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    Penicillin and Beta-Lactamase Inhibitor Combination Antibiotics

    DEA CLASS

    Rx

    DESCRIPTION

    Extended-spectrum penicillin/irreversible beta-lactamase inhibitor combination used to treat gram-negative and anaerobic infections, including intra-abdominal, skin and soft-tissue, and lower respiratory tract infections; combination does not have any more activity against P. aeruginosa than does piperacillin alone. Restricted activity against class I beta-lactamases may limit use of this drug.

    COMMON BRAND NAMES

    Zosyn

    HOW SUPPLIED

    Piperacillin Sodium, Tazobactam Sodium/Piperacillin, Tazobactam/Zosyn Intravenous Inj Pwd F/Sol: 2.25g, 3.375g, 4.5g, 40.5g
    Zosyn Intravenous Inj Sol: 50mL, 100mL, 2-0.25g, 3-0.375g, 4-0.5g

    DOSAGE & INDICATIONS

    For the treatment of moderate to severe complicated and uncomplicated skin and skin structure infections (e.g., cellulitis, skin abscesses, ischemic diabetic foot ulcer).
    Intravenous dosage
    Adults

    3.375 g (3 g piperacillin and 0.375 g tazobactam) IV every 6 hours for 7 to 10 days.

    Infants 9 months and older†, Children†, and Adolescents†

    100 mg/kg/dose (piperacillin component) IV every 8 hours (Max: 4 g/dose piperacillin [4.5 g/dose piperacillin; tazobactam]) has been recommended in general by the American Academy of Pediatrics (AAP) and is FDA-approved for other pediatric indications. In general, piperacillin; tazobactam is recommended in guidelines for treatment of infections in which Pseudomonas aeruginosa is suspected or in significant infections with mixed flora.

    Infants 1 to 8 months†

    80 mg/kg/dose (piperacillin component) IV every 8 hours has been recommended in general by the American Academy of Pediatrics (AAP) and is FDA-approved for other pediatric indications. In general, piperacillin; tazobactam is recommended in guidelines for treatment of infections in which Pseudomonas aeruginosa is suspected or in significant infections with mixed flora.

    Premature and Term Neonates 8 to 29 days†

    100 mg/kg/dose (piperacillin component) IV every 8 hours is recommended by the American Academy of Pediatrics (AAP). Doses of 80 mg/kg/dose (piperacillin component) IV every 8 hours have also been used. In general, piperacillin; tazobactam is recommended in guidelines for treatment of infections in which Pseudomonas aeruginosa is suspected or in significant infections with mixed flora.

    Premature and Term Neonates 0 to 7 days†

    100 mg/kg/dose (piperacillin component) IV every 12 hours is recommended by the American Academy of Pediatrics (AAP). Higher doses (80 mg/kg/dose piperacillin component IV every 8 hours) have also been used. In general, piperacillin; tazobactam is recommended in guidelines for treatment of infections in which Pseudomonas aeruginosa is suspected or in significant infections with mixed flora.

    For the treatment of intraabdominal infections, including peritonitis and appendicitis complicated by rupture or intraabdominal abscess.
    For intraabdominal infections using conventional dosing.
    Intravenous dosage
    Adults, Adolescents, and Children more than 40 kg

    3.375 g (3 g piperacillin and 0.375 g tazobactam) IV every 6 hours for 4 to 7 days is recommended by the Infectious Diseases Society of America (IDSA). For Pseudomonas infection, dose may be increased to 3.375 g (3 g piperacillin and 0.375 g tazobactam) IV every 4 hours or 4.5 g (4 g piperacillin and 0.5 g tazobactam) IV every 6 hours. For acute appendicitis without evidence of perforation, abscess, or local peritonitis, treatment should be discontinued within 24 hours. The FDA-approved dose is 3.375 g (3 g piperacillin and 0.375 g tazobactam) IV every 6 hours for 7 to 10 days.

    Infants 9 months and older, Children, and Adolescents 40 kg or less

    200 to 300 mg/kg/day (piperacillin component) IV divided every 6 to 8 hours for 4 to 7 days is recommended by the Infectious Diseases Society of America (IDSA). For acute appendicitis without evidence of perforation, abscess, or local peritonitis, treatment should be discontinued within 24 hours. The FDA-approved dose of 100 mg/kg/dose (piperacillin component) IV every 8 hours for 7 to 10 days is also recommended by the American Academy of Pediatrics (AAP).

    Infants 2 to 8 months

    200 to 300 mg/kg/day (piperacillin component) IV divided every 6 to 8 hours for 4 to 7 days is recommended by the Infectious Diseases Society of America (IDSA). For acute appendicitis without evidence of perforation, abscess, or local peritonitis, treatment should be discontinued within 24 hours. The FDA-approved dose of 80 mg/kg/dose (piperacillin component) IV every 8 hours for 7 to 10 days is also recommended by the American Academy of Pediatrics (AAP).

    Infants younger than 2 months†

    200 to 300 mg/kg/day (piperacillin component) IV divided every 6 to 8 hours for 4 to 7 days is recommended by the Infectious Diseases Society of America (IDSA). For acute appendicitis without evidence of perforation, abscess, or local peritonitis, treatment should be discontinued within 24 hours.

    Premature and Term Neonates 8 to 29 days†

    100 mg/kg/dose (piperacillin component) IV every 8 hours is recommended by the American Academy of Pediatrics (AAP). Doses of 80 mg/kg/dose (piperacillin component) IV every 8 hours have also been used. In general, piperacillin; tazobactam is recommended in clinical practice guidelines for treatment of infections in which Pseudomonas aeruginosa is suspected or in significant infections with mixed flora.

    Premature and Term Neonates 0 to 7 days†

    100 mg/kg/dose (piperacillin component) IV every 12 hours is recommended by the American Academy of Pediatrics (AAP). Higher doses (80 mg/kg/dose piperacillin component IV every 8 hours) have also been used. In general, piperacillin; tazobactam is recommended in clinical practice guidelines for treatment of infections in which Pseudomonas aeruginosa is suspected or in significant infections with mixed flora.

