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Piperacillin and tazobactam: Drug information

Piperacillin and tazobactam: Drug information
(For additional information see "Piperacillin and tazobactam: Patient drug information" and see "Piperacillin and tazobactam: Pediatric drug information")

For abbreviations and symbols that may be used in Lexicomp (show table)
Brand Names: US
  • Zosyn
Brand Names: Canada
  • JAMP-Pip/Taz
Pharmacologic Category
  • Antibiotic, Penicillin
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 2009a; 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 2021a; 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 2021a; Baddour 2021b; 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 2021a; 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 2020). 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 2020).

Intra-abdominal infection:

Cholecystitis, acute: IV: 3.375 g 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 2021).

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 transition to oral antibiotics) is 4 to 5 days following adequate source control (Gomi 2018; Sawyer 2015; SIS [Mazuski 2017]); for diverticulitis or uncomplicated appendicitis managed without intervention, duration is 7 to 10 days (Barshak 2021; Pemberton 2021). Note: For patients who are critically ill or at risk for infection with drug-resistant pathogens, some experts favor the extended infusion method (Barshak 2021; 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 2021; 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 2020).

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 2020). Some experts prefer the extended-infusion method, particularly in those who are critically ill (Moehring 2021a; SCCM [Rhodes 2017]).

Pneumonia:

Community-acquired pneumonia: For empiric therapy of inpatients at risk of infection with a 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; a longer course may be required for patients with an immunocompromising condition, severe or complicated infection, or for P. aeruginosa infection. Patients should be clinically stable with normal vital signs prior to discontinuation (ATS/IDSA [Metlay 2019]; Ramirez 2020).

Hospital-acquired or ventilator-associated pneumonia: For empiric therapy (often as part of an appropriate combination regimen) or pathogen-specific therapy of resistant gram-negative pathogen(s), including P. aeruginosa:

IV: 4.5 g every 6 hours. Duration of therapy varies based on disease severity and response to therapy; treatment is typically given for 7 days (IDSA/ATS [Kalil 2016]). Note: Some experts prefer extended or continuous infusion for critical illness or when treating a susceptible organism with an elevated minimum inhibitory concentration (Moehring 2021a; SCCM [Rhodes 2017]).

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 2020c). 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 2021a; 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 2021). 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 2020c).

Urinary tract infection, complicated (pyelonephritis or urinary tract infection with systemic signs/symptoms) (off-label use): IV: 3.375 g every 6 hours. Note: Switch to an appropriate oral regimen once symptoms improve, if culture and susceptibility results allow. Total duration of therapy ranges from 5 to 14 days and depends on clinical response and the antimicrobial chosen to complete the regimen (Hooton 2021; IDSA/ESCMID [Gupta 2011]).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Renal Impairment: Adult

The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.

Note: 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). When utilizing extended infusions, 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]).

Altered kidney function: IV:

Piperacillin/Tazobactam Dosage Adjustments in Altered Kidney Functiona,b

Traditional infusion method (over 30 minutes)

Extended infusion method (over 4 hours)

CrCl (mL/minute)

If the usual recommended dose is 3.375 g every 6 hours

If the usual recommended dose is 4.5 g every 6 hours

If the usual recommended dose is 3.375 g infused over 4 hours every 8 hours

aChoose the usual recommended dose based on indication and disease severity (see adult dosing), then choose the adjusted dose from that column corresponding to the patient's CrCl.

bPatel 2010; Thabit 2017; expert opinion; manufacturer's labeling.

100 to <130

Extended infusion preferred

Extended infusion preferred

3.375 or 4.5 g infused over 4 hours every 6 hours

40 to <100 (usual recommended dose)

3.375 g every 6 hours

4.5 g every 6 hours

3.375 g infused over 4 hours every 8 hours

20 to <40

2.25 g every 6 hours

4.5 g every 8 hours or 3.375 g every 6 hours

3.375 g infused over 4 hours every 8 to 12 hours

<20

2.25 g every 8 hours

4.5 g every 12 hours or 2.25 g every 6 hours

3.375 g infused over 4 hours every 12 hours

Augmented renal clearance (measured urinary CrCl ≥130 mL/minute/1.73 m2): Augmented renal clearance (ARC) is a condition that occurs in certain critically ill patients without organ dysfunction and with normal serum creatinine concentrations. Young patients (<55 years of age) admitted post trauma or major surgery are at highest risk for ARC, as well as those with sepsis, burns or hematological malignancies. An 8 to 24 hour measured urinary creatinine clearance is necessary to identify these patients (Bilbao-Meseguer 2018; Udy 2010).

CrCl 130 to <170 mL/minute: IV: Loading dose: 4.5 g, followed immediately by a daily continuous infusion of 18 g over 24 hours (Carrié 2018).

