ATC Class:J01CA12

VA Class:AM113

AHFS Class:

• Extended-spectrum Penicillins 8:12.16.16

Generic Name(s):

• Piperacillin Sodium and Tazobactam Sodium

• Piperacillin Sodium

• Tazobactam Sodium

Chemical Name:

• [2 S -[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

• [2 S -(2α,3β,5α)]-4,4-Dioxide-3-methyl-7-oxo-3-(1 H -1,2,3-triazol-1-ylmethyl)-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid sodium salt

Molecular Formula:

• C₂₃H₂₇N₅O₇S•Na

• C₁₀H₁₁N₄NaO₅S

Piperacillin sodium and tazobactam sodium (piperacillin/tazobactam) is a fixed combination of the sodium salts of piperacillin (an extended-spectrum penicillin antibiotic) and tazobactam (a β-lactamase inhibitor);1,3,5,6,12,35,36,37,38,43,45,46 tazobactam inactivates certain bacterial β-lactamases and expands piperacillin's spectrum of activity against some bacteria that produce these β-lactamases.1,2,4,5,6,8,10,11,12,28,43,46,60

The fixed combination of piperacillin sodium and tazobactam sodium (piperacillin/tazobactam) is used for the treatment of moderate to severe infections caused by susceptible β-lactamase-producing bacteria and certain other gram-negative or anaerobic bacteria.1,12,13,14,15,16,21,43,46,197,375 Piperacillin/tazobactam is used principally for the treatment of infections caused by susceptible gram-negative bacteria and for empiric treatment of polymicrobial infections such as mixed aerobic-anaerobic infections.12,21,43,46,197,315,375,512,543,708

When piperacillin/tazobactam is used for the treatment of infections known or suspected of being caused by Pseudomonas aeruginosa , the drug usually is used in conjunction with another anti-infective with antipseudomonal activity (e.g., antipseudomonal fluoroquinolone, aminoglycoside).1,43,46,197,315,512

Gynecologic and Obstetric Infections

Piperacillin/tazobactam is used for the treatment of postpartum endometritis or pelvic inflammatory disease (PID) caused by susceptible β-lactamase-producing Escherichia coli .1,21

Piperacillin/tazobactam is not included in US Centers for Disease Control and Prevention (CDC) recommendations for the treatment of PID.344 If a penicillin is used for empiric treatment of PID, CDC and other clinicians recommend a parenteral regimen that includes the fixed combination of ampicillin sodium and sulbactam sodium (ampicillin/sulbactam) in conjunction with doxycycline.344,345

Intra-abdominal Infections

Piperacillin/tazobactam is used for the 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

Piperacillin/tazobactam has been used for the treatment of various intra-abdominal infections,43,708 and has been 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

Community-acquired Pneumonia

Piperacillin/tazobactam is used for the treatment of moderately severe community-acquired pneumonia (CAP) caused by susceptible β-lactamase-producing Haemophilus influenzae .1 The drug also is used for the treatment of CAP caused by susceptible Enterobacteriaceae† or anaerobic bacteria†.512

Piperacillin/tazobactam has been recommended as one of several options for empiric treatment of CAP in hospitalized patients requiring treatment in an intensive care unit (ICU).512 If Ps. aeruginosa is known or suspected to be involved, the Infectious Diseases Society of America (IDSA) and American Thoracic Society (ATS) state that piperacillin/tazobactam should be used 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 the risk of Ps. aeruginosa infection in CAP patients include severe CAP requiring treatment in an ICU, structural lung disease (e.g., bronchiectasis), repeated exacerbations of severe chronic obstructive pulmonary disease (COPD), alcoholism, chronic corticosteroid therapy, and frequent anti-infective therapy.512

Nosocomial Pneumonia

Piperacillin/tazobactam is used for the 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 .1,43,197 If Ps. aeruginosa is involved, piperacillin/tazobactam should be used in conjunction with an aminoglycoside or a fluoroquinolone with antipseudomonal activity (e.g., ciprofloxacin, levofloxacin).1,315,197

IDSA and ATS state that piperacillin/tazobactam is one of several options for initial empiric treatment of hospital-acquired pneumonia (HAP) not associated with mechanical ventilation and initial empiric treatment of ventilator-associated bacterial pneumonia (VAP).315

In adults with HAP (not associated with mechanical ventilation) who are not at high risk of mortality, IDSA and ATS state that use of piperacillin/tazobactam alone (monotherapy) can be considered for initial empiric treatment if no factors are present that increase the likelihood of methicillin-resistant S. aureus (MRSA; also known as oxacillin-resistant S. aureus or ORSA); however, these experts state that piperacillin/tazobactam should be used in conjunction with an antibacterial active against MRSA (vancomycin, linezolid) if such factors are present or if the patient is at high risk of mortality or has received IV anti-infectives during the prior 90 days.315

In adults with clinically suspected VAP, IDSA and ATS state that use of piperacillin/tazobactam alone (monotherapy) can be considered for initial empiric treatment in those not at increased risk for MRSA.315 However, in patients with factors that increase the risk of MRSA or multidrug-resistant gram-negative bacteria, these experts state that piperacillin/tazobactam should be used in conjunction with an anti-infective active against MRSA (vancomycin, linezolid) plus an antipseudomonal fluoroquinolone (ciprofloxacin, levofloxacin), aminoglycoside (amikacin, gentamicin, tobramycin), or polymyxin B.315

Septicemia

Piperacillin/tazobactam has been used for the treatment of septicemia†.39,40,41,43,197 The drug has been recommended as one of several options for initial empiric treatment of sepsis and bacteremia.39,42,43,197

Skin and Skin Structure Infections

Piperacillin/tazobactam is used for the treatment of uncomplicated and complicated skin and skin structure infections (including cellulitis, cutaneous abscesses, ischemic/diabetic foot infections) caused by susceptible β-lactamase-producing S. aureus .1,12,15,43,197,543 Piperacillin/tazobactam has been recommended as a possible option for empiric monotherapy of complicated skin and skin structure infections that could be polymicrobial and are unlikely to involve MRSA;197 the drug should not be used alone in infections that may be caused by MRSA.197

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

Piperacillin/tazobactam used in conjunction with vancomycin is considered one of several possible regimens for empiric treatment of severe cellulitis or treatment of clostridial myonecrosis† (gas gangrene).543

Piperacillin/tazobactam used in conjunction with vancomycin or linezolid also is one of several possible regimens for empiric treatment of necrotizing fasciitis†.543

Urinary Tract Infections

Piperacillin/tazobactam has been used with or without an aminoglycoside for the treatment of urinary tract infections† in hospitalized patients.43,197

