The suitable dosage for each patient should be prescribed by a doctor.

Method of Administration:

Administration: I.V.

Administer by I.V. infusion over 30 minutes. For extended infusion administration (unlabeled dosing), administer over 3-4 hours (Kim 2007; Shea, 2009).

Extended infusion: Extended-infusion strategies have been shown to improve the pharmacodynamics of piperacillin/tazobactam as compared to traditional 30-minute intermittent-infusion regimens (Kim, 2007). For the beta-lactam antibiotics, the time in which unbound drug concentrations remain above the MIC (T>MIC) of an infecting pathogen is the pharmacodynamic parameter that predicts clinical and microbiologic efficacy.

Various strategies aimed at improving the T>MIC include increasing the dose, frequency of dosing, and/or infusion times (including utilizing continuous infusions) (Shea, 2009). However, utilizing a continuous infusion may be impractical as a dedicated intravenous catheter would be required for drug administration. On the other hand, prolonging the length of the infusion to 3-4 hours enhances drug exposure while allowing time for other drugs to be administered through the same intravenous catheter. This approach has the added benefit of lower daily doses than are required by other dose optimization strategies, thereby decreasing drug expenditures. At doses ≥3.375 g every 8 hours, 4-hour infusions of piperacillin/tazobactam achieved excellent target attainment with lower daily doses as compared to standard regimens when MICs were ≤16 μg/mL (Shea, 2009).

Usual dosage range:

Adults: I.V.: 3.375 g every 6 hours or 4.5 g every 6-8 hours; maximum: 18 g/day

Extended infusion method (unlabeled dosing): 3.375-4.5 g I.V. over 4 hours every 8 hours (Kim, 2007; Shea, 2009); an alternative regimen of 4.5 g I.V. over 3 hours every 6 hours has also been described (Kim, 2007)

Indication-specific dosing: I.V.:

>40 kg: refer to Adult dosing

Cystic fibrosis, pseudomonal infections (unlabeled use): 350-450 mg/kg/day in divided doses

Adults:

Diverticulitis, intra-abdominal abscess, peritonitis: I.V.: 3.375 g every 6 hours; Note: Some clinicians use 4.5 g every 8 hours for empiric coverage since the %time>MIC is similar between the regimens for most pathogens; however, this regimen is NOT recommended for nosocomial pneumonia or Pseudomonas coverage.

Intra-abdominal infection, severe: I.V.: 3.375 g every 6 hours for 4-7 days (provided source controlled). Note: Increase to 3.375 g every 4 hours or 4.5 g every 6 hours if P. aeruginosa suspected. Not recommended for mild-to-moderate, community-acquired intra-abdominal infections due to risk of toxicity and the development of resistant organisms (Solomkin, 2010).

Pneumonia (nosocomial): I.V.: 4.5 g every 6 hours for 7-14 days (when used empirically, combination with an aminoglycoside or antipseudomonal fluoroquinolone is recommended; consider discontinuation of additional agent if P. aeruginosa is not isolated)

Severe infections: I.V.: 3.375 g every 6 hours for 7-10 days; Note: Some clinicians use 4.5 g every 8 hours for empiric coverage since the %time>MIC is similar between the regimens for most pathogens; however, this regimen is NOT recommended for nosocomial pneumonia or Pseudomonas coverage.

Children Dosage:

Usual dosage range:

Children: I.V.:

2-8 months: 80 mg of piperacillin component/kg every 8 hours

≥9 months and ≤40 kg: 100 mg of piperacillin component/kg every 8 hours

Indication-specific dosing: I.V.:
Children: Note: Dosing based on piperacillin component:

Appendicitis, peritonitis:

2-8 months: 80 mg/kg every 8 hours
≥9 months and ≤40 kg: 100 mg/kg every 8 hours
>40 kg: refer to Adult dosing

Cystic fibrosis, pseudomonal infections (unlabeled use): 350-450 mg/kg/day in divided doses

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. Tazobactam inhibits many beta-lactamases, including staphylococcal penicillinase and Richmond and Sykes types II, III, IV, and V, including extended spectrum enzymes; it has only limited activity against class I beta-lactamases other than class Ic types

Warnings/Precautions

Concerns related to adverse effects:

• Anaphylactoid/hypersensitivity reactions: Serious and occasionally severe or fatal hypersensitivity (anaphylactoid) reactions have been reported in patients on penicillin therapy, especially with a history of beta-lactam hypersensitivity, history of sensitivity to multiple allergens, or previous IgE-mediated reactions (eg, anaphylaxis, angioedema, urticaria). Use with caution in asthmatic patients.