    For intraabdominal infections using extended-infusion dosing†.
    Intravenous dosage
    Infants, Children, and Adolescents

    Data are very limited. 100 mg/kg/dose (piperacillin component) administered over 4 hours IV every 8 hours (Max: 4 g/dose piperacillin [4.5 g/dose piperacillin; tazobactam]).

    For the treatment of pneumonia, including community-acquired pneumonia (CAP) and nosocomial pneumonia.
    For pneumonia using conventional dosing.
    Intravenous dosage
    Adults

    4.5 g (4 g piperacillin and 0.5 g tazobactam) IV every 6 hours in combination with appropriate antimicrobials is recommended by guidelines. FDA-approved labeling suggests 3.375 g (3 g piperacillin and 0.375 g tazobactam) IV every 6 hours for community acquired pneumonia (CAP) and 4.5 g (4 g piperacillin and 0.5 g tazobactam) IV every 6 hours for nosocomial pneumonia. In patients with risk factors for MRSA, add vancomycin or linezolid. For CAP, guidelines recommend piperacillin; tazobactam in combination with ciprofloxacin or levofloxacin. Alternatively, piperacillin; tazobactam may be given with an aminoglycoside plus a respiratory fluoroquinolone (levofloxacin, moxifloxacin) or azithromycin. The IDSA/ATS recommend treatment for a minimum of 5 days and the patient should be afebrile for 48 to 72 hours with no more than 1 sign of clinical instability before discontinuation. For patients with nosocomial pneumonia and risk factors for gram-negative resistance or with a high mortality risk, add a second non-beta-lactam agent with antipseudomonal activity (quinolone, aminoglycoside, polymyxin). For nosocomial pneumonia, guidelines recommend a 7-day treatment course ; the FDA-labeling recommends a 7- to 14-day course of therapy.

    Infants 9 months and older†, Children†, and Adolescents†

    100 mg/kg/dose (piperacillin component) IV every 8 hours (Max: 4 g/dose piperacillin [4.5 g/dose piperacillin; tazobactam]) has been recommended in general by the American Academy of Pediatrics (AAP) and is FDA-approved for other pediatric indications. In general, piperacillin; tazobactam is recommended in guidelines for treatment of infections in which Pseudomonas aeruginosa is suspected or in significant infections with mixed flora.

    Infants 1 to 8 months†

    80 mg/kg/dose (piperacillin component) IV every 8 hours has been recommended in general by the American Academy of Pediatrics (AAP) and is FDA-approved for other pediatric indications. In general, piperacillin; tazobactam is recommended in guidelines for treatment of infections in which Pseudomonas aeruginosa is suspected or in significant infections with mixed flora.

    Premature and Term Neonates 8 to 29 days†

    100 mg/kg/dose (piperacillin component) IV every 8 hours is recommended by the American Academy of Pediatrics (AAP). Doses of 80 mg/kg/dose (piperacillin component) IV every 8 hours have also been used. In general, piperacillin; tazobactam is recommended in guidelines for treatment of infections in which Pseudomonas aeruginosa is suspected or in significant infections with mixed flora.

    Premature and Term Neonates 0 to 7 days†

    100 mg/kg/dose (piperacillin component) IV every 12 hours is recommended by the American Academy of Pediatrics (AAP). Higher doses (80 mg/kg/dose piperacillin component IV every 8 hours) have also been used. In general, piperacillin; tazobactam is recommended in guidelines for treatment of infections in which Pseudomonas aeruginosa is suspected or in significant infections with mixed flora.

    For pneumonia using extended-infusion dosing†.
    Intravenous dosage
    Infants, Children, and Adolescents

    Data are very limited. 100 mg/kg/dose (piperacillin component) administered over 4 hours IV every 8 hours (Max: 4 g/dose piperacillin [4.5 g/dose piperacillin; tazobactam]).

    For the treatment of moderate to severe infections including pelvic inflammatory disease (PID) and endometritis.
    Intravenous dosage
    Adults

    3.375 g (3 g piperacillin and 0.375 g tazobactam) IV every 6 hours for 7—10 days. The Centers for Disease Control and Prevention does not recommend piperacillin; tazobactam for PID.

    For the treatment of pyelonephritis† and complicated urinary tract infection (UTI)† caused by susceptible organisms.
    Intravenous dosage
    Adults

    The usual dose in adults for FDA-approved infections is 3.375 g (3 g piperacillin and 0.375 g tazobactam) IV every 6 hours. In a randomized study, piperacillin-tazobactam 2.5 g (2 g piperacillin and 0.25 g tazobactam) IV every 8 hours was at least as effective as imipenem-cilastatin (1 g IV every 8 hours) for the treatment of pyelonephritis and complicated UTI. Extended-spectrum penicillins have been recommended for the treatment of women with pyelonephritis.

    For surgical infection prophylaxis† for patients undergoing liver transplantation.
    Intravenous dosage
    Adults, Adolescents, and Children weighing more than 40 kg

    3.375 g (3 g piperacillin and 0.375 g tazobactam) IV once within 60 minutes before surgical incision, and redose during surgery every 2 hours from the initiation of the preoperative dose. The duration of prophylaxis should not exceed 24 hours.

    Infants older than 9 months, Children, and Adolescents weighing 40 kg or less

    100 mg/kg/dose (piperacillin component) IV once within 60 minutes before surgical incision, and redose during surgery every 2 hours from the initiation of the preoperative dose. The duration of prophylaxis should not exceed 24 hours.

    Infants 2 to 9 months

    80 mg/kg/dose (piperacillin component) IV once within 60 minutes before surgical incision, and redose during surgery every 2 hours from the initiation of the preoperative dose. The duration of prophylaxis should not exceed 24 hours.

    For the treatment of acute pulmonary exacerbations in patients with cystic fibrosis†.
    For acute pulmonary exacerbations in patients with cystic fibrosis using conventional dosing.
    Intravenous dosage
    Adults

    4.5 g/dose (4 g piperacillin and 0.5 g tazobactam) IV every 6 to 8 hours is recommended by the UK CF Trust Working Group. Higher doses of 4.5 g/dose (4 g piperacillin and 0.5 g tazobactam) IV every 4 hours may be warranted.

