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Piperacillin Sodium and Tazobactam Sodium

Piperacillin sodium and tazobactam sodium is a fixed combination of the sodium salts of piperacillin (an extended-spectrum penicillin antibiotic) and tazobactam (a b-lactamase inhibitor); tazobactam synergistically expands piperacillin’s spectrum of activity against many strains of b-lactamase-producing bacteria.

Uses

Piperacillin sodium and tazobactam sodium is used parenterally for the treatment of moderate to severe infections caused by, or suspected of being caused by, susceptible b-lactamase-producing bacteria when piperacillin alone would be ineffective. Although piperacillin sodium and tazobactam sodium also may be effective in the treatment of infections caused by non-b-lactamase-producing bacteria susceptible to piperacillin alone, some clinicians suggest that the fixed-combination preparation be reserved for use in the treatment of infections caused by, or suspected of being caused by, b-lactamase-producing organisms when an extended-spectrum penicillin or a cephalosporin alone would be ineffective. Piperacillin sodium and tazobactam sodium may be particularly useful for the empiric treatment of polymicrobial infections such as mixed aerobic-anaerobic infections or infections suspected of being caused by both piperacillin-resistant and piperacillin-susceptible organisms. When piperacillin sodium and tazobactam sodium is used for the treatment of nosocomial infections, including pneumonia, concomitant therapy with an aminoglycoside should be considered. Concomitant use of an aminoglycoside is particularly important when Pseudomonas aeruginosa is suspected as a causative organism; if Ps. aeruginosa is not isolated, it may be possible to discontinue the aminoglycoside. Piperacillin sodium and tazobactam sodium is used for the treatment of intra-abdominal infections, including peritonitis, appendicitis (complicated by rupture or abscess), postpartum endometritis, or pelvic inflammatory disease caused by piperacillin-resistant, b-lactamase-producing strains of Escherichia coli and for peritonitis or appendicitis caused by piperacillin-resistant, b-lactamase-producing Bacteroides fragilis, B. ovatus, B. thetaiotamicron, or B. vulgatus. The drug also is used for the treatment of uncomplicated and complicated skin and skin structure infections (including cellulitis, cutaneous abscesses, ischemic/diabetic foot infections) caused by piperacillin-resistant, b-lactamase-producing Staphylococcus aureus; for moderately severe community-acquired pneumonia caused by piperacillin-resistant, b-lactamase-producing Haemophilus influenzae; and for moderate to severe nosocomial pneumonia caused by piperacillin-resistant b-lactamase-producing S. aureus or Acinetobacter baumanii, H. influenzae, Klebsiella pneumoniae, and Pseudomonoas aeruginosa susceptible to piperacillin sodium and tazobactam sodium. Because in vitro studies indicate that concomitant use of tazobactam with piperacillin does not result in synergism against Ps. aeruginosa, concomitant use of an aminoglycoside is indicated in the treatment of nosocomial pneumonia caused by Ps. aeruginosa. In one study in adults with mild to moderately severe community-acquired respiratory tract infections caused by H. influenzae, S. pneumoniae, or other pathogens such as Moraxella catarrhalis, therapy with piperacillin sodium and tazobactam sodium was associated with a slightly greater bacteriologic cure rate than therapy with ticarcillin disodium and clavulanate potassium. However, the relative efficacy of piperacillin sodium and tazobactam sodium compared with other anti-infective combinations that include a b-lactamase inhibitor (e.g., ampicillin sodium and sulbactam sodium, ticarcillin disodium and clavulanate potassium) has not been elucidated fully to date. For the treatment of nosocomial pneumonia, a higher dosage of piperacillin sodium and tazobactam sodium is necessary compared with that used for other infections.In addition, concomitant use of an aminoglycoside in necessary for initial empiric therapy in patients with nosocomial pneumonia. If Ps. aeruginosa is identified as a causative organism, the aminoglycoside should be continued with piperacillin sodium and tazobactam sodium; if Ps. aeruginosa is not isolated, the aminoglycoside may be discontinued.

