Piperacillin + Tazobactam

Indications
This is indicated for the treatment of the following systemic and/or local bacterial infections:
Nosocomial pneumonia (moderate to severe)
Community-acquired pneumonia (moderate severity only)
Uncomplicated and complicated skin and skin structure infections, including cellulitis, cutaneous
Abscesses and ischemic/diabetic foot infections
Postpartum endometritis or pelvic inflammatory disease
Appendicitis (complicated by rupture or abscess) and peritonitis
Management of neutropenic patients (adults, adolescents and children) with fever suspected to be due to bacterial infections.

Therapeutic Class
Broad spectrum penicillins, Other beta-lactam Antibiotics

Pharmacology
Piperacillin, a broad spectrum, semi-synthetic penicillin active against many gram-positive and gram-negative aerobic and anaerobic bacteria, exerts bactericidal activity by inhibition of both septum and cell wall synthesis.
Tazobactam is a penicillanic acid sulfone derivative with β-lactamase inhibitory properties. In combination, tazobactam enhances the activity of piperacillin against β-lactamase-producing bacteria. Piperacillin and tazobactam has a wide range of activity and is active against gm+ve and gm-ve aerobic and anaerobic bacteria.

Dosage & Administration
Adults and children over 12 years: Piperacillin & Tazobactam may be given by slow intravenous infusion (over 20-30 minutes). The usual dosage for adults and children over 12 years is Piperacillin 4 gm and Tazobactam 0.5 gm IV infusion given every eight hours. The total daily dose of Piperacillin & Tazobactam depends on the severity and localization of the infection and can vary from 2.25 gm to 4.50 gm administered every six or eight hours. In neutropenia the recommended dose is Piperacillin 4 gm and Tazobactam 0.5 gm given every six hours in combination with an aminoglycoside.
For children weighing less than 40 kg: The dose should be adjusted to 90 mg/kg administered every six hours, in combination with an aminoglycoside, not exceeding 4.5 gm every six hours.
Children under 2 years: Piperacillin & Tazobactam is not recommended for use in children below 2 years old due to insufficient data on safety.

Interaction
Interaction with Probenecid: Concurrent administration of Probenecid and Piperacillin/Tazobactam produced a longer half-life and lower renal clearance for both Piperacillin and Tazobactam. However, peak plasma concentrations of either drug are unaffected.
Interaction with anticoagulants: During simultaneous administration of heparin, oral anticoagulants and other drugs which may affect the blood coagulation system including thrombocyte function, appropriate coagulation tests should be performed more frequently and monitored regularly.
Interaction with vecuronium: 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 polarizing muscle relaxants could be prolonged in the presence of Piperacillin. This should be taken into account when Piperacillin/Tazobactam is used perioperatively.
Interaction with methotrexate: Piperacillin may reduce the excretion of methotrexate. Serum levels of methotrexate should be monitored in patients on methotrexate therapy

Contraindications
Piperacillin and tazobactam is contraindicated in patients with a history of allergic reactions to any of the penicillins, cephalosporins, or beta-Iactamase inhibitors.

Side Effects
Adverse events primarily involving the skin, including rash and pruritus; the gastrointestinal system, including diarrhea, nausea, and vomiting; and allergic reactions. Adverse local reactions that were reported, irrespective of relationship to therapy with piperacillin and tazobactam were phlebitis, IV infusion site reaction, pain, infiammation, thrombophlebitis, and edema. Gastrointestinal-hepatitis, cholestatic jaundice. Hematologic-hemolytic anemia, anemia, thrombocytosis, agranulocytosis, pancytopenia. Immune hypersensitivity reactions, anaphylactic/anaphylactoid reactions (including shock). Infections-candidal superinfections. Renal-interstitial nephritis, renal failure. Skin and Appendages-erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Pregnancy & Lactation
Pregnancy Category B. Piperacillin and tazobactam cross the placenta in humans. Piperacillin is excreted in low concentrations in human milk; tazobactam concentrations in human milk have not been studied. Caution should be exercised when piperacillin and tazobactam for IV infusion is administered to a nursing woman

Precautions & Warnings
Bleeding manifestations have occurred in some patients receiving j3-lactam antibiotics, including piperacillin. These reactions have sometimes been associated with abnormalities of coagulation tests such as clotting time, platelet aggregation and prothrombin time, and are more likely to occur in patients with renal failure. If bleeding manifestations occur, piperacillin and tazobactam for IV infusion should be discontinued and appropriate therapy instituted. The possibility of the emergence of resistant organisms that might cause superinfections should be kept in mind. If this occurs, appropriate measures should be taken. As with other penicillins, patients may experience neuromuscular excitability or convulsions if higher than recommended doses are given intravenously (particularly in the presence of renal failure). piperacillin and tazobactam contains a total of 2.79 mEq (64 mg) of Na+ per gram of piperacillin in the combination product. This should be considered when treating patients requiring restricted salt intake. Periodic electrolyte determinations should be performed in patients with low potassium reserves, and the possibility of hypokalemia should be kept in mind with patients who have potentially low potassium reserves and who are receiving cytotoxic therapy or diuretics. As with other semisynthetic penicillins, piperacillin therapy has been associated with an increased incidence of fever and rash in cystic fibrosis patients. In patients with cteatinine clearance> 40 mL/min and dialysis patients (hemodialysis and CAPO), the intravenous dose should be adjusted to the degree of renal function impairment.

Use in Special Populations
Pediatric Use: Use of piperacillin and tazobactam in pediatric patients 2 months of age or older with appendicitis and/or peritonitis is supported by evidence from well-controlled studies and pharmacokinetic studies in adults and in pediatric patients. Safety and efficacy in pediatric patients less than 2 months of age have not been established. There are no dosage recommendations for piperacillin and tazobactam in pediatric patients with impaired renal function.
Geriatric Use: Patients over 65 years are not at an increased risk of developing adverse effects solely because of age. However, dosage should be adjusted in the presence of renal insufficiency.

Overdose Effects
The majority of those events experienced, including nausea, vomiting, and diarrhea, have also been reported with the usual recommended dosages. Patients may experience neuromuscular excitability or convulsions if higher than recommended doses are given intravenously (particularly in the presence of renal failure). Treatment should be supportive and symptomatic according the patient's clinical presentation. Excessive serum concentrations of either piperacillin or tazobactam may be reduced by hemodialysis. Following a single 3.375 g dose of piperacillin and tazobactam, the percentage of the piperacillin & tazobactam dose removed by hemodialysis was approximately 31% and 39%, respectively

Reconstitution
Reconstitute initially (2.25 g in 10 mL, 4.5 g in 20 mL) with water for inj, glucose 5% or NaCl 0.9%, then further dilute to 50-150 mL with compatible infusion soln.

Storage Conditions
Prior to reconstitution, store piperacillin and tazobactam powder for intravenous injection at controlled room temperature below (30°C). Keep out of the reach of children.