    Infants, Children, and Adolescents

    400 mg/kg/day piperacillin component (450 mg/kg/day piperacillin; tazobactam) IV divided every 6 hours is recommended by the Cystic Fibrosis Foundation and 240 to 320 mg/kg/day piperacillin component (270 to 360 mg/kg/day piperacillin; tazobactam) IV divided every 6 to 8 hours (Max: 4 g/dose piperacillin [4.5 g/dose piperacillin; tazobactam]) is recommended by the UK CF Trust Working Group. However, a review of the literature suggests that higher doses of 450 to 600 mg/kg/day piperacillin component (506 to 675 mg/kg/day piperacillin; tazobactam) IV divided every 4 hours (Max: 4 g/dose piperacillin [4.5 g/dose piperacillin; tazobactam]) may be warranted based on piperacillin studies and pharmacokinetic/pharmacodynamic modeling. These higher doses may be needed to maintain adequate serum concentrations in the treatment of pseudomonal isolates with higher MICs.

    For acute pulmonary exacerbations in patients with cystic fibrosis using extended-infusion dosing.
    Intravenous dosage
    Infants, Children, and Adolescents

    Data are very limited. 100 mg/kg/dose (piperacillin component) administered over 4 hours IV every 8 hours (Max: 4 g/dose piperacillin [4.5 g/dose piperacillin; tazobactam]).

    For the treatment of bacteremia† and septicemia†.
    For bacteremia and septicemia using conventional dosing.
    Intravenous dosage
    Adults

    For most infections, 3.375 g (3 g piperacillin and 0.375 g tazobactam) IV every 6 hours for 7 to 10 days. For life-threatening infections, a maximum daily dose of 4.5 g (4 g piperacillin and 0.5 g tazobactam) IV every 6 hours may be considered.

    Infants 9 months and older, Children, and Adolescents

    100 mg/kg/dose (piperacillin component) IV every 8 hours (Max: 4 g/dose piperacillin [4.5 g/dose piperacillin; tazobactam]) has been recommended in general by the American Academy of Pediatrics (AAP) and is FDA-approved for other pediatric indications. In general, piperacillin; tazobactam is recommended in guidelines for treatment of infections in which Pseudomonas aeruginosa is suspected or in significant infections with mixed flora.

    Infants 1 to 8 months

    80 mg/kg/dose (piperacillin component) IV every 8 hours has been recommended in general by the American Academy of Pediatrics (AAP) and is FDA-approved for other pediatric indications. In general, piperacillin; tazobactam is recommended in guidelines for treatment of infections in which Pseudomonas aeruginosa is suspected or in significant infections with mixed flora.

    Premature and Term Neonates 8 to 29 days

    100 mg/kg/dose (piperacillin component) IV every 8 hours is recommended by the American Academy of Pediatrics (AAP). Doses of 80 mg/kg/dose (piperacillin component) IV every 8 hours have also been used. In general, piperacillin; tazobactam is recommended in guidelines for treatment of infections in which Pseudomonas aeruginosa is suspected or in significant infections with mixed flora.

    Premature and Term Neonates 0 to 7 days

    100 mg/kg/dose (piperacillin component) IV every 12 hours is recommended by the American Academy of Pediatrics (AAP). Higher doses (80 mg/kg/dose piperacillin component IV every 8 hours) have also been used. In general, piperacillin; tazobactam is recommended in guidelines for treatment of infections in which Pseudomonas aeruginosa is suspected or in significant infections with mixed flora.

    For bacteremia and septicemia using extended-infusion dosing.
    Intravenous dosage
    Infants, Children, and Adolescents

    Data are very limited. 100 mg/kg/dose (piperacillin component) administered over 4 hours IV every 8 hours (Max: 4 g/dose piperacillin [4.5 g/dose piperacillin; tazobactam]).

    For the empiric treatment of febrile neutropenia†.
    For febrile neutropenia in adults using conventional dosing.
    Intravenous dosage
    Adults

    4.5 g (4 g piperacillin and 0.5 g tazobactam) IV every 6 hours. Clinical practice guidelines suggest monotherapy with an antipseudomonal beta-lactam; other antimicrobials (aminoglycosides, fluoroquinolones, and/or vancomycin) may be added for the management of complications or when antimicrobial resistance is suspected or proven.

    For febrile neutropenia in pediatric patients using extended-infusion dosing.
    Intravenous dosage
    Infants, Children, and Adolescents

    Data are very limited. 100 mg/kg/dose (piperacillin component) administered over 4 hours IV every 8 hours (Max: 4 g/dose piperacillin [4.5 g/dose piperacillin; tazobactam]).

    For febrile neutropenia in pediatric patients using conventional dosing.
    Intravenous dosage
    Infants, Children, and Adolescents

    80 mg/kg/dose (piperacillin component) IV every 6 hours (Max: 4 g/dose piperacillin component [4.5 g/dose piperacillin; tazobactam]). Piperacillin; tazobactam, an antipseudomonal penicillin, has been successfully used for the empiric treatment of febrile neutropenia in pediatric patients as monotherapy or in combination with an aminoglycoside. Guidelines for the management of fever and neutropenia in cancer patients recommend monotherapy with an antipseudomonal beta-lactam or a carbapenem as empiric treatment in high-risk patients; addition of a second gram-negative antimicrobial agent (i.e., aminoglycoside, aztreonam) is recommended for patients who are clinically unstable, when a resistant infection is suspected, or for centers with high rates of resistant pathogens.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    18 g/day (16 g piperacillin and 2 g tazobactam) IV.

    Geriatric

    18 g/day (16 g piperacillin and 2 g tazobactam) IV.

    Adolescents

    more than 40 kg: 18 g/day (16 g piperacillin and 2 g tazobactam) IV is FDA-approved dosage; however, doses up to 600 mg/kg/day (piperacillin component) IV (Max: 27 g/day [24 g piperacillin and 3 g tazobactam]) have been used off-label for patients with cystic fibrosis.
    40 kg or less: 300 mg/kg/day piperacillin component IV is FDA-approved dosage; however, doses up to 600 mg/kg/day (piperacillin component) IV have been used off-label for patients with cystic fibrosis.