CrCl ≥170 mL/minute: IV: Loading dose: 4.5 g, followed immediately by a daily continuous infusion of 22.5 g over 24 hours (Carrié 2018).

Hemodialysis, intermittent (thrice weekly): Dialyzable (30% to 40%):

IV: 4.5 g every 12 hours or 2.25 g every 8 hours (Thabit 2017; manufacturer's labeling); administration of scheduled doses after hemodialysis on dialysis days is preferred but not required (expert opinion).

Peritoneal dialysis: Dialyzable (6% of piperacillin, 21% of tazobactam):

IV: 4.5 g every 12 hours or 2.25 g every 8 hours (Debruyne 1990; Manley 2000).

CRRT: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement (Jamal 2014). Recommendations assume high-flux dialyzers and effluent flow rates of 20 to 25 mL/kg/hour (~1,500 to 3,000 mL/hour), unless otherwise noted. Appropriate dosing requires consideration of adequate drug concentrations (eg, site of infection [Varghese 2014]) and consideration of initial loading doses. Close monitoring of response and adverse reactions due to drug accumulation is important.

CVVH/CVVHD/CVVHDF: Note: Given piperacillin/tazobactam’s favorable safety profile, some experts recommend initiating therapy with relatively high doses (especially in critically ill patients) (Hayashi 2010; Jamal 2015). Dose should be adjusted during CRRT interruptions as ongoing dosing may lead to accumulation and potential increased risk of toxicity.

IV: 4.5 g every 8 hours (Arzuaga 2005; Asin-Prieto 2014; Shotwell 2016; Varghese 2014) or 4.5 g loading dose followed by 2.25 g every 6 hours (Jamal 2015).

Continuous IV infusion: 4.5 g loading dose (expert opinion) followed immediately by a 9 g over 24 hours daily maintenance dose (Jamal 2015).

PIRRT (eg, sustained low-efficiency diafiltration): Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Appropriate dosing requires consideration of adequate drug concentrations (eg, site of infection). Close monitoring of response and adverse reactions due to drug accumulation is important.

IV:

Sustained low-efficiency dialysis (8-hour daily sessions with blood flow rate 200 mL/minute and effluent flow rate 300 mL/minute): 3.375 g every 8 hours (Kanji 2018).

Extended high-volume hemofiltration (10-hour sessions with blood flow rate 200 mL/minute and effluent flow rate >500 mL/minute): 4.5 g every 8 hours (Tamme 2016).

Dosing: Hepatic Impairment: Adult

No dosage adjustment necessary.

Dosing: Pediatric

(For additional information see "Piperacillin and tazobactam: Pediatric drug information")

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

Children and Adolescents weighing >40 kg: 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]).

Nosocomial pneumonia:

Infants 2 to 9 months: IV: 80 mg piperacillin/kg/dose every 6 hours.

Infants >9 months, Children, and Adolescents weighing ≤40 kg: IV: 100 mg piperacillin/kg/dose every 6 hours; maximum dose: 4,000 mg piperacillin/dose.

Children and Adolescents weighing >40 kg: IV: 4,000 mg piperacillin every 6 hours; maximum daily dose: 16 g piperacillin/day.

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).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Renal Impairment: Pediatric

Infants, Children, and Adolescents: There are no dosage adjustments provided in the manufacturer's labeling; however, the following have been used by some clinicians (Aronoff 2007): Note: Dosage recommendations are based on the piperacillin component. 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 adjustment required

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

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: Pediatric

No dosing adjustment required

Dosing: Geriatric

Refer to adult dosing.

Dosing: Obesity: Adult

The recommendations for dosing in obese patients are based upon the best available evidence and clinical expertise. Senior Editorial Team: Jeffrey F. Barletta, PharmD, FCCM; Manjunath P. Pai, PharmD, FCP; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC.

Principles of body weight dosing:

Note: There are limited data on the effect of obesity on dosing requirements for piperacillin and tazobactam. Data are available from hospitalized patients (eg, critically ill) predominantly at steady state. Consistently lower unbound trough concentrations and increased drug clearance estimates and volume of distribution (with greater coefficients of variation) are reported in patients who are obese compared with patients who are not obese (Alobaid 2016). Despite a higher proportion of patients who are obese who have subtherapeutic trough concentrations (eg, augmented renal clearance, elevated pathogen minimum inhibitory concentration [MIC ≥16 mg/L]), administration of higher doses (eg, 4.5 g every 6 hours) may increase drug concentrations and the likelihood of target concentration attainment, particularly when administered as a prolonged infusion (eg, 3 to 4 hours) (Alobaid 2017; Cheatham 2013; Hites 2014; expert opinion). The effect of obesity on first-dose pharmacokinetics remains unknown.

