Piperacillin and Tazobactam

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Note: 8:1 ratio of piperacillin sodium/tazobactam sodium

Infusion [premixed iso-osmotic solution] [preservative free]:

Zosyn: 2.25 g: Piperacillin 2 g and tazobactam 0.25 g (50 mL) [contains edetate disodium, sodium 128 mg (5.58 mEq)]

Zosyn: 3.375 g: Piperacillin 3 g and tazobactam 0.375 g (50 mL) [contains edetate disodium, sodium 192 mg (8.38 mEq)]

Zosyn: 4.5 g: Piperacillin 4 g and tazobactam 0.5 g (100 mL) [contains edetate disodium, sodium 256 mg (11.17 mEq)]

Injection, powder for reconstitution:

Generic: Piperacillin 2 g and tazobactam 0.25 g; piperacillin 3 g and tazobactam 0.375 g; piperacillin 4 g and tazobactam 0.5 g; piperacillin 12 g and tazobactam 1.5 g; piperacillin 36 g and tazobactam 4.5 g

Injection, powder for reconstitution [preservative free]:

Zosyn: 2.25 g: Piperacillin 2 g and tazobactam 0.25 g [contains edetate disodium, sodium 130 mg (5.68 mEq)]

Zosyn: 3.375 g: Piperacillin 3 g and tazobactam 0.375 g [contains edetate disodium, sodium 195 mg (8.52 mEq)]

Zosyn: 4.5 g: Piperacillin 4 g and tazobactam 0.5 g [contains edetate disodium, sodium 260 mg (11.36 mEq)]

Zosyn: 40.5 g: Piperacillin 36 g and tazobactam 4.5 g [contains edetate disodium, sodium 2304 mg (100.4 mEq); bulk pharmacy vial]

Generic: Piperacillin 2 g and tazobactam 0.25 g; piperacillin 3 g and tazobactam 0.375 g; piperacillin 4 g and tazobactam 0.5 g

Pharmacology

Mechanism of Action

Piperacillin inhibits bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins (PBPs); which in turn inhibits the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls, thus inhibiting cell wall biosynthesis. Bacteria eventually lyse due to ongoing activity of cell wall autolytic enzymes (autolysins and murein hydrolases) while cell wall assembly is arrested. Piperacillin exhibits time-dependent killing. Tazobactam inhibits many beta-lactamases, including staphylococcal penicillinase and Richmond-Sykes types 2, 3, 4, and 5, including extended spectrum enzymes; it has only limited activity against class 1 beta-lactamases other than class 1C types.

Pharmacokinetics/Pharmacodynamics

Distribution

Well into lungs, intestinal mucosa, uterus, ovary, fallopian tube, interstitial fluid, gallbladder, and bile; penetration into CSF is low in subjects with noninflamed meninges

V_d:

Piperacillin:

Neonates and Infants <2 months: Steady state: Median: 0.42 L/kg (Cohen-Wolkowiez 2014)

Infants 2 to 5 months: Single dose: 0.37 ± 0.1 L/kg (Reed 1994)

Infants 6 months to Children <6 years: Single dose: 0.36 ± 0.1 L/kg (Reed 1994)

Children 6 to 12 years: Single dose: 0.36 ± 0.2 L/kg (Reed 1994)

Note: Critically ill children 9 months to 6 years have been shown to have higher V_d of 0.511 ± 0.366 L/kg (Cies 2014)

Adolescents and Adults: 0.243 L/kg

Metabolism

Piperacillin: 6% to 9% to desethyl metabolite (weak activity)

Tazobactam: ~22% to inactive metabolite

Excretion

Excretion: Clearance of both piperacillin and tazobactam are directly proportional to renal function

Piperacillin: Urine (68% as unchanged drug); feces (10% to 20%)

Tazobactam: Urine (80% as unchanged drug; remainder as inactive metabolite)

Time to Peak

Immediately following completion of 30-minute infusion

Half-Life Elimination

Piperacillin:

Neonates and Infants <2 months: Median: 3.5 hours; range: 1.7 to 8.9 hours (Cohen-Wolkowiez 2014)

Infants 2 to 5 months: 1.4 ± 0.5 hours (Reed 1994)

Infants and Children 6 to 23 months: 0.9 ± 0.3 hours (Reed 1994)

Children 2 to 5 years: 0.7 ± 0.1 hours (Reed 1994)

Children 6 to 12 years: 0.7 ± 0.2 hours (Reed 1994)