Empiric Therapy in Febrile Neutropenic Patients

Piperacillin/tazobactam has been used alone (monotherapy) or in conjunction with other anti-infectives (e.g., an aminoglycoside) for empiric anti-infective therapy in febrile neutropenic patients†.43,197,359,787

Piperacillin/tazobactam has been recommended as one of several options for initial outpatient management of febrile neutropenia in adults receiving treatment for malignancy.787

Perioperative Prophylaxis

Piperacillin/tazobactam 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 However, piperacillin/tazobactam generally is not recommended for perioperative prophylaxis.43,360

The fixed combination of piperacillin sodium and tazobactam sodium (piperacillin/tazobactam) is administered by IV infusion.1,35,36,37,38

Piperacillin/tazobactam usually is administered by intermittent IV infusion,1,25,35,36,37,38,43 but also has been administered by continuous IV infusion†.25,43,49,56,58

The drug should not be given by rapid IV injection.25

IV Infusion

Piperacillin/tazobactam should not be admixed with other drugs in a syringe or infusion bottle and should not be added to blood products or albumin hydrolysates.1,35,36,37,38,45

If concomitant use of an aminoglycoside is indicated (e.g., treatment of nosocomial pneumonia), the drugs should be reconstituted, diluted, and administered separately.1,35,36,37,38,45 (See Concomitant Use with Aminoglycosides under Administration: IV Infusion, in Dosage and Administration.)

Piperacillin/tazobactam (Zosyn^®) and generic preparations of piperacillin/tazobactam commercially available in the US are not identical.1,35,36,37,38,45 Piperacillin/tazobactam (Zosyn^®) is formulated with edetate disodium dihydrate (EDTA) and sodium citrate;1 the generic preparations do not contain EDTA or sodium citrate.35,36,37,38,45 Because EDTA acts as a metal-chelating agent and sodium citrate acts as a buffer, certain aspects of chemical degradation and particulate formation are inhibited and there is a lower risk of particulate matter formation and accumulation following reconstitution of Zosyn^® with commonly used diluents or storage of solutions of the drug.44 In addition, the presence of EDTA and sodium citrate allows coadministration of Zosyn^® and lactated Ringer's injection via Y-site infusion.1,44

Reconstitution and Dilution

Single-dose vials of piperacillin/tazobactam (Zosyn^®, generic) labeled as 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) should be reconstituted with 10, 15, or 20 mL, respectively, of compatible diluent and swirled until the contents are dissolved.1,35,37,38 Diluents that can be used for reconstitution include 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 Reconstituted solutions prepared from single-dose vials of piperacillin/tazobactam should be further diluted and any unused reconstituted solution should be discarded after 24 hours if stored at room temperature (20-25°C) or after 48 hours if refrigerated at 2-8°C.1 Prior to IV infusion, reconstituted piperacillin/tazobactam solutions should be diluted to the desired volume (usually 50-150 mL) with a compatible diluent (0.9% sodium chloride injection, sterile water for injection [maximum recommended volume is 50 mL], 5% dextrose injection, or 6% dextran in sodium chloride injection).1,37,38 Lactated Ringer's injection is compatible only with piperacillin/sodium solutions prepared using piperacillin/tazobactam formulated with EDTA (i.e., Zosyn^®) for coadministration via Y-site infusion;1,44 lactated Ringer's injection is incompatible with and cannot be used with generic piperacillin/tazobactam preparations that do not contain EDTA.1,35,37,38,45

Single-dose ADD-Vantage^® vials of piperacillin/tazobactam (generic) should be reconstituted and diluted according to the manufacturer's labeling.45 When reconstituted as directed in 0.9% sodium chloride injection or 5% dextrose injection, piperacillin/tazobactam solutions prepared from ADD-Vantage^® vials are stable for 24 hours at room temperature;45 these reconstituted solutions should not be refrigerated or frozen.45

Pharmacy bulk vials or bottles of piperacillin/tazobactam (Zosyn^®, generic) containing 40.5 g (36 g of piperacillin and 4.5 g of tazobactam) should be reconstituted by adding 152 mL of a compatible IV solution to the vial to provide a solution containing 200 mg/mL of piperacillin and 25 mg/mL of tazobactam.1,36 Pharmacy bulk vials or bottles of the drug are not intended for direct IV infusion;1,36 prior to administration, solutions reconstituted in the pharmacy bulk package must be further diluted with a compatible IV solution.1,36

The commercially available single-dose frozen premixed injections of piperacillin/tazobactam in dextrose (Zosyn^® in Galaxy^® containers) should be thawed at room temperature (20-25°C) or under refrigeration (2-8°C);1 frozen injections should not be thawed by immersion in water baths or by microwave irradiation.1 Precipitates that may have formed in the frozen injection usually will dissolve with little or no agitation when the injection reaches room temperature;1 potency is not affected.1 After thawing at room temperature, the injection should be agitated and the container checked for minute leaks by firmly squeezing the bag.1 The injection should be discarded if container seals or outlet ports are not intact or leaks are found or if the solution is cloudy or contains an insoluble precipitate.1 The injection 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.1 Once thawed, the solutions are stable for 24 hours at a room temperature of 20-25°C or 14 days when refrigerated at 2-8°C and should not be refrozen.1

Rate of Administration

IV infusions of piperacillin/tazobactam usually are given over 30 minutes.1,25,35,36,37,38,43

Piperacillin/tazobactam 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 that 4-hour intermittent IV infusions or continuous IV infusion of piperacillin/tazobactam may be beneficial in certain clinical situations (e.g., critically ill patients, pathogen with high piperacillin/tazobactam minimum inhibitory concentration [MIC]);25,43,52,53,54,58 there is some evidence that lengthening the duration of piperacillin/tazobactam infusions may maximize the 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 the drugs should be reconstituted, diluted, and administered separately if concomitant use is 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 is considered necessary, this can be accomplished using 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, tobramycin or any aminoglycoside other than amikacin or gentamicin should not be used.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

Dosage

Piperacillin/tazobactam is a fixed combination of piperacillin sodium and tazobactam sodium;1,35,36,37,38,45 potency of each component is expressed in terms of the base.1,35,36,37,38,45 The commercially available fixed combination contains an 8:1 ratio of piperacillin to tazobactam.1,35,36,37,38,45

Dosage of piperacillin/tazobactam usually is 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 of piperacillin/tazobactam for pediatric patients often is expressed in terms of the piperacillin component.24,25,292,543,708

Pediatric Dosage

General Neonatal Dosage

The American Academy of Pediatrics (AAP) recommends that dosage of IV piperacillin/tazobactam in neonates 28 days of age or younger† should be based on postmenstrual age (i.e., gestational age plus chronologic age).292 AAP recommends that neonates with postmenstrual age of 30 weeks or less receive IV piperacillin/tazobactam in a dosage of 100 mg/kg (of piperacillin) every 8 hours and that those with postmenstrual age greater than 30 weeks receive a dosage of 80 mg/kg (of piperacillin) every 6 hours.292

