Piperacillin and tazobactam - Drug Monograph

Introduction

Piperacillin and tazobactam is a combination antibacterial medication consisting of piperacillin, an extended-spectrum penicillin antibiotic, and tazobactam, a beta-lactamase inhibitor. Marketed under the brand name Zosyn among others, this combination product is widely used in hospital settings for the treatment of moderate to severe infections caused by susceptible bacteria. The addition of tazobactam extends piperacillin's spectrum of activity by protecting it from degradation by bacterial beta-lactamase enzymes.

Mechanism of Action

Piperacillin exerts bactericidal activity by binding to penicillin-binding proteins (PBPs) located inside bacterial cell walls, thereby inhibiting the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls. This results in cell death. Tazobactam irreversibly binds to and inhibits many beta-lactamases that would otherwise hydrolyze and inactivate piperacillin, particularly those produced by gram-negative bacteria including TEM, SHV, and some extended-spectrum beta-lactamases (ESBLs). Tazobactam has minimal antibacterial activity itself but significantly enhances piperacillin's spectrum.

Indications

FDA-approved indications include:

• Intra-abdominal infections
• Skin and skin structure infections
• Community-acquired pneumonia (moderate severity only)
• Nosocomial pneumonia
• Gynecological infections

It is also commonly used off-label for:

• Complicated urinary tract infections
• Febrile neutropenia
• Sepsis of unknown origin
• Bone and joint infections

Dosage and Administration

• CrCl 20-40 mL/min: 2.25 g every 6 hours
• CrCl <20 mL/min: 2.25 g every 8 hours
• Hemodialysis: 2.25 g every 12 hours (administer after dialysis)

• Hepatic impairment: No dosage adjustment required
• Elderly: Consider renal function adjustments
• Pediatrics: 100 mg piperacillin/12.5 mg tazobactam per kg every 8 hours

Pharmacokinetics

Contraindications

• History of severe hypersensitivity reactions to piperacillin, other penicillins, or beta-lactamase inhibitors
• History of severe hypersensitivity reactions to other beta-lactam antibiotics
• Patients with a history of drug-induced immune thrombocytopenia from piperacillin/tazobactam

Warnings and Precautions

• Serious hypersensitivity reactions: May cause anaphylaxis and serious skin reactions
• Bleeding manifestations: Has been associated with coagulation abnormalities and bleeding
• Leukopenia/neutropenia: May occur, especially with prolonged therapy
• Pseudomembranous colitis: May range from mild to life-threatening
• Electrolyte imbalances: Contains 2.79 mEq (64 mg) of sodium per gram of piperacillin
• Seizures: May occur, especially in patients with renal impairment
• Nephrotoxicity: Monitor renal function during therapy

Drug Interactions

• Probenecid: Decreases renal clearance of piperacillin
• Heparin: Increased risk of bleeding
• Oral anticoagulants: May enhance anticoagulant effect
• Methotrexate: May decrease methotrexate clearance
• Vecuronium: May prolong neuromuscular blockade
• Aminoglycosides: May inactivate aminoglycosides if mixed in same solution

Adverse Effects

• Diarrhea (11-34%)
• Headache (2-20%)
• Constipation (1-16%)
• Nausea (2-12%)
• Insomnia (1-11%)
• Rash (1-5%)

• Anaphylaxis (<0.5%)
• Stevens-Johnson syndrome (<0.1%)
• Blood dyscrasias (neutropenia, thrombocytopenia)
• Acute interstitial nephritis
• Hepatitis and cholestatic jaundice
• Seizures (<0.5%)
• Clostridium difficile-associated diarrhea

Monitoring Parameters

• Complete blood count with differential (weekly during prolonged therapy)
• Renal function tests (baseline and periodically)
• Liver function tests (baseline and periodically)
• Coagulation parameters in at-risk patients
• Signs and symptoms of infection resolution
• Signs of hypersensitivity reactions
• Serum electrolytes in patients receiving prolonged therapy
• Neurological status in patients with renal impairment

Patient Education

• Complete the full course of therapy even if feeling better
• Report any signs of allergic reaction (rash, itching, swelling, difficulty breathing)
• Report unusual bleeding or bruising
• Report severe diarrhea, especially if containing blood or mucus
• Inform all healthcare providers of current medication use
• This medication may cause diarrhea; do not treat with anti-diarrheals without consulting physician
• Maintain adequate hydration during therapy
• Report any new neurological symptoms (seizures, confusion)

References

1. Piperacillin and Tazobactam [package insert]. New York, NY: Pfizer Inc; 2021. 2. Gilbert DN, Chambers HF, Saag MS, et al. The Sanford Guide to Antimicrobial Therapy. 52nd ed. Antimicrobial Therapy, Inc; 2022. 3. Lexicomp Online. Piperacillin and Tazobactam. Wolters Kluwer Clinical Drug Information, Inc; 2023. 4. Tamma PD, Aitken SL, Bonomo RA, et al. Infectious Diseases Society of America 2022 Guidance on the Treatment of Extended-Spectrum β-lactamase Producing Enterobacterales (ESBL-E), Carbapenem-Resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with Difficult-to-Treat Resistance (DTR-P. aeruginosa). Clin Infect Dis. 2022;75(2):187-212. 5. Roberts JA, Paul SK, Akova M, et al. DALI: defining antibiotic levels in intensive care unit patients: are current β-lactam antibiotic doses sufficient for critically ill patients? Clin Infect Dis. 2014;58(8):1072-1083.