A six-month intravenous repeated dose toxicity study of Tazobactam/Piperacillin and Tazobactam in dogs

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. A six-month intravenous repeated dose toxicity study of TAZ/PIPC and TAZ including a one-month recovery period were carried out using male and female dogs. The doses were 200, 400 and 800 mg/kg/day for TAZ/PIPC, and 40, 80 and 160 mg/kg/day for TAZ. The results were as follows. 1. No test article-related deaths occurred during the study period. No effects on clinical findings, body weight and food consumption were evident. 2. No test article-related changes were noted in hematological, serum biochemical and urinalysis evaluations, and ophthalmological and electrocardiographic examinations. 3. There were no test article-related changes in macroscopic findings or organ weight. 4. The histopathological examination revealed deposition of marked PAS-positive aggregates in liver cells of dogs given 400 mg/kg/day or more of TAZ/PIPC and 80 mg/kg/day or more of TAZ/PIPC and 80 mg/kg/day or more of TAZ. Electron micrographs of hepatocytes revealed glycogen granules to be accumulated in the cytoplasm, and an increase of smooth endoplasmic reticulum. 5. After a one-month recovery period, the histopathological changes had generally disappeared, suggesting that they were reversible. 6. From the histopathological changes of liver, the no-toxic dose levels for TAZ/PIPC and TAZ were 200 mg/kg/day and 40 mg/kg/day, respectively.