Adults: 0.7 to 1.2 hours

Metabolite: 1 to 1.5 hours

Tazobactam:

Infants 2 to 5 months: 1.6 ± 0.5 hours (Reed 1994)

Infants and Children 6 to 23 months: 1 ± 0.4 hours (Reed 1994)

Children 2 to 5 years: 0.8 ± 0.2 hours (Reed 1994)

Children 6 to 12 years: 0.9 ± 0.4 hours (Reed 1994)

Adults: 0.7 to 0.9 hour

Protein Binding

Piperacillin: ~26% to 33%; Tazobactam: 31% to 32%

Use in Specific Populations

Special Populations: Renal Function Impairment

Half-life increases 2-fold for piperacillin and 4-fold for tazobactam in patients with CrCl <20 mL/minute.

Use: Labeled Indications

Intraabdominal infections: Treatment of appendicitis complicated by rupture or abscess and peritonitis caused by beta-lactamase-producing strains of Escherichia coli, Bacteroides fragilis, Bacteroides ovatus, Bacteroides thetaiotaomicron, or Bacteroides vulgatus.

Pelvic infections: Treatment of postpartum endometriosis or pelvic inflammatory disease caused by beta-lactamase-producing strains of E. coli.

Pneumonia, community-acquired: Treatment of moderate severity community-acquired pneumonia (CAP) caused by beta-lactamase-producing strains of Haemophilus influenzae. Infectious Diseases Society of America/American Thoracic Society (IDSA/ATS) guidelines only recommend piperacillin/tazobactam for CAP caused by Pseudomonas aeruginosa or due to aspiration (IDSA/ATS [Mandell 2007]).

Pneumonia, hospital-acquired (nosocomial): Treatment of moderate to severe hospital-acquired (nosocomial) pneumonia caused by beta-lactamase-producing strains of Staphylococcus aureus and by piperacillin/tazobactam-susceptible Acinetobacter baumannii, H. influenzae, Klebsiella pneumoniae, and P. aeruginosa.

Skin and skin structure infections: Treatment of skin and skin structure infections, including cellulitis, cutaneous abscesses, and ischemic/diabetic foot infections caused by beta-lactamase-producing strains of S. aureus.

Use: Off Label

Bite wound infection, treatment (animal or human bite)yes

Based on the Infectious Diseases Society of America (IDSA) guidelines for the diagnosis and management of skin and soft tissue infections (SSTIs), piperacillin and tazobactam is an effective and recommended treatment of animal bite wound infections.

Clinical experience supports the utility of piperacillin and tazobactam in the treatment of human bite wound infections Baddour 2019b.

Bloodstream infection (gram-negative bacteremia)byes

Limited data support the use of piperacillin and tazobactam in the treatment of gram-negative bacteremia Wise 1993. Clinical experience also suggests the utility of piperacillin and tazobactam in the treatment of gram-negative bacteremia Moehring 2019b. In addition, according to the IDSA clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection, piperacillin and tazobactam is effective and recommended for the treatment of intravascular catheter-related infection caused by Pseudomonas aeruginosa.

Cystic fibrosis, severe acute pulmonary exacerbationyes

Based on the Cystic Fibrosis Foundation's cystic fibrosis pulmonary guidelines, piperacillin and tazobactam, as part of an appropriate combination regimen (which should most often include an additional antipseudomonal agent), is effective and recommended for the treatment of Pseudomonas infection during an acute exacerbation of cystic fibrosis pulmonary disease.

Malignant (necrotizing) external otitisc

Clinical experience suggests the utility of piperacillin and tazobactam in the treatment of malignant (necrotizing) external otitis Grandis 2017.

Neutropenic fever, high-risk cancer patients (empiric therapy)yes

Based on the IDSA clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer, piperacillin and tazobactam, in combination with other agents when appropriate, is effective and recommended for the management of neutropenic fever in high-risk cancer patients (ie, ANC expected to be ≤100 cells/mm³ for >7 days, clinically unstable, or significant comorbidity).

Sepsis and septic shockyes

Based on the Society of Critical Care Medicine international guidelines for management of sepsis and septic shock, piperacillin and tazobactam, in combination with other appropriate agents, is effective and recommended for broad-spectrum antibacterial coverage (including P. aeruginosa) in the management of sepsis and septic shock.

Urinary tract infection, complicated (including pyelonephritis)c

Data from a multicenter, open-label, noncomparative study suggest that piperacillin and tazobactam may be beneficial for the treatment of complicated urinary tract infection, including pyelonephritis Nowé 1994.

