Version October 2024
Dosage guidance:
Dosing: 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 or continuous infusion method (off-label methods).
Usual dosage range:
Traditional infusion method (over 30 minutes): IV:
Mild to moderate infection: 3.375 g every 6 hours.
Severe infection: 4.5 g every 6 to 8 hours (limited data for every 8 hours frequency; refer to indication-specific dosing below) (Ref).
Pseudomonas aeruginosa infection: 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 (Ref). 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) (Ref).
Continuous- infusion method (off-label method):
IV: 18 g infused over 24 hours (Ref); may give a loading dose of 4.5 g over 30 minutes, especially when rapid attainment of therapeutic drug concentrations (eg, sepsis) is desired (Ref).
Extended and continuous infusion methods are based largely on pharmacokinetic and pharmacodynamic modeling data; clinical efficacy data are limited (Ref).
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 (Ref).
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 (Ref). Some experts also prefer extended or continuous infusions for critical illness or when treating a susceptible organism with an elevated minimum inhibitory concentration (MIC) (Ref).
Community-acquired infection, immunocompetent host: IV: 3.375 g every 6 hours (Ref).
Health care-associated infection, including catheter-related, immunosuppressed host, or for coverage of P. aeruginosa: IV: 4.5 g every 6 hours (Ref).
Duration of therapy: Usual duration is 7 to 14 days, depending on source, pathogen, extent of infection, and clinical response (Ref); a 7-day duration is recommended for patients with uncomplicated Enterobacteriaceae infection who respond appropriately to antibiotic therapy (Ref). Note: If neutropenic, extend treatment until afebrile for 2 days and neutrophil recovery (ANC ≥500 cells/mm3 and increasing) (Ref). For P. aeruginosa bacteremia in neutropenic patients, some experts treat for a minimum of 14 days and until recovery of neutrophils (Ref).
Cystic fibrosis, severe acute pulmonary exacerbation or failure of oral therapy, for coverage of Pseudomonas aeruginosa (off-label use):
IV: 4.5 g every 6 hours usually as part of an appropriate combination regimen (Ref). Note: Some experts prefer the extended or continuous infusion method to optimize exposure (Ref). Duration is usually 10 to 14 days, depending on clinical response (Ref).
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 (Ref).
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 (Ref). For diverticulitis or uncomplicated appendicitis managed without intervention, duration is 10 to 14 days (Ref); for perforated appendicitis managed with laparoscopic appendectomy, 2 to 4 days may be sufficient (Ref). Note: For patients who are critically ill or at risk for infection with drug-resistant pathogens, some experts favor the extended infusion method (Ref).
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 (Ref).
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 (Ref).
Neutropenic fever, high-risk patients with cancer (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) (Ref); some experts use an ANC cutoff <500 cells/mm3 to define high-risk patients (Ref).
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 (Ref). Some experts prefer extended or continuous infusion for critical illness (Ref).
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 (Ref).
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 (Ref). Note: Some experts prefer extended or continuous infusion for critical illness or when treating a susceptible organism with an elevated MIC (Ref).
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) (Ref). Initiate therapy as soon as possible and within 1 hour of recognition of sepsis or septic shock. Duration is dependent on underlying source and patient response; short courses are preferred, when appropriate. Consider discontinuation if a noninfectious etiology is identified (Ref). Some experts prefer the extended or continuous infusion method (Ref).
Skin and soft tissue infection, moderate to severe :
Note: For patients with necrotizing infections, select surgical-site infections (intestinal, GU tract), or patients with or at risk for gram-negative pathogens (eg, P. aeruginosa) (Ref).
IV: 3.375 g every 6 hours or 4.5 g every 8 hours; often used as part of an appropriate combination regimen (Ref). For treatment of P. aeruginosa infection: 4.5 g every 6 hours (Ref). Usual duration (including oral step-down therapy) is 5 to 14 days based on severity and clinical response; for necrotizing infection, continue until further debridement is not necessary, patient has clinically improved, and patient is afebrile for ≥48 hours (Ref).