Cautions

Adverse effects reported with piperacillin sodium and tazobactam sodium are similar to those reported with piperacillin alone and generally are transient and mild to moderate in severity. Adverse effects have been reported in about 10% or less of patients receiving parenteral piperacillin sodium and tazobactam sodium, and have been severe enough to require discontinuance in 3% or less of patients. The most frequent adverse effects reported with piperacillin sodium and tazobactam sodium are GI effects, headache, and dermatologic reactions. For information on adverse effects reported with piperacillin and other extended-spectrum penicillins as well as the usual precautions and contraindications associated with these drugs

GI Effects

Diarrhea, nausea, and constipation have been reported in up to 11% of patients receiving parenteral piperacillin sodium and tazobactam sodium. Vomiting, dyspepsia, stool changes, and abdominal pain have been reported in up to 3%, and melena, flatulence, hemorrhage, gastritis, hiccups, and ulcerative stomatitis have been reported in 1% or less of patients receiving the drug. Clostridium difficile-associated diarrhea and colitis (also known as antibiotic-associated pseudomembranous colitis) has been reported in at least one patient receiving parenteral piperacillin sodium and tazobactam sodium. Colitis may occur during or following discontinuance of anti-infective therapy and may range in severity from mild to life-threatening. Mild cases of colitis may respond to discontinuance of piperacillin sodium and tazobactam sodium alone, but diagnosis and management of moderate to severe cases should include appropriate bacteriologic studies and treatment with fluid, electrolyte, and protein supplementation as indicated. If colitis is moderate to severe or is not relieved by discontinuance of the drug, appropriate anti-infective therapy (e.g., oral metronidazole or vancomycin) should be administered.

Dermatologic and Sensitivity Reactions

Rash (maculopapular, bullous, urticarial, eczemoid), pruritus, and fever have been reported in up to 4% of patients receiving piperacillin sodium and tazobactam sodium. Bronchospasm has been reported rarely with the drug. Although erythema multiforme and Stevens-Johnson syndrome have not been reported to date with piperacillin sodium and tazobactam sodium, these adverse effects have been reported rarely with piperacillin sodium alone. Serious and occasionally fatal hypersensitivity reactions, including anaphylaxis, can occur during penicillin therapy. Anaphylaxis has been reported rarely with piperacillin sodium and tazobactam sodium. If a severe hypersensitivity reaction occurs during piperacillin sodium and tazobactam sodium therapy, the drug should be discontinued and the patient given appropriate treatment (e.g., epinephrine, corticosteroids, maintenance of an adequate airway, oxygen) as indicated.

Hematologic Effects

Decreases in hemoglobin and hematocrit, thrombocytopenia, increases in platelet count, transient eosinophilia, transient leukopenia, and neutropenia have been reported in patients receiving piperacillin sodium and tazobactam sodium. In most reported cases, leukopenia and neutropenia occurred after prolonged therapy with the drug (e.g., after 21 days or more) and generally were reversible; systemic symptoms (e.g., fever, rigors, chills) also occurred in some patients. Positive direct antiglobulin (Coombs’) test results, prolonged prothrombin time, and prolonged partial thromboplastin time have been reported in patients receiving piperacillin sodium and tazobactam sodium. Epistaxis and purpura have been reported in 1% or less of patients receiving the drug. Manifestations of bleeding, occasionally associated with abnormal results in coagulation tests (e.g., clotting time, platelet aggregation, prothrombin time), have occurred in some patients receiving b-lactam anti-infectives, including piperacillin. Bleeding manifestations are more likely to occur in patients with renal failure than in patients with normal renal function.

Nervous System Effects

Headache and insomnia have been reported in up to 7-8%, and agitation, dizziness, and anxiety have been reported in 2% or less of patients receiving piperacillin sodium and tazobactam sodium. Tremor, seizures, vertigo, confusion, hallucination, malaise, and depression have been reported in 1% or less of patients receiving the drug. As with other penicillins, neuromuscular excitability or seizures could occur if higher than recommended doses of piperacillin sodium and tazobactam sodium are given IV, especially in patients with renal failure.

Renal, Electrolyte, and Genitourinary Effects

Increases in serum concentrations of creatinine and BUN have been reported rarely in patients receiving piperacillin sodium and tazobactam sodium. Changes in serum electrolytes, including increases and decreases in serum sodium, potassium, and calcium, have occurred in patients receiving piperacillin sodium and tazobactam sodium. Urinary retention, dysuria, oliguria, hematuria, and incontinence have been reported in 1% or less, and proteinuria, pyuria, leukorrhea, and vaginitis also have been reported in patients receiving piperacillin sodium and tazobactam sodium. Although a causal relationship has not been established, interstitial nephritis and renal failure have been reported rarely in patients receiving piperacillin sodium and tazobactam sodium.