Clinical experience suggests the utility of piperacillin and tazobactam in the treatment of acute complicated urinary tract infections, including pyelonephritis Hooton 2019, Johnson 2018.

Contraindications

Hypersensitivity to penicillins, cephalosporins, beta-lactamase inhibitors, or any component of the formulation

Dosage and Administration

Dosing: Adult

Note: Adult doses are expressed as the combined amount of piperacillin and tazobactam. Infusion method: Dosing is presented based on the traditional infusion method over 30 minutes, unless otherwise specified as the extended infusion method over 4 hours or continuous infusion method over 24 hours (off-label methods).

Usual dosage range:

Traditional infusion method (over 30 minutes): IV:

Mild to moderate infections: 3.375 g every 6 hours.

Severe infections: 4.5 g every 6 to 8 hours (Cornely 2004; Gyssens 2011; Saltoglu 2010).

For coverage of Pseudomonas aeruginosa: 4.5 g every 6 hours. Usual maximum dose: 18 g/day.

Extended-infusion method (off-label method):

IV: 3.375 or 4.5 g every 8 hours infused over 4 hours (Lodise 2007; Shea 2009; Yang 2015). Note: A loading dose of 3.375 to 4.5 g over 30 minutes can be given, especially when rapid attainment of therapeutic drug concentrations is necessary (eg, sepsis) (SCCM [Rhodes 2017]).

Continuous-infusion method (off-label method):

IV: 18 g infused over 24 hours (Abdul-Aziz 2016); may give a loading dose of 4.5 g over 30 minutes, especially when rapid attainment of therapeutic drug concentrations (eg, sepsis) is desired (Abdul-Aziz 2016; SCCM [Rhodes 2017]).

Extended and continuous infusion methods are based largely on pharmacokinetic and pharmacodynamic modeling data; clinical efficacy data are limited (Abdul-Aziz 2016; Lodise 2007; MacVane 2014; Moehring 2019a; Rhodes 2014; Vardakas 2018).

Indication-specific dosing:

Bite wound infection, treatment (animal or human bite) (off-label use):

IV: 3.375 g every 6 to 8 hours. Duration of treatment for established infection (which may include oral step-down therapy) is typically 5 to 14 days. Additional coverage for methicillin-resistant Staphylococcus aureus may be needed for empiric treatment (Baddour 2019a; Baddour 2019b; IDSA [Stevens 2014]).

Bloodstream infection (gram-negative bacteremia) (off-label use):

Note: For empiric therapy of known or suspected gram-negative (including P. aeruginosa) bloodstream infection in patients with neutropenia, severe burns, sepsis, or septic shock, some experts recommend giving piperacillin and tazobactam in combination with a second gram-negative active agent (Kanj 2019a; SCCM [Rhodes 2017]). Some experts also prefer the extended-infusion method in critical illness or to optimize exposure if treating a susceptible organism with an elevated minimum inhibitory concentration (Moehring 2019a; SCCM [Rhodes 2017]).

Community-acquired infection, immunocompetent host: IV: 3.375 g every 6 hours (Moehring 2019b).

Health care-associated infection, including catheter-related, immunosuppressed host, or for coverage of P. aeruginosa: IV: 4.5 g every 6 hours (IDSA [Mermel 2009]; Moehring 2019b).

Duration of therapy: Usual duration is 7 to 14 days, depending on source, pathogen, extent of infection, and clinical response (Moehring 2019b); a 7-day duration is recommended for patients with uncomplicated Enterobacteriaceae infection who respond appropriately to antibiotic therapy (Chotiprasitsakul 2018; Moehring 2019b; Yahav 2018). Note: If neutropenic, extend treatment until afebrile for 2 days and neutrophil recovery (ANC ≥500 cells/mm³ and increasing) (IDSA [Freifeld 2011]). For P. aeruginosa bacteremia in neutropenic patients, some experts treat for a minimum of 14 days and until recovery of neutrophils (Kanj 2019a).

Cystic fibrosis, severe acute pulmonary exacerbation or failure of oral therapy, for coverage of P. aeruginosa (off-label use):

IV: 4.5 g every 6 hours usually as part of an appropriate combination regimen (Flume 2009; Simon 2019). Note: Some experts prefer the extended or continuous infusion method to optimize exposure (Butterfield 2014; Simon 2019). Duration is usually 10 days to 3 weeks or longer based on clinical response (Flume 2009; Simon 2019).

