Comparative neurotoxicity of benzylpenicillin, imipenem/cilastatin and FCE 22101, a new injectible penem

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Abstract
Rabbits were given benzylpenicillin, imipenem/cilastatin and a penem β-lactam, FCE 22101, as constant intravenous infusions with intervals of ≥7 days between doses. Neurotoxicity was defined as epileptogenic electroencephalographic (EEG) activity. Mean doses precipitating neurotoxicity were 486 mg/kg of benzylpenicillin, 86 mg/kg of imipenem and 102 mg/kg of FCE 22101 leading to mean serum concentrations of 606, 55 and 30 mg/l, respectively. Doses and serum concentrations of benzylpenicillin were significantly (P <0.001) higher than those of imipenem or FCE 22101. Neurotoxicity was seen at significantly (P < 0.02) higher serum concentrations of imipenem than of FCE 22101. Neurotoxicity seemed to be related to antibiotic concentrations in brain tissue fluid (BTF) rather than to CSF concentrations which were < 0.2 mg/l in 10 of 11 animals tested after administration of imipenem or FCE 22101. In BTF, significantly (P < 0.001 higher concentrations of benzylpenicillin than of imipenem or FCE 22101 were found. When related to concurrent serum concentrations, BTF penetration of benzylpenicillin and FCE 22101 did not differ significantly but both these antibiotics penetrated significantly better than imipenem. In conclusion, imipenem/cilastatin and FCE 22101 were more neurotoxic in rabbits than benzylpenicillin but did not show major differences from each other.