• Bleeding disorders: Particularly in patients with renal impairment, bleeding disorders have been observed; discontinue if thrombocytopenia or bleeding occurs.

• Superinfection: Prolonged use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment.

Disease-related concerns:

• Cystic fibrosis: An increased frequency of fever and rash has been reported in patients with cystic fibrosis.

• Renal impairment: Use with caution in patients with renal impairment or underdeveloped kidneys; due to sodium load and to the adverse effects of high serum concentrations of penicillins. Dosage adjustment recommended.

• Seizure disorders: Use with caution in patients with a history of seizure disorder; high levels, particularly in the presence of renal impairment, may increase risk of seizures.

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Adverse events have not been observed in animal studies; therefore, piperacillin/tazobactam is classified as pregnancy category B. Piperacillin and tazobactam both cross the placenta and are found in the fetal serum, placenta, amniotic fluid, and fetal urine. When used during pregnancy, the clearance and volume of distribution of piperacillin/tazobactam are increased; half-life and AUC are decreased.

Although no information is available on the use of piperacillin and tazobactam during breastfeeding, limited information indicates that maternal doses of piperacillin produce low levels in milk that are not expected to cause adverse effects in breastfed infants. Occasionally, disruption of the infant's gastrointestinal flora, resulting in diarrhea or thrush, has been reported with penicillins, but these effects have not been adequately evaluated. Piperacillin and tazobactam is acceptable to use during breastfeeding.

Low concentrations of piperacillin are excreted in breast milk; information for tazobactam is not available. The manufacturer recommends that caution be exercised when administering piperacillin/tazobactam to nursing women. Other penicillins are considered safe for use during breast-feeding. Nondose-related effects could include modification of bowel flora. When given alone in the early postpartum period, some pharmacokinetic parameters of piperacillin may be altered (refer to Piperacillin monograph for details).

>10%: Gastrointestinal: Diarrhea (7% to 11%)

>1% to 10%:

Cardiovascular: Hypertension (2%)

Central nervous system: Insomnia (7%), headache (8%), fever (2% to 5%), agitation (2%), pain (2%)

Dermatologic: Rash (4%), pruritus (3%)

Gastrointestinal: Constipation (1% to 8%), nausea (7%), vomiting (3% to 4%), dyspepsia (3%), stool changes (2%), abdominal pain (1% to 2%)

Hepatic: Transaminases increased

Local: Local reaction (3%), abscess (2%)

Respiratory: Pharyngitis (2%)

Miscellaneous: Moniliasis (2%), sepsis (2%), infection (2%)

≤1%, postmarketing, and/or case reports: Agranulocytosis, anaphylaxis/anaphylactoid reaction, anemia, anxiety, arrhythmia, arthralgia, atrial fibrillation, back pain, bradycardia, bronchospasm, candidiasis, cardiac arrest, cardiac failure, circulatory failure, chest pain, cholestatic jaundice, confusion, convulsions, coughing, depression, diaphoresis, dizziness, dyspnea, dysuria, edema, epistaxis, erythema multiforme, flatulence, flushing, gastritis, genital pruritus, hallucination, hematuria, hemolytic anemia, hemorrhage, hepatitis, hiccough, hypoglycemia, hypotension, ileus, incontinence, inflammation, injection site reaction, interstitial nephritis, leukorrhea, malaise, mesenteric embolism, myalgia, myocardial infarction, oliguria, pancytopenia, phlebitis, photophobia, pseudomembranous colitis, pulmonary edema, pulmonary embolism, purpura, renal failure, rhinitis, rigors, Stevens-Johnson syndrome, syncope, tachycardia (supraventricular and ventricular), taste perversion, thirst, thrombocytopenia, thrombocytosis, thrombophlebitis, tinnitus, toxic epidermal necrolysis, tremor, ulcerative stomatitis, urinary retention, vaginitis, ventricular fibrillation, vertigo