Abstract
To investigate single dose toxicity of cefepime (CFPM diHC1/L-arginine blend), the test drug was administered to rats [Crj: CD (SD)] of both sexes at dose levels of 500, 1,000 and 2,000 mg/kg using intravenous continuous infusion or subcutaneous injection, and to male beagle dogs at 1,000 and 2,000 mg/kg using intravenous continuous infusion. As the control, two additional groups of each animals were given either saline or L-arginine alone which was used in the test formulation to adjust pH values of CFPM diHCl solutions.
The obtained results are summarized as follows:
1. Rats dosed with 2,000 mg/kg CFPM through intravenous continuous infusion showed slightly decreased spontaneous physical activity. One male rat dosed with L-arginine alone via continuous infusion also showed slightly decreased activity. Slight to severe inflammatory reactions at injection sites including sloughing of the tail were prominent at doses of 1,000 or 2,000 mg/kg of CFPM, or L-arginine alone. Average body weights of rats in the test groups of either sex were comparable to the controls in all of the dose groups of the same sex during the 14-day test period.
2. Rats receiving 2,000 mg/kg CFPM in single subcutaneous injection showed slightly diminished activities. Slight to moderate reactions occurred around the injection site (viz., hardening, depilation, scab-formation and necrosis) in rats injected any of the 3 doses of CFPM. Though body weight gains were slightly retarded in male rats receiving 2,000 mg/kg CFPM during the last half of the observation period, such weight gain retardation was not observed in rats of other dose groups.
3. No death occurred in any groups of any injection routs or dose levels during the 14-day observation period in rats. Necropsy showed that the dose-related changes were restricted to the injection sites without showing other abnormalities.
4. Dogs to which 1,000 or 2,000 mg/kg of CFPM or L-arginine alone was administered via intravenous continuous infusion showed vomiting, flushing, swelling of face and decreased physical activities. Tachypnea, staying in a prone position, walking with staggering gait, persistent urination, depression of stimulation response, discoloration of mucus membranes of oral cavity and excessive salivation resulted when CFPM was administered at 1,000 or 2,000 mg/kg. These transient signs of toxicity disappeared in 15 to 60 min after the completion of dosing with L-arginine alone, or in 6 hours with CFPM. Though the recovery of these signs of toxicity was slow when CFPM was administered compared to the dose of L-arginine alone, no difference was observed between the 2 groups of dogs administered with 1,000 and 2,000 mg/kg CFPM. No drug-related difference was detected in body weight changes, amounts of food consumed or by pathological examinations.
Based on these results, the single dose toxicity of CFPM in rats administered via intravenous continuous infusion appeared to be low, and it was comparable to that via single dose subcutaneous injection. Lethal doses of CFPM in rats were higher than 2,000 mg/kg by either route of administration under the experimental conditions employed in this study. Since no significant toxicity was detected in dogs dosed with 2,000 mg/kg of CFPM using intravenous continuous infusion, the lethal dose for dogs seems higher than this level.