    Children

    more than 40 kg: 18 g/day (16 g piperacillin and 2 g tazobactam) IV is FDA-approved dosage; however, doses up to 600 mg/kg/day (piperacillin component) IV (Max: 27 g/day [24 g piperacillin and 3 g tazobactam]) have been used off-label for patients with cystic fibrosis.
    40 kg or less: 300 mg/kg/day piperacillin component IV is FDA-approved dosage; however, doses up to 600 mg/kg/day (piperacillin component) IV have been used off-label for patients with cystic fibrosis.

    Infants

    9 months and older: 300 mg/kg/day (piperacillin component) IV is FDA-approved dosage; however, doses up to 600 mg/kg/day (piperacillin component) IV have been used off-label for patients with cystic fibrosis.
    2 to 8 months: 240 mg/kg/day (piperacillin component) IV is FDA-approved dosage; however, doses up to 600 mg/kg/day (piperacillin component) IV have been used off-label for patients with cystic fibrosis.
    younger than 2 months: Safety and efficacy have not been established; however, doses up to 300 mg/kg/day (piperacillin component) IV have been used off-label.

    Neonates

    Premature and Term Neonates older than 7 days: Safety and efficacy have not been established; however, doses up to 300 mg/kg/day (piperacillin component) IV have been used off-label.
    Premature and Term Neonates 0 to 7 days: Safety and efficacy have not been established; however, doses up to 240 mg/kg/day (piperacillin component) IV have been used off-label.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Patients with hepatic cirrhosis experience increases in the half-life of piperacillin and of tazobactam by approximately 25% and 18%, respectively, compared to healthy subjects. However, dosage adjustments are not required.

    Renal Impairment

    Adult patients
    CrCl more than 40 mL/min: No dosage adjustment needed.
    CrCl 20 to 40 mL/min: For nosocomial pneumonia, reduce dose to 3.375 g (3 g piperacillin and 0.375 g tazobactam) IV every 6 hours. For all other indications, reduce dose to 2.25 g (2 g piperacillin and 0.25 g tazobactam) IV every 6 hours.
    CrCl less than 20 mL/min: For nosocomial pneumonia, reduce dose to 2.25 g (2 g piperacillin and 0.25 g tazobactam) IV every 6 hours. For all other indications, reduce dose to 2.25 g (2 g piperacillin and 0.25 g tazobactam) IV every 8 hours.
     
    Pediatric patients
    In pediatric patients, recommended dosage adjustments include :
    CrCl more than 50 mL/min/1.73 m2: No dosage adjustment needed.
    CrCl 30 to 50 mL/min/1.73 m2: 35 to 50 mg/kg/dose (piperacillin component) IV every 6 hours.
    CrCl 29 mL/min/1.73 m2 or less: 35 to 50 mg/kg/dose (piperacillin component) IV every 8 hours.
     
    Intermittent hemodialysis
    The maximum recommended dose for nosocomial pneumonia in adults is 2.25 g (2 g piperacillin and 0.25 g tazobactam) IV every 8 hours; for all other indications, the maximum dose is 2.25 g (2 g piperacillin and 0.25 g tazobactam) IV every 12 hours. Because 30 to 40% of a dose of piperacillin; tazobactam is removed during hemodialysis, give one additional dose of 0.75 g (0.67 g piperacillin and 0.08 g tazobactam) IV after each dialysis period. In pediatric patients, the recommended dose is 50 to 75 mg/kg/dose (piperacillin component) IV every 12 hours.
     
    Continuous renal replacement therapy (CRRT)
    For adult patients, a dose of 4.5 g (4 g piperacillin and 0.5 g tazobactam) IV every 8 hours is recommended. For pediatric patients, the recommended dose is 35 to 50 mg/kg/dose (piperacillin component) IV every 8 hours.
     
    Peritoneal dialysis (CAPD)
    The maximum recommended dose for nosocomial pneumonia in adults is 2.25 g (2 g piperacillin and 0.25 g tazobactam) IV every 8 hours; for all other indications, the maximum dose is 2.25 g (2 g piperacillin and 0.25 g tazobactam) IV every 12 hours. No additional doses after the dialysis session are required for CAPD patients. In pediatric patients, the recommended dose is 50 to 75 mg/kg/dose (piperacillin component) IV every 12 hours.

    ADMINISTRATION

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
    Piperacillin; tazobactam 2.25 g corresponds to 2 g piperacillin and 0.25 g tazobactam.
    Piperacillin; tazobactam 3.375 g corresponds to 3 g piperacillin and 0.375 g tazobactam.
    Piperacillin; tazobactam 4.5 g corresponds to 4 g piperacillin and 0.5 g tazobactam.

    Intravenous Administration

    Powder vials for injection:
    Reconstitution:
    Reconstitute with the following volumes of a compatible solution (e.g. 0.9% Sodium Chloride Injection, 5% Dextrose Injection, Sterile Water for Injection):
            2.25 g (2 g piperacillin and 0.25 g tazobactam) single dose vial      10 mL
            3.375 g (3 g piperacillin and 0.375 g tazobactam) single dose vial   15 mL
            4.5 g (4 g piperacillin and 0.5 g tazobactam)single dose vial           20 mL
            40.5 g 36 g piperacillin and 4.5 g tazobactam) pharmacy bulk vial   152 mL (reconstituted concentration = 200 mg/mL piperacillin)
    Swirl vial until powder is fully dissolved.
    Pharmacy Bulk Vials: After reconstitution, entry into the vial must be made with a sterile dispensing device. Use entire contents of the vial promptly.
    Storage: Reconstituted vials should be used immediately. Discard any unused portion after 24 hours if stored at room temperature (20—25 degrees C or 68—77 degrees F) or after 48 hours if refrigerated (2—8 degrees C or 36—46 degrees F). Do not freeze reconstituted vials.
    Dilution:
    Reconstituted vials should be further diluted to a usual concentration of 20—60 mg/mL piperacillin component (range: 15—90 mg/mL) in a compatible intravenous solution (e.g., 0.9% Sodium Chloride Injection, 5% Dextrose Injection); however, one pediatric reference reports that up to 200 mg/mL piperacillin component can be used if necessary.
    Lactated Ringer's Injection is ONLY compatible with piperacillin; tazobactam containing edetate disodium dihydrate (EDTA).
    If Sterile Water for Injection is used as the diluent, do not exceed a maximum final volume of 50 mL.
    Storage: Diluted solutions in IV glass or plastic containers are stable for up to 24 hours at room temperature and up to one week under refrigeration.
     
