 43} (See Hepatic Impairment under Cautions.)

Renal Impairment

Adjust dosage in adults with Cl_cr ≤40 mL/minute, including those undergoing hemodialysis or CAPD.^{1 7 12 43} (See Table 3.)

Dosage recommendations not available for pediatric patients with renal impairment.¹

Hemodialysis removes approximately 30–40% of a dose of piperacillin/tazobactam (see Special Populations under Pharmacokinetics); supplemental dose of the drug needed after each hemodialysis session.¹

Supplemental doses of piperacillin/tazobactam not needed in CAPD patients.¹

Geriatric Patients

Select dosage with caution, usually starting at low end of dosage range, because of age-related decreases in hepatic, renal, and/or cardiac function.¹ (see Geriatric Use under Cautions.)

Cautions for Piperacillin/Tazobactam

Contraindications

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

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity Reactions

Serious and occasionally fatal hypersensitivity reactions, including anaphylaxis and anaphylactoid reactions, reported with piperacillin/tazobactam.¹ Such reactions more likely to occur in those with history of penicillin, cephalosporin, or carbapenem hypersensitivity or history of sensitivity to multiple allergens.¹

Prior to initiation of piperacillin/tazobactam, make careful inquiry regarding previous hypersensitivity reactions to the drug, other β-lactams (including cephalosporins), or other allergens.¹

If a severe hypersensitivity reaction occurs, discontinue immediately and institute appropriate therapy as indicated.¹

Dermatologic Effects

Rash (maculopapular, bullous, urticarial)^{1 12 21} and pruritus^{1 12 21} reported.

Postmarketing reports of severe cutaneous adverse effects, including Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis, and exfoliative dermatitis.¹

If rash develops, monitor closely;¹ discontinue piperacillin/tazobactam if lesions progress.¹

Hematologic Effects

Decreased hemoglobin and hematocrit,¹ anemia,¹ thrombocytopenia,¹ increased platelet count,¹ transient eosinophilia,¹ transient leukopenia,¹ and neutropenia reported in patients receiving piperacillin/tazobactam.¹ In most reported cases, leukopenia and neutropenia occurred after prolonged therapy (e.g., ≥21 days) and generally were reversible;¹ systemic symptoms (e.g., fever, rigors, chills) also occurred in some patients.¹ Postmarketing reports of hemolytic anemia, agranulocytosis, and pancytopenia.¹

Positive direct antiglobulin (Coombs’) test results, prolonged PT, and prolonged PTT reported.^{1 12}

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

Periodically evaluate hematologic function in patients receiving piperacillin/tazobactam, especially in those receiving prolonged treatment (i.e., ≥21 days).¹

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

Nervous System Effects

Headache¹ and insomnia¹ reported in patients receiving piperacillin/tazobactam. Postmarketing reports of delirium.¹

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

Nephrotoxicity

Increased S_cr and BUN reported in patients receiving piperacillin/tazobactam.^{1 12} Rare reports of renal failure;¹ postmarketing reports of interstitial nephritis.¹

When used in critically ill patients, piperacillin/tazobactam found to be an independent risk factor for renal failure and has been associated with delayed recovery of renal function compared with other β-lactam anti-infectives.¹ In addition, concomitant use of vancomycin and piperacillin/tazobactam in critically ill patients has been associated with increased risk of acute kidney injury.^{1 50 51} (See Specific Drugs and Laboratory Tests under Interactions.)

Consider alternatives to piperacillin/tazobactam in critically ill patients;¹ if alternatives inadequate or unavailable, monitor renal function during piperacillin/tazobactam treatment.¹

Electrolyte Effects

Changes in serum electrolytes, including increased and decreased serum sodium, potassium, and calcium concentrations, reported in patients receiving piperacillin/tazobactam.¹

Periodically determine electrolyte concentrations when piperacillin/tazobactam used in patients with low potassium reserves;¹ consider possibility of hypokalemia in those with potentially low potassium reserves who are receiving cytotoxic therapy or diuretics.¹