BMI ≥30 kg/m2:

Extended infusion method: Note: To increase the likelihood of therapeutic concentrations and target attainment. When rapid attainment of therapeutic drug concentrations is necessary, use a loading dose of 4.5 g over 30 minutes (SCCM [Rhodes 2017]).

Life-threatening infections caused by resistant pathogens (eg, MIC 16 mg/L); or infection site penetration limitations; or patients with extreme morbid obesity (BMI ≥50 kg/m2): IV: 4.5 g every 6 hours infused over 3 hours (Alobaid 2017; expert opinion).

Critically ill patients with augmented renal function (eg, creatinine clearance >100 mL/minute): IV: 4.5 g every 8 hours infused over 4 hours or 4.5 g every 6 hours infused over 3 hours (expert opinion).

Traditional infusion method (over 30 minutes): IV: 4.5 g every 6 hours (Meng 2017).

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution, Intravenous [preservative free]:

Zosyn: Piperacillin 2 g and tazobactam 0.25 g per 50 mL (50 mL); Piperacillin 4 g and tazobactam 0.5 g per 100 mL (100 mL); Piperacillin 3 g and tazobactam 0.375 g per 50 mL (50 mL) [contains edetate (edta) disodium dihydrate]

Solution Reconstituted, Intravenous:

Generic: Piperacillin 2 g and tazobactam 0.25 g (1 ea); Piperacillin 3 g and tazobactam 0.375 g (1 ea); Piperacillin 36 g and tazobactam 4.5 g (1 ea); Piperacillin 4 g and tazobactam 0.5 g (1 ea)

Solution Reconstituted, Intravenous [preservative free]:

Zosyn: Piperacillin 2 g and tazobactam 0.25 g (1 ea [DSC]); Piperacillin 3 g and tazobactam 0.375 g (1 ea [DSC]); 4.5 g: Piperacillin 4 g and tazobactam 0.5 g (1 ea [DSC]); 2.25 g: Piperacillin 2 g and tazobactam 0.25 g (1 ea [DSC]); 40.5 g: Piperacillin 36 g and tazobactam 4.5 g (1 ea [DSC]); 3.375 g: Piperacillin 3 g and tazobactam 0.375 g (1 ea [DSC]) [contains edetate (edta) disodium]

Generic: 2.25 g: Piperacillin 2 g and tazobactam 0.25 g (1 ea); 3.375 g: Piperacillin 3 g and tazobactam 0.375 g (1 ea); 4.5 g: Piperacillin 4 g and tazobactam 0.5 g (1 ea); 40.5 g: Piperacillin 36 g and tazobactam 4.5 g (1 ea); Piperacillin 12 g and tazobactam 1.5 g (1 ea); Piperacillin 2 g and tazobactam 0.25 g (1 ea); Piperacillin 3 g and tazobactam 0.375 g (1 ea); Piperacillin 36 g and tazobactam 4.5 g (1 ea); Piperacillin 4 g and tazobactam 0.5 g (1 ea)

Generic Equivalent Available: US

May be product dependent

Dosage Forms: Canada

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

Solution Reconstituted, Intravenous:

Generic: Piperacillin 12 g and tazobactam 1.5 g (1 ea); Piperacillin 2 g and tazobactam 0.25 g (1 ea); Piperacillin 3 g and tazobactam 0.375 g (1 ea); Piperacillin 36 g and tazobactam 4.5 g (1 ea); Piperacillin 4 g and tazobactam 0.5 g (1 ea)

Administration: Adult

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

Limited retrospective data with IV push administration over 2 to 5 minutes (vial reconstituted with NS [10 mL for a 3.375 g vial and 20 mL for a 4.5 g vial] or SWFI [20 mL for a 2.25 g, 3.375 g, or 4.5 g vial]) have demonstrated this method of administration to be generally safe and tolerable, but clinical outcomes were not assessed; patients should be monitored for phlebitis and other infusion-related reactions if administered IV push (Hays 2020; Petitt 2018).

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.

Administration: Pediatric

Parenteral:

Intermittent IV infusion: Administer over 30 minutes.

Extended IV infusion: Administer over 4 hours (Knoderer 2017; Nichols 2016a).

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.

Use: Labeled Indications

Intra-abdominal infections: Treatment of appendicitis complicated by rupture or abscess and peritonitis in adults and pediatric patients ≥2 months of age caused by beta-lactamase-producing strains of Escherichia coli, Bacteroides fragilis, Bacteroides ovatus, Bacteroides thetaiotaomicron, or Bacteroides vulgatus.

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

Pneumonia, community-acquired: Treatment of moderate severity community-acquired pneumonia in adults caused by beta-lactamase-producing strains of Haemophilus influenzae.