Diabetic foot infection, moderate to severe:

IV: 3.375 g every 6 hours or 4.5 g every 8 hours (Gyssens 2011; Saltoglu 2010; Tan 1993). For treatment of P. aeruginosa infection: 4.5 g every 6 hours (Weintrob 2019). Note: Empiric Pseudomonas coverage with this dose is usually not indicated unless patient is at risk (eg, significant water exposure, warm climate). Duration (which may include oral step-down therapy) is usually 2 to 4 weeks in the absence of osteomyelitis (IDSA [Lipsky 2012]; Weintrob 2019).

Intra-abdominal infection:

Cholecystitis, acute: IV: 3.375 or 4.5 g every 6 hours; continue for 1 day after gallbladder removal or until clinical resolution in patients managed nonoperatively (Gomi 2018; SIS [Mazuski 2017]; SIS/IDSA [Solomkin 2010]; Vollmer 2019).

Other intra-abdominal infection (eg, cholangitis, perforated appendix, diverticulitis, intra-abdominal abscess):

IV: 3.375 g or 4.5 g every 6 hours. Total duration of therapy (which may include oral step-down therapy) is 4 to 7 days following adequate source control (Barshak 2019; Gomi 2018; Pemberton 2019; SIS [Mazuski 2017]; SIS/IDSA [Solomkin 2010]); for infections managed without surgical or percutaneous intervention, a longer duration may be necessary (Barshak 2019; Pemberton 2019). Note: For patients who are critically ill or at risk for infection with drug-resistant pathogens, some experts favor the extended infusion method (Barshak 2019; WSES [Sartelli 2017).

Note: Reserve 4.5 g dose for health care-associated infection, severe community-acquired infection, or patients with community-acquired infection at high risk of adverse outcome and/or resistance (Barshak 2019; SIS/IDSA [Solomkin 2010]).

Malignant (necrotizing) external otitis, hospitalized patients (alternative agent) (off-label use): IV: 4.5 g every 6 hours. Total duration of therapy, including oral step-down, is 6 to 8 weeks (Grandis 2018).

Neutropenic fever, high-risk cancer patients (empiric therapy) (off-label use):

Note: High-risk patients are those expected to have an ANC ≤100 cells/mm³ for >7 days or an ANC ≤100 cells/mm³ for any expected duration if there are ongoing comorbidities (eg, sepsis, mucositis, significant hepatic or renal dysfunction) (IDSA [Freifeld 2011]); some experts use an ANC cutoff <500 cells/mm³ to define high-risk patients (Wingard 2019).

IV: 4.5 g every 6 to 8 hours until afebrile for ≥48 hours and resolution of neutropenia (ANC ≥500 cells/mm³ and increasing) or standard duration for the specific infection identified, if longer than the duration for neutropenia. If there is significant concern for Pseudomonas infection (particularly in those who are severely ill or were not receiving fluoroquinolone prophylaxis), 4.5 g every 6 hours should be given. Additional agent(s) may be needed depending on clinical status (IDSA [Freifeld 2011]; Wingard 2019). Some experts prefer the extended-infusion method, particularly in those who are critically ill (Moehring 2019a; SCCM [Rhodes 2017]).

Pneumonia:

Community-acquired pneumonia, as a component of empiric therapy for inpatients at risk for infection with a multidrug-resistant gram-negative pathogen(s), including P. aeruginosa: IV: 4.5 g every 6 hours as part of an appropriate combination regimen. Total duration (which may include oral step-down therapy) is for a minimum of 5 days and varies based on disease severity and response to therapy; a longer course may be required for severe or complicated infection or for P. aeruginosa infection (Kanj 2019b). Patients should be afebrile for ≥48 hours and clinically stable prior to discontinuation (File 2019; IDSA/ATS [Mandell 2007]).

Hospital-acquired or ventilator-associated pneumonia, as a component of empiric therapy or pathogen-specific therapy of gram-negative bacteria resistant to other agents (eg, P. aeruginosa): IV: 4.5 g every 6 hours, as part of an appropriate combination regimen. Duration of therapy varies based on disease severity and response to therapy; treatment is typically given for 7 days (IDSA/ATS [Kalil 2016]), but a longer course may be required for severe or complicated infection or for P. aeruginosa infection (Kanj 2019b). Note: Some experts prefer the extended- or continuous-infusion method, particularly in those who are critically ill (Moehring 2019a; Rhodes 2014).

