Cephalosporin-induced changes in the ultrastructure of canine bone marrow

Fourteen healthy dogs were given 540 to 840 mg/kg of cefazedone (Refosporen) intravenously for up to 4 months or until peripheral blood cell count were depressed. Within 6 to 10 weeks treated dogs developed pancytopenia (5/14), thrombocytopenia (11/14), moderate to severe neutropenia (8/14), and/or normocytic anemia with erythroblastemia (8/14). Ultrastructural changes in bone marrow of severely cytopenic dogs included mitochondrial damage in hematopoietic and nonhematopoietic cells, thickening of endosteal bone lining layers, increased adventitial coverage of vascular sinuses, and an increased number of active macrophages. Swollen, ruptured mitochondria were in erythroid, granulocytic, and megakaryocytic cells, and, to a lesser extent, in macrophages, reticular endothelial, and bone lining cells. Maturation arrest was evident in both erythroid and granulocytic cell lines. There was also evidence of ineffective erythropoiesis and granulopoiesis. None of these changes were observed in bone marrow of controls, treated dogs that did not develop cytopenia, or dogs allowed to recover after cessation of dosing.