Pneumonia, hospital-acquired (nosocomial): Treatment of moderate to severe hospital-acquired (nosocomial) pneumonia in adults and pediatric patients ≥2 months of age caused by beta-lactamase-producing strains of Staphylococcus aureus and by piperacillin/tazobactam-susceptible Acinetobacter baumannii, H. influenzae, Klebsiella pneumoniae, and Pseudomonas aeruginosa.

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

Use: Off-Label: Adult

Bite wound infection, treatment (animal or human bite); Bloodstream infection (gram-negative bacteremia); Cystic fibrosis, severe acute pulmonary exacerbation; Malignant (necrotizing) external otitis; Neutropenic fever, high-risk cancer patients (empiric therapy); Sepsis and septic shock; Urinary tract infection, complicated (pyelonephritis or urinary tract infection with systemic signs/symptoms)

Medication Safety Issues
Sound-alike/look-alike issues:

Zosyn may be confused with Zofran, Zyvox.

International issues:

Tazact [India] may be confused with Tazac brand name for nizatidine [Australia]; Tiazac brand name for dilTIAZem [US, Canada].

Adverse Reactions (Significant): Considerations
Clostridioides difficile infection

Clostridioides difficile infection, including Clostridioides difficile associated diarrhea and Clostridioides difficile colitis, has been reported with use (Ref). Clinical symptoms range from mild diarrhea to life-threatening colitis, toxic megacolon, and sepsis. With severe infection, frequent symptoms include watery diarrhea, abdominal pain, fever, nausea, anorexia, and malaise (Ref).

Mechanism: Non–dose-related; antibiotics disrupt the indigenous gut microbiota which promotes C. difficile spore germination, growth, and toxin production, leading to epithelial damage and colitis (Ref).

Onset: Varied; may start on the first day of antibiotic therapy or up to 3 months postantibiotic (Ref).

Risk factors:

Antibiotic exposure (highest risk factor); antibiotics most frequently associated with C. difficile include clindamycin, fluoroquinolones, and third-/fourth-generation cephalosporins (Ref)

Long duration in a hospital or other health care setting (recent or current) (Ref)

Advanced age (Ref)

Immunocompromised conditions or serious underlying conditions (Ref)

GI surgery/manipulation (Ref)

Antiulcer medications, such as proton pump inhibitors and H2 blockers (suggested risk factor) (Ref)

Chemotherapy (suggested risk factor) (Ref)

Drug-induced immune thrombocytopenia

Drug-induced immune thrombocytopenia (DITP) has been associated with use (Ref).

Mechanism: Non–dose-related; piperacillin may act as a hapten by binding to the platelet membrane and forming a drug-platelet complex, leading to synthesis of drug-dependent antibodies (Ref); drug-dependent antibodies may then bind to platelet membrane glycoproteins, causing platelet consumption and thrombocytopenia (Ref). Another proposed mechanism is drug-induced production of antibodies which then bind to the membrane protein in the presence of the soluble drug (Ref).

Onset: Varied; DITP generally occurs within 1 to 2 weeks after initiating therapy or after intermittent use for a longer time (Alzaharani 2018). Case reports have described an onset from 4 days to >21 days, with a median onset of 6.5 days following initial continuous exposure (Ref). Rapid onset (within 12 to 24 hours) has also been reported very rarely, although most of these were in the setting of reexposure (Ref).

Hematologic effects

Myelosuppression (bone marrow depression), commonly manifested as neutropenia, has been associated with piperacillin. Other less commonly reported manifestations include leukopenia, thrombocytopenia (nonimmune), agranulocytosis, and pancytopenia (Ref). Rarely, piperacillin-induced platelet dysfunction leading to epistaxis or serious bleeding events, such as intracranial hemorrhage (periprocedural), has been reported (Ref).

Mechanism: Non–dose-related; mechanism behind neutropenia is unknown; suggested to be immune-mediated or the result of direct toxicity to the myeloid precursors (Ref). Bleeding events have been attributed to platelet dysfunction (or platelet aggregation), rather than thrombocytopenia (Ref).

Onset: Varied; neutropenia was found to only occur after >15 days of therapy in a systematic review (Ref); other literature suggests it may occur after ≥10 days of therapy (Ref); has also been observed after 3 days of therapy in a patient 91-years of age in 1 case report (Ref). Neutropenia is usually reversible upon discontinuation (Ref) and total blood counts reportedly returned to normal 4 days after discontinuation in 1 case report (Ref).

Risk factors:

• Prolonged duration of treatment (Ref)

• High cumulative doses (Ref)

• Underweight patients (Ref)

Hypersensitivity reactions (delayed)

Delayed hypersensitivity reactions, including severe cutaneous adverse reactions (SCARs), such as toxic epidermal necrosis (TEN), Stevens-Johnson syndrome (SJS), acute generalized exanthematous pustulosis, and drug rash with eosinophilia and systemic symptoms (DRESS), have been reported. SJS, TEN, and DRESS may be life-threatening (Ref).