In neonates weighing less than 1 kg†, some clinicians recommend that those 14 days of age or younger receive IV piperacillin/tazobactam in a dosage of 100 mg/kg (of piperacillin) every 12 hours and that those 15-28 days of age receive 100 mg/kg (of piperacillin) every 8 hours.24 These clinicians recommend that neonates weighing 1 kg or greater† receive a dosage of 100 mg/kg (of piperacillin) every 12 hours if they are 7 days of age or younger or 100 mg/kg (of piperacillin) every 8 hours if they are 8-28 days of age.24

For the treatment of severe infections in neonates and infants younger than 2 months of age†, some clinicians suggest that IV piperacillin/tazobactam be given in a dosage of 80 mg/kg (of piperacillin) every 6 hours and others recommend a dosage of 80 mg/kg (of piperacillin) every 4 hours.24 Some clinicians suggest that shortening the dosing interval to every 6 hours and prolonging the duration of the IV infusion to 4 hours will maximize the pharmacokinetic/pharmacodynamic properties of the drug.24

General Pediatric Dosage

AAP states that the usual dosage of IV piperacillin/tazobactam in pediatric patients beyond the neonatal period is 240-300 mg/kg (of piperacillin) daily in 3 or 4 divided doses.292 These experts state that a dosage of 400-600 mg/kg (of piperacillin) daily in 6 divided doses may be appropriate in some cystic fibrosis patients.292

For the treatment of severe infections, some clinicians suggest that pediatric patients 2-9 months of age receive IV piperacillin/tazobactam in a dosage of 80 mg/kg (of piperacillin) every 6-8 hours and that those older than 9 months of age receive a dosage of 100 mg/kg (of piperacillin) every 6-8 hours.24

AAP and some other clinicians state that the maximum recommended dosage of IV piperacillin/tazobactam in most pediatric patients is 16 g (of piperacillin) daily;24,292 however, AAP states that a maximum dosage of 24 g (of piperacillin) daily may be appropriate in some cystic fibrosis patients.292

Intra-abdominal Infections

For the treatment of appendicitis and/or peritonitis in pediatric patients 2-9 months of age, the manufacturer recommends that IV piperacillin/tazobactam be given in a dosage of 80 mg/kg (of piperacillin) and 10 mg/kg (of tazobactam) every 8 hours.1

For the treatment of appendicitis and/or peritonitis in pediatric patients 9 months of age or older weighing 40 kg or less with normal renal function, the manufacturer recommends that IV piperacillin/tazobactam be given in a dosage of 100 mg/kg (of piperacillin) and 12.5 mg/kg (of tazobactam) every 8 hours.1 The manufacturer states that pediatric patients with normal renal function weighing more than 40 kg should receive the usual adult dosage of piperacillin/tazobactam.1

For the treatment of complicated intra-abdominal infections in pediatric patients, some clinicians recommend that IV piperacillin/tazobactam be given in a dosage of 200-300 mg/kg (of piperacillin) daily in divided doses every 6-8 hours.708

Some clinicians state that the usual duration of treatment for intra-abdominal infections is 4-7 days, unless it is difficult to achieve adequate source control.708 These clinicians state that longer treatment durations have not been associated with improved outcomes.708

Skin and Skin Structure Infections

If IV piperacillin/tazobactam is used for the treatment of necrotizing infections of the skin, fascia, and muscle†, some clinicians recommend that pediatric patients receive a dosage of 60-75 mg/kg (of piperacillin) every 6 hours in conjunction with vancomycin.543

Adult Dosage

General Adult Dosage

The manufacturer states that the usual dosage of IV piperacillin/tazobactam for adults is 3.375 g (3 g of piperacillin and 0.375 g of tazobactam) every 6 hours for 7-10 days.1

The maximum dosage of IV piperacillin/tazobactam recommended in adults usually is 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 The manufacturer recommends a maximum dosage of 18 g (16 g of piperacillin and 2 g of tazobactam) daily.1

Gynecologic and Obstetric Infections

For the treatment of postpartum endometritis or pelvic inflammatory disease (PID), the manufacturer states that the usual dosage of IV piperacillin/tazobactam in adults is 3.375 g (3 g of piperacillin and 0.375 g of tazobactam) every 6 hours for 7-10 days.1

Intra-abdominal Infections

For the treatment of appendicitis and/or peritonitis, the manufacturer states that the usual dosage of IV piperacillin/tazobactam in adults is 3.375 g (3 g of piperacillin and 0.375 g of tazobactam) every 6 hours for 7-10 days.1

For the treatment of complicated intra-abdominal infections in adults, some clinicians recommend that IV piperacillin/tazobactam be given in a dosage of 3.375 g (3 g of piperacillin and 0.375 g of tazobactam) every 6 hours; however, if Pseudomonas aeruginosa is identified, these clinicians state that dosage of the drug may be increased to 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 that the usual duration of treatment for intra-abdominal infections is 4-7 days, unless it is difficult to achieve adequate source control.708 These clinicians state that longer treatment durations have not been associated with improved outcomes.708

Community-acquired Pneumonia

For the treatment of moderately severe community-acquired pneumonia (CAP), the manufacturer states that the usual dosage of IV piperacillin/tazobactam in adults is 3.375 g (3 g of piperacillin and 0.375 g of tazobactam) every 6 hours for 7-10 days.1

Nosocomial Pneumonia

For initial empiric treatment of nosocomial pneumonia in adults, the manufacturer recommends that IV piperacillin/tazobactam be given in a dosage of 4.5 g (4 g of piperacillin and 0.5 g of tazobactam) every 6 hours in conjunction with an aminoglycoside.1 The manufacturer states that the recommended duration of piperacillin/tazobactam therapy for the treatment of nosocomial pneumonia is 7-14 days;1 if Ps. aeruginosa is identified, the aminoglycoside should be continued concomitantly for the full duration of piperacillin/tazobactam treatment.1

When IV piperacillin/tazobactam is used with or without other anti-infectives for initial empiric treatment of hospital-acquired pneumonia (HAP) not associated with mechanical ventilation or initial empiric treatment of ventilator-associated pneumonia (VAP), some clinicians recommend that adults receive a dosage of 4.5 g (4 g of piperacillin and 0.5 g of tazobactam) every 6 hours.315 These experts recommend a treatment duration of 7 days; however, depending on clinical response, a longer or shorter duration may be indicated.315