Consider sodium content of piperacillin/tazobactam when used in geriatric patients or patients requiring restricted salt intake.¹ (See Geriatric Use under Cautions.) Piperacillin/tazobactam (Zosyn) contains 2.84 mEq (65 mg) of sodium per gram of piperacillin.¹ Most generic preparations of piperacillin/tazobactam contain 2.35 mEq (54 mg) of sodium per gram of piperacillin;^{36 37 45} some contain 2.43 mEq (56 mg) of sodium per gram of piperacillin.^{35 38}

C. difficile-associated Diarrhea and Colitis (CDAD)

Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridioides difficile (formerly known as Clostridium difficile).^{1 302 303 304} C. difficile infection and C. difficile-associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) reported with nearly all anti-infectives, including piperacillin/tazobactam, and may range in severity from mild diarrhea to fatal colitis.^{1 302 303 304} C. difficile produces toxins A and B, which contribute to development of CDAD;^{1 302} hypertoxin-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

Consider CDAD if diarrhea develops during or after therapy and manage accordingly.^{1 302 303 304} Obtain careful medical history since CDAD may occur as late as ≥2 months after anti-infective therapy discontinued.¹

If CDAD suspected or confirmed, discontinue anti-infectives not directed against C. difficile as soon as possible.³⁰² Initiate appropriate anti-infective therapy directed against C. difficile (e.g., vancomycin, fidaxomicin, metronidazole), supportive therapy (e.g., fluid and electrolyte management, protein supplementation), and surgical evaluation as clinically indicated.^{1 302 303 304}

Selection and Use of Anti-infectives

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

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

Information on test methods and quality control standards for in vitro susceptibility testing of antibacterial agents and specific interpretive criteria for such testing recognized by FDA is available at [Web].¹

Specific Populations

Pregnancy

Available human data regarding use of piperacillin/tazobactam during pregnancy inadequate to inform a drug-associated risk for major birth defects and miscarriage.¹

Piperacillin and tazobactam both cross the placenta.¹

Lactation

Piperacillin distributed into milk;¹ not known whether tazobactam distributed into milk.¹ Effects of the drugs on breast-fed infants or milk production unknown.¹

Consider developmental and health benefits of breast-feeding along with mother’s clinical need for piperacillin/tazobactam and potential adverse effects on the breast-fed infant from the drug or the underlying maternal condition.¹

Pediatric Use

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

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

Adverse effects reported in pediatric patients with severe intra-abdominal infections (including appendicitis and/or peritonitis) are similar to those reported in adults.¹

Geriatric Use

Geriatric patients >65 years of age are not at increased risk of developing adverse effects to piperacillin/tazobactam based solely on age.¹

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

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

Consider sodium content of piperacillin/sodium when used in geriatric patients.¹ Geriatric patients may respond to salt loading with blunted natriuresis;¹ this may be clinically important patients with diseases such as heart failure.¹

Piperacillin/tazobactam (Zosyn) contains 65 mg (2.84 mEq) of sodium per gram of piperacillin;¹ patients receive 780–1040 mg (34.1–45.5 mEq) of sodium daily with usually recommended dosages of this preparation.¹ Sodium content of commercially available generic preparations of piperacillin/tazobactam varies depending on manufacturer.^{35 36 37 38 45} (See Electrolyte Effects under Cautions.)

Hepatic Impairment

Serum half-lives of piperacillin and tazobactam are prolonged in patients with hepatic cirrhosis;^{1 3} not considered clinically important.^{1 3 12} Dosage adjustments not required.^{1 3 12}

Renal Impairment

Adjust dosage in adults with Cl_cr ≤40 mL/minute, including those undergoing hemodialysis or CAPD.¹ Dosage recommendations not available for pediatric patients with impaired renal function.¹ (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

GI effects (diarrhea, nausea, constipation), headache, insomnia, dermatologic effects.¹

Interactions for Piperacillin/Tazobactam

Specific Drugs and Laboratory Tests

Piperacillin/Tazobactam Pharmacokinetics

Absorption

Bioavailability

Following IV infusion of piperacillin/tazobactam, peak plasma concentrations of piperacillin and tazobactam attained immediately or 1–2 hours after completion of the infusion.^{1 43}

