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Linezolid and Reversible Myelosuppression
To the Editor: Linezolid is the first oxazolidinone antibiotic with labeling approved to treat methicillin-resistant Staphylococcus aureus (MRSA) infection. We report 3 cases of myelosuppression with red cell hypoplasia that occurred following therapy with linezolid. Although reversible thrombocytopenia has been reported in patients receiving more than 2 weeks of therapy,1 we found additional bone marrow changes that appear similar to those seen in reversible chloramphenicol toxicity.
Report of Cases
The first patient was a 70-year-old man who received linezolid, 600 mg twice daily for 4 months, for an MRSA infection in a femoral-popliteal Gore-Tex graft. During this period, the platelet count decreased from 215 x 103/µL to 60 x 103/µL, and hemoglobin decreased from 14.3 g/dL (143 g/L) to 7.0 g/dL (70 g/L), with a reticulocyte count of 0%. Vitamin B12 and folate levels were normal, serum iron was 158 µg/dL (28.3 µmol/L) with a total iron binding capacity of 166 µg/dL (29.7 µmol/L), and iron saturation was 95%. Examination of the bone marrow demonstrated 30% hematopoietic tissue, increased iron stores, megaloblastoid white blood cell maturation, abundant megakaryocytes, and erythroid aplasia (myeloid/erythroid ratio = 174:1) with vacuolated erythroblasts (Figure 1). Ten days after discontinuing linezolid, platelet counts and hemoglobin levels returned to normal, the iron saturation fell to 25%, and the reticulocyte count increased to 5.8%.
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Figure. Vacuolated Erythroblasts in the Bone Marrow of Patient 1 After Receiving Linezolid for 4 Months
Pathology performed with Wright stain (original magnification x1000).
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The second patient was a 43-year-old woman who received linezolid, 600 mg twice a day for 6 weeks, for a chronic MRSA infection of a facial sinus. During this period, the platelet count decreased from 399 x 103/µL to 206 x 103/µL, and hemoglobin concentration decreased from 14.1 g/dL (141 g/L) to 12.8 g/dL (128 g/L), with a reticulocyte count of 0%. Parvovirus B-19 IgM and IgG titers were undetectable. Vitamin B12 and folate levels were normal, and serum iron was 214 µg/dL (38.3 µmol/L). Total iron binding capacity was 286 µg/dL (51.2 µmol/L) with an iron saturation of 74%. Linezolid was discontinued at this point, and 5 days later a bone marrow biopsy specimen showed decreased iron stores and rare vacuolated erythroblasts. One week later, platelet counts and hemoglobin levels returned to normal, the iron saturation decreased to 9%, and the reticulocyte count increased to 2.4%.
The third patient was a 61-year-old woman with type 2 diabetes who received linezolid, 600 mg twice daily, for MRSA metatarsal osteomyelitis. During 2 weeks, reticulocytes declined from 1.4% to 0% and iron saturation increased from 22% to 65%. The drug was discontinued for 2 weeks, then, with the patient's consent, continued for 4 more weeks. During that time, the reticulocytes decreased again from 4.5% to 0%, platelets from 294 x 103/µL to 125 x 103/µL, hemoglobin from 9.9 g/dL (99 g/L) to 8.0 g/dL (80 g/L), and iron saturation increased from 10% to 96%. Similarly to the other 2 patients, all values returned to normal levels after linezolid discontinuation.
Comment
These 3 cases illustrate features strikingly similar to those of the reversible form of chloramphenicol toxicity, which is a dose-dependent reversible pancytopenia usually observed after 2 weeks of therapy. With both of these drugs, increasing levels of serum iron and iron saturation appear to precede the decrease in peripheral blood cell counts, and erythroblast vacuolization appears to occur.2 The 3 patients described herein concurrently received other medications that do not usually cause myelosuppression. Linezolid was the only drug they had in common, and there was a strong temporal association between linezolid use, hematologic changes, and recovery. Since linezolid may potentially replace vancomycin in situations requiring long-term or outpatient therapy, it is important for clinicians to be aware of this toxicity and to closely monitor iron levels and reticulocyte counts in patients receiving linezolid for prolonged periods.
AUTHOR INFORMATION
Financial Disclosure: Dr Green was a clinical investigator in trials of linezolid using a research grant from Pharmacia, the manufacturer of the drug. None of the patients described in this letter were participants in those clinical trials and all reported events occurred after Dr Green's financial relationship with Pharmacia concluded.
Stephen L. Green, MD;
John C. Maddox, MD;
Eric D. Huttenbach, MD
Riverside Regional Medical Center
Newport News, Va
1. Linezolid (Zyvox). In: The Medical Letter. 2000;42:45-46.
2. Williams DM. Pancytopenia, aplastic anemia, and pure red cell aplasia. In: Lee GR, Foerster J, Lukens J, Paraskevas F, Greer J, Rodgers G, eds. Wintrobe's Clinical Hematology. 10th ed. Baltimore, Md: Williams & Wilkins; 1999:1455-1459.
Letters Section Editors: Stephen J. Lurie, MD, PhD, Senior Editor; Jody W. Zylke, MD, Contributing Editor.
JAMA. 2001;285:1291.
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