What are the seizure risks associated with Zosyn (piperacillin/tazobactam) in patients with impaired renal function or a history of seizure disorders?

From the Guidelines

Zosyn (piperacillin/tazobactam) can reduce the seizure threshold, particularly in patients with impaired renal function or a history of seizure disorders, and requires careful dose adjustment and monitoring. The risk of seizures is increased due to the accumulation of piperacillin and tazobactam to neurotoxic levels in the bloodstream and cerebrospinal fluid when renal function is compromised 1. According to the Surviving Sepsis Campaign guidelines, patients with creatinine clearance less than 20 mL/min should receive a reduced dose of Zosyn, with a recommended reduction of 25-50% of the standard dose 1.

Key factors that contribute to the increased seizure risk include:

• High doses of Zosyn
• Rapid administration
• Concurrent use of other seizure-threshold-lowering medications
• Electrolyte abnormalities, especially low sodium
• Central nervous system disorders

The mechanism of seizure risk involves the beta-lactam component interfering with GABA neurotransmission in the brain, lowering the seizure threshold 1. If seizures occur, temporary discontinuation of Zosyn and administration of anticonvulsants may be necessary, with consideration of alternative antibiotics if appropriate.

It is essential to carefully monitor patients with a history of seizures or renal impairment while on Zosyn, and to adjust the dose accordingly to minimize the risk of seizures. The optimal dosing strategy for Zosyn involves optimizing the time that the plasma concentration of the drug is above the pathogen MIC relative to the dosing interval (T > MIC), with a minimum T > MIC of 60% generally sufficient to allow a good clinical response in mild to moderate illness 1.

From the FDA Drug Label

As with other penicillins, piperacillin and tazobactam may cause neuromuscular excitability or seizures. Patients receiving higher doses, especially patients with renal impairment may be at greater risk for central nervous system adverse reactions Closely monitor patients with renal impairment or seizure disorders for signs and symptoms of neuromuscular excitability or seizures [see Adverse Reactions (6.2)].

Zosyn (piperacillin/tazobactam) may reduce seizure threshold, especially in patients with renal impairment or a history of seizure disorders.

• Patients receiving higher doses are at greater risk for central nervous system adverse reactions, including seizures.
• Closely monitor patients with renal impairment or seizure disorders for signs and symptoms of neuromuscular excitability or seizures 2.
• The same warning is also present in another study 2.

From the Research

Seizure Risks Associated with Zosyn (Piperacillin/Tazobactam)

• Zosyn (piperacillin/tazobactam) has been reported to reduce the seizure threshold, particularly in patients with impaired renal function or a history of seizure disorders 3, 4, 5.
• The neurological adverse effects of piperacillin/tazobactam, such as seizures and hallucinations, are often described in patients with renal insufficiency (>70%) and underlying brain abnormalities 3.
• A systematic review of antibiotic-related seizures found that evidence for antibiotic-related symptomatic seizures is low to very low, but numerous reports point to an increased risk for symptomatic seizures, especially in patients with renal dysfunction, brain lesions, and epilepsy 4.
• A case report described a patient with end-stage renal disease who developed seizures after receiving piperacillin/tazobactam, which were rapidly reversed by high-flux hemodialysis 5.
• Another study found that imipenem/cilastatin/relebactam was noninferior to piperacillin/tazobactam in treating hospital-acquired or ventilator-associated bacterial pneumonia, but did not specifically address seizure risks 6.
• A review of antiseizure medications for adults with epilepsy noted that the decision to initiate an antiseizure drug should be individualized, but should be strongly considered after 2 unprovoked seizures or after 1 unprovoked seizure that occurred during sleep and/or in the presence of epileptiform activity on an electroencephalogram and/or in the presence of a structural lesion on the brain magnetic resonance imaging 7.

Key Factors Contributing to Seizure Risk

• Impaired renal function: Patients with renal insufficiency are at higher risk for seizures due to decreased clearance of piperacillin/tazobactam 3, 5.
• History of seizure disorders: Patients with a history of seizure disorders are at higher risk for seizures due to the potential for piperacillin/tazobactam to reduce the seizure threshold 3, 4.
• Underlying brain abnormalities: Patients with underlying brain abnormalities, such as brain lesions or epilepsy, are at higher risk for seizures due to the potential for piperacillin/tazobactam to exacerbate these conditions 3, 4.