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Piperacillin and Tazobactam

Medically reviewed on September 10, 2018

Pronunciation

(pi PER a sil in & ta zoe BAK tam)

Index Terms

  • Piperacillin and Tazobactam Sodium
  • Piperacillin Sodium and Tazobactam Sodium
  • Piperacillin Sodium/Tazobactam
  • Piperacillin/Tazobactam Sod
  • Tazobactam and Piperacillin

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]:

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: 2.25 g: Piperacillin 2 g and tazobactam 0.25 g; 3.375 g: Piperacillin 3 g and tazobactam 0.375 g; 4.5 g: Piperacillin 4 g and tazobactam 0.5 g; 40.5 g: Piperacillin 36 g and tazobactam 4.5 g

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]

Brand Names: U.S.

  • Zosyn

Pharmacologic Category

  • Antibiotic, Penicillin

Pharmacology

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.

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; Vd: Children and Adults: 0.243 L/kg

Metabolism

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

Tazobactam: ~22% to inactive metabolite

Excretion

Clearance of both piperacillin and tazobactam are directly proportional to renal function; Infants and Children 9 months to 12 years: 5.64 mL/minute/kg

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

Note: Pediatric data: Reed 1994

Piperacillin:

Infants 2 to 5 months: 1.4 hours

Infants and Children 6 to 23 months: 0.9 hour

Children 2 to 12 years: 0.7 hour

Adults: 0.7 to 1.2 hours

Metabolite: 1 to 1.5 hours

Tazobactam:

Infants 2 to 5 months: 1.6 hours

Infants and Children 6 to 23 months: 1 hour

Children 2 to 12 years: 0.8 to 0.9 hour

Adults: 0.7 to 0.9 hour

Protein Binding

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

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

Intra-abdominal 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.

Off Label Uses

Bite wound infections

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 prophylaxis and treatment of animal bite wound infections.

Clinical experience also supports the utility of piperacillin and tazobactam in the prophylaxis and treatment of human bite wound infections [Baddour 2017b].

Bloodstream infection (gram-negative bacteremia)

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 2017b]. 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, exacerbation

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.

Endocarditis, treatment (pediatric)

Based on the American Heart Association (AHA) scientific statement on infective endocarditis in childhood, piperacillin and tazobactam, in combination with an aminoglycoside, is effective and recommended for the treatment of infective endocarditis due to gram-negative bacilli in children and adolescents.

Malignant (necrotizing) external otitis

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

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).

Pleural empyema (hospital-acquired infection, immunocompromised host, or coverage of P. aeruginosa)

Clinical experience suggests the utility of piperacillin and tazobactam in the treatment of pleural empyema, including hospital-acquired infection, infection in immunocompromised hosts, and for coverage of P. aeruginosa [Psallidas 2014].

Sepsis and septic shock

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.

Skin and soft tissue infection, necrotizing

Based on the IDSA guidelines for the diagnosis and management of SSTIs, piperacillin and tazobactam, as part of an appropriate combination regimen, is effective and recommended for the empiric treatment of necrotizing infections of the skin, fascia, and muscle caused by polymicrobial (mixed) infections.

Suppurative parotitis (acute bacterial) and deep neck space infections

Clinical experience suggests the utility of piperacillin and tazobactam in the treatment of suppurative parotitis (acute bacterial) and deep neck space infections that are health care-associated, in immunocompromised hosts, or for coverage of P. aeruginosa [Chow 2017a], [Chow 2017b].

Surgical site infections

Based on the IDSA guidelines for the diagnosis and management of SSTIs, piperacillin and tazobactam is an effective and recommended option for treatment of incisional surgical site infections occurring after surgery of the intestinal or genitourinary tract that warrant expanded coverage for gram-negative and anaerobic pathogens.

Urinary tract infection, complicated (including pyelonephritis)

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 2018], [Johnson 2018].

Contraindications

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

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 (off-label method).