Skin and Skin Structure Infections

For the treatment of skin and skin structure infections in adults, the manufacturer states that the usual dosage of IV piperacillin/tazobactam is 3.375 g (3 g of piperacillin and 0.375 g of tazobactam) every 6 hours for 7-10 days.1

For the treatment of incisional surgical site infections†, some clinicians recommended that adults receive IV piperacillin/tazobactam in a dosage of 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

If IV piperacillin/tazobactam is used for the treatment of infected human or animal bite wounds†, a dosage of 3.375 g (3 g of piperacillin and 0.375 g of tazobactam) every 6-8 hours has been recommended.543

If IV piperacillin/tazobactam is used for the treatment of necrotizing infections of the skin, fascia, and muscle†, some clinicians recommend that adults receive a dosage of 3.375 g (3 g of piperacillin and 0.375 g of tazobactam) every 6-8 hours in conjunction with vancomycin.543

Dosage in Renal and Hepatic Impairment

Renal Impairment

Because serum concentrations of piperacillin and tazobactam are higher and prolonged in patients with renal impairment than in patients with normal renal function, doses and/or frequency of administration of piperacillin/tazobactam should be decreased in patients with renal impairment.1,3,7,12,43

In adults with creatinine clearances of 40 mL/minute or less, including patients undergoing hemodialysis or continuous ambulatory peritoneal dialysis (CAPD), dosage of piperacillin/tazobactam should be decreased based on the degree of renal impairment.1,7,12,43 (See Table 3.)

The manufacturer makes no dosage recommendations for pediatric patients with impaired renal function.1

Hepatic Impairment

Although serum half-lives of piperacillin and tazobactam are prolonged in patients with hepatic cirrhosis compared with healthy patients,1,3,43 this effect is not clinically important and does not necessitate a change in dosage of piperacillin/tazobactam when the drug is used in patients with hepatic cirrhosis.1,3,12,43

Adverse effects reported with the fixed combination of piperacillin sodium and tazobactam sodium (piperacillin/tazobactam) are similar to those reported with piperacillin alone12,43 and generally are transient and mild to moderate in severity.1,12 Adverse effects have been severe enough to require discontinuance of piperacillin/tazobactam in 3% or less of patients receiving the drug.1,12,13 The most frequent adverse effects (reported in more than 5% of patients receiving piperacillin/tazobactam) include GI effects (diarrhea, nausea, constipation),1,12,13,14,15,16,21 headache,1 and insomnia.1

GI Effects

Diarrhea,1,12,13,14,15,21 nausea,1,12,14,21 and constipation1 have been reported in up to 11% of patients receiving IV piperacillin/tazobactam.1 Vomiting,1 dyspepsia,1 and abdominal pain1 have been reported in up to 3%.1

C. difficile-associated Diarrhea and Colitis

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 (CDI) and C. difficile -associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) have been reported with nearly all anti-infectives, including piperacillin/tazobactam, and may range in severity from mild diarrhea to fatal colitis.1,302,303,304C. difficile produces toxins A and B, which contribute to the development of CDAD; hypertoxin-producing strains cause increased morbidity and mortality since these infections may be refractory to anti-infective therapy and may require colectomy.1,302 CDAD should be considered if diarrhea develops during or after therapy and managed accordingly.1,302,303,304 (See Precautions Related to C. difficile-associated Diarrhea and Colitis under Cautions: Precautions and Contraindications.)

Dermatologic and Sensitivity Reactions

Rash (maculopapular, bullous, urticarial),1,12,21 pruritus,1,12,21 and fever1 have been reported in up to 4% of patients receiving piperacillin/tazobactam.1,12 There also have been postmarketing reports of erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis, and exfoliative dermatitis in patients receiving the drug.1 (See Precautions Related to Dermatologic and Sensitivity Reactions under Cautions: Precautions and Contraindications.)

Serious and occasionally fatal hypersensitivity reactions, including anaphylaxis or anaphylactoid reactions, have been reported in patients receiving piperacillin/tazobactam.1 Such reactions are more likely to occur in individuals with a history of penicillin, cephalosporin, or carbapenem hypersensitivity or a history of sensitivity to multiple allergens.1 (See Precautions Related to Dermatologic and Sensitivity Reactions under Cautions: Precautions and Contraindications.)

Hematologic Effects

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

Positive direct antiglobulin (Coombs') test results, prolonged prothrombin time, and prolonged partial thromboplastin time have been reported in patients receiving piperacillin/tazobactam.1,12

Epistaxis and purpura have been reported in 1% or less of patients receiving the drug.1 Manifestations of bleeding, occasionally associated with abnormal results in coagulation tests (e.g., clotting time, platelet aggregation, prothrombin time), have occurred in some patients receiving β-lactam anti-infectives, including piperacillin.1 Bleeding manifestations are more likely to occur in patients with renal failure than in patients with normal renal function.1 (See Precautions Related to Hematologic Effects under Cautions: Precautions and Contraindications.)

Nervous System Effects

Headache1 and insomnia1 have been reported in up to 8% of patients receiving piperacillin/tazobactam.1 There have been postmarketing reports of delirium in patients receiving the drug.1

As with other penicillins, neuromuscular excitability or seizures could occur if higher than recommended doses of IV piperacillin/tazobactam are given, especially in patients with renal failure.1

Renal and Electrolyte Effects

Increased concentrations of serum creatinine and BUN have been reported in patients receiving piperacillin/tazobactam.1,12 Renal failure has been reported rarely and there have been postmarketing reports of interstitial nephritis in patients receiving the drug.1

When used in critically ill patients, piperacillin/tazobactam has been found to be an independent risk factor for renal failure and was associated with delayed recovery of renal function compared with other β-lactam anti-infectives in such patients.1 In addition, concomitant use of vancomycin with piperacillin/tazobactam in critically ill patients has been associated with an increased incidence of acute kidney injury.1,50,51 (See Drug Interactions: Vancomycin.)

Changes in serum electrolytes, including increased and decreased serum sodium, potassium, and calcium concentrations, have occurred in patients receiving piperacillin/tazobactam.1 (See Precautions Related to Renal and Electrolyte Effects under Cautions: Precautions and Contraindications.)