Urinary tract infection, complicated (pyelonephritis or urinary tract infection with systemic signs/symptoms) (off-label use): IV: 3.375 g every 6 hours. 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; for patients with symptomatic improvement within the first 48 to 72 hours of therapy, some experts recommend shorter courses of 5 to 10 days (or 7 to 10 days if therapy is completed with piperacillin/tazobactam) (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
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) (Ref).
Altered kidney function: IV:
|
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 (Ref).
CrCl 130 to <170 mL/minute: IV: 4.5 g every 6 hours infused over 3 hours (Ref) or Loading dose: 4.5 g, followed immediately by a daily continuous infusion of 18 g over 24 hours (Ref).
CrCl ≥170 mL/minute: IV: Loading dose: 4.5 g, followed immediately by a daily continuous infusion of 22.5 g over 24 hours (Ref).
Hemodialysis, intermittent (thrice weekly): Dialyzable (30% to 40%):
IV: 4.5 g every 12 hours or 2.25 g every 8 hours (Ref); administration of scheduled doses after hemodialysis on dialysis days is preferred but not required (Ref).
Peritoneal dialysis: Dialyzable (6% of piperacillin, 21% of tazobactam):
IV: 4.5 g every 12 hours or 2.25 g every 8 hours (Ref).
CRRT: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement (Ref). 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 (Ref)) 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) (Ref). 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 (Ref) or 4.5 g loading dose followed by 2.25 g every 6 hours (Ref).
Continuous IV infusion: 4.5 g loading dose (Ref) followed immediately by a 9 g over 24 hours daily maintenance dose (Ref).
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 (Ref).
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 (Ref).
No dosage adjustment necessary.
The recommendations for dosing in patients with obesity are based upon the best available evidence and clinical expertise. Senior Editorial Team: Jeffrey F. Barletta, PharmD, FCCM; Manjunath P. Pai, PharmD, FCP; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC.
Class 1, 2, or 3 obesity (BMI ≥30 kg/m2):
Extended infusion method (off-label 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 (Ref).
Life-threatening infections caused by less-susceptible pathogens (eg, minimum inhibitory concentration [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 (Ref).
Critically ill patients with augmented renal clearance:
Measured urinary CrCl 130 to <170 mL/minute:
IV: 4.5 g every 6 hours infused over 3 hours or Loading dose: 4.5 g, followed immediately by a daily continuous infusion of 18 g over 24 hours (Ref).
Measured urinary CrCl ≥170 mL/minute:
Note: Continuous infusion regimen is recommended to optimize therapeutic concentrations and target attainment (expert opinion).
IV: Loading dose: 4.5 g, followed immediately by a daily continuous infusion of 22.5 g over 24 hours (Ref).
Traditional infusion method (over 30 minutes): IV: 4.5 g every 6 hours (Ref).
Rationale for recommendations:
There are limited data evaluating the effect of obesity on dosing requirements for piperacillin and tazobactam. Data are available from hospitalized patients (eg, critically ill) predominantly at steady state concentrations. 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 (Ref). Despite a higher proportion of patients who are obese who have subtherapeutic trough concentrations (eg, due to augmented renal clearance, elevated pathogen MIC [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, over 3 to 4 hours) (Ref). The effect of obesity on first-dose pharmacokinetics remains unknown.
Refer to adult dosing.
(For additional information see "Piperacillin and tazobactam: Pediatric drug information")
Dosage guidance:
Dosing: Zosyn (piperacillin/tazobactam) is a combination product that contains piperacillin sodium and tazobactam sodium in an 8:1 ratio; for every 1,000 mg of piperacillin there is 125 mg of tazobactam, which is equivalent to 1,125 mg of total piperacillin and tazobactam. Dosage recommendations are based on the piperacillin component. Dosing is presented in mg/kg/dose and mg/kg/day; use caution.