Mechanism: Non–dose-related; immunologic; SCARs are type IV delayed T-cell mediated hypersensitivity reactions (Ref).

Onset: Varied; type IV reactions typically occur 2 to 7 days after drug exposure, but may also not occur for several weeks following exposure, such as with TEN (2 to 3 weeks) or DRESS (2 to 8 weeks) (Ref).

Risk factors:

• Cystic fibrosis (Ref)

Hypersensitivity reactions (immediate)

Piperacillin, an extended spectrum beta-lactam antibiotic of the acylaminopenicillin group, may cause hypersensitivity reactions (type I reactions), including anaphylaxis and anaphylactic shock, which are considered immediate hypersensitivity reactions (vs delayed reactions) and are IgE-mediated. These reactions can manifest as pruritus, flushing, urticaria, angioedema, bronchospasm, laryngeal edema, abdominal distress, hypotension, and/or anaphylactic shock or anaphylaxis, and are potentially life-threatening. Of note, some of these, such as pruritus, urticaria, or angioedema, may also occur in delayed hypersensitivity reactions (Ref).

Mechanism: Non–dose-related; immunologic. Type I reactions are IgE-mediated, with specific antibodies formed against a drug allergen following initial exposure (Ref). There are also reports of piperacillin/tazobactam-induced anaphylaxis in patients with negative penicillin skin tests, suggesting a side chain determinant of piperacillin, rather than the beta-lactam component (or possibly the tazobactam component), was responsible (Ref).

Onset: Rapid; type 1 reactions usually occur within 1 hour of administration but may occur up to 6 hours after the last dose. Selected type 1 hypersensitivity reactions (eg, urticaria, angioedema, wheezing, laryngeal edema) may occur up to 4 days into therapy but within 1 to 6 hours from the last administration (Ref).

Risk factors:

• Frequent, repeated exposure (Ref)

• History of beta-lactam hypersensitivity (Ref)

• History of sensitivity to multiple allergens (Ref)

• Occupational exposure (Ref)

• Cystic fibrosis (Ref)

Nephrotoxicity

Observational studies involving predominately noncritically ill adults have suggested a higher rate of nephrotoxicity or acute kidney injury (AKI, or acute kidney failure) when piperacillin/tazobactam is given in combination with vancomycin compared to either agent alone (Ref); however, evidence is primarily of low quality and controversy regarding this association exists. In critically ill patients, limited data have been inconsistent regarding an increased risk of AKI with the combination of piperacillin/tazobactam and vancomycin; additional data are needed (Ref).

Mechanism: Non–dose-related; one proposed mechanism is piperacillin/tazobactam may cause subclinical interstitial nephritis which is augmented by the oxidative stress induced by vancomycin; another proposed mechanism is piperacillin/tazobactam may potentially decrease the clearance of vancomycin, leading to vancomycin accumulation within the nephron. However, there is no experimental evidence to support either of these hypotheses (Ref). Of note, evidence also suggests that piperacillin/tazobactam alone is associated with delayed recovery of renal function in critically ill patients and reversible nephrotoxicity (Ref).

Onset: Rapid; median duration of combination therapy with piperacillin/tazobactam and vancomycin prior to the development of AKI was 3 days (Ref). Another study reported a peak incidence at day 5 (Ref).

Risk factors:

Piperacillin/tazobactam combined with vancomycin:

• Vancomycin loading dose (Ref)

• Concomitant nephrotoxins (Ref)

• Durations of empirical therapy >72 hours (Ref)

• Increased total body weight (Ref)

Neurotoxicity

Piperacillin is reportedly less neurotoxic than penicillin; however, there are case reports of piperacillin-induced encephalopathy (PIPE) characterized by dysarthria, tremor, slurred speech, auditory and visual hallucinations, behavioral changes, disorientation, progressive confusion, and generalized tonic-clonic seizures (Ref).

Mechanism: Non–dose-related; beta-lactam-induced neurotoxicity is attributed to the lactam ring, which is believed to exert an inhibitory effect on binding of the gamma-aminobutyric acid (GABA) to its receptor; this theory is further supported by studies showing the epileptogenic potential is lost when the beta-lactam ring is enzymatically cleaved (Ref).

Risk factors:

Risk factors for antibiotic-induced neurotoxicity in general:

• Renal dysfunction (Ref)

• Prior CNS disease, including history of seizures (Ref)

• Older adults (Ref)

• Critically-ill patients (Ref)

• Higher doses (Ref)

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Also see Piperacillin monograph.

