title: Species specificity of 2-aryl carbapenem-induced immune-mediated hemolytic anemia in primates.
abstract: L-695,256 is a novel 2-fluorenonyl carbapenem antibiotic with significant antimicrobial activity against strains of methicillin-resistant Staphylococci. This prototype compound was administered intravenously to rhesus monkeys (Macaca mulatta) at does of 50 or 200 mg/kg/day for 2 weeks to assess toxicity and found to induce a hemolytic anemia characterized by extravascular hemolysis and splenomegaly. A subsequent study in this species in which 100 mg/kg/day was administered i.v. for 4 weeks showed that all animals were direct antiglobulin test (Coombs' test) positive for IgG with 20-25% reductions in the erythron. Following 3 weeks of recovery, the erythron had returned to normal, although it took an additional 2 months for the Coombs' test to become negative. Challenge of these same animals with 0.5 million U/kg (300 mg/kg/day) of penicillin intravenously indicated no apparent cross-reactivity. Since attempts to establish a model for this immune-mediated hemolytic anemia with this drug in rats or mice were unsuccessful, a 2-week i.v. study in squirrel monkeys (Saimiri sciureus) was conducted at a dose of 200 mg/kg/day. All animals in this study remained Coombs' test negative with no changes in the erythron, suggesting an increased sensitivity to beta-lactam-induced anemia in rhesus monkeys compared to other species. Further support for this hypothesis was obtained using the cephalosporin antibiotic, cefotetan. This compound induced a high incidence of Coombs' test positive hemolytic anemia at clinically relevant doses in rhesus monkeys, despite a very low incidence of this adverse effect in patients with many years of clinical use. These data suggest that although rhesus monkeys respond in a qualitatively similar manner to humans with regard to high doses of beta-lactam antibiotics, their sensitivity may overestimate the risk of immune-mediated hemolytic anemia for clinical use.
authors.affiliation: Merck Research Laboratories, Department of Safety Assessment, West Point, PA 19486, USA.
authors.forename: G R
authors.initials: GR
authors.lastname: Lankas
authors.forename: J B
authors.initials: JB
authors.lastname: Coleman
authors.forename: H J
authors.initials: HJ
authors.lastname: Klein
authors.forename: Y
authors.initials: Y
authors.lastname: Bailly
mesh_terms: D000744:Anemia, Hemolytic, Autoimmune / Q000139:chemically induced*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000633:toxicity*; D015780:Carbapenems / Q000008:administration & dosage / Q000633:toxicity; D015313:Cefotetan / Q000633:toxicity; D003298:Coombs Test; D004334:Drug Administration Schedule; D004342:Drug Hypersensitivity / Q000209:etiology*; D005260:Female; D006400:Hematocrit; D006454:Hemoglobins / Q000032:analysis; D007093:Imidazoles / Q000008:administration & dosage / Q000633:toxicity; D007275:Injections, Intravenous; D008253:Macaca mulatta; D008297:Male; D010400:Penicillin G / Q000633:toxicity; D012453:Saimiri; D013045:Species Specificity
chemical_list: D000900:Anti-Bacterial Agents; D015780:Carbapenems; D006454:Hemoglobins; D007093:Imidazoles; C093180:L 695256; D015313:Cefotetan; D010400:Penicillin G