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: Give a loading dose of 3.375 to 4.5 g over 30 minutes, especially when rapid attainment of therapeutic drug concentrations is necessary (eg, sepsis). Extended infusion method is supported by data suggesting equal or better attainment of pharmacokinetic targets and observational data suggesting clinical benefit in patients with elevated risk of drug-resistant pathogens, severe infections, altered pharmacokinetics, and in other high-risk clinical situations (Lodise 2007; MacVane 2014; Moehring 2017a; Rhodes 2014; Vardakas 2018).

Indication-specific dosing:

Bite wound infections (off-label use): Note: Additional coverage for methicillin-resistant Staphylococcus aureus (MRSA) may be needed.

Animal bite wound, prophylaxis for high-risk wound or treatment: IV: 3.375 g every 6 to 8 hours. Duration for prophylaxis is 3 to 5 days (IDSA [Stevens 2014]); duration of treatment for established infection ranges from 5 to 14 days and varies based on clinical response and patient-specific factors (Baddour 2017a).

Human bite wound, prophylaxis or treatment: IV: 4.5 g every 8 hours. Duration for prophylaxis is 3 to 5 days; duration of treatment for established infection ranges from 5 to 14 days based on clinical response and patient-specific factors. Complicated infections (eg, osteomyelitis) require prolonged therapy (Baddour 2017b).

Bloodstream infection (gram-negative bacteremia) (off-label use): Note: For empiric therapy of known or suspected pseudomonal bloodstream infection in patients with neutropenia, severe burns, sepsis, or septic shock; give as part of an appropriate combination regimen (Kanj 2017a; Moehring 2017b; SCCM [Rhodes 2017]). Some experts prefer the extended infusion method in critical illness or to optimize exposure if treating a susceptible organism with an elevated minimum inhibitory concentration (MIC). If critically ill, give first dose over 30 minutes as a loading dose, followed 4 hours later by extended infusion (Moehring 2017a; SCCM [Rhodes 2017]).

Community-acquired infection, immunocompetent host: IV: 3.375 g every 6 hours (Moehring 2017b).

Health care-associated infection, including catheter-related, immunosuppressed host, or for coverage of Pseudomonas aeruginosa: IV: 4.5 g every 6 hours (IDSA [Mermel 2009]; Moehring 2017b).

Duration of therapy: Individualize duration according to patient-specific factors and response; usual duration is 7 to 14 days. If neutropenic, extend treatment until afebrile for 2 days and recovery of neutrophils (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 2017a).

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. Note: Most often given as part of an appropriate combination regimen, which should include an additional antipseudomonal agent (Flume 2009; Simon 2017).

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 2017). Note: Empiric Pseudomonas coverage with this dose is usually not indicated unless patient is at risk (eg, significant water exposure, warm climate) (IDSA [Lipsky 2012]; Weintrob 2017).

Duration of therapy: Varies by patient-specific factors; usual duration is 2 to 4 weeks (in the absence of osteomyelitis). May switch to oral agents when appropriate to complete course of therapy (IDSA [Lipsky 2012]; Weintrob 2017).

Intra-abdominal infection:

Appendicitis, perforated: IV: 3.375 or 4.5 g every 6 hours for 4 to 7 days (IDSA [Solomkin 2010])

Diverticulitis, hospitalized patient: IV: 3.375 or 4.5 g every 6 hours for 4 to 7 days (IDSA [Solomkin 2010]). Once stable, some experts transition to oral antibiotics to complete a 10- to 14-day total course of therapy (Pemberton 2017).

Intra-abdominal abscess: IV: 3.375 or 4.5 g every 6 hours for 4 to 7 days following adequate source control (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 (ANC expected to be ≤100 cells/mm3 for >7 days, clinically unstable, or significant comorbidity) (off-label use): 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 2018). Note: Some experts consider patients expected to have an ANC <500 cells/mm3 for >7 days to be at high risk (Wingard 2018).