    ADD-Vantage IV solution:
    Reconstitution:
    Reconstitute only with 0.9% Sodium Chloride Injection or 5% Dextrose Injection in the appropriate flexible diluent container provided.
    Remove the protective covers from the top of the vial and vial port. Remove vial cap (do not access with a syringe) and vial port cover. Screw the vial into the vial port until it will go no further to assure a seal. Once vial is sealed to the port, do not remove. To activate the contents of the vial, squeeze the bottom of the diluent container gently to inflate the portion of the container surrounding the end of the drug vial. With the other hand, push the drug vial down into the container telescoping walls of the container and grasp the inner cap of the vial through the walls of the container. Pull the inner cap from the drug vial. Verify the rubber stopper has been pulled out, allowing the drug and diluent to mix. Mix the container contents thoroughly.
    Storage after reconstitution: The admixture solution may be stored for up to 24 hours at room temperature. Do not refrigerate or freeze after reconstitution.
    Do not use in series connections with flexible containers.
     
    Pre-mixed Galaxy IV solution:
    Thaw frozen containers at room temperature (20—25 degrees C or 68—77 degrees F) or under refrigeration (2—8 degrees C or 36—46 degrees F). Do no force thaw by immersion in water baths or by microwave irradiation. Check for leaks by squeezing bag firmly.
    Do not add supplementary medication.
    Contents of the solution may precipitate in the frozen state and should dissolve with little or no agitation once the solution has reached room temperature.
    Storage: The thawed solution is stable for 24 hours at room temperature or for 14 days under refrigeration. Do not refreeze thawed product.
    Do not use plastic containers in series connections as this could result in an embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is complete.
     
    Intravenous infusion:
    Infuse IV over at least 30 minutes. Ambulatory intravenous infusion pumps can be used; the solution is stable for up to 12 hours at room temperature.
     
    Ambulatory IV Infusion
    Doses diluted to a final volume of 37.5 mL or 25 mL have been shown to be stable for 12 hours at room temperature in medication reservoirs that were fitted into preprogrammed ambulatory IV infusion pumps.

    STORAGE

    Zosyn:
    - Reconstituted product is stable for up to 24 hours at room temperature and 48 hours under refrigeration
    - Store unreconstituted product at 68 to 77 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Piperacillin; tazobactam does not treat viral infections (e.g., common cold). Prescribing this drug in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Patients should be told to complete the full course of treatment, even if they feel better earlier.
     
    Antibiotic therapy can result in superinfection or suprainfection with non susceptible organisms. Overgrowth of Candida, Serratia, Klebsiella, or P. aeruginosa can occur with extended-spectrum penicillin therapy. Patients should be monitored closely during therapy.

    Dialysis, renal failure, renal impairment

    Piperacillin; tazobactam should be used with caution in patients with renal impairment or renal failure because the drug is eliminated via renal mechanisms. Dosage adjustments are required in patients with renal impairment or in those who are receiving dialysis.

    Urinary tract infection (UTI)

    Clinical trial data for the treatment of complicated urinary tract infection (UTI) demonstrated inadequate efficacy at the dosage of piperacillin; tazobactam studied (i.e., 3.375 g IV every 8 hours). There are no other adequate and well-controlled trial data to support the use of piperacillin; tazobactam in the treatment of complicated urinary tract infections.

    Biliary obstruction

    Piperacillin and tazobactam are partially excreted unchanged in the bile. Excretion can be reduced in patients with biliary obstruction.

    Electrolyte imbalance, heart failure, hypokalemia, neonates, sodium restriction

    Use piperacillin; tazobactam cautiously in patients with fluid and electrolyte imbalance and in patients who are particularly sensitive to sodium intake (e.g., neonates, elderly, patients with heart failure) or who may require sodium restriction. Consult specific product labeling for precise sodium content. Because piperacillin; tazobactam therapy has been associated with hypokalemia, it should be used with caution in patients who already have hypokalemia or who may have low potassium stores.

    Asthma, carbapenem hypersensitivity, cephalosporin hypersensitivity, cystic fibrosis, penicillin hypersensitivity

    Piperacillin; tazobactam is a penicillin and beta-lactamase combination product and is contraindicated in patients with penicillin hypersensitivity or a beta-lactamase hypersensitivity. The manufacturer also states that piperacillin; tazobactam is contraindicated in patients with cephalosporin hypersensitivity; however, cross-reactivity between penicillins and cephalosporins does not always occur. Due to piperacillin's structural similarity to the carbapenems, it should be used cautiously in patients with carbapenem hypersensitivity because these patients are more susceptible to cross-hypersensitivity reactions. Patients with allergies or allergic conditions, including asthma, eczema, hives, or hay fever, may have a greater risk of having hypersensitivity reactions to penicillins. Patients with cystic fibrosis also have a higher incidence of hypersensitivity reactions to the extended-spectrum penicillins. This may be due to these patients having a greater cumulative exposure to the drugs than other patients as well as a high rate of generalized immune response and atopy.

    Anticoagulant therapy, bleeding, coagulopathy, hemophilia

    Piperacillin should be used with caution in patients with a coagulopathy (e.g., hemophilia) because the drug can inhibit platelet aggregation. Its use in these patients or in patients with other bleeding disorders can increase the risk of bleeding. Hematologic parameters should be periodically monitored during therapy, particularly with prolonged therapy (i.e., >= 21 days). Coagulation parameters should be tested more frequently and monitored regularly during simultaneous administration of anticoagulant therapy or other drugs that may affect the blood coagulation system or the thrombocyte function.