Local Reactions

Adverse reactions at the IV infusion site, including phlebitis and thrombophlebitis, have been reported in 1% or less of patients receiving piperacillin/tazobactam.1

Hepatic Effects

Transient increases in AST, ALT, alkaline phosphatase, and bilirubin have been reported in patients receiving piperacillin/tazobactam.1,12,21 There have been postmarketing reports of hepatitis and jaundice.1

Other Adverse Effects

Candidiasis, including oral candidiasis, has been reported in 2-4% of patients receiving piperacillin/tazobactam.1 Stomatitis has been reported in 1% or less of patients receiving the drug.1

Hypotension, rigors, myalgia, arthralgia, hypoglycemia, and flushing have been reported in 1% or less of patients receiving piperacillin/tazobactam.1 There have been postmarketing reports of eosinophilic pneumonia in patients receiving the drug.1

Precautions and Contraindications

Piperacillin/tazobactam is contraindicated in patients hypersensitive to any penicillin, cephalosporin, or β-lactamase inhibitor.1

Precautions Related to Dermatologic and Sensitivity Reactions

Piperacillin/tazobactam shares the toxic potentials of the penicillins, including the risk of hypersensitivity reactions, and the usual precautions of penicillin therapy should be observed.1 (See Cautions: Hypersensitivity Reactions, in the Natural Penicillins General Statement 8:12.16.04.) Serious hypersensitivity reactions are more likely to occur in individuals with a history of penicillin, cephalosporin, or carbapenem hypersensitivity.1

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

Patients should be advised that serious hypersensitivity reactions, including serious allergic cutaneous reactions, could occur that require immediate treatment.1

If a severe hypersensitivity reaction occurs during piperacillin/tazobactam therapy, the drug should be discontinued and the patient given appropriate treatment as indicated.1

Precautions Related to Hematologic Effects

Because manifestations of bleeding have been reported with some β-lactam anti-infectives, including piperacillin, the possibility of bleeding complications should be considered in patients receiving piperacillin/tazobactam, especially when the drug is used in patients with renal impairment.1 If bleeding manifestations occur, piperacillin/tazobactam should be discontinued and appropriate therapy instituted.1

Hematologic function should be evaluated periodically during piperacillin/tazobactam therapy, especially in patients receiving prolonged therapy with the drug (i.e., 21 days or longer).1

Precautions Related to Renal and Electrolyte Effects

Renal systems should be evaluated periodically during prolonged therapy with piperacillin/tazobactam.2

Because there is evidence that piperacillin/tazobactam is an independent risk factor for renal failure and has been associated with delayed recovery of renal function compared with other β-lactam anti-infectives when used in critically ill patients,1 the manufacturer states that alternatives to piperacillin/tazobactam should be considered in such patients.1 If use of piperacillin/tazobactam is considered necessary in critically ill patients because alternative treatment options are inadequate or unavailable, renal function should be monitored during treatment with the drug.1

Serum electrolytes should be determined periodically when piperacillin/tazobactam is used in patients with low potassium reserves, and the possibility of hypokalemia should be considered when the drug is used in those with potentially low potassium reserves who are receiving cytotoxic therapy or diuretics.1

The sodium content of piperacillin/tazobactam should be considered when the drug is used in geriatric patients or patients whose sodium intake is restricted.1 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

Precautions Related to C. difficile-associated Diarrhea and Colitis

Because CDAD has been reported with the use of nearly all anti-infectives, including piperacillin/tazobactam, it should be considered in the differential diagnosis of patients who develop diarrhea during or after anti-infective therapy.1,302,303,304 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

If CDAD is suspected or confirmed, anti-infective therapy not directed against C. difficile should be discontinued as soon as possible.302 Patients should be managed with 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.1,302,303,303

Patients should be advised that diarrhea is a common problem caused by anti-infectives and usually resolves when the drug is discontinued; however, they should contact 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

Selection and Use of Anti-infectives

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

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

Patients should be advised 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 Patients also should be advised about the importance of completing the full course of therapy, even if feeling better after a few days, and that skipping doses or not completing 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

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

Pediatric Precautions

Safety and efficacy of piperacillin/tazobactam in children younger than 2 months of age have not been established.1

The manufacturer states that use of piperacillin/tazobactam for the treatment of appendicitis and/or peritonitis in pediatric patients 2 months of age or older is supported by evidence from well-controlled studies and pharmacokinetic studies in adults and pediatric patients.1

Adverse effects reported when piperacillin/tazobactam was used in pediatric patients 2-12 years of age with severe intra-abdominal infections (including appendicitis and/or peritonitis) have been similar to those reported in adults.1

Geriatric Precautions

Geriatric patients older than 65 years of age receiving piperacillin/tazobactam are not at increased risk of developing adverse effects based solely on their age.1 However, geriatric patients are more likely to have decreased renal function compared with younger adults and the risk of toxic reactions to the drug may be greater in patients with impaired renal function.1

Because of the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease and drug therapy in geriatric patients, dosage of piperacillin/tazobactam generally should be selected cautiously in these patients, usually initiating therapy at the low end of the dosage range, and it may be useful to monitor renal function.1 In geriatric patients with renal impairment, dosage should be modified in response to the degree of renal impairment.1 (See Renal Impairment under Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

When piperacillin/tazobactam is used in geriatric patients, the sodium content of the specific preparation used should be considered.1 Geriatric patients may respond to salt loading with a blunted natriuresis and this may be clinically important in 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 would receive 780-1040 mg (34.1-45.5 mEq) of sodium daily with usually recommended dosages of this preparation.1 The sodium content of commercially available generic preparations of piperacillin/tazobactam differs depending on the manufacturer.35,36,37,38,45 (See Precautions Related to Renal and Electrolyte Effects under Cautions: Precautions and Contraindications.)

Mutagenicity and Carcinogenicity

The mutagenic potential of piperacillin/tazobactam has been evaluated in vitro and in vivo.1 There was no in vitro evidence of mutagenicity when the fixed combination was used in microbial mutagenicity assays, unscheduled DNA synthesis tests, mammalian point mutation assays in Chinese hamster ovary cell HPRT, or mammalian cell (BALB/c-3T3) transformation assays.1 In addition, in vivo studies in rats using piperacillin/tazobactam indicated that the drug did not induce chromosomal aberrations.1

Long-term studies have not been performed to evaluate the carcinogenic potential of piperacillin, tazobactam, or piperacillin/tazobactam.1

Pregnancy, Fertility, and Lactation

Pregnancy

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

Reproduction studies in pregnant mice and rats using IV piperacillin/tazobactam (up to 1-2 times the human dosage of piperacillin and 2-3 times the human dosage of tazobactam based on body surface area) did not reveal evidence of teratogenicity or fetal structural abnormalities;1 however, intraperitoneal administration in rats at doses less than the maximum recommended human daily dosage based on body surface area given prior to mating and throughout gestation or from gestation day 17 through lactation day 21 resulted in maternal toxicity, reduced litter size, and effects on peri- and postnatal development (e.g., reduced pup weights, increased stillbirths, increased pup mortality, ossification delays, rib variations).1

Fertility

There was no evidence of impaired fertility in reproduction studies in rats using IV piperacillin/tazobactam in dosages similar to the maximum recommended human daily dosage based on body surface area.1