Piperacillin plasma concentrations following IV infusion of piperacillin/tazobactam over 30 minutes are similar to those attained with equivalent doses of piperacillin administered alone.¹

Distribution

Extent

Both piperacillin and tazobactam widely distributed into tissues and body fluids, including intestinal mucosa,¹ gallbladder,¹ female reproductive tissues (uterus, ovary, fallopian tube),¹ lung,^{1 43} skin,⁴³ bone,⁴³ interstitial fluid,¹ synovial fluid,⁴³ and bile.¹

Only low concentrations of piperacillin and tazobactam distributed into CSF in patients with uninflamed meninges.^{1 43}

Both piperacillin and tazobactam cross the placenta.¹

Piperacillin distributed into milk;¹ not known whether tazobactam distributed into milk.¹

Plasma Protein Binding

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

Elimination

Metabolism

Piperacillin metabolized to a minor microbiologically active desethyl metabolite^{1 43} and an inactive metabolite.⁴³

Tazobactam metabolized to a single metabolite that lacks pharmacologic and antibacterial activity.^{1 43}

Elimination Route

Piperacillin, tazobactam, and their metabolites eliminated principally in urine by glomerular filtration and active tubular secretion;^{1 43} also excreted in bile.¹

Following IV infusion, 68% of piperacillin dose and 80% of tazobactam dose eliminated unchanged in urine.¹

Half-life

Plasma half-lives of piperacillin and tazobactam range from 0.7–1.2 hours in healthy adults.¹

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

Patients with renal impairment: Half-lives of piperacillin and tazobactam increase with decreasing Cl_cr.¹ In those with Cl_cr <20 mL/minute, half-life of piperacillin is twofold higher and half-life of tazobactam is fourfold higher compared with patients with normal renal function.¹

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

Geriatric adults 65–80 years of age: Mean half-lives of piperacillin and tazobactam increased by 32 and 55%, respectively, compared with adults 18–35 years of age;¹ possibly the result of age-related changes in Cl_cr.¹

Hemodialysis patients: Approximately 31 and 39% of piperacillin and tazobactam doses, respectively, removed by hemodialysis;¹ an additional 5% of tazobactam dose removed as the tazobactam metabolite.¹

Peritoneal dialysis patients: Approximately 6 and 21% of piperacillin and tazobactam doses, respectively, removed;¹ up to 16% of tazobactam dose removed as the tazobactam metabolite.¹

Stability

Storage

Parenteral

Powder for IV Infusion

Single-dose vials (Zosyn, generic): 20–25°C.^{1 35 37 38} Following reconstitution, use immediately;^{1 37 38} discard any unused portions after 24 hours if stored at 20–25°C or after 48 hours if refrigerated at 2–8°C.^{1 35 37 38}

Single-dose ADD-Vantage vials (generic): 20–25°C.⁴⁵ Reconstituted solutions prepared using 0.9% sodium chloride or 5% dextrose as directed by manufacturer are stable for 24 hours at room temperature;⁴⁵ do not refrigerate or freeze.⁴⁵

Bulk vials or bottles (Zosyn or generic): 20–25°C.^{1 36} Following reconstitution, use promptly;^{1 36} discard any unused portions after 24 hours if stored at 20–25°C or after 48 hours if refrigerated at 2–8°C.^{1 36} Do not freeze.^{1 36}

Injection (Frozen) for IV Infusion

−20° C or lower.¹ Thawed solutions are stable for 24 hours at room temperature (20–25°C) or 14 days at 2–8°C.¹

Do not refreeze after thawing.¹

Compatibility

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

Solution Compatibility

Sterile water for injection: If used for dilution, maximum recommended volume is 50 mL.^{1 35 36 37 38}

Lactated Ringer’s injection: Compatible only with piperacillin/tazobactam formulated with EDTA (i.e., Zosyn) for coadministration at Y-site;¹ incompatible with generic piperacillin/tazobactam preparations that do not contain EDTA.^{1 35 36 37 38}

Chemically unstable in solutions containing only sodium bicarbonate and solutions that alter pH.^{1 35 36 37 38 45}

Drug Compatibility

Actions and Spectrum

• Piperacillin/tazobactam is a fixed combination of piperacillin (an extended-spectrum penicillin) and tazobactam (a β-lactamase inhibitor).^{1 3 5 6 7 9 12 35 36 37 38 43 45 46}

• Piperacillin/tazobactam (Zosyn) and generic preparations of piperacillin/tazobactam commercially available in US are not identical.^{1 35 36 37 38 45} Zosyn is formulated with EDTA and sodium citrate;^{1 44 44} generic preparations do not contain EDTA and sodium citrate.^{35 36 37 38} (See IV Infusion under Dosage and Administration.)