Sepsis and septic shock (broad-spectrum empiric therapy, including P.aeruginosa) (off-label use): IV: 4.5 g every 6 hours in combination with other appropriate agent(s) (Kanj 2019c). Initiate therapy as soon as possible and within 1 hour of recognition of sepsis or septic shock. Usual duration of treatment is dependent on underlying source, but is typically 7 to 10 days or longer, depending upon clinical response (SCCM [Rhodes 2017]). Consider discontinuation if a noninfectious etiology is identified (SCCM [Rhodes 2017]; Schmidt 2019). Some experts prefer the extended- or continuous-infusion method (Moehring 2019a; SCCM [Rhodes 2017]).

Skin and soft tissue infection (moderate to severe infection, necrotizing infection, select surgical site infections [intestinal, GU tract]), broad-spectrum empiric coverage, including P. aeruginosa: IV: 3.375 g every 6 hours or 4.5 g every 8 hours as part of an appropriate combination regimen (IDSA [Stevens 2014]). For treatment of P. aeruginosa infection: 4.5 g every 6 hours (Kanj 2019c). Usual duration is 10 to 14 days based on clinical response; for necrotizing infection, continue until further debridement is not necessary, patient has clinically improved, and patient is afebrile for ≥48 hours (IDSA [Stevens 2014]; Kanj 2019c).

Urinary tract infection, complicated (including pyelonephritis) (off-label use): IV: 3.375 g every 6 hours or, if Pseudomonas is a concern, 4.5 g every 6 hours. Note: Switch to an appropriate oral regimen once patient has improvement in symptoms or if culture and susceptibility results allow; duration of therapy depends on the antimicrobial chosen to complete the regimen and ranges from 5 to 14 days. If piperacillin and tazobactam is continued for the entire treatment course, the duration of therapy is 10 to 14 days (Hooton 2019).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Zosyn (piperacillin/tazobactam) is a combination product; each 3.375 g vial contains 3 g piperacillin sodium and 0.375 g tazobactam sodium in an 8:1 ratio. Dosage recommendations are based on the piperacillin component. Some centers divide doses every 6 hours for enhanced pharmacodynamic profile. Unless otherwise specified, dosing presented is based on traditional infusion method (IV infusion over 30 minutes). Dosing is presented in mg/kg/dose and mg/kg/day; use precaution.

General dosing, susceptible infection: Severe infection:

Traditional dosing:

Infants <2 months: IV: 240 to 300 mg piperacillin/kg/day divided in 3 to 4 doses; maximum daily dose: 16 g/day (Red Book [AAP 2018]); some experts have recommended 80 mg piperacillin/kg/dose every 4 hours based on a pharmacokinetic study (Cohen-Wolkowiez 2014).

Infants ≥2 months, Children, and Adolescents: IV: 240 to 300 mg piperacillin/kg/day divided in 3 to 4 doses; maximum daily dose: 16 g/day (Red Book [AAP 2018]).

Extended infusion dosing: Limited data available: Children and Adolescents: IV: 100 mg piperacillin/kg/dose infused over 4 hours every 6 to 8 hours; dosing based on pharmacokinetic and pharmacodynamic studies as well as a retrospective case series (Cies 2014; Knoderer 2017; Nichols 2016a; Tamma 2012).

Appendicitis and/or peritonitis: IV:

Infants 2 to 9 months: 80 mg of piperacillin/kg/dose every 8 hours.

Infants >9 months and Children weighing ≤40 kg: 100 mg piperacillin/kg/dose every 8 hours; maximum dose: 3,000 mg piperacillin/dose.

Children weighing >40 kg and Adolescents: 3,000 mg piperacillin every 6 hours; maximum daily dose: 16 g piperacillin/day.

Cystic fibrosis, pseudomonal lung infection: Infants, Children, and Adolescents: Note: Multiple dosing approaches have been evaluated; optimal dose may vary based on disease severity, susceptibility patterns (eg, MIC), or patient tolerability:

Standard dosing range: IV: 240 to 400 mg piperacillin/kg/day divided every 8 hours (Kliegman 2011); others have used 350 to 400 mg/kg/day divided every 4 hours in early piperacillin trials (Zobell 2013).