Lactation

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

The developmental and health benefits of breast-feeding should be considered along with the woman's clinical need for piperacillin/tazobactam and potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.1

Aminoglycosides

The antibacterial activities of piperacillin and aminoglycosides (e.g., amikacin, gentamicin, tobramycin) have been synergistic in vitro against some strains of Enterobacteriaceae and Pseudomonas aeruginosa .43,46

The fixed combination of piperacillin sodium and tazobactam sodium (piperacillin/tazobactam) is physically and/or chemically incompatible with aminoglycosides and can inactivate aminoglycosides in vitro if the drugs are admixed or administered using the same IV infusion line.1,35,36,37,38,45,83,236 If concomitant therapy with piperacillin/tazobactam and an aminoglycoside is indicated, the drugs should be reconstituted, diluted, and administered separately.1,35,36,37,38,45 Piperacillin/tazobactam can be coadministered with amikacin or gentamicin (but not tobramycin or other aminoglycosides) via Y-site infusion only under certain specific conditions.1,44 (See Concomitant Use with Aminoglycosides under Administration: IV Infusion, in Dosage and Administration.)

Piperacillin also can inactivate aminoglycosides in vivo.1,35,36,37,38,45,89,236,240 Decreased aminoglycoside serum concentrations and half-lives have been reported in patients receiving concomitant piperacillin therapy, usually when high piperacillin dosage was used or the patient had impaired renal function.83,89,236 Although sequential administration of piperacillin/tazobactam and tobramycin in patients with normal renal function or mild to moderate renal impairment has resulted in modestly decreased serum tobramycin concentrations, the manufacturer of piperacillin/tazobactam states that dosage adjustments are not needed.1,35,36,37,38,45

Because concomitant use of piperacillin and an aminoglycoside in patients with end-stage renal disease (ESRD) requiring hemodialysis may result in substantially decreased serum concentrations of the aminoglycoside (especially tobramycin), aminoglycoside serum concentrations should be monitored closely in patients receiving piperacillin/tazobactam and an aminoglycoside.1,35,36,37,38,45,89

Anticoagulants

Coagulation parameters should be monitored more frequently if piperacillin/tazobactam is used concomitantly with oral anticoagulants, high doses of heparin, or other drugs that affect blood coagulation or thrombocyte function.1

Methotrexate

Concomitant use of methotrexate and piperacillin may result in decreased renal clearance of methotrexate due to competition for renal secretion;1 the effect of tazobactam on methotrexate elimination has not been evaluated.1

If concurrent therapy with methotrexate and piperacillin/tazobactam is necessary, serum methotrexate concentrations should be evaluated frequently and the patient should be monitored for signs and symptoms of methotrexate toxicity.1

Neuromuscular Blocking Agents

Prolonged neuromuscular blockade has been reported when vecuronium was used concomitantly with piperacillin, and this also could occur if vecuronium is used concomitantly with piperacillin/tazobactam.1 Because other nondepolarizing muscle relaxants have similar mechanisms of action, a similar effect could occur if piperacillin/tazobactam is used concomitantly with any of these drugs.1

If piperacillin/tazobactam is used concomitantly with a neuromuscular blocking agent, the patient should be monitored for adverse effects related to neuromuscular blockade.1

Probenecid

Probenecid inhibits tubular renal secretion of both piperacillin and tazobactam and prolongs their half-lives by 21 and 71%, respectively.1

Concomitant use of probenecid and piperacillin/tazobactam is not recommended unless benefits outweigh risks.1

Vancomycin

Concomitant use of vancomycin and piperacillin/tazobactam in critically ill patients has been associated with an increased incidence of acute kidney injury compared with use of vancomycin alone.1,50,51

If vancomycin and piperacillin/tazobactam are used concomitantly, renal function should be monitored.1 In addition, because vancomycin and some piperacillin/tazobactam preparations may be physically and/or chemically incompatible,61,300 it has been recommended that the drugs should be administered separately.61

Pharmacokinetic interactions between vancomycin and piperacillin/tazobactam have not been reported.1

Laboratory Test Interferences

Tests for Aspergillus

False-positive test results for Aspergillus were reported when the Bio-Rad Laboratories Platelia Aspergillus EIA test was performed in patients receiving the fixed combination of piperacillin sodium and tazobactam sodium (piperacillin/tazobactam).1 Cross reactions with non- Aspergillus polysaccharides and polyfuranoses have been reported with the Bio-Rad Laboratories Platelia Aspergillus EIA test.1 Positive Platelia Aspergillus EIA test results in patients receiving piperacillin/tazobactam should be interpreted with caution and confirmed using other diagnostic methods.1

Tests for Urinary Glucose

As with other penicillins, piperacillin/tazobactam may result in false-positive urinary glucose determinations with tests that use copper reduction (e.g., Clinitest^®).1 Glucose tests based on enzymatic glucose oxidase reactions should be used.1

Acute Toxicity

There have been postmarketing reports of overdosage of the fixed combination of piperacillin sodium and tazobactam sodium (piperacillin/tazobactam).1 Adverse effects reported with such overdosages have included adverse effects reported with usual dosages of the drug (e.g., nausea, vomiting, diarrhea).1 Neuromuscular excitability or convulsions may occur if higher than recommended dosages of IV piperacillin/tazobactam are given, especially in patients with renal failure.1

If acute overdosage of piperacillin/tazobactam occurs, supportive and symptomatic treatment should be initiated as indicated.1 Because piperacillin and tazobactam are removed by hemodialysis (see Pharmacokinetics: Elimination), this procedure may be effective in reducing excessive serum concentrations of the drugs.1

Mechanism of Action

The fixed combination of piperacillin sodium and tazobactam sodium (piperacillin/tazobactam) is bactericidal in action.1,28,43

Like other penicillins, piperacillin inhibits bacterial septum formation and cell wall synthesis in susceptible bacteria.1 The mechanism of action of penicillins is mediated through binding to penicillin-binding proteins (PBPs).43,46

Tazobactam alone has only limited intrinsic antibacterial activity1,60 because of reduced affinity for PBPs.1 However, tazobactam is a β-lactamase inhibitor that generally acts as an irreversible inhibitor and can inactivate both plasmid- and chromosome-mediated β-lactamases.21,4,5,12,28,60 In vitro studies indicate that tazobactam can inhibit staphylococcal β-lactamases2,4,10,12 and β-lactamases classified as Richmond-Sykes types II,12 III (TEM type, HSV-1),1,2,4,12 IV,2,4,12 and V (PSE and OXA types).11,12 Tazobactam is effective against some type I β-lactamases, including type IC,4,9,12 and may be slightly more active against type I enzymes than some other β-lactamase inhibitors (e.g., clavulanic acid, sulbactam).4,9 Unlike clavulanic acid, tazobactam generally does not induce production of type I chromosomally mediated cephalosporins in Pseudomonas or Enterobacteriaceae.9,12

Because tazobactam inactivates certain β-lactamases, concomitant use with piperacillin can protect the penicillin from degradation by these β-lactamases and expand its spectrum of activity to include some β-lactamase-producing bacteria that are resistant to piperacillin alone.1,2,4,5,6,7,8,10,12,28,60

Spectrum

Based on its spectrum of activity, the fixed combination of piperacillin sodium and tazobactam sodium (piperacillin/tazobactam) is classified as an extended-spectrum penicillin.43,46 For information on the classification of penicillins based on spectrum of activity, see the Preface to the Penicillins 8:12.16.

