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.