Some experts prefer the extended infusion method, particularly in those who are critically ill; give first dose over 30 minutes as a loading dose, followed 4 hours later by extended infusion (Moehring 2017a; SCCM [Rhodes 2017]).

Pleural empyema (hospital-acquired infection, immunocompromised host, or coverage of P. aeruginosa) (off-label use): IV: 4.5 g every 6 hours (IDSA/ATS [Kalil 2016]). Note: Use in conjunction with surgical drainage. Additional agent for coverage of MRSA may be needed in patents with hospital-acquired or postprocedural empyema (Psallidas 2014; Strange 2017).

Pneumonia:

Community-acquired pneumonia (CAP), as a component of empiric therapy for coverage of P. aeruginosa (hospitalized patient): IV: 4.5 g every 6 hours in combination with other appropriate agent(s) for 5 to 7 days and individualized based on response to therapy (File 2017; IDSA/ATS [Mandell 2007]). A longer course (7 to 21 days) may be required if P. aeruginosa is the cause (Kanj 2017b).

Hospital-acquired or ventilator-associated pneumonia (HAP, VAP): IV: 4.5 g every 6 hours, in combination with other agent(s) when appropriate, for 7 days and individualized based on response to therapy (IDSA/ATS [Kalil 2016]). A longer course may be required if P. aeruginosa is the cause (Kanj 2017b). Some experts prefer the extended infusion method, particularly in those who are critically ill; give first dose over 30 minutes as a loading dose, followed 4 hours later by extended infusion (File 2017; Moehring 2017a; Rhodes 2014).

Sepsis and septic shock (broad-spectrum coverage, including P.aeruginosa) (off-label use): IV: 4.5 g every 6 hours in combination with other appropriate agent(s) (Kanj 2017c). Initiate therapy as soon as possible and within 1 hour of recognition of sepsis or septic shock. Usual duration of treatment is 7 to 10 days or longer depending upon clinical response (SCCM [Rhodes 2017]). Some experts prefer the extended infusion method; give first dose over 30 minutes as a loading dose, followed 4 hours later by extended infusion (Moehring 2017a; SCCM [Rhodes 2017]).

Skin and soft tissue infection, due to P. aeruginosa: IV: 4.5 g every 6 hours. Usual duration of treatment is 10 to 14 days and is individualized based on response to therapy (Kanj 2017c).

Skin and soft tissue infection, necrotizing (broad-spectrum coverage of gram-positive [not including MRSA], gram-negative, and anaerobic pathogens) (off-label use): IV: 3.375 g every 6 to 8 hours as part of an appropriate combination regimen. Continue until further debridement is not necessary, patient has improved clinically, and is afebrile for 48 to 72 hours (IDSA [Stevens 2014]).

Suppurative parotitis (acute bacterial) and deep neck space infections, health care-associated, immunocompromised host, or for coverage of P. aeruginosa (off-label use): IV: 4.5 g every 6 hours. For empiric therapy, give in combination with an agent appropriate for coverage of MRSA (Chow 2017a; Chow 2017b).

Duration of therapy: 10 to 14 days (including oral step-down) for uncomplicated suppurative parotitis (Chow 2017a); ≥2 to 3 weeks of IV therapy for deep neck space infections (Chow 2017b).

Surgical site infections, incisional (eg, intestinal, genitourinary tract), warranting expanded coverage of gram-negative and anaerobic pathogens (off-label use): IV: 3.375 g every 6 hours or 4.5 g every 8 hours (IDSA [Stevens 2014]). For treatment of P. aeruginosa infection: 4.5 g every 6 hours (Kanj 2017c). Duration is dependent upon severity, need for debridement, and clinical response (IDSA [Stevens 2014]).

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 2018).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Piperacillin and 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 in pediatric patients are based on the piperacillin component. Dosing presented is based on traditional infusion method (IV infusion over 30 minutes) unless otherwise specified as the extended infusion method (IV infusion over 4 hours [off-label method]).