• Like other penicillins, antibacterial activity of piperacillin results from inhibition of bacterial septum formation and cell wall synthesis in susceptible bacteria and is mediated by penicillin-binding proteins (PBPs).^{1 43 46}

• Tazobactam is a penicillanic acid sulfone β-lactamase inhibitor structurally similar to sulbactam.^{1 3 5 6 9 12 28 46 60} Because tazobactam inactivates certain β-lactamases, concomitant use with piperacillin expands piperacillin’s spectrum of activity against many β-lactamase-producing bacteria.^{1 2 4 5 6 7 8 10 12 28 43 46 60}

• Piperacillin/tazobactam usually is bactericidal in action.^{1 28 43}

• Spectrum of activity of piperacillin/tazobactam includes many gram-positive and -negative aerobes and some anaerobes.^{1 2 4 5 6 9 10 11 15 18 19 20 21 22 43} Inactive against Mycoplasma and Chlamydia.⁴³

• Gram-positive aerobes: Active in vitro and in clinical infections against S. aureus (methicillin-susceptible strains only).^{1 43} Also active in vitro against S. epidermidis (methicillin-susceptible strains only),^{1 43} Streptococcus pyogenes (group A β-hemolytic streptococci; GAS),^{1 43} S. agalactiae (group B streptococci; GBS),^{1 43} S. pneumoniae (penicillin-susceptible strains only),^{1 43} viridans streptococci,^{1 43} and Enterococcus faecalis (ampicillin- or penicillin-susceptible strains only).^{1 43} Not active against MRSA or methicillin-resistant S. epidermidis.⁴³

• Gram-negative aerobes: Active in vitro and in clinical infections against A. baumannii,¹ E. coli,^{1 43} H. influenzae (except β-lactamase-negative, ampicillin-resistant strains; BLNAR),^{1 43} K. pneumoniae,^{1 43} and Ps. aeruginosa.^{1 43} Also active in vitro against Citrobacter koseri,^{1 43} Enterobacter,⁴³ Moraxella catarrhalis,^{1 43} Morganella morganii,^{1 43} Neisseria,¹ Proteus mirabilis,^{1 43} P. vulgaris,^{1 43} Providencia stuartii,¹ P. rettgeri,¹ Salmonella,^{1 43} Shigella,⁴³ and Serratia marcescens.^{1 43}

• Anaerobes: Active in vitro and in clinical infections against B. fragilis,^{1 43} B. ovatus,^{1 43} B. thetaiotaomicron,^{1 43} and B. vulgatus.^{1 43} Also active in vitro against Bacillus,⁴³ B. distasonis,^{1 43} Clostridium perfringens,^{1 43} Cutibacterium acnes (formerly Propionibacterium acnes),⁴³ Fusobacterium,⁴³ Peptostreptococcus,⁴³ and Prevotella melaninogenica.^{1 43}

• Resistance or reduced susceptibility to piperacillin/tazobactam can occur.^{43 60}

Advice to Patients

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

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

• 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/tazobactam or other antibacterials in the future.¹

• Advise patients that serious hypersensitivity reactions, including serious allergic cutaneous reactions, that require immediate treatment could occur.¹

• Importance of informing clinicians of prior hypersensitivity reactions to piperacillin/tazobactam, other β-lactams (including cephalosporins), or other allergens.¹ Importance of discontinuing the drug and informing clinician if an allergic reaction occurs.¹

• Advise patients that diarrhea is a common problem caused by anti-infectives and usually ends when the drug is discontinued.¹ 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 after the last dose.¹

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.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.¹ (See Cautions.)

Preparations

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

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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