Piperacillin/tazobactam has a wide spectrum of activity and is active in vitro against various gram-positive and -negative aerobic and anaerobic bacteria.1,2,4,5,6,9,10,11,15,18,19,20,21,22,43 The fixed combination is active against bacteria susceptible to piperacillin alone.43 In addition, because tazobactam has a high affinity for and binds to certain β-lactamases that generally inactivate piperacillin, piperacillin/tazobactam is active against many β-lactamase-producing bacteria that are resistant to piperacillin alone, including piperacillin-resistant strains of staphylococci, Haemophilus , Enterobacteriaceae, and Bacteroides .2,4,5,6,7,9,10,11,12,15,18,19,20,21,28,60

Piperacillin/tazobactam is not active against Mycoplasma and Chlamydia .43

Gram-positive Aerobic Bacteria

Piperacillin/tazobactam is active in vitro and in clinical infections against Staphylococcus aureus (methicillin-susceptible strains only).1,43

Piperacillin/tazobactam also is 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 group streptococci,1,43 and Enterococcus faecalis (ampicillin- or penicillin-susceptible strains only).1,43

Although piperacillin/tazobactam is active against β-lactamase-producing S. aureus and S. epidermidis , the fixed combination is not active against methicillin-resistant S. aureus (MRSA; also known as oxacillin-resistant S. aureus or ORSA) or methicillin-resistant S. epidermidis .43

Gram-negative Aerobic Bacteria

Enterobacteriaceae

Piperacillin/tazobactam is active in vitro and in clinical infections against Escherichia coli 1,43 and Klebsiella pneumoniae .1,43

Piperacillin/tazobactam also is active in vitro against Citrobacter koseri ,1,43 Enterobacter ,43 Morganella morganii ,1,43 Proteus mirabilis ,1,43 P. vulgaris ,1,43 Providencia stuartii ,1 P. rettgeri ,1 Salmonella ,1,43 Shigella ,43 and Serratia marcescens .1,43

Pseudomonas

Piperacillin/tazobactam is active in vitro and in clinical infections against Pseudomonas aeruginosa .1,43

Other Gram-negative Aerobic Bacteria

Piperacillin/tazobactam is active in vitro and in clinical infections against Acinetobacter (including A. baumannii )1 and Haemophilus influenzae (except β-lactamase negative, ampicillin-resistant strains; BLNAR).1,43 The drug also is active in vitro against Moraxella catarrhalis 1,43 and Neisseria .1

Piperacillin/tazobactam has some in vitro activity against Legionella ; however, the drug is not effective against intracellular Legionella and is unlikely to be effective for the treatment of Legionella infections.43

Anaerobic Bacteria

Piperacillin/tazobactam is active in vitro and in clinical infections against some gram-negative anaerobic bacteria, including Bacteroides fragilis ,1,43 B. ovatus ,1,43 B. thetaiotaomicron ,1 and B. vulgatus .1,43 The drug also is active in vitro against B. distasonis ,1,43 Fusobacterium ,43 and Prevotella melaninogenica .1,43

Piperacillin/tazobactam is active in vitro against some gram-positive anaerobic bacteria, including Bacillus ,43 Clostridium perfringens ,1,43 Cutibacterium acnes (formerly Propionibacterium acnes ),43 and Peptostreptococcus .43

Resistance

Resistance or reduced susceptibility to the fixed combination of piperacillin sodium and tazobactam sodium (piperacillin/tazobactam) can occur.43,60

The major mechanism of resistance to piperacillin/tazobactam in gram-positive bacteria is alteration in penicillin-binding proteins (PBPs).43 Methicillin-resistant Staphylococcus aureus (MRSA; also known as oxacillin-resistant S. aureus or ORSA) and Enterococcus faecium are intrinsically resistant to piperacillin/tazobactam because of low affinity of PBPs.43

Resistance to piperacillin/tazobactam in gram-negative bacteria may be multifactorial and may involve β-lactamases, transferable multidrug-resistance genes, alterations in outer membrane porins, and antibiotic efflux.43 Piperacillin/tazobactam may be active against some Enterobacteriaceae that produce extended-spectrum β-lactamases (ESBLs), but strains that produce multiple ESBLs or have additional mechanisms of resistance (e.g., AmpC β-lactamases) may have reduced susceptibility or resistance to the drug.60 Pseudomonas resistant to piperacillin generally also are resistant to piperacillin/tazobactam.5,10,11,12

β-Lactamase-negative, ampicillin-resistant Haemophilus influenzae (BLNAR H. influenzae ) are resistant to piperacillin/tazobactam.1,5

Pharmacokinetics

Absorption

Following IV infusion of the fixed combination of piperacillin sodium and tazobactam sodium (piperacillin/tazobactam), peak plasma concentrations of piperacillin and tazobactam are attained immediately or 1-2 hours after completion of the infusion.1,43 Studies in adults indicate that piperacillin plasma concentrations attained following IV infusion of piperacillin/tazobactam over 30 minutes are similar to those attained with equivalent doses of piperacillin administered alone.1

Distribution

Both piperacillin and tazobactam are 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 Mean tissue concentrations generally are 50-100% of plasma concentrations.1

Only low concentrations of piperacillin and tazobactam are distributed into CSF in patients with uninflamed meninges.1,43

Both piperacillin and tazobactam cross the placenta.1

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

The mean volume of distribution of piperacillin is 0.243 L/kg and is independent of age.1

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

Elimination

Piperacillin is metabolized to a minor microbiologically active desethyl metabolite1,43 and an inactive metabolite.43

Tazobactam is metabolized to a single metabolite that lacks pharmacologic and antibacterial activity.1,43

Both piperacillin and tazobactam are eliminated in urine by glomerular filtration and tubular secretion.1,43 In addition, piperacillin, desethylpiperacillin, and tazobactam are eliminated in bile.1