Usual dosage range: IV:

Infants 2 to 9 months: 80 mg piperacillin/kg/dose every 8 hours (Red Book [AAP 2012]):

Infants >9 months, Children, and Adolescents: 100 mg piperacillin/kg/dose every 8 hours (maximum dose: 16 g piperacillin/day) (Red Book [AAP 2012]):

Children and Adolescents: Extended infusion method: Limited data available: 100 mg piperacillin/kg/dose infused over 4 hours 3 times daily. Dosing based on a prospective, observational study (n=332) in a single children's hospital comparing the extended infusion method to traditional dosing (Nichols 2012).

Indication-specific dosing: Infants, Children, and Adolescents: Note: In pediatric patients, dosage recommendations are based on the piperacillin component. Dosing is presented in mg/kg/dose and mg/kg/day; use caution.

Appendicitis, peritonitis:

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

Infants >9 months, Children, and Adolescents ≤40 kg: IV: 100 mg piperacillin/kg/dose every 8 hours (maximum: 3,000 mg piperacillin/dose)

Children and Adolescents >40 kg: Refer to adult dosing.

Cystic fibrosis, pseudomonal lung infections (off-label use):

Standard dosing: 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 (off-label use): 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])

Intra-abdominal infection, complicated (off-label use): IV: 200 to 300 mg piperacillin/kg/day divided every 6 to 8 hours (maximum dose: 12 g piperacillin/day) (IDSA [Solomkin 2010])

Skin and soft tissue necrotizing infections (off-label use): IV: 60 to 75 mg piperacillin/kg 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 (perioperative) prophylaxis (off-label use): Note: Doses may be repeated in 2 hours if procedure is lengthy or if there is excessive blood loss (Bratzler 2013): IV:

Infants 2 to 9 months: 80 mg piperacillin/kg within 60 minutes prior to surgical incision (maximum: 3,000 mg piperacillin/dose)

Infants >9 months, Children, and Adolescents ≤40 kg: 100 mg piperacillin/kg within 60 minutes prior to surgical incision (maximum: 3,000 mg piperacillin/dose)

Adolescents weighing >40 kg: 3,000 mg piperacillin 30 to 60 minutes prior to procedure

Dosing: Renal Impairment

Adults:

Traditional infusion method (ie, IV infusion over 30 minutes): Manufacturer’s labeling:

CrCl >40 mL/minute: No dosage adjustment necessary.

CrCl 20 to 40 mL/minute: Administer 2.25 g every 6 hours (3.375 g every 6 hours for hospital-acquired or ventilator-associated pneumonia)

CrCl <20 mL/minute: Administer 2.25 g every 8 hours (2.25 g every 6 hours for hospital-acquired or ventilator-associated pneumonia)

Note: Some clinicians suggest adjusting the dose at CrCl ≤20 mL/minute (rather than CrCl <40 mL/minute) in patients receiving either traditional or extended-infusion methods, particularly if treating serious gram-negative infections (empirically or definitively) (Patel 2010).

Extended infusion method (off-label dosing): CrCl ≤20 mL/minute: 3.375 g IV over 4 hours every 12 hours (Patel 2010)

End-stage renal disease (ESRD):

Intermittent hemodialysis (IHD): 2.25 g every 12 hours (2.25 g every 8 hours for hospital-acquired or ventilator-associated pneumonia); Hemodialysis removes 30% to 40% of a piperacillin/tazobactam dose. Note: Dosing dependent on the assumption of 3 times/week, complete IHD sessions. Administer scheduled doses after hemodialysis on dialysis days; if next regularly scheduled dose is not due right after dialysis session, administer an additional dose of 0.75 g after the dialysis session.

Peritoneal dialysis (PD): 2.25 g every 12 hours (2.25 g every 8 hours for hospital-acquired or ventilator-associated pneumonia); peritoneal dialysis removes 6% of piperacillin and 21% of tazobactam.

