Penicillin- and Carbapenem-Induced Neurotoxicity: How to Reduce the Risk

Penicillin-induced neurotoxicity was first recognized by Johnson and Walker in 1945 after intraventricular administration of benzylpenicillin.^1,2 Subsequently, the β-lactams have been shown to have a higher rate of CNS effects than other classes of antibiotics.^3,4 The neurotoxic effects of penicillin and carbapenems, particularly in patients with renal failure, include confusion, psychosis, myoclonus, and seizures.⁴

Here we discuss the mechanism by which β-lactam–induced neurotoxicity occurs, predisposing factors, and prevention and management strategies.

MECHANISM OF NEUROTOXICITY

There are many theories behind the mechanism of neurotoxicity induced by penicillin and carbapenem antibiotics. The most widely accepted theory involves the binding of γ-aminobutyric acid (GABA) to GABAa receptors. These ligand-gated ion channels are involved in inhibitory synaptic transmission. Therefore, a reduction in GABA-mediated inhibition may increase CNS excitation.²

A relationship between the molecular structure of β-lactam antibiotics and the potential to cause neurotoxicity has been described in the literature. The epileptogenic properties of penicillins have been traced to the β-lactam structure.² However, it is the side chain on the second carbon atom in the carbapenem nucleus that is thought to cause the GABAa interaction. The very basic nature of imipenem’s C-2 side chain is thought to make it more epileptogenic than meropenem(Drug information on meropenem), which has a much less basic C-2 side chain.⁵ Animal studies have found that doripenem may have a lower potential for seizure activity than other carbapenems, but postmarketing reports from outside the United States have identified seizures as a possible adverse effect.⁶

RISK FACTORS FOR NEUROTOXICITY

All penicillin and carbapenem antibiotics are neurotoxic to some extent, but not all patients exposed to these antibiotics exhibit signs and symptoms of neurotoxicity.⁷ Therefore, it is important to recognize factors that may predispose patients to neurotoxicity. The following factors have been identified⁷:

• Elderly age.
• Previous seizure.
• Damage to the blood-brain barrier.
• Previous neurotrauma.
• Concurrent use of drugs that may lower the seizure threshold.
• Excessive antibiotic doses.
• Decreased clearance because of renal impairment.
• Use of nephrotoxic drugs that may cause renal impairment.

Because many of these factors cannot be controlled or modified, special care should be taken to minimize neurotoxic complications whenever possible. Renal failure causes decreased elimination of the drug, which leads to increased accumulation and passive diffusion into the cerebrospinal fluid.⁸ Dosage adjustment to compensate for renal insufficiency is the key strategy to reduce the risk of adverse CNS effects.^2,9,10

MANAGEMENT OF PENICILLIN- AND CARBAPENEM-INDUCED SEIZURES

The time to onset of epileptogenic activity ranges from 12 hours to 9 days after β-lactam antibiotic therapy is initiated.^11-13 Treatment of penicillin- and carbapenem-induced seizures remains controversial.⁹ Cessation of seizure activity has been reported 12 to 72 hours after therapy is discontinued.^11-13

Clinical and experimental data suggest that benzodiazepines and barbiturates may be more efficacious than other anticonvulsants such as phenytoin.^2,3 Benzodiazepines and barbiturates are positive modulators of GABAa receptors. Their efficacy is based on the hypothetical mechanism by which β-lactams induce seizures.²