General dosing:
Intermittent infusion method (eg, 30-minute infusion):
Infants ≤6 months: IV: 240 to 300 mg piperacillin/kg/day in divided doses every 6 to 8 hours; maximum daily dose: 16 g/day (Ref). Based on pharmacokinetic modeling, 75 to 80 mg/kg/dose every 4 hours has been recommended to improve exposure for pathogens with higher minimum inhibitory concentrations (MICs) (eg, 16 mg/L) (Ref).
Infants >6 months, Children, and Adolescents: IV: 240 to 300 mg piperacillin/kg/day in divided doses every 6 to 8 hours; maximum daily dose: 16 g/day (Ref). Note: Based on pharmacokinetic modeling, intermittent dosing every 8 hours may be suboptimal, particularly for infections caused by bacteria with MICs ≥2 mg/L (Ref). Higher total daily doses are recommended for some indications (eg, pneumonia, cystic fibrosis, neutropenic fever) (Ref).
Extended infusion dosing (eg, 4-hour infusion): Limited data available: Children and Adolescents: IV: 100 mg piperacillin/kg/dose infused over 3 to 4 hours every 6 to 8 hours; maximum daily dose: 16 g/day (Ref).
Continuous infusion dosing: Very limited data available: Infants ≥6 months, Children, and Adolescents: IV: Initial loading dose: 75 mg piperacillin/kg infused over 30 minutes, followed by 300 mg piperacillin/kg/day infused over 24 hours; maximum daily dose: 16 g/day. Dosing from an observational pharmacokinetic and safety study in critically ill patients; due to potential risk for overexposure, therapeutic drug monitoring is recommended (Ref).
Cystic fibrosis, acute pulmonary exacerbation: Note: Optimal dose may vary based on disease severity, susceptibility patterns (eg, minimum inhibitory concentration), or patient tolerability. Treatment duration varies and is dependent on patient-specific factors including response to therapy; typical duration is 10 to 21 days (Ref).
Infants, Children, and Adolescents:
Standard dose: IV: 240 to 400 mg piperacillin/kg/day divided every 8 hours, infused over 30 minutes or 4 hours (Ref); others have used 350 to 400 mg/kg/day divided every 4 hours in early piperacillin trials (Ref).
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 in 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 (Ref).
Endocarditis: 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 (Ref). Note: 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) is recommended when using every-8-hour dosing (Ref).
Intra-abdominal infection: Infants, Children, and Adolescents: IV: 240 to 300 mg piperacillin/kg/day divided every 6 to 8 hours. Doses up to 400 mg piperacillin/kg/day divided every 6 hours have been reported. Maximum dose: 4,000 mg piperacillin/dose; some experts suggest that 3,000 mg piperacillin/dose is adequate (Ref). Duration dependent upon age, source of infection, and surgical status. Typical duration is 4 to 7 days unless source control inadequate; in some circumstances (ie, acute or gangrenous appendicitis without perforation managed with surgery), therapy should be limited to ≤24 hours (Ref).
Neutropenic fever, empiric treatment:
Intermittent infusion: Infants, Children, and Adolescents: IV: 300 to 400 mg piperacillin/kg/day in divided doses every 6 hours, infused over 30 to 60 minutes; maximum dose: 4,000 mg piperacillin/dose (Ref).
Continuous infusion: Children and Adolescents: IV: Initial loading dose: 75 to 100 mg piperacillin/kg infused over 2 to 30 minutes, followed by 300 mg piperacillin/kg/day infused over 24 hours; maximum daily dose: 16 g/day. Based on pharmacokinetic modeling, continuous infusion improves exposure for pathogens with higher minimum inhibitory concentrations (MICs) as compared to intermittent infusion (Ref).