High dose: Limited data available: IV: 450 mg piperacillin/kg/day divided every 4 to 6 hours or 600 mg piperacillin/kg/day divided every 4 hours has been described from early studies of piperacillin alone; usual maximum daily dose: 18 to 24 g piperacillin/day. Note: Piperacillin doses >600 mg/kg/day or an extended duration of therapy (>14 days) have been associated with dose-related adverse effects including serum sickness, immune-mediated hemolytic anemia and bone marrow suppression (Zobell 2013).

Endocarditis, treatment: Children and Adolescents: IV: 240 mg piperacillin/kg/day divided every 8 hours in combination with an aminoglycoside for at least 6 weeks; maximum daily dose: 18 g piperacillin/day (AHA [Baltimore 2015]); based on pharmacokinetic/pharmacodynamic data for piperacillin/tazobactam, guideline dosing may be suboptimal and not achieve the desired targets needed to treat endocarditis; a higher total daily dose given more frequently (~300 mg piperacillin/kg/day divided every 6 hours) has been suggested; extended infusion (eg, infuse over 3 to 4 hours) would be needed if using every 8 hour dosing (Nichols 2016b).

Intra-abdominal infection, complicated: Infants, Children, and Adolescents: IV: 200 to 300 mg piperacillin/kg/day divided every 6 to 8 hours; maximum daily dose: 12 g piperacillin/day (IDSA [Solomkin 2010]).

Skin and soft tissue necrotizing infections: Infants, Children, and Adolescents: IV: 60 to 75 mg piperacillin/kg/dose every 6 hours (in combination with vancomycin for empiric therapy); continue until further debridement is not necessary, patient has clinically improved, and patient is afebrile for 48 to 72 hours (IDSA [Stevens 2014]).

Surgical antimicrobial prophylaxis (ASHP/IDSA [Bratzler 2013]): IV:

Infants 2 to 9 months: 80 mg piperacillin/kg within 60 minutes prior to surgical incision; may repeat in 2 hours for prolonged procedure or excessive blood loss (eg, >1,500 mL in adults).

Infants >9 months, Children, and Adolescents weighing ≤40 kg: 100 mg piperacillin/kg within 60 minutes prior to surgical incision; may repeat in 2 hours for prolonged procedure or excessive blood loss (eg, >1,500 mL in adults). Maximum dose: 3,000 mg piperacillin/dose.

Adolescents weighing >40 kg: 3,000 mg piperacillin within 60 minutes prior to surgical incision; may repeat in 2 hours for prolonged procedure or excessive blood loss (eg, >1,500 mL in adults).

Reconstitution

Galaxy containers: Thaw at 20°C to 25°C (68°F to 77°F) or 2°C to 8°C (36°F to 46°F). Do not thaw in microwave or by bath immersion.

Vials: Reconstitute single-dose vials with 10 mL of diluent (2.25 g vial), 15 mL of diluent (3.375 g vial), or 20 mL of diluent (4.5 g vial); further dilute in D5W or NS to a volume of 50 to 150 mL. Reconstitute pharmacy bulk vials with 152 mL of diluent to yield a concentration of piperacillin 200 mg/mL and tazobactam 25 mg/mL; transfer reconstituted solution and further dilute in D5W or NS to a volume of 50 to 150 mL. Note: If using sterile water for injection for dilution, the maximum recommended volume per dose is 50 mL for single-dose and bulk vials

Administration

IV: Administer by IV infusion over 30 minutes. For extended infusion administration (off-label method), administer over 4 hours (Shea 2009).

Some penicillins (eg, carbenicillin, ticarcillin, and piperacillin) have been shown to inactivate aminoglycosides in vitro. This has been observed to a greater extent with tobramycin and gentamicin, while amikacin has shown greater stability against inactivation. Concurrent use of these agents may pose a risk of reduced antibacterial efficacy in vivo, particularly in the setting of profound renal impairment. However, definitive clinical evidence is lacking. If combination penicillin/aminoglycoside therapy is desired in a patient with renal dysfunction, separation of doses (if feasible), and routine monitoring of aminoglycoside levels, CBC, and clinical response should be considered. Note: Reformulated Zosyn containing EDTA has been shown to be compatible in vitro for Y-site infusion with amikacin and gentamicin diluted in NS or D5W (applies only to specific concentrations and varies by product; consult manufacturer’s labeling). Reformulated Zosyn containing EDTA is not compatible with tobramycin.

Dietary Considerations

Some products may contain sodium.

