Investigations of the potential for five beta-lactam antibiotics to elicit type II hypersensitivity reactions in rats and monkeys.
Immunologic reactions are occasionally elicited in patients by various beta-lactam antibiotics (e.g., penicillins and cephalosporins). A relatively rare reaction (type II hypersensitivity) may involve antibody-mediated destruction of erythrocytes, leukocytes, and/or platelets. During the safety evaluation of several modified beta-lactam compounds (carbapenems), hemolytic anemia and/or neutropenia were observed in rhesus monkeys, and anemia, neutropenia, and thrombocytopenia in rats, after approximately 2 weeks of intravenous administration. Antiglobulin tests and other clinicopathologic findings indicated an immune basis for the cytopenias. A review of summaries of the preclinical data for numerous marketed beta-lactam antibiotics revealed that various cytopenias of unknown etiology were commonly seen in animals given high doses of these compounds. To determine whether these hematologic abnormalities were related to those produced by the above carbapenems, we investigated the potential of five widely used beta-lactam antibiotics (penicillin G, cephalothin, cefazolin, cefoperazone, and cefamandole) to elicit immune-mediated cytopenias in rhesus monkeys and Sprague-Dawley rats when given intravenously. After approximately 1 month of administration of these compounds at a dose level of 500 mg/kg/day, slight anemia occurred in several drug-treated monkeys; however, direct and indirect antiglobulin tests were negative for all animals, indicating that the anemias were not immune-mediated. In rats, no drug-induced hematologic changes were observed after 1 month of intravenous administration of 500 and 1000 mg/kg/day of each of the beta-lactams. In addition, direct antiglobulin tests were negative in rats. Therefore, it appears that the ability of certain carbapenem antibiotics to produce a high incidence of type II hypersensitivity reactions in animals is not typical of beta-lactam compounds in general.
Kornbrust
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D
Merck Sharp & Dohme Research Laboratories, Department of Safety Assessment, West Point, Pennsylvania 19486.
Eydelloth
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R
Garratty
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G
D000818:Animals; D000900:Anti-Bacterial Agents / Q000276:immunology / Q000633:toxicity*; D000906:Antibodies / Q000032:analysis; D000888:Antibodies, Anti-Idiotypic / Q000032:analysis; D003176:Complement C3 / Q000032:analysis; D004342:Drug Hypersensitivity / Q000503:physiopathology*; D004912:Erythrocytes / Q000276:immunology; D007074:Immunoglobulin G / Q000032:analysis; D007075:Immunoglobulin M / Q000032:analysis; D007958:Leukocyte Count; D008253:Macaca mulatta; D009504:Neutrophils / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity; D047090:beta-Lactams
D000900:Anti-Bacterial Agents; D000906:Antibodies; D000888:Antibodies, Anti-Idiotypic; D003176:Complement C3; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D047090:beta-Lactams