Linezolid induces ring sideroblasts.

Linezolid, an oxazolidinone antibiotic approved for the treatment of respiratory tract and skin infection caused by Gram-positive bacteria, is known to have mitochondrial toxicity. Mitochondrial toxicity is explained by linezolid’s specific binding to mitochondrial ribosomes, leading to inhibition of mitochondrial protein synthesis. Ring sideroblasts (RS) are erythroid precursors with mitochondrial iron accumulation appearing as perinuclear granules on bone marrow (BM) smears after staining with Prussian blue. Ring sideroblasts are mainly observed in myelodysplastic syndromes (MDS) particularly refractory anemia with ring sideroblasts (RARS) and less often in several types of inherited sideroblastic anemia. RARS is defined by both the presence of dyserythropoiesis and 15% or more RS among the erythroid precursors. Molecular mechanisms leading to RS in RARS are not well understood. Recently, mutations of SF3B1, a gene implicated in the spliceosome machinery, were found in up to 60-75% of RARS. Altered function of SF3B1 protein seems responsible for the phenotype observed in RARS. Several drugs induce reversible sideroblastic anemia, including isoniazid and chloramphenicol. Linezolid is known to have hematologic toxicity, including anemia and thrombocytopenia. Pre-clinical studies with linezolid in dogs have shown the presence of ring sideroblasts on bone marrow (BM) smears. Clinical cases of linezolid-induced and reversible sideroblastic anemia have been reported. To establish the incidence of induced ring sideroblasts and sideroblastic anemia on linezolid therapy, we retrospectively analyzed BM smears of patients who were treated by linezolid in our center over a period of one year. Approval of this study was obtained from the Institutionnal Review Board of CHRU of Lille (N. CSTMT101). All medical prescriptions of linezolid made in the University Hospital of Lille, France, in 2011 were reviewed. Overall, 921 patients received the drug for at least one day. Seventy-three patients had at least one BM smear in the three months following treatment, resulting in a total of 94 BM smears as some patients were treated several times). Most patients (55 of 73) had a history of hematologic malignancy; this fact could be explained by the large use of BM aspirates in the diagnostic procedure and follow up of these diseases. After excluding 2 patients with no smear available for blue Prussian staining, 92 BM smears from 71 patients were stained. Counting of ring sideroblasts (RS) was performed by 2 separate morphologists. In case of discrepancy, a third count was made by another morphologist. BM smears with less than 5% erythroblasts were excluded (13 BM smears corresponding to 5 patients). Thus, 79 BM smears (66 patients) were finally analyzed. Among the 66 patients, 48 had a history of hematologic malignancy (acute myeloid leukemia (AML) in 39 patients). No patient had a history of MDS. BM examina-