Preclinical toxicologic studies of netilmicin.
1-N-Ethylsisomicin (netilmicin), a semisynthetic aminoglycoside antibiotic, was given parenterally to mice, rats, guinea pigs, rabbits, and dogs for toxicological evaluation. Acute signs of toxicity were consistent with neuromuscular blockade. Results of teratological studies in rats and rabbits were negative; the only effect observed was wavy ribs, a minor developmental variation, in rats. No effects were found on fertility, reproduction, or development of offspring. Single daily doses of 60 mg/kg s.c. for 10 weeks in young rats and 30 days in young dogs were non-toxic. No indication of toxicity was found in rats and dogs given single daily doses of 7.5 mg/kg i.v. for 2 weeks. Daily i.m. doses caused signs of neuromuscular blockade in rats after 2 weeks at 100 mg/kg and after 1 month at 50 mg/kg, and in dogs after 2 months at 75 mg/kg; dose levels of 150 mg/kg did not cause renal failure. No ocular changes or impairment of vestibular or auditory function were evident at any dose studied. Comparison with tobramycin, gentamicin, and kanamycin at s.c. doses of 50 or 150 mg/kg per day for 4 weeks showed netilmicin to be less nephrotoxic in rats than tobramycin or gentamicin and only slightly more nephrotoxic than kanamycin. Only mild changes were seen microscopically in kidneys of dogs given netilmicin at daily doses of 75 mg/kg i.m. for 3 months. The renal effects of netilmicin given at high multiples of the human therapeutic dose were one-half to one-third less that those of gentamicin and were not severe at any dosage.