Continuous renal replacement therapy (CRRT) (Heintz 2009; Trotman 2005): Drug clearance is highly dependent on the method of renal replacement, filter type, and flow rate. Appropriate dosing requires close monitoring of pharmacologic response, signs of adverse reactions due to drug accumulation, as well as drug concentrations in relation to target trough (if appropriate). The following are general recommendations only (based on dialysate flow/ultrafiltration rates of 1 to 2 L/hour and minimal residual renal function) and should not supersede clinical judgment (Trotman 2005):

CVVH: 2.25 to 3.375 g every 6 to 8 hours

CVVHD: 2.25 to 3.375 g every 6 hours

CVVHDF: 3.375 g every 6 hours

Note: Higher dose of 3.375 g should be considered when treating resistant pathogens (especially Pseudomonas spp); alternative recommendations suggest dosing of 4.5 g every 8 hours (Valtonen 2001); regardless of regimen, there is some concern of tazobactam (TAZ) accumulation, given its lower clearance relative to piperacillin (PIP). Some clinicians advocate dosing with PIP to alternate with PIP/TAZ, particularly in CVVH-dependent patients, to lessen this concern.

Infants, Children, and Adolescents: There are no dosage adjustments provided in the manufacturer's labeling; however, the following adjustments have been recommended (Aronoff, 2007): Dosing based on a usual dose of 200 to 300 mg piperacillin/kg/day in divided doses every 6 hours.

GFR >50 mL/minute/1.73 m2: No dosage adjustment necessary.

GFR 30 to 50 mL/minute/1.73 m2: 35 to 50 mg piperacillin/kg/dose every 6 hours

GFR <30 mL/minute/1.73 m2: 35 to 50 mg piperacillin/kg/dose every 8 hours

End-stage renal disease (ESRD) on intermittent hemodialysis (IHD): Hemodialysis removes 30% to 40% of a piperacillin/tazobactam dose: 50 to 75 mg piperacillin/kg/dose every 12 hours

Peritoneal dialysis (PD): Peritoneal dialysis removes 21% of tazobactam and 6% of piperacillin: 50 to 75 mg piperacillin/kg/dose every 12 hours

Continuous renal replacement therapy (CRRT): 35 to 50 mg piperacillin/kg/dose every 8 hours

Dosing: Hepatic Impairment

No dosage adjustment necessary.

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

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 Penicillins. Management: Avoid the routine use of penicillins and probenecid, but this combination may be used advantageously in select cases with careful monitoring. Monitor for toxic effects of penicillins if probenecid is initiated or the dose is increased. 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. Consider therapy modification

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%), purpura (≤1%)

Endocrine & metabolic: Hypoglycemia (≤1%)

Gastrointestinal: Constipation (8%), nausea (7%), dyspepsia (3%), vomiting (3%), abdominal pain (1%), pseudomembranous 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 disturbance (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 ALT, increased serum AST, increased serum bilirubin

Renal: Increased blood urea nitrogen, increased serum creatinine, renal failure (in critically ill patients)

<1%, postmarketing, and/or case reports: Acute generalized exanthematous pustulosis, agranulocytosis, anaphylactoid reaction, Clostridium difficile-associated diarrhea, convulsions, DRESS syndrome, eosinophilic pneumonitis, erythema multiforme, exfoliative dermatitis, hemolytic anemia, hepatitis, hypersensitivity reaction, interstitial nephritis, jaundice, pancytopenia, 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.

• 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 Considerations

Piperacillin and tazobactam both cross the placenta and are found in the fetal serum, placenta, amniotic fluid, and fetal urine. When used during pregnancy, the clearance and volume of distribution of piperacillin/tazobactam are increased; half-life and AUC are decreased (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

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, nausea, diarrhea, constipation, or insomnia. Have patient report immediately to prescriber signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), bruising, bleeding, seizures, extra muscle movement, signs of Clostridium difficile (C. diff)-associated diarrhea (abdominal pain or cramps, severe diarrhea or watery stools, or bloody stools), pharyngitis, signs of infection, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

Further information

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