Storage

Vials: Store intact vials at 20°C to 25°C (68°F to 77°F). Use single-dose or bulk vials immediately after reconstitution. Discard any unused portion after 24 hours if stored at 20°C to 25°C (68°F to 77°F) or after 48 hours if stored at 2°C to 8°C (36°F to 46°F). Do not freeze vials after reconstitution. Stability in D5W or NS has been demonstrated for up to 24 hours at room temperature and up to 1 week at refrigerated temperature. Stability in an ambulatory IV infusion pump has been demonstrated for a period of 12 hours at room temperature.

Galaxy containers: Store at or below -20°C (-4°F). The thawed solution is stable for 14 days at 2°C to 8°C (36°F to 46°F) or 24 hours at 20°C to 25°C (68°F to 77°F). Do not refreeze.

Drug Interactions

Acemetacin: May increase the serum concentration of Penicillins. Monitor therapy

Aminoglycosides: Penicillins may decrease the serum concentration of Aminoglycosides. Primarily associated with extended spectrum penicillins, and patients with renal dysfunction. Consider therapy modification

BCG (Intravesical): Antibiotics may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG Vaccine (Immunization): Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization). Monitor therapy

Cholera Vaccine: Antibiotics may diminish the therapeutic effect of Cholera Vaccine. Management: Avoid cholera vaccine in patients receiving systemic antibiotics, and within 14 days following the use of oral or parenteral antibiotics. Avoid combination

Dichlorphenamide: Penicillins may enhance the hypokalemic effect of Dichlorphenamide. Monitor therapy

Dichlorphenamide: OAT1/3 Inhibitors may increase the serum concentration of Dichlorphenamide. Monitor therapy

Flucloxacillin: Piperacillin may increase the serum concentration of Flucloxacillin. Monitor therapy

Lactobacillus and Estriol: Antibiotics may diminish the therapeutic effect of Lactobacillus and Estriol. Monitor therapy

Methotrexate: Penicillins may increase the serum concentration of Methotrexate. Monitor therapy

Mycophenolate: Penicillins may decrease serum concentrations of the active metabolite(s) of Mycophenolate. This effect appears to be the result of impaired enterohepatic recirculation. Monitor therapy

Probenecid: May increase the serum concentration of Betalactamase Inhibitors. Management: Coadministration of probenecid with amoxicillin/clavulanate is not recommended per official package labeling. Consider therapy modification

Sodium Picosulfate: Antibiotics may diminish the therapeutic effect of Sodium Picosulfate. Management: Consider using an alternative product for bowel cleansing prior to a colonoscopy in patients who have recently used or are concurrently using an antibiotic. Consider therapy modification

Tetracyclines: May diminish the therapeutic effect of Penicillins. Monitor therapy

Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Management: Vaccination with live attenuated typhoid vaccine (Ty21a) should be avoided in patients being treated with systemic antibacterial agents. Use of this vaccine should be postponed until at least 3 days after cessation of antibacterial agents. Consider therapy modification

Vancomycin: Piperacillin may enhance the nephrotoxic effect of Vancomycin. Monitor therapy

Vecuronium: Piperacillin may enhance the neuromuscular-blocking effect of Vecuronium. Monitor therapy

Vitamin K Antagonists (eg, warfarin): Penicillins may enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Test Interactions

Positive Coombs' [direct] test; false positive reaction for urine glucose using copper-reduction method (Clinitest); may result in false positive results with the Platelia Aspergillus enzyme immunoassay (EIA); confirm with other diagnostic methods.

Adverse Reactions

Also see Piperacillin monograph.

>10%: Gastrointestinal: Diarrhea (11%)

1% to 10%:

Cardiovascular: Phlebitis (1%), flushing (≤1%), hypotension (≤1%), thrombophlebitis (≤1%)

Central nervous system: Headache (8%), insomnia (7%), rigors (≤1%)

Dermatologic: Skin rash (4%), pruritus (3%), purpuric disease (≤1%)

Endocrine & metabolic: Hypoglycemia (≤1%)

Gastrointestinal: Constipation (8%), nausea (7%), dyspepsia (3%), vomiting (3%), abdominal pain (1%), Clostridium difficile colitis (≤1%)

Hypersensitivity: Anaphylaxis (≤1%)

Infection: Candidiasis (2%)

Local: Injection site reaction (≤1%)

Neuromuscular & skeletal: Arthralgia (≤1%), myalgia (≤1%)

Respiratory: Epistaxis (≤1%)

Miscellaneous: Fever (2%)

Frequency not defined:

