Safety evaluation of meropenem in animals: studies on the kidney.
The effect of meropenem on animal kidneys has been assessed in rats (5 of each sex/group), rabbits (3 of each sex/group) and monkeys (3 of each sex/group) in comparative iv studies with ceftazidime, cefotaxime, cephaloridine and imipenem (without cilastatin). Diarrhoea occurred in rabbits and monkeys dosed with imipenem or meropenem. Emesis occurred only after the administration of imipenem to monkeys. After 14 days administration to rats evidence of nephrotoxicity was seen only in males dosed with cephaloridine (850 mg/kg); no changes were seen with ceftazidime, cefotaxime or meropenem (all at 1000 mg/kg). Four days after a single dose to rabbits renal tubular necrosis was seen in all animals receiving imipenem (150 mg/kg) and cephaloridine (250 mg/kg). Minimal histopathological changes to the kidneys were seen with cefotaxime, ceftazidime and meropenem (all at 400 mg/kg). After seven days' administration to cynomolgus monkeys imipenem (180 mg/kg) caused moderate to severe tubular necrosis. No tubular damage was seen with meropenem at 180 mg/kg or with cefotaxime or ceftazidime (both at 500 mg/kg). At 500 mg/kg meropenem caused mild tubular regeneration and/or fat accumulation in 3/6 animals, with mild tubular necrosis in one of these. The data from these three species indicate that meropenem has a low nephrotoxic potential in these animal models.
Topham
J C
JC
ICI Pharmaceuticals, Safety of Medicines Department, Macclesfield, Cheshire, UK.
Murgatroyd
L B
LB
Jones
D V
DV
Goonetilleke
U R
UR
Wright
J
J
D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity; D001774:Blood Chemical Analysis; D015780:Carbapenems / Q000633:toxicity*; D002439:Cefotaxime / Q000633:toxicity; D002442:Ceftazidime / Q000633:toxicity; D002509:Cephaloridine / Q000633:toxicity; D005260:Female; D007674:Kidney Diseases / Q000139:chemically induced*; D008252:Macaca fascicularis; D008297:Male; D000077731:Meropenem; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity; D013845:Thienamycins / Q000633:toxicity*
D000900:Anti-Bacterial Agents; D015780:Carbapenems; D013845:Thienamycins; D002442:Ceftazidime; D000077731:Meropenem; D002509:Cephaloridine; D002439:Cefotaxime