>10%: Gastrointestinal: Diarrhea (11%)

1% to 10%:

Cardiovascular: Flushing (≤1%), hypotension (≤1%), phlebitis (1%), thrombophlebitis (≤1%)

Dermatologic: Pruritus (3%), skin rash (4%)

Endocrine & metabolic: Hypoglycemia (≤1%)

Gastrointestinal: Abdominal pain (1%), Clostridioides difficile colitis (≤1%), constipation (8%), dyspepsia (3%), nausea (7%), vomiting (3%)

Hematologic & oncologic: Purpuric disease (≤1%)

Hypersensitivity: Anaphylaxis (≤1%)

Infection: Candidiasis (2%)

Local: Injection site reaction (≤1%)

Nervous system: Headache (8%), insomnia (7%), rigors (≤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, positive direct Coombs test, prolonged bleeding time, prolonged partial thromboplastin time, prolonged prothrombin time

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

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

Postmarketing:

Dermatologic: Acute generalized exanthematous pustulosis (rare: <1%) (Peermohamed 2011), dermatologic disorder (linear IgA bullous dermatosis) (Ho 2018), erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome (Lin 2014), toxic epidermal necrolysis (rare: <1%) (Copaescu 2020)

Gastrointestinal: Clostridioides difficile-associated diarrhea (Watson 2018), melanoglossia (Ren 2020)

Hematologic & oncologic: Agranulocytosis (rare: <1%) (He 2013), bone marrow depression (rare: <1%) (He 2013), hemolytic anemia (Bollotte 2014), immune thrombocytopenia (rare: <1%) (Boyce 2016), leukopenia (rare: <1%) (Reichardt 1999), neutropenia (rare: <1%) (Darwiche 2017), pancytopenia (rare: <1%) (Lee 2009), thrombocytopenia (rare: <1%) (Kumar 2003)

Hepatic: Hepatic insufficiency (He 2013), hepatitis, jaundice

Hypersensitivity: Anaphylactic shock, nonimmune anaphylaxis

Immunologic: Drug reaction with eosinophilia and systemic symptoms (rare: <1%) (Cabañas 2014), serum sickness like reaction (Linares 2011)

Nervous system: Delirium (Tong 2004), encephalopathy (rare: <1%) (Grill 2011), intracranial hemorrhage (periprocedural; rare: <1%) (Bower 2018), tonic-clonic epilepsy (rare: <1%) (Lin 2007)

Renal: Acute kidney injury (Kadomura 2019), interstitial nephritis (Liu 2012), nephrotoxicity (Kadomura 2019)

Respiratory: Eosinophilic pneumonitis (García-Moguel 2019)

Miscellaneous: Drug fever (Linares 2011)

Contraindications

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

Warnings/Precautions

Concerns related to adverse effects:

• Electrolyte abnormalities: Sodium content (2.8 mEq per gram of piperacillin) should be considered in patients requiring sodium restriction. Assess electrolytes periodically in patients with low potassium reserves.

• Superinfection: Use may result in fungal or bacterial superinfection.

Disease-related concerns:

• Renal impairment: Use with caution in patients with renal impairment or in hemodialysis patients. Dosage adjustment recommended.

Metabolism/Transport Effects

Refer to individual components.

Drug Interactions

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

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

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

BCG Vaccine (Immunization): Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization). Risk C: 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. Risk X: Avoid combination

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

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

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

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

Methotrexate: Penicillins may increase the serum concentration of Methotrexate. Risk C: 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. Risk C: 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. Risk D: 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. Risk D: Consider therapy modification

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

Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Management: Avoid use of live attenuated typhoid vaccine (Ty21a) in patients being treated with systemic antibacterial agents. Postpone vaccination until 3 days after cessation of antibiotics and avoid starting antibiotics within 3 days of last vaccine dose. Risk D: Consider therapy modification

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

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

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

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).

As a class, penicillin antibiotics are widely used in pregnant women. Based on available data, penicillin antibiotics are generally considered compatible for use during pregnancy (Ailes 2016; Bookstaver 2015; Crider 2009; Damkier 2019; Lamont 2014; Muanda 2017a; Muanda 2017b).

Piperacillin/tazobactam is approved for the treatment of postpartum gynecologic infections, including endometritis or pelvic inflammatory disease, caused by susceptible organisms. Untreated intraamniotic infection (chorioamnionitis) may lead to adverse pregnancy outcomes including pneumonia, meningitis, and sepsis in the newborn. Maternal complications may include postpartum uterine atony with hemorrhage, endometritis, peritonitis, sepsis, or adult respiratory distress syndrome. Piperacillin/tazobactam is an alternative option for the treatment of intraamniotic infection (ACOG 2017).

Piperacillin/tazobactam is considered compatible with pregnancy when used for the treatment airway diseases, such as cystic fibrosis, in pregnant women (ERS/TSANZ [Middleton 2020]).

