Single-dose toxicity studies of Tazobactam/Piperacillin and Tazobactam

Abstract

Tazobactam (TAZ) is a newly developed β-lactamase inhibitor. Tazobactam/Piperacillin (TAZ/PIPC) is a formulation consisting of TAZ and PIPC in a ratio of 1:4. Single-dose toxicity studies of TAZ/PIPC and TAZ were carried out using mice and rats of both sexes and male dogs. The results were as follows. 1. A common clinical sign in mice and rats administered TAZ/PIPC or TAZ by all routes was soft stool. Other signs in mice and rats included a decrease in spontaneous motor activity and/or a decreased respiratory rate for the intraperitoneal (i.p.), subcutaneous (s.c.) or intravenous (i.v.) route. The animals administered by the i.v. route showed tremor for mice and clonic convulsion for rats before death. Hyperemia, hemorrhage or edema of the lung, and hemorrhage of the digestive tract were observed in these animals at necropsy. An enlargement of the spleen was seen in some of the surviving animals treated with TAZ/PIPC. 2. In dogs, TAZ/PIPC caused vomiting, and TAZ caused vomiting, respiratory abnormality, soft stool and diarrhea by the intravenous (i.v.) administration. 3. TAZ/PIPC or TAZ caused clinical signs such as the loss of hair at the injection site for the s.c. route, and necrosis of the tail for the i.v. route in mice and rats, also caused limping of the injected anterior limb in dogs. Necrosis and hemorrhage at the injection site, and peritonitis by the i.p. injection were observed at necropsy. These findings were due to the irritation of TAZ/PIPC or TAZ. 4. The LD50 values of TAZ/PIPC were as follows: more than 5,000 mg/kg for both sexes in mice and rats by the oral (p.o.), s.c. or i.p. route; more than 5,000 mg/kg for males, 4,565 mg/kg for females in mice, 3,157 mg/kg for males, 3,992 mg/kg for females in rats and more than 5,000 mg/kg for males in dogs by the i.v. route. The LD50 value of TAZ was more than 5,000 mg/kg for both sexes in mice and rats by the p.o., s.c., i.p. or i.v. route and in male dogs by the i.v. route.