Note: Duration of empiric therapy is typically until blood cultures are negative at 48 hours and patient has been clinically well and afebrile ≥24 hours with evidence of marrow recovery (Ref).
Pneumonia, nosocomial:
Infants 2 to 9 months: IV: 320 mg piperacillin/kg/day in divided doses every 6 hours.
Infants >9 months, Children, and Adolescents: IV: 400 mg piperacillin/kg/day in divided doses every 6 hours; maximum dose: 4,000 mg piperacillin/dose.
Note: Data on optimal duration of treatment in children are lacking; however, in adults with hospital-acquired or ventilator-associated pneumonia, 7 days of therapy is recommended (Ref).
Skin and soft tissue infection, necrotizing: Infants, Children, and Adolescents: IV: 240 to 300 mg piperacillin/kg/day in divided doses every 6 hours as part of an appropriate combination regimen (Ref). Continue until further debridement is not necessary, patient has clinically improved, and patient is afebrile for 48 to 72 hours; this typically results in a treatment duration of 2 to 3 weeks. Step-down to oral therapy may be considered after improvement in signs and symptoms of infection (Ref).
Surgical antimicrobial prophylaxis:
Infants 2 to 9 months: IV: 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) (Ref).
Infants >9 months, Children, and Adolescents weighing ≤40 kg: IV: 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 (Ref).
Adolescents weighing >40 kg: IV: 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) (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Altered kidney function:
Note: Dosing is based on pharmacokinetic parameters, limited pediatric studies, adult studies, and expert opinion (Ref).
Infants, Children, and Adolescents: IV:
|
Traditional infusion method (over 30 minutes) |
Extended infusion method (over 3 to 4 hours) | ||||
|---|---|---|---|---|---|
|
a Choose usual recommended dose based on indication and disease severity (see "Dosing: Pediatric"), then choose the adjusted dose from that column corresponding to the patient's eGFR. b Maximum dose: 4,000 mg/dose. c When targeting pathogens with elevated minimal inhibitory concentrations (MICs), consider dose needed for normal renal function in addition to severity and site of infection; consider monitoring serum concentrations if available. d For dose recommendations >400 mg/kg/day, use clinical judgment (eg, assessment of risks and benefits) to make patient-specific dose adjustment if kidney function is altered; consider therapeutic drug monitoring if available. | |||||
|
If the usual recommended dose is 200 to 300 mg/kg/day |
If the usual recommended dose is 300 to 400 mg/kg/day d |
If the usual recommended dose is 300 to 400 mg/kg/day d | |||
|
eGFR |
Usual dose: 67 to 100 mg piperacillin/kg/dose every 8 hours |
Usual dose: 50 to 75 mg piperacillin/kg/dose every 6 hours |
Usual dose: 100 to 133 mg piperacillin/kg/dose every 8 hours |
Usual dose: 75 to 100 mg piperacillin/kg/dose every 6 hours |
Usual dose: 100 mg piperacillin/kg/dose infused over 3 to 4 hours every 6 to 8 hoursc |
|
≥40 mL/minute/1.73 m2 (usual recommended dose) |
No dosage adjustment necessary |
No dosage adjustment necessary |
No dosage adjustment necessary |
No dosage adjustment necessary |
No dosage adjustment necessary |
|
20 to <40 mL/minute/1.73 m2 |
45 to 70 mg piperacillin/kg/dose every 8 hours |
35 to 50 mg piperacillin/kg/dose every 6 hours |
70 to 90 mg piperacillin/kg/dose every 8 hours |
50 to 70 mg piperacillin/kg/dose every 6 hours |
70 mg piperacillin/kg/dose infused over 3 to 4 hours every 8 hoursc |
|
<20 mL/minute/1.73 m2 |
45 to 70 mg piperacillin/kg/dose every 12 hours |
35 to 50 mg piperacillin/kg/dose every 8 hours |
70 to 90 mg piperacillin/kg/dose every 12 hours |
50 to 70 mg piperacillin/kg/dose every 8 hours |
70 mg piperacillin/kg/dose infused over 3 to 4 hours every 12 hoursc |
Hemodialysis, intermittent: Dialyzable: 30% to 40% of administered drug removed by dialysis (Ref).
