Neurotoxicity of β-lactam antibiotics: predisposing factors and pathogenesis

Abstract

Neurotoxic reactions caused by beta-lactam antibiotics occur frequently following direct application of antibiotic to the brain surface or into the cerebral cisterns. Epileptogenic reactions have also been observed after administration of very high systemic doses. There seem to be considerable differences in the neurotoxic potential of the various beta-lactams; benzylpenicillin, cefazolin and, lately, imipenem/cilastatin appear to be drugs with higher neurotoxic potential than other compounds. There is now strong evidence that the concentration of beta-lactam in the brain, and not that in the cerebrospinal fluid, is the decisive factor for the risk of neurotoxic reactions. Factors known to increase the risk of neurotoxicity are excessive doses, decreased renal function, damage to the blood-brain barrier, preexisting diseases of the central nervous system, old age and concurrent use of drugs that are nephrotoxic or that may lower the seizure threshold. Another factor that may be of importance is blockage of the transport system that is responsible for transport of beta-lactams out of the central nervous system.

Pharmacokinetics of meropenem in subjects with various degrees of renal impairment

“…Especially in subject 19, who has undergone bilateral nephrectomy, all clearance from plasma must have been nonrenal. As with other neurotoxic beta-lactam antibiotics, imipenem combined with cilastatin appears to evoke seizures by blocking gamma aminobutyric acid receptors (14,16). Animal experiments show that the concentrations of betalactam in brain tissue are better correlated to neurotoxic effects than are the concentrations measured in cerebrospinal fluid (13).…”

The Effect of Asphyxia on the Pharmacokinetics of Ceftazidime in the Term Newborn

“…not indicated to improve clinical efficacy. However, f3-lactam antibiotics are all neurotoxic to some extent (13,14). Several factors have been identified or suggested to contribute to the neurotoxicity of the f3-lactam antibiotics: excessive dosage, renal insufficiency, disruption of the blood-brain barrier, preexisting CNS diseases , and competitive inhibition of the transport system that exports f3-lactam antibiotics out of the CNS.…”

Pharmacokinetic-Pharmacodynamic Modeling of the Electroencephalogram Effect of Imipenem in Healthy Rats

“…These are observed with fluoroquinolones (5,39) and ␤-lactams, in particular carbapenems (33). In this family the leading compound, imipenem, presents a relatively high risk of convulsions (1,3), especially in patients with renal impairment or with bacterial meningitis (2,41).…”