Breast-Feeding Considerations

Piperacillin is present in breast milk; information for tazobactam is not available.

According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother. Piperacillin/tazobactam is considered compatible with breastfeeding in women when used for the treatment of airway diseases, such as cystic fibrosis. Bioavailability is expected to be low if ingested orally (eg, via breast milk); however, intestinal absorption may be increased in neonates (ERS/TSANZ [Middleton 2020]). In general, antibiotics that are present in breast milk may cause non-dose-related modification of bowel flora. Monitor infants for GI disturbances, such as thrush and diarrhea (WHO 2002).

Dietary Considerations

Some products may contain sodium.

Monitoring Parameters

Creatinine, BUN, hematologic parameters (especially with prolonged [≥21 days] use; eg, CBC with differential, PT, PTT), serum electrolytes, LFTs, urinalysis; signs of bleeding; monitor for signs of anaphylaxis during first dose, if a skin rash develops monitor closely, CNS effects.

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.

Pharmacodynamics and Pharmacokinetics

Note: Both AUC and peak concentrations are dose proportional.

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:

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 Vd of 0.511 ± 0.366 L/kg (Cies 2014)

Adolescents and Adults: 0.243 L/kg

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

Metabolism:

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

Tazobactam: ~22% to inactive metabolite

Bioavailability: IM: Piperacillin: 71%; Tazobactam: 84%

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

Time to peak, plasma: Immediately following completion of 30-minute infusion

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)

Pharmacodynamics and Pharmacokinetics: Additional Considerations

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

Anti-infective considerations:

Parameters associated with efficacy:

Piperacillin (in combination with tazobactam): Time dependent; associated with free time (fT) > minimum inhibitory concentration (MIC); goal: ≥50% fT > MIC (bactericidal) (Lodise 2006). In critically ill patients in the ICU, minimum goal: ≥50% fT > MIC; preferred goal: ≥100% fT > MIC (Abdul-Aziz 2020; Al-Shaer 2020; Roberts 2014); some experts favor ≥100% fT > 4 times the MIC (Guilhaumou 2019).

Tazobactam (in combination with piperacillin): Time dependent, associated with fT > MIC, goal: ≥77% fT > MIC (1-log kill) (Pogue 2019).

Expected drug concentrations in patients with normal renal function:

Pediatric patients: Cmax (peak): IV:

30-minute infusion, single dose: Piperacillin 100 mg/tazobactam 12.5 mg per kg: Infants ≥2 months of age and children ≤12 years of age: Piperacillin: 360 mg/L; tazobactam: 39 mg/L (Reed 1994).

4-hour infusion, multiple dose: Piperacillin 100 mg/tazobactam 12.5 mg per kg every 8 hours: Children ≤9 years of age: Piperacillin: 119.9 ± 36.3 mg/L; tazobactam: 17.6 ± 5.1 mg/L (Nichols 2016a).

Adults: Cmax (peak): IV:

Note: Adult doses are expressed as the combined amount of piperacillin and tazobactam.

30-minute infusion, multiple dose:

2.25 g every 6 hours: Piperacillin: 134 mg/L; tazobactam: 15 mg/L.

3.375 g every 6 hours: Piperacillin: 242 mg/L; tazobactam: 24 mg/L.

4.5 g every 6 hours: Piperacillin: 298 mg/L; tazobactam: 34 mg/L.

4-hour infusion, multiple dose: 4.5 g every 8 hours: Piperacillin: 108.2 ± 31.7 mg/L; tazobactam: 21.7 ± 7.8 mg/L (Shea 2009b).

Postantibiotic effect: Generally little to no postantibiotic effect (<1 hour) for gram-negative bacilli (including P. aeruginosa) (Craig 1991; Craig 1998; Li 1997).

Parameters associated with toxicity:

Continuous infusion: Critically ill adults: A piperacillin serum concentration of 157.2 mg/L was associated with neurotoxicity (Quinton 2017).

Intermittent infusion: Hospitalized adults: Piperacillin Cmin >361.4 mg/L associated with 50% risk of developing neurotoxicity; piperacillin Cmin >452.65 mg/L associated with 50% risk of developing nephrotoxicity (evaluated by increases in serum creatinine) (Imani 2017).