Infants, Children, and Adolescents: IV: 50 to 100 mg piperacillin/kg/dose every 12 hours; administer scheduled doses after hemodialysis on dialysis days if possible (Ref).
Peritoneal dialysis: Dialyzable: ~6% piperacillin and 21% tazobactam (Ref).
Infants, Children, and Adolescents: IV: 50 to 100 mg piperacillin/kg/dose every 12 hours (Ref).
CRRT:
Note: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Recommendations are based on high-flux dialyzers and ultrafiltration rates of 68 mL/kg/hour unless otherwise noted; flow rates vary widely in pediatric patients. Appropriate dosing requires consideration of drug penetration to site of infection, MIC of bacteria, and severity of illness. Close monitoring of response and adverse reactions due to drug accumulation (eg, neurotoxicity) is important. Due to minimal data in pediatric patients receiving CRRT, consider monitoring serum concentrations (eg, trough concentration) if available.
Children and Adolescents:
Intermittent infusion: IV: 100 mg piperacillin/kg/dose every 8 hours (Ref).
Continuous infusion: IV: 200 mg piperacillin/kg/dose infused over 24 hours (Ref).
Augmented renal clearance:
Note: Augmented renal clearance (ARC) is a condition that occurs in certain critically ill patients without organ dysfunction and with normal serum creatinine concentrations that results in increased drug elimination. An 8- to 24-hour measured urinary CrCl is necessary to identify these patients (Ref). When available, consider utilizing extended infusion due to higher probability of attaining pharmacodynamic targets (Ref).
Children and Adolescents: GFR ≥130 mL/minute/1.73 m2:
Traditional or extended infusion: IV: 100 mg piperacillin/kg/dose every 6 hours; infuse over 3 to 4 hours if possible (Ref).
Continuous infusion: IV: Loading dose: 100 mg piperacillin/kg infused over 30 minutes, followed by 400 mg/kg/dose infused over 24 hours (Ref).
Infants ≥2 months, Children, and Adolescents: No dosing adjustment necessary.
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 (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).
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)
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)
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)
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)
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: 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)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults. 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, calcium), hyperglycemia, hypokalemia
Hematologic & oncologic: Decreased hematocrit, decreased hemoglobin, eosinophilia, positive direct Coombs' test, prolonged bleeding time, prolonged partial thromboplastin time, prolonged prothrombin time
Hepatic: Increased gamma-glutamyl transferase, increased serum alanine aminotransferase, increased serum alkaline phosphatase, increased serum aspartate aminotransferase, increased serum bilirubin
Renal: Increased blood urea nitrogen, increased serum creatinine, kidney failure
Postmarketing:
Dermatologic: Acute generalized exanthematous pustulosis (Peermohamed 2011), dermatologic disorder (linear IgA bullous dermatosis) (Ho 2018), erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome (Lin 2014), toxic epidermal necrolysis (Copaescu 2020)
Gastrointestinal: Clostridioides difficile-associated diarrhea (Watson 2018), melanoglossia (Ren 2020)
Hematologic & oncologic: Agranulocytosis (He 2013), bone marrow depression (He 2013), hemolytic anemia (Bollotte 2014), hemophagocytic lymphohistiocytosis (Miyabayashi 2018), immune thrombocytopenia (Boyce 2016), leukopenia (Reichardt 1999), neutropenia (Darwiche 2017), pancytopenia (Lee 2009), thrombocytopenia (Kumar 2003)
Hepatic: Hepatic impairment (He 2013), hepatitis (Kraleti 2016), jaundice
Hypersensitivity: Anaphylactic shock, drug reaction with eosinophilia and systemic symptoms (Cabañas 2014), nonimmune anaphylaxis, serum sickness-like reaction (Linares 2011)
Nervous system: Delirium (Tong 2004), encephalopathy (Grill 2011), intracranial hemorrhage (periprocedural) (Bower 2018), tonic-clonic seizure (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)
Hypersensitivity to penicillins, cephalosporins, beta-lactamase inhibitors, or any component of the formulation.