    Colitis, diarrhea, GI disease, inflammatory bowel disease, pseudomembranous colitis, ulcerative colitis

    Almost all antibacterial agents, like piperacillin; tazobactam, have been associated with pseudomembranous colitis (antibiotic-associated colitis) which may range in severity from mild to life-threatening. In the colon, overgrowth of Clostridia may exist when normal flora is altered subsequent to antibacterial administration. The toxin produced by Clostridium difficile is a primary cause of pseudomembranous colitis. It is known that systemic use of antibiotics predisposes patients to development of pseudomembranous colitis. Consideration should be given to the diagnosis of pseudomembranous colitis in patients presenting with diarrhea following antibacterial administration. Systemic antibiotics should be prescribed with caution to patients with inflammatory bowel disease such as ulcerative colitis or other GI disease. If diarrhea develops during therapy, the drug should be discontinued. Following diagnosis of pseudomembranous colitis, therapeutic measures should be instituted. In milder cases, the colitis may respond to discontinuation of the offending agent. In moderate to severe cases, fluids and electrolytes, protein supplementation, and treatment with an antibacterial effective against Clostridium difficile may be warranted. Products inhibiting peristalsis are contraindicated in this clinical situation. Practitioners should be aware that antibiotic-associated colitis has been observed to occur over two months or more following discontinuation of systemic antibiotic therapy; a careful medical history should be taken.

    Pregnancy

    Piperacillin; tazobactam is classified as FDA pregnancy risk category B. Animal studies have indicated no teratogenic effects. Piperacillin and tazobactam do cross the placenta in humans. However, no studies have been performed in pregnant women. Piperacillin; tazobactam should be used during pregnancy only if clearly needed.

    Breast-feeding

    Piperacillin is excreted in low concentrations in human breast milk; tazobactam concentrations in human milk have not been studied. Penicillins may cause diarrhea (due to disruption of GI flora), candidiasis, and skin rash in the breast-feeding infant. Unless the infant is allergic to penicillins, breast-feeding is generally safe during maternal penicillin therapy; the infant should be observed for potential effects. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Geriatric

    Geriatric patients are not likely to have an increased risk of developing adverse reactions solely because of age. However, piperacillin; tazobactam dosage should be adjusted in the presence of renal impairment. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

    Diabetes mellitus

    A false-positive reaction for glucose in the urine has been observed in patients receiving penicillins and using Benedict's solution, Fehling's solution, or Clinitest tablets for urine glucose testing. However, this reaction has not been observed with Tes-tape (glucose Enzymatic Test Strip, USP, Lilly) or Clinistix. Patients with diabetes mellitus who test their urine for glucose should use glucose tests based on enzymatic glucose oxidase reactions while on piperacillin; tazobactam treatment.

    Serious rash

    Serious skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been observed in patients receiving piperacillin; tazobactam therapy. Monitor patients who experience a skin rash closely, and discontinue treatment in patients who develop a serious rash.

    Sexually transmitted disease

    While piperacillin; tazobactam may be used to treat certain sexually transmitted diseases (STD), the drug may mask or delay the symptoms of incubating syphilis when given as part of an STD treatment regimen. All patients with a diagnosed or suspected STD should be tested for other STDs, which may include HIV, syphilis, chlamydia, and gonorrhea, at the time of diagnosis. Initiate appropriate therapy and perform follow-up testing as recommended based upon sexually transmitted disease diagnosis.

    ADVERSE REACTIONS

    Severe

    anaphylactic shock / Rapid / 0-1.0
    anaphylactoid reactions / Rapid / 0-1.0
    renal failure (unspecified) / Delayed / 0-1.0
    toxic epidermal necrolysis / Delayed / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    acute generalized exanthematous pustulosis (AGEP) / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
    seizures / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    hemolytic anemia / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    interstitial nephritis / Delayed / Incidence not known
    eosinophilic pneumonia / Delayed / Incidence not known

    Moderate

    constipation / Delayed / 7.7-8.4
    bullous rash / Early / 3.9-4.2
    candidiasis / Delayed / 1.6-3.9
    thrombocytosis / Delayed / 1.4-1.4
    elevated hepatic enzymes / Delayed / 0-1.4
    hypotension / Rapid / 0-1.3
    phlebitis / Rapid / 0-1.3
    stomatitis / Delayed / 0-1.0
    hypokalemia / Delayed / 0-1.0
    thrombocytopenia / Delayed / 0-1.0
    anemia / Delayed / 0-1.0
    eosinophilia / Delayed / 0-1.0
    pseudomembranous colitis / Delayed / 0-1.0
    hypoglycemia / Early / 0-1.0
    hypernatremia / Delayed / Incidence not known
    bleeding / Early / Incidence not known
    leukopenia / Delayed / Incidence not known
    platelet dysfunction / Delayed / Incidence not known
    neutropenia / Delayed / Incidence not known
    prolonged bleeding time / Delayed / Incidence not known
    superinfection / Delayed / Incidence not known
    hyperglycemia / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    hyperbilirubinemia / Delayed / Incidence not known

    Mild

    diarrhea / Early / 11.3-20.0
    headache / Early / 4.5-7.7
    nausea / Early / 5.8-6.9
    insomnia / Early / 4.5-6.6
    maculopapular rash / Early / 3.9-4.2
    urticaria / Rapid / 3.9-4.2
    rash (unspecified) / Early / 3.9-4.2
    vomiting / Early / 2.7-3.3
    dyspepsia / Early / 1.9-3.3
    fever / Early / 2.4-3.2
    pruritus / Rapid / 3.1-3.2
    abdominal pain / Early / 1.3-1.8
    flushing / Rapid / 0-1.0
    injection site reaction / Rapid / 0-1.0
    purpura / Delayed / 0-1.0
    epistaxis / Delayed / 0-1.0
    arthralgia / Delayed / 0-1.0
    myalgia / Early / 0-1.0