Following IV administration, 68 and 80% of the piperacillin and tazobactam doses, respectively, are eliminated unchanged in urine.1

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

In adults with cirrhosis, the half-lives of piperacillin and tazobactam are increased by approximately 25 and 18%, respectively, compared with adults with normal hepatic function.1

In adults with renal impairment, the half-lives of piperacillin and tazobactam increase with decreasing creatinine clearance.1 In adults with creatinine clearances less than 20 mL/minute, the half-life of piperacillin is twofold higher and the half-life of tazobactam is fourfold higher compared with adults with normal renal function.1

In geriatric adults 65-80 years of age, the mean half-lives of piperacillin and tazobactam are increased by 32 and 55%, respectively, compared with adults 18-35 years of a 1 this increase may be the result of age-related changes in creatinine clearance.1

In children 9 months to 12 years of age, clearance of piperacillin and tazobactam 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 younger than 2 months of age compared with older children.1

Both piperacillin and tazobactam are removed by hemodialysis1,3,7,12,43 and, to a lesser extent, by peritoneal dialysis.1,3,7,43 Hemodialysis removes approximately 31 and 39% of the piperacillin and tazobactam dose, respectively;1 an additional 5% of the tazobactam dose is removed as the tazobactam metabolite.1 Peritoneal dialysis removes approximately 6 and 21% of the piperacillin and tazobactam dose, respectively;1 up to 16% of the tazobactam dose is removed as the tazobactam metabolite.1

Chemistry and Stability

Chemistry

Piperacillin sodium and tazobactam sodium (piperacillin/tazobactam) is a fixed combination of the sodium salts of piperacillin and tazobactam.1

Piperacillin, a piperazine derivative of ampicillin,43,63,155 is an extended-spectrum penicillin.5,6,7,12,155 Piperacillin is commercially available in the US only in fixed combination with tazobactam.1,35,36,37,38,45

Tazobactam, a β-lactamase inhibitor, is a synthetic penicillanic acid sulfone that is structurally similar to sulbactam.1,3,5,6,9,12,28,46,60 Although tazobactam has only limited intrinsic antibacterial activity alone,1,9,10,12,22 the combined use of tazobactam and certain penicillins or cephalosporins (e.g., amoxicillin, ampicillin, ceftazidime, ceftolozane, piperacillin) results in a synergistic effect that expands the spectrum of activity of the penicillin or cephalosporin against many strains of β-lactamase-producing bacteria.1,4,5,6,7,8,10,12,28,46,60

Piperacillin/tazobactam contains an 8:1 ratio of piperacillin to tazobactam;1,35,36,37,38,45 potency of the fixed combination is expressed in terms of the piperacillin content plus the tazobactam content.1,35,36,37,38,45

Piperacillin/tazobactam (Zosyn^®) and generic preparations of piperacillin/tazobactam commercially available in the US are not identical.1,35,36,37,38 Piperacillin/tazobactam (Zosyn^®) is formulated with edetate disodium dihydrate (EDTA) and sodium citrate;1,44 the generic preparations do not contain EDTA or sodium citrate.35,36,37,38 Because EDTA acts as a metal-chelating agent and sodium citrate acts as a buffer, certain aspects of chemical degradation and particulate formation are inhibited and there is a lower risk of particulate matter formation and accumulation following reconstitution of Zosyn^® with commonly used diluents or storage of solutions of the drug.44 In addition, the presence of EDTA and sodium citrate allows coadministration of Zosyn^® and lactated Ringer's injection via Y-site infusion.1,44 (See IV Infusion under Dosage and Administration: Administration.)

Each single-dose vial of piperacillin/tazobactam sterile powder (Zosyn^®) contains 2.84 mEq (65 mg) of sodium and 0.25 mg of EDTA per gram of piperacillin.1

Commercially available piperacillin/tazobactam sterile powder (generic) in single-dose ADD-Vantage^® vials contains 2.35 mEq (54 mg) of sodium per gram of piperacillin.45

Bulk vials of piperacillin/tazobactam (Zosyn^®) containing 40.5 g (36 g of piperacillin and 4.5 g of tazobactam) contain 100.4 mEq (2304 mg) of sodium and 9 mg of EDTA.1 Bulk bottles of piperacillin/tazobactam (generic) containing 40.5 g (36 g of piperacillin and 4.5 g of tazobactam) contain 84.6 mEq (1945 mg) of sodium and do not contain EDTA.36

Commercially available single-dose frozen premixed piperacillin/tazobactam injections in dextrose (Zosyn^® in Galaxy^® containers) are sterile, nonpyrogenic, iso-osmotic solutions of the drug formulated with EDTA.1 The single-dose frozen injection contains 2.79 mEq (64 mg) of sodium and 0.25 mg of EDTA per gram of piperacillin.1 Sodium bicarbonate and/or hydrochloric acid may have been added to adjust the pH of the injections to 5.5-6.8.1

Stability

Piperacillin/tazobactam powder for injection provided in single-dose vials (Zosyn^®, generic) should be stored at 20-25°C.1,35,37,38 Following reconstitution, the solutions should be used immediately;1,35,37,38 any unused portions should be discarded after 24 hours if stored at 20-25°C or after 48 hours if refrigerated at 2-8°C.1,35,37,38 These reconstituted solutions should not be frozen.1,37,38

Single-dose ADD-Vantage^® vials of piperacillin/tazobactam (generic) should be stored at 20-25°C.45 Following reconstitution with 0.9% sodium chloride injection or 5% dextrose injection according to the manufacturer's directions, these IV solutions are stable for 24 hours at room temperature and should not be refrigerated or frozen.45

Piperacillin/tazobactam powder for injection provided in bulk vials or bottles (Zosyn^®, generic) should be stored at 20-25°C.1,36 Following reconstitution, the solutions should be used promptly;1,36 any unused portions should be discarded after 24 hours if stored at 20-25°C or after 48 hours if refrigerated at 2-8°C.1,36 These reconstituted solutions should not be frozen.1,36

The commercially available single-dose frozen premixed piperacillin/tazobactam injections in dextrose (Zosyn^® in Galaxy^® containers) should be stored at -20°C or lower.1 The frozen premixed injections should be thawed at room temperature (20-25°C) or under refrigeration (2-8°C) and, once thawed, should not be refrozen.1 Thawed solutions of the commercially available frozen injection are stable for 24 hours at room temperature (20-25°C) or 14 days at 2-8°C.1

Piperacillin/tazobactam is potentially physically and/or chemically incompatible with some drugs, including aminoglycosides, but the compatibility depends on several factors (e.g., concentration of the drugs, specific diluents used, resulting pH, temperature).78,83,236,300 Specialized references should be consulted for specific compatibility information.300

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