Ｃｅｆｏｓｅｌｉｓの中枢神経症状発現のリスクファクターに関する知見

Cefoselis (CFSL; trade name: Wincef^®), a new injectable cephem with intensified antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA), besides the antimicrobial activity of the third injectable cephem, was marketed in Japan beginning in September, 1998. It was recommended for use with patients with a predisposition or susceptibility to acquiring infections or those refractory to other antibiotic treatment. However, central nervous system symptoms, such as convulsions and disorders of consciousness, were encountered in 64 out of about 40, 000 patients (estimation from the amount sold) who received it within the first 4 months after launching. These symptoms were not predicted from the results of clinical and non-clinical studies up to the time of new-drug approval, and analysis of the background of these patients indicated that these symptoms occurred predominantly in patients with lowered renal functions, such as those with severe renal impairment including dialysis patients and the elderly (in particular, 75 years of age or older). Among those patients with central nervous system symptoms and normal renal function, other factors were present, such as anamnesis of cerebral infarction, cerebral hemorrhage, brain tumor, convulsions, or meningitis, or a predisposition to convulsions. Although the usual administration of Wincef^® is intravenous drip infusion of 0.5-1g/time twice daily, the daily amount administered to most of the patients with central nervous system symptoms was 1g uid in the case of dialysis patients, and 1g bid in the case of other patients. Symptoms occurred 4-5 days after the start of administration in most cases, and most symptoms occurred within one week. Cefoselis is a drug of the kidney-elimination type, as are most existing cephems, and the elimination half-life in blood may be prolonged by renal impairment. Most of these patients with adverse drug reactions had lowered renal function, so it is presumed that central nervous system symptoms occurred due to the transfer of cefoselis into the brain through the blood brain barrier (BBB) or the blood liquid barrier (BLB), as a result of the persistence of high blood concentration following consecutive administration. With respect to the mechanism of action of cefoselis in the brain, reports which indicate the involvement of the β-aminobutyric acid (GABA) receptor or the N-methyl-D-aspartate (NMDA) receptor have been published, but the details remain unclear. For further promotion of appropriate use of this drug, clarification of the risk factors for the occurrence of central nervous system symptoms is needed, for which clarification of the transferability of this drug into the brain, and its mechanism of action, is necessary.