Absence of convulsive liability of doripenem, a new carbapenem antibiotic, in comparison with β-lactam antibiotics

Abstract

β-Lactam antibiotics have been suggested to have some degree of convulsive activity and neurotoxicity in experimental animals as well as in clinical situations. We examined the convulsive activities of a new carbapenem antibiotic, (+)-(4 R,5 S,6 S)-6-[(1 R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[[(3 S,5 S)-5-[(sulfamoylamino)methyl]-3-pyrrolidinyl]thio]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxic acid monohydrate (doripenem) using several animals and compared them with β-lactam antibiotics. In intravenous (IV) injection studies, imipenem/cilastatin, at 400/400 mg/kg produced seizure discharges on electroencephalogram (EEG) accompanied with clonic convulsions in rats. Meropenem showed only wet dog shaking behavior at 200 and 400 mg/kg. Doripenem caused no changes in the EEG and behavior in rats at 400 mg/kg. Imipenem/cilastatin IV potentiated the pentylenetetrazol (PTZ)-induced convulsions in mice at 250/250 mg/kg, while meropenem, panipenem/betamipron, cefazolin or doripenem did not cause any marked effects at up to 500 mg/kg. In mouse intracerebroventricular (ICV) injection studies, imipenem, panipenem and cefazolin induced clonic convulsions in a dose-dependent manner in mice. Doripenem and meropenem did not induce convulsions at up to 100 μg/mouse. In dog ICV injection studies, imipenem produced generalized seizure discharge with clonic convulsions at 100 μg/dog. Meropenem also produced spikes or seizure discharges at 100, 300 and 1000 μg/dog. However, doripenem had no effects on the EEG and behavior in dogs at any doses. In in vitro binding studies, imipenem, panipenem, cefazolin and meropenem inhibited [ 3H]muscimol binding to the GABA A receptor in mouse brain homogenates while doripenem did not cause any inhibition at up to 10 mM. In addition, doripenem had no influence on the anti-convulsant actions of valproic acid in the PTZ- or bicuculine-induced convulsive model. These results clearly indicate that doripenem has no convulsive activity, suggesting that its neurotoxicity may be negligible in clinical use.