Reproductive and developmental toxicity studies of tazobactam/piperacillin or tazobactam (3)--Perinatal and postnatal study in rats with intraperitoneal administration

Abstract

Tazobactam (TAZ) is a newly developed beta-lactamase inhibitor and piperacillin (PIPC) is an antibiotics which is used in clinical field widely. The combination of TAZ and PIPC (TAZ/PIPC), which is combined with TAZ and PIPC at rate of 1:4, has been developed because of PIPC is unstable to various beta-lactamases. Perinatal and postnatal toxicity were studied in rats given daily intraperitoneal doses of TAZ/PIPC (200, 800 or 1600 mg/kg/day) or TAZ (40, 320 or 1280 mg/kg/day). TAZ/PIPC or TAZ were given from day 17 of pregnancy through day 21 of lactation. Total daily doses were administered in two equally divided doses. In this study, evaluation of the late stage of gestation, parturition, lactation and maternal behavior in adult rats and postnatal evaluation of the growth and development, and reproductive performance of the F1 generation occurred. In the TAZ/PIPC, maternal toxicity (decreased food consumption) was observed at 800 and 1600 mg/kg groups during perinatal period. A slight decrease in body weight gain during perinatal period and increased pup mortality and decreased pup weight in lactation period were observed at 1600 mg/kg group. An increase in stillbirths also was observed at 1600 mg/kg group. In the TAZ, maternal toxicity (decreased food consumption) was observed at all dosage groups during perinatal period. A decrease in body weight gain also were observed during perinatal period at 1280 mg/kg group. At maternotoxic doses of 320 and 1280 mg/kg groups, decreased pup weight were observed during lactation period. An increase in stillbirths also was observed at 1280 mg/kg group. Transient, significant decrease in pup body weights at 1280 mg/kg group in early postweaning period. No other effects occurred for the F1 generation rats. In conclusion, perinatal development and postnatal growth and development of offspring were affected only at the intermediate and high doses that caused maternal toxicity in this study. Therefore it is seemed that non-observed effect dose levels (NOELs) of TAZ/PIPC for dams is less than 200 mg/kg/day and that of TAZ is less than 40 mg/mg/day, and NOELs of TAZ/PIPC is 200 mg/kg/day and that of TAZ is 40 mg/kg/day for offspring under the condition of this study.