CHANGES ASSOCIATED WITH LONG-TERM ORAL-ADMINISTRATION OF THE PENEM ANTIBIOTIC FCE-22891 TO RATS AND MONKEYS WITH PARTICULAR EMPHASIS ON THEURINARY-TRACT AND THE URINE

FCE 22891, a synthetic beta-lactam antibiotic of the penem class, was administered by gavage to Sprague-Dawley rats and cynomolgus monkeys f or 26 wk (with and without a 6-wk recovery), Rats received the test ma terial at doses of 0, 200, 500, and 1,250 mg/kg/day, and monkeys were given doses of 0, 100, 200, 400, and 600 mg/kg/day. At the end of the 26-wk treatment period, approximately two-thirds of the animals (both species) were sacrificed, and the remaining animals were held without treatment for a further 6 wk. A treatment-related mortality occurred i n female monkeys receiving 600 mg/kg. There was a reduction in body we ight gain in the high-dose groups of both species. Male rats were more affected than the females and, conversely, female monkeys were affect ed more than the males, At higher dose levels, both species exhibited an early, but transient, azotemia and oliguria with an increase in spe cific gravity and reduced pH. In rats, microscopic examination reveale d treatment-related renal cortical tubular degenerative and regenerati ve changes with associated interstitial inflammation and fibrosis and diffuse urothelial hyperplasia in the urinary bladder. In general, fem ale rats were less severely affected, and in both sexes there was a tr end to recovery of most of these effects. In monkeys given 600 mg/kg o f the test material, renal cortical tubular degeneration was seen only in those females that died in the first 5 wk of dosing. In other anim als at this dose level, the renal lesions were determined to be revers ible.