Pricing: US

Solution (Zosyn Intravenous)

2-0.25 gm/50 mL (per mL): $0.36

3-0.375 gm/50 mL (per mL): $0.48

4-0.5 g/100 mL (per mL): $0.30

Solution (reconstituted) (Piperacillin Sod-Tazobactam So Intravenous)

2.25 (2-0.25) g (per each): $3.60 - $14.50

3.375 (3-0.375) g (per each): $3.60 - $21.76

4.5 (4-0.5) g (per each): $6.73 - $27.55

13.5 (12-1.5) g (per each): $48.75 - $58.61

40.5 (36-4.5) g (per each): $78.00 - $206.16

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Advoctam (EG);
  • Ampito (LK);
  • Astaz-P (TH);
  • Aurotaz (QA);
  • Aurotaz-P (BH);
  • Bagotaz (AR);
  • Betamycin (TW);
  • Caplin (ZA);
  • Co-Tazo (TW);
  • Curitaz 4.5 (ZW);
  • Jeita (TW);
  • Pipercin (IE);
  • Pipertaz (TH);
  • Pipetam (NZ);
  • Piprataz (EG);
  • Piptabac (CR, DO, EC, GT, HN, NI, PA, SV);
  • PipTaz (AU, NZ);
  • Piptaz (PH, VN);
  • Pirabax (ZA);
  • Pisa (LK);
  • Plepra-T 4.5 (PH);
  • Pletzolyn (PH);
  • Prizma (BH, LB, QA);
  • Pybactam (HK);
  • Sixacin (PY);
  • Tabaxin (KR);
  • Tasovak (MX);
  • Tazar (UA);
  • Tazepen (MT);
  • Tazin (LK);
  • Tazip (CZ);
  • Tazobac (CH, LI);
  • Tazobact (HR);
  • Tazobak (LK, PH);
  • Tazobax (ZA);
  • Tazocilina (BR);
  • Tazocillin (BD);
  • Tazocilline (FR);
  • Tazocin (AE, BG, BH, BR, CN, CO, CR, CY, DK, EC, EE, EG, GB, GT, HK, HN, HR, ID, IE, IL, IQ, IR, IT, JO, KR, KW, LB, LI, LT, LU, LY, MT, MX, NI, OM, PA, PE, PH, PK, PL, QA, RO, SA, SG, SI, SK, SV, SY, TH, TR, TW, VN, YE, ZA);
  • Tazocin 4 EF (ZW);
  • Tazocin EF (AU, DO, MY, NZ);
  • Tazomax (UY);
  • Tazonam (AR, AT, CL, PY);
  • Tazopelin (VN);
  • Tazopen (BD, PH);
  • Tazopenil (IT);
  • Tazoperan (KR);
  • Tazopip (AU, IL);
  • Tazopril (VE);
  • Tazorex (HK, MT);
  • Tazosyn (BD);
  • Tazpen (MY, SG, UA);
  • Tebranic (TH);
  • Victalis (CR, DO, GT, HN, NI, PA, SV);
  • Vigocid (PH);
  • Yanoven (LB);
  • Zobaction (LK);
  • Zopercin (VN);
  • Zosyn (BB, IN, JP, LI);
  • Zytobakt (HU)


For country abbreviations used in Lexicomp (show table)

REFERENCES

  1. Abdul-Aziz MH, Alffenaar JC, Bassetti M, et al; Infection Section of European Society of Intensive Care Medicine (ESICM); Pharmacokinetic/pharmacodynamic and critically ill patient study groups of European Society of Clinical Microbiology and Infectious Diseases (ESCMID); Infectious diseases group of International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT); Infections in the ICU and sepsis working group of International Society of Antimicrobial Chemotherapy (ISAC). Antimicrobial therapeutic drug monitoring in critically ill adult patients: a position paper. Intensive Care Med. 2020;46(6):1127-1153. doi:10.1007/s00134-020-06050-1 [PubMed 32383061]
  2. Abdul-Aziz MH, Sulaiman H, Mat-Nor MB, et al. Beta-Lactam Infusion in Severe Sepsis (BLISS): a prospective, two-centre, open-labelled randomised controlled trial of continuous versus intermittent beta-lactam infusion in critically ill patients with severe sepsis. Intensive Care Med. 2016;42(10):1535-1545. doi:10.1007/s00134-015-4188-0 [PubMed 26754759]
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  5. Alobaid AS, Brinkmann A, Frey OR, et al. What is the effect of obesity on piperacillin and meropenem trough concentrations in critically ill patients? J Antimicrob Chemother. 2016;71(3):696-702. doi:10.1093/jac/dkv412 [PubMed 26702922]
  6. Alobaid AS, Wallis SC, Jarrett P, et al. Population pharmacokinetics of piperacillin in nonobese, obese, and morbidly obese critically ill patients. Antimicrob Agents Chemother. 2017;61(3):e01276-16. doi:10.1128/AAC.01276-16 [PubMed 28052849]
  7. Al-Shaer MH, Rubido E, Cherabuddi K, Venugopalan V, Klinker K, Peloquin C. Early therapeutic monitoring of β-lactams and associated therapy outcomes in critically ill patients. J Antimicrob Chemother. 2020;75(12):3644-3651. doi:10.1093/jac/dkaa359 [PubMed 32910809]
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