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.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
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 12 g and tazobactam 1.5 g (1 ea); Piperacillin 36 g and tazobactam 4.5 g (1 ea)
Solution Reconstituted, Intravenous [preservative free]:
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)
May be product dependent
Solution (Zosyn Intravenous)
2-0.25 gm/50 mL (per mL): $0.37
3-0.375 gm/50 mL (per mL): $0.49
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): $3.59 - $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): $27.60 - $78.79
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.
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)
IV: Administer by IV infusion over 30 minutes. For extended infusion administration (off-label method), administer over 3 or 4 hours (Ref). For continuous infusion method (off-label method), administer total dose (18 g) over 24 hours as a continuous infusion (Ref).
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 (Ref).
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.
Parenteral:
Intermittent IV infusion: Administer over 30 minutes.
Extended IV infusion:
Neonatal: Administer over 3 hours (Ref).
Pediatric: Administer over 3 to 4 hours (Ref).
Continuous IV infusion: Administer total daily dose over 24 hours as a continuous infusion. If a loading dose is used, administer over 2 to 30 minutes prior to initiation of the continuous infusion (Ref).
Intra-abdominal infection: 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 infection: 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 soft tissue infection: Treatment of skin and soft tissue infection, including cellulitis, cutaneous abscess, and ischemic/diabetic foot infection, in adults caused by beta-lactamase-producing strains of S. aureus.
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 patients with cancer (empiric therapy); Sepsis and septic shock; Urinary tract infection, complicated (pyelonephritis or urinary tract infection with systemic signs/symptoms)
Zosyn may be confused with Zofran, Zyvox.
Tazact [India] may be confused with Tazac brand name for nizatidine [Australia]; Tiazac brand name for dilTIAZem [US, Canada].
Refer to individual components.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
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
Bacillus clausii: Antibiotics may diminish the therapeutic effect of Bacillus clausii. Management: Bacillus clausii should be taken in between antibiotic doses during concomitant therapy. Risk D: Consider therapy modification
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
Clofarabine: OAT1/3 Inhibitors may increase the serum concentration of Clofarabine. Risk C: Monitor therapy
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
Fecal Microbiota (Live) (Oral): May diminish the therapeutic effect of Antibiotics. Risk X: Avoid combination
Fecal Microbiota (Live) (Rectal): Antibiotics may diminish the therapeutic effect of Fecal Microbiota (Live) (Rectal). Risk X: Avoid combination
Flucloxacillin: Piperacillin may increase the serum concentration of Flucloxacillin. Risk C: Monitor therapy
Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies): Antibiotics may diminish the therapeutic effect of Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies). 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: Antibiotics may decrease serum concentrations of the active metabolite(s) of Mycophenolate. Specifically, concentrations of mycophenolic acid (MPA) may be reduced. 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 Benzoate: Penicillins may diminish the therapeutic effect of Sodium Benzoate. Risk C: Monitor therapy
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
Vadadustat: OAT1/3 Inhibitors may increase the serum concentration of Vadadustat. Risk C: Monitor therapy
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
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]).
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).
Some products may contain sodium.
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.
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.
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)
Altered kidney function: 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).
Infusion specific:
Standard infusion and up to 4 hours extended infusion: Goal: 40% to 70% fT > MIC (Hong 2023).
Continuous infusion: Goal: 100% fT > MIC with concentrations that exceed up to 4 to 8 times free drug over the steady-state concentration (fCss) (Hong 2023).
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).
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