    DRUG INTERACTIONS

    Acetaminophen; Aspirin, ASA; Caffeine: Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as penicillins, and sulfonamides. An enhanced effect of the displaced drug may occur.
    Anticoagulants: Some penicillins (e.g., piperacillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type, however, is relatively rare. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary in patients receiving warfarin.
    Antithrombin III: Some penicillins (e.g., piperacillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type, however, is relatively rare. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary in patients receiving warfarin.
    Apixaban: Some penicillins (e.g., piperacillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type, however, is relatively rare. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary in patients receiving warfarin.
    Argatroban: Some penicillins (e.g., piperacillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type, however, is relatively rare. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary in patients receiving warfarin.
    Aspirin, ASA: Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    Aspirin, ASA; Butalbital; Caffeine: Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    Aspirin, ASA; Caffeine; Dihydrocodeine: Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    Aspirin, ASA; Carisoprodol: Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    Aspirin, ASA; Carisoprodol; Codeine: Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    Aspirin, ASA; Dipyridamole: Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    Aspirin, ASA; Omeprazole: Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    Aspirin, ASA; Oxycodone: Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    Aspirin, ASA; Pravastatin: Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    Bivalirudin: Some penicillins (e.g., piperacillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type, however, is relatively rare. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary in patients receiving warfarin.
    Choline Salicylate; Magnesium Salicylate: Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as penicillins, and sulfonamides. An enhanced effect of the displaced drug may occur.
    Dabigatran: Some penicillins (e.g., piperacillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type, however, is relatively rare. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary in patients receiving warfarin.
    Dalteparin: Some penicillins (e.g., piperacillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type, however, is relatively rare. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary in patients receiving warfarin.
    Danaparoid: Some penicillins (e.g., piperacillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type, however, is relatively rare. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary in patients receiving warfarin.
    Desirudin: Some penicillins (e.g., piperacillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type, however, is relatively rare. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary in patients receiving warfarin.
    Dichlorphenamide: Use dichlorphenamide and penicillins together with caution. Dichlorphenamide increases potassium excretion and can cause hypokalemia and should be used cautiously with other drugs that may cause hypokalemia including penicillins. Measure potassium concentrations at baseline and periodically during dichlorphenamide treatment. If hypokalemia occurs or persists, consider reducing the dose or discontinuing dichlorphenamide therapy.
    Digoxin: Displacement of penicillins from plasma protein binding sites by highly protein bound drugs like digoxin will elevate the level of free penicillin in the serum. The clinical significance of this interaction is unclear. It is recommended to monitor these patients for increased adverse effects.
    Edoxaban: Some penicillins (e.g., piperacillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type, however, is relatively rare. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary in patients receiving warfarin.
    Enoxaparin: Some penicillins (e.g., piperacillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type, however, is relatively rare. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary in patients receiving warfarin.
    Erythromycin; Sulfisoxazole: Sulfonamides may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. These combinations should be used with caution and patients monitored for increased side effects.
    Ethacrynic Acid: Ethacrynic acid may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. This combination should be used with caution and patients monitored for increased side effects.
    Fondaparinux: Some penicillins (e.g., piperacillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type, however, is relatively rare. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary in patients receiving warfarin.
    Furosemide: Furosemide may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. This combination should be used with caution and patients monitored for increased side effects.
    Heparin: Some penicillins (e.g., piperacillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type, however, is relatively rare. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary in patients receiving warfarin.
    Ibuprofen lysine: Use caution in combining ibuprofen lysine with renally eliminated medications like penicillins, as ibuprofen may reduce renal blood flow.
    Indomethacin: Indomethacin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. This combination should be used with caution and patients monitored for increased side effects.
    Lepirudin: Some penicillins (e.g., piperacillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type, however, is relatively rare. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary in patients receiving warfarin.
    Magnesium Salicylate: Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as penicillins, and sulfonamides. An enhanced effect of the displaced drug may occur.
    Methotrexate: Penicillins may reduce the renal clearance of methotrexate. Increased serum concentrations of methotrexate with concomitant hematologic and gastrointestinal toxicity have been observed with concurrent administration of high or low doses of methotrexate and penicillins. Patients should be carefully monitored while receiving this combination.
    Oral Contraceptives: It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Pancuronium: Piperacillin when used concomitantly with vecuronium has been implicated in the prolongation of the neuromuscular blockade of vecuronium. Due to their similar mechanism of action, it is expected that the neuromuscular blockade produced by any of the non-depolarizing neuromuscular blockers could be prolonged in the presence of piperacillin.
    Pentosan: Some penicillins (e.g., piperacillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type, however, is relatively rare. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary in patients receiving warfarin.
    Phenytoin: Penicillin G is 60% bound to albumin or moderately protein bound. Displacement of penicillins from plasma protein binding sites by highly protein bound drugs (e.g., phenytoin, fosphenytoin) will elevate the level of free penicillin in the serum. The clinical significance of this interaction is unclear. It is recommended to monitor these patients for increased adverse effects.
    Probenecid: Probenecid competitively inhibits renal tubular secretion and causes higher, prolonged serum levels of penicillins. In general, this pharmacokinetic interaction is not harmful and can be used therapeutically if needed. Probenecid may prolong serum concentrations of tazobactam when coadministered with ceftolozane; tazobactam. Probenecid has been shown to prolong the half-life of tazobactam by 71% when coadministered. The clinical significance of this interaction has not been established.
    Pyrimethamine; Sulfadoxine: Sulfonamides may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. These combinations should be used with caution and patients monitored for increased side effects.
    Rivaroxaban: Some penicillins (e.g., piperacillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type, however, is relatively rare. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary in patients receiving warfarin.
    Rocuronium: Due to their similar mechanism of action, it is expected that the neuromuscular blockade produced by rocuronium could be prolonged in the presence of piperacillin.
    Salsalate: Due to high protein binding, salicylates could be displaced from binding sites or could displace other highly protein-bound drugs such as penicillins. An enhanced effect of the displaced drug may occur.
    Sodium Benzoate; Sodium Phenylacetate: Antibiotics that undergo tubular secretion such as penicillins may compete with phenylacetlyglutamine and hippuric acid for active tubular secretion. The overall usefulness of sodium benzoate; sodium phenylacetate is due to the excretion of its metabolites. An increase in metabolite concentrations could contribute to failed treatment and worsening of the patient's clinical status. This combination should be used with caution.
    Sodium picosulfate; Magnesium oxide; Anhydrous citric acid: Prior or concomitant use of antibiotics with sodium picosulfate; magnesium oxide; anhydrous citric acid may reduce efficacy of the bowel preparation as conversion of sodium picosulfate to its active metabolite bis-(p-hydroxy-phenyl)-pyridyl-2-methane, BHPM is mediated by colonic bacteria. If possible, do not schedule a colonoscopy right after or during therapy with antibiotics. Certain antibiotics (i.e, tetracyclines and quinolones) may chelate with the magnesium in sodium picosulfate; magnesium oxide; anhydrous citric acid solution. Therefore, these antiobiotics should be taken at least 2 hours before and not less than 6 hours after the administration of sodium picosulfate; magnesium oxide; anhydrous citric acid solution.
    Sulfadiazine: Sulfonamides may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. These combinations should be used with caution and patients monitored for increased side effects.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: Sulfonamides may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. These combinations should be used with caution and patients monitored for increased side effects.
    Sulfasalazine: Sulfonamides may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. These combinations should be used with caution and patients monitored for increased side effects.
    Sulfisoxazole: Sulfonamides may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. These combinations should be used with caution and patients monitored for increased side effects.
    Sulfonamides: Sulfonamides may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. These combinations should be used with caution and patients monitored for increased side effects.
    Tinzaparin: Some penicillins (e.g., piperacillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type, however, is relatively rare. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary in patients receiving warfarin.
    Typhoid Vaccine: Antibiotics which possess bacterial activity against salmonella typhi organisms may interfere with the immunological response to the live typhoid vaccine. Allow 24 hours or more to elapse between the administration of the last dose of the antibiotic and the live typhoid vaccine.
    Vancomycin: Piperacillin; tazobactam, when used concomitantly with vancomycin, may increase the risk of acute kidney injury. A limited number of retrospective studies have detected an increased incidence of acute kidney injury in patients administered concomitant piperacillin; tazobactam and vancomycin as compared to those who received vancomycin alone. Careful patient monitoring while on concurrent therapy with vancomycin is recommended.
    Vecuronium: When used in the perioperative period, piperacillin has been implicated in the prolongation of the neuromuscular blockade of vecuronium. Caution is indicated when piperacillin is used perioperatively.
    Warfarin: Some penicillins (e.g., piperacillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type, however, is relatively rare. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary in patients receiving warfarin.