Local Reactions

Adverse reactions at the injection site have been reported in 1% or less of patients receiving parenteral piperacillin sodium and tazobactam sodium. Adverse local reactions have included phlebitis, pain, inflammation, thrombophlebitis, and edema.

Hepatic Effects

Transient increases in AST (SGOT), ALT (SGPT), alkaline phosphatase, and bilirubin have been reported in patients receiving piperacillin sodium and tazobactam sodium.

Other Adverse Effects

Hypertension, chest pain, edema, moniliasis, rhinitis, dyspnea, hypotension, ileus, syncope, and rigors have been reported in 2% or less of patients receiving piperacillin sodium and tazobactam sodium. Tachycardia, including supraventricular and ventricular tachycardia; bradycardia; arrhythmia, including atrial fibrillation and ventricular fibrillation; cardiac arrest; cardiac failure; circulatory failure; and myocardial infarction have been reported in 1% or less of patients receiving the drug. In addition, rigors, back pain, myalgia, arthralgia, symptomatic hypoglycemia, mesenteric embolism, pulmonary embolism, thirst, pharyngitis, coughing, diaphoresis, taste perversion, flushing, tinnitus, and photophobia have been reported in 1% or less of patients receiving piperacillin sodium and tazobactam sodium.

Precautions and Contraindications

Piperacillin sodium and tazobactam sodium is contraindicated in patients who are hypersensitive to any penicillin, cephalosporin, or b-lactamase inhibitor. Piperacillin sodium and tazobactam sodium shares the toxic potentials of the penicillins, including the risk of hypersensitivity reactions, and the usual precautions of penicillin therapy should be observed. Prior to initiation of therapy with piperacillin sodium and tazobactam sodium, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, or other drugs. There is clinical and laboratory evidence of partial cross-allergenicity among penicillins and other b-lactam antibiotics including cephalosporins and cephamycins. Although it has not been proven that allergic reactions to antibiotics are more frequent in atopic individuals, the manufacturer states that these reactions are more likely to occur in individuals with a history of sensitivity to multiple allergens. Renal, hepatic, and hematologic systems should be evaluated periodically during prolonged therapy with piperacillin sodium and tazobactam sodium; monitoring hematopoietic function is especially important when the duration of therapy is 21 days or longer. Serum electrolytes should be monitored when piperacillin sodium and tazobactam sodium is used in patients with low potassium reserves, and the possibility of hypokalemia should be considered when the drug is used in patients who have potentially low potassium reserves and who are receiving diuretics or cytotoxic therapy. The fact that piperacillin sodium and tazobactam sodium contains 2.35 mEg (54 mg) of sodium per g of piperacillin should be considered when the drug is administered to patients whose sodium intake is restricted. Because C. difficile-associated diarrhea and colitis has been reported with the use of most anti-infective agents, including piperacillin sodium and tazobactam sodium, it should be considered in the differential diagnosis of patients who develop diarrhea during piperacillin sodium and tazobactam sodium therapy. Manifestations of bleeding have been reported with some b-lactam anti-infectives, including piperacillin, and the possibility that bleeding complications could occur during therapy with piperacillin sodium and tazobactam sodium should be considered, especially when the drug is used in patients with renal impairment. If bleeding manifestations occur, the drug should be discontinued and appropriate therapy instituted. As with use of other anti-infective agents, use of piperacillin sodium and tazobactam sodium may result in overgrowth of nonsusceptible organisms. Careful monitoring of the patient is important and periodic in vitro susceptibility tests warranted based on the clinical progression of the infection. If superinfection occurs, the drug should be discontinued and appropriate therapy initiated. Because serum concentrations of piperacillin and tazobactam are higher and prolonged in patients with renal impairment than in patients with normal renal function, doses and/or frequency of administration of piperacillin sodium and tazobactam sodium should be decreased in patients with renal impairment. (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.) For a more complete discussion of these and other precautions associated with the use of piperacillin.

Pediatric Precautions

The manufacturer states that safety and efficacy of piperacillin sodium and tazobactam sodium in children younger than 12 years of age have not been established.

