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

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, (+)-(4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[[(3S,5S)-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 GABAA 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.