    PREGNANCY AND LACTATION

    Pregnancy

    Piperacillin; tazobactam is classified as FDA pregnancy risk category B. Animal studies have indicated no teratogenic effects. Piperacillin and tazobactam do cross the placenta in humans. However, no studies have been performed in pregnant women. Piperacillin; tazobactam should be used during pregnancy only if clearly needed.

    Piperacillin is excreted in low concentrations in human breast milk; tazobactam concentrations in human milk have not been studied. Penicillins may cause diarrhea (due to disruption of GI flora), candidiasis, and skin rash in the breast-feeding infant. Unless the infant is allergic to penicillins, breast-feeding is generally safe during maternal penicillin therapy; the infant should be observed for potential effects. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Piperacillin is a beta-lactam antibiotic and is mainly bactericidal. It inhibits the third and final stage of bacterial cell wall synthesis by preferentially binding to specific penicillin-binding proteins (PBPs) that are located inside the bacterial cell wall. Penicillin-binding proteins are responsible for several steps in the synthesis of the cell wall and are found in quantities of several hundred to several thousand molecules per bacterial cell. Penicillin-binding proteins vary among different bacterial species. Thus, the intrinisic activity of piperacillin, as well as the other penicillins, against a particular organism depends on its ability to gain access to and bind with the necessary PBP. Like all beta-lactam antibiotics, piperacillin's ability to interfere with PBP-mediated cell wall synthesis ultimately leads to cell lysis. Lysis is mediated by bacterial cell wall autolytic enzymes (i.e., autolysins). The relationship between PBPs and autolysins is unclear, but it is possible that the beta-lactam antibiotic interferes with an autolysin inhibitor.
     
    Tazobactam, like sulbactam and clavulanic acid, is an irreversible inhibitor of bacterial beta-lactamases. Tazobactam protects piperacillin against Richmond and Sykes types II, III, IV, and V beta-lactamases; staphylococcal penicillinase; and extended-spectrum beta-lactamases. However, tazobactam has only species-specific activity against class I chromosomally-mediated beta-lactamases. Resistant organisms include some Citrobacter spp., Enterobacter spp., Serratia spp., Xanthomonas maltophilia, and Enterococcus faecium. Tazobactam has little useful antibacterial activity by itself. Tazobactam does not alter the actions of piperacillin.

    PHARMACOKINETICS

    Piperacillin; tazobactam is administered intravenously as an infusion. Both piperacillin and tazobactam are approximately 30% bound to plasma protein and are unaffected by the presence of each other. Protein binding of the tazobactam metabolite is negligible. Piperacillin and tazobactam are widely distributed into tissues and body fluids including the intestinal mucosa, lung, female reproductive tissues (uterus, ovary, and fallopian tube), interstitial fluid, and bile. Mean tissue concentrations are generally 50—100% of those in plasma. Minimal concentrations are reached within the CSF when the meninges are uninflamed; these levels increase in the presence of inflammation. Piperacillin crosses the placenta.
     
    Piperacillin is metabolized to a minor active desethyl metabolite. Tazobactam is metabolized to a single metabolite that lacks pharmacological and antibacterial activity. Both piperacillin and tazobactam are excreted into the urine primarily via tubular secretion and glomerular filtration. Approximately 68% of piperacillin and 80% of tazobactam are excreted as unchanged drug. Biliary excretion accounts for a portion of the dose, and a small percentage is excreted in breast milk. In patients with normal renal function, the elimination half-life of piperacillin and tazobactam ranges from 0.7 to 1.5 hours.

    Intravenous Route

    Piperacillin; tazobactam is administered intravenously as a 30-minute infusion. Peak serum concentrations of piperacillin and tazobactam are attained immediately after the completion of the infusion. Mean peak plasma concentrations of piperacillin are approximately 134, 242, and 298 mcg/ml for the 2.25 g, 3.375 g, and 4.5 g doses, respectively. Piperacillin concentrations obtained after administration of piperacillin; tazobactam are similar to those attained with equivalent doses of piperacillin alone. Steady state serum concentrations are similar to those attained after the first dose. The half-lives of piperacillin and tazobactam were unaffected by dose or duration of infusion.