Geriatric Precautions

Geriatric adults (adults older than 65 years of age) are not at increased risk of developing adverse effects based solely on their age. However, geriatric patients are more likely to have decreased renal function compared with younger adults and the risk of toxic reactions to the drug may be greater in patients with impaired renal function. Although serum half-lives of piperacillin and tazobactam are slightly longer in geriatric adults than in younger adults, dosage of piperacillin sodium and tazobactam sodium does not need to be modified in geriatric patients with renal function normal for their age. In geriatric patients with renal impairment, dosage should be modified in response to the degree of renal impairment, severity of infection, and susceptibility of the causative organism. Because of the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease and drug therapy in geriatric patients, dosage of piperacillin sodium and tazobactam sodium generally should be selected cautiously in these patients, usually initiating therapy at the low end of the dosage range. It may be useful to monitor renal function in geriatric patients. In addition, the sodium content of piperacillin sodium and tazobactam sodium should be considered when the drug is used in geriatric patients since they will receive 648 or 864 mg of sodium daily (28.2 or 37.6 mEq of sodium) when the usually recommended dosage of the drug is used. Geriatric patients may respond with a blunted natriuresis to salt loading.

Mutagenicity and Carcinogenicity

Various combinations of piperacillin and tazobactam have been used in vitro and in vivo to evaluate the mutagenic potential of piperacillin sodium and tazobactam sodium. There was no in vitro evidence of mutagenicity when the combinations were used in microbial mutagenicity assays, unscheduled DNA synthesis tests, mammalian point mutation assays in Chinese hamster ovary cell HPRT, or mammalian cell (BALB/c-3T3) transformation assays. In addition, in vivo studies in rats using IV piperacillin and tazobactam in dosages similar to the maximum recommended human daily dosage (based on body surface area) indicated that the drugs did not induce chromosomal aberrations. With the exception of a mammalian point mutation (mouse lymphoma cells) assay in which piperacillin was positive at concentrations of 2.5 mg/mL or greater and tazobactam was positive at concentrations of 3 mg/mL or greater, all other in vitro and in vivo assays using piperacillin alone or tazobactam alone have been negative for mutagenic effects. Long-term studies have not been performed to date to evaluate the carcinogenic potential of piperacillin, tazobactam, or piperacillin sodium and tazobactam sodium.

Piperacillin Sodium

Pregnancy, Fertitlity and Lactation

Safe use of piperacillin sodium and tazobactam sodium during pregnancy has not been established definitely. There are no adequate or controlled studies using piperacillin or tazobactam alone or piperacillin sodium and tazobactam sodium in pregnant women, and the drug should be used during pregnancy only when clearly needed. Reproduction studies in mice and rats using various combinations of piperacillin and tazobactam (up to 1-2 times the human dosage of piperacillin and 2-3 times the human dosage of tazobactam based on body surface area) have not revealed evidence of harm to the fetus. In addition, studies in mice and rats using piperacillin alone (up to the maximum recommended human daily dosage based on body surface area) or tazobactam alone (up to 6-14 times the human dosage based on body surface area) have not revealed evidence of harm to the fetus. There was no evidence of impaired fertility in reproduction studies in rats using piperacillin sodium and tazobactam sodium in dosages similar to the maximum recommended human daily dosage based on body surface area. Because piperacillin is distributed into milk in low concentrations and because it is not known whether tazobactam is distributed into milk, piperacillin sodium and tazobactam sodium should be used with caution in nursing women.