Endocrine & metabolic: Decreased serum albumin, decreased serum glucose, decreased serum total protein, electrolyte disorder (increases and decreases in sodium, potassium, and calcium), hyperglycemia, hypokalemia, increased gamma-glutamyl transferase

Hematologic & oncologic: Decreased hematocrit, decreased hemoglobin, eosinophilia, leukopenia, neutropenia, positive direct Coombs test, prolonged bleeding time, prolonged partial thromboplastin time, prolonged prothrombin time, thrombocythemia, thrombocytopenia

Hepatic: Increased serum alkaline phosphatase, increased serum alanine aminotransferase, increased serum aspartate aminotransferase, increased serum bilirubin

Renal: Increased blood urea nitrogen, increased serum creatinine, renal failure syndrome

<1%, postmarketing, and/or case reports: Acute generalized exanthematous pustulosis, agranulocytosis, Clostridioides difficile associated diarrhea, delirium, drug reaction with eosinophilia and systemic symptoms, eosinophilic pneumonitis, erythema multiforme, exfoliative dermatitis, hemolytic anemia, hepatitis, hypersensitivity reaction, interstitial nephritis, jaundice, nonimmune anaphylaxis, pancytopenia, seizure, shock, Stevens-Johnson syndrome, toxic epidermal necrolysis

Warnings/Precautions

Concerns related to adverse effects:

• Anaphylactoid/hypersensitivity reactions: Serious and occasionally severe or fatal hypersensitivity (anaphylactic/anaphylactoid) reactions have been reported in patients on penicillin therapy, especially with a history of beta-lactam hypersensitivity or history of sensitivity to multiple allergens. Discontinue treatment and institute appropriate therapy if an allergic reaction occurs.
• Dermatologic effects: Serious skin reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), acute exanthematous pustulosis, and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported. If a skin rash develops, monitor closely. Discontinue if lesions progress.
• Electrolyte abnormalities: Sodium content (2.84 mEq per gram of piperacillin) should be considered in patients requiring sodium restriction. Assess electrolytes periodically in patients with low potassium reserves, especially those receiving cytotoxic therapy or diuretics.
• Hematologic effects: Prothrombin time, platelet aggregation, and clotting time abnormalities have been reported with piperacillin and particularly in patients with renal impairment. Discontinue if thrombocytopenia or bleeding occurs. Leukopenia/neutropenia may occur; appears to be reversible and most frequently associated with prolonged administration. Assess hematologic parameters periodically, especially with prolonged (≥21 days) use.
• Nephrotoxicity: Risk of nephrotoxicity is increased when piperacillin and tazobactam is given in combination with vancomycin compared to vancomycin alone or vancomycin in combination with other beta-lactams (eg, cefepime) (Mellen 2017).
• Superinfection: Use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment.

Disease-related concerns:

• Cystic fibrosis: An increased frequency of fever and rash has been reported in patients with cystic fibrosis receiving piperacillin.
• Renal impairment: Use with caution in patients with renal impairment or in hemodialysis patients. Dosage adjustment recommended.
• Seizure disorders: Use with caution in patients with a history of seizure disorder; high levels, particularly in the presence of renal impairment, may increase risk of seizures.

Special populations:

• Critically ill patients: Use of piperacillin and tazobactam in critically ill patients may delay renal recovery as compared to other beta-lactam antibacterial drugs; consider alternative treatment options in critically ill patients. If alternative treatment options are inadequate or unavailable, closely monitor renal function.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Monitoring Parameters

Creatinine, BUN, CBC with differential, PT, PTT, serum electrolytes, LFTs, urinalysis; signs of bleeding; monitor for signs of anaphylaxis during first dose

Pregnancy

Pregnancy Considerations

Piperacillin and tazobactam cross the placenta.

Due to pregnancy-induced physiologic changes, some pharmacokinetic properties of piperacillin/tazobactam may be altered (Bourget 1998). Piperacillin/tazobactam is approved for the treatment of postpartum gynecologic infections, including endometritis or pelvic inflammatory disease, caused by susceptible organisms.

Patient Education

What is this drug used for?

• It is used to treat bacterial infections.

Frequently reported side effects of this drug

• Headache
• Nausea
• Diarrhea
• Constipation
• Trouble sleeping

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain.
• Bruising
• Bleeding
• Seizures
• Extra muscle movement
• Clostridium difficile (C. diff)-associated diarrhea like abdominal pain or cramps, severe diarrhea or watery stools, or bloody stools.
• Infection
• Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes.
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.