Description

Piperacillin sodium and tazobactam sodium is a fixed combination of the sodium salts of piperacillin and tazobactam. Piperacillin is an extended-spectrum penicillin. Tazobactam, a b-lactamase inhibitor, is a synthetic penicillinate sulfone containing a b-lactam ring and derived from 6-aminopenicillanic acid. Although tazobactam has minimal antibacterial activity when used alone, the combined use of tazobactam and certain penicillins or cephalosporins (e.g., amoxicillin, ampicillin, cefoperazone, cefpirome, ceftazidime, mezlocillin, piperacillin) results in a synergistic effect that expands the spectrum of activity of the penicillin or cephalosporin against many strains of b-lactamase-producing bacteria. Piperacillin sodium and tazobactam sodium is commercially available as a sterile powder for parenteral use containing an 8:1 ratio of piperacillin to tazobactam. Potency of the combination drug is expressed in terms of the total piperacillin content plus the total tazobactam content. Each 2.25 g of the commercially available sterile powder (2 g of piperacillin and 0.25 g of tazobactam) contains 4.7 mEq (108 mg) of sodium. Piperacillin sodium and tazobactam sodium also is commercially available for IV administration as frozen injections containing a 8:1 ratio of piperacillin to tazobactam provided in Galaxy® containers. The pH of the injections is 4.5-6.8; pH and is adjusted with sodium bicarbonate and hydrochloric acid. Piperacillin sodium and tazobactam sodium has a wide spectrum of activity and is active against many gram-positive and -negative aerobic and anaerobic bacteria. Because tazobactam has a high affinity for and binds to certain b-lactamases that generally inactivate piperacillin, concurrent administration of the drugs results in a synergistic bactericidal effect that expands the spectrum of activity of piperacillin against many b-lactamase-producing organisms that are resistant to piperacillin alone, including piperacillin-resistant strains of staphylococci, Haemophilus, Enterobacteriaceae, and Bacteroides. Tazobactam generally acts as an irreversible inhibitor and inactivates both plasmid- and chromosome-mediated b-lactamases. In vitro studies indicate that tazobactam can inhibit staphylococcal b-lactamases and b-lactamases classified as Richmond-Sykes types II, III (TEM type, HSV-1), IV, and V (PSE and OXA types).

Tazobactam is effective against some type I b-lactamases, including type Ic, and may be slightly more active against type I enzymes than some other b-lactamase inhibitors (e.g., clavulanic acid, sulbactam). Unlike clavulanic acid, tazobactam generally does not induce production of type I chromosomally mediated cephalosporins in Pseudomonas or Enterobacteriaceae. Pseudomonas resistant to piperacillin generally also are resistant to piperacillin sodium and tazobactam sodium. In addition, staphylococci resistant to penicillinase-resistant penicillins (e.g., nafcillin, oxacillin), non-b-lactamase-producing H. influenzae resistant to ampicillin (BLNAR H. influenzae), and highly penicillin-resistant enterococci generally also are resistant to piperacillin sodium and tazobactam sodium. SumMon®. For additional information on this drug until a more detailed monograph is developed and published, the manufacturer’s labeling should be consulted. It is essential that the labeling be consulted for information on the usual cautions, precautions, and contraindications concerning potential drug interactions and/or laboratory test interferences and for information on acute toxicity. In addition, for further information on chemistry and stability, mechanism of action, spectrum, resistance, pharmacokinetics, uses, cautions, drug interactions, laboratory test interferences, and dosage and administration of piperacillin

Preparations

Piperacillin Sodium and Tazobactam Sodium Parenteral For injection, for 2 g (of piperacillin) and Zosyn®, IV infusion 0.25 g (of tazobactam) Wyeth (labeled as a combined total potency of 2.25 g) Zosyn® ADD-Vantage®, Wyeth 3 g (of piperacillin) and Zosyn®, 0.375 g (of tazobactam) Wyeth (labeled as a combined total potency of 3.375 g) Zosyn® ADD-Vantage® , Wyeth 4 g (of piperacillin) and Zosyn®, 0.5 g (of tazobactam) Wyeth (labeled as a combined total potency of 4.5 g) Zosyn® ADD-Vantage®, Wyeth Zosyn® Piggyback, Wyeth 36 g (of piperacillin) and Zosyn®, 4.5 g (of tazobactam) Wyeth (labeled as a combined total potency of 40.5 g) pharmacy bulk package Piperacillin Sodium and Tazobactam Sodium in Dextrose Parenteral Injection (frozen) 40 mg (of piperacillin) per Zosyn® Iso-osmotic in Dextrose , for IV infusion mL (2 g) and 5 mg (of Injection, (Galaxy® [Baxter]) tazobactam) per mL (0. g) Wyeth (labeled as a combined total potency of 2.25 g) in 2% Dextrose 40 mg (of piperacillin) per Zosyn® Iso-osmotic in Dextrose mL (4 g) and 5 mg (of Injection, (Galaxy® [Baxter]) tazobactam) per mL (0. g) Wyeth (labeled as a combined total potency of 4.5 g) in 2% Dextrose 60 mg of (of piperacillin) Zosyn® Iso-osmotic in Dextrose per mL (3 g) and 7.5 mg (of Injection, (Galaxy® [Baxter]) tazobactam) per mL (0. g) Wyeth (labeled as a combined total potency of 3.375 g) in 0.7% Dextrose

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