EBM Consult

How does the antibiotic linezolid (Zyvox) cause thrombocytopenia?

Summary:

  • Linezolid (Zyvox) is an orally available antibiotic with activity against methicillin-resistant Staphylococcus aureus (MRSA) and other gram+ infections.  This makes it an attractive treatment option for long term and/or outpatient management of MRSA infections.       
  • Unfortunately, linezolid can cause reductions in platelet counts by 36 to 94% from baseline with an incidence of 12.9% in pediatric and 3 - 24.5% in adult patients taking 600 mg twice daily.
  • To date, the exact mechanism of linezolid induced thrombocytopenia has not been fully elucidated; however, there is evidence that this is an immune-mediated reaction rather than a suppression of the bone marrow as seen with other anemias associated with linezolid.  Interestingly, this immune-mediated reaction appears to be very similar to the drop in platelets seen with quinine/quinidine-mediated antibody production. 
  • It appears that linezolid, or one of its metabolites, binds to the platelet membrane glycoprotein 1b/IX and/or glycoprotein IIb/IIIa thereby forming an "antigenic" complex that is then recognized by the Fab portion of IgG antibodies.  This binding and subsequent recognition allows the Fc region of the antibody to activate macrophages to destroy the platelet.

Editor-in-Chief: Anthony J. Busti, MD, PharmD, FNLA, FAHA

Last Reviewed: February 2018

Explanation

  • Linezolid (Zyvox) is an oxazolidinone antibiotic commonly used for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) and other gram+ infections.(1)  The availability of linezolid in an oral dosage form makes it an attractive treatment option for the long term and/or outpatient management of MRSA infections.  Unfortunately, linezolid has been associated with causing both anemia and thrombocytopenia.(2-5)  Specifically, the current FDA approved product insert warns about the risk of developing thrombocytopenia in patients taking linezolid for > 2 weeks.(1)  Reductions in platelet counts by 36 to 94% from baseline have been documented with the earliest case being reported after only 7 days of therapy.(2-5)  While the exact incidence for this adverse drug event is not known, reports show that 12.9% of pediatric and 3 - 24.5% of adult patients may experience a reduction in platelets while taking 600 mg twice daily.(1,6)  

    How does linezolid contribute to this reduction in platelet count?

    • The exact mechanism has not been elucidated; however, there is evidence that linezolid-induced thrombocytopenia is an immune mediated adverse response rather than a suppression of the bone marrow as seen with the other anemias associated with linezolid.(2,4) 
    • In fact, this immune-mediated reaction appears to be very similar to the drop in platelets seen with quinine/quinidine-mediated antibody production.(4,7,8)  

    What it is the mechanism that might cause this thrombocytopenia?

    • In normal antibody-mediated immune activation, antibodies are produced from B-lymphocytes which recognize certain antigens or proteins as "foreign" and turn on/activate the immune system.  More specifically, the fragment antigen binding (Fab) region (also called the variable region) on the antibody is what identifies and binds to the foreign appearing antigen.
    • Upon binding of the Fab region to the antigen, the other end of the antibody, known as the Fc region, will bind to cell surface Fc receptors on immune cells resulting in their activation. This activation generally aids in the removal/destruction of the antigen from the body.   
    • As it relates to linezolid, it appears that the parent drug or one of its metabolites binds to the platelet membrane glycoprotein 1b/IX and/or glycoprotein IIb/IIIa thereby forming an "antigenic" complex that is then recognized by the Fab portion of IgG antibodies.(4,7,8) 
    • Once the Fab region of IgG antibody is bound to the linezolid/platelet complex the IgG's Fc portion can then bind to the cell surface Fc receptor on macrophages.  This results in activation of macrophages, which will then attack/destroy the platelet and remove it from circulation.   
    • Linezolid-induced platelet destruction occurs without any apparent effect on the bone marrow as evidenced by the presence of adequate megakaryocytes (precursor cells of platelets) in the marrow and improvement in the rate of decline of platelets after administering IVIG (intravenous antibody that binds to Fc receptors preventing the activation of the reticuloendothelial system (phagocytic cells) by IgG Fc region on antibodies).4 

    Are there any predictors for who is at risk?

    • A few risk factors have been identified and include: baseline low platelet counts, dose of linezolid (with 600 mg twice daily having a higher incidence) and duration of therapy (with most cases occurring after 10 days of treatment).(1,6)
    • While this can happen and is certainly something that should be considered or monitored for, not all reductions in platelets are considered to be clinically significant nor does it always signify an increase in risk for major bleeding.(9,10) 
    • Nevertheless, clinicians should monitor complete blood cell counts and signs and symptoms of bleeding, especially with long term use (i.e., > 7 days).  If significant thrombocytopenia occurs, stopping linezolid will result in an improvement in the platelet count with normalization occurring between 7 and 30 days, in most cases.(2,3)

References

    1. Linezolid (Zyvox┬«) product package insert.  Pfizer Inc. New York, NY.  July 2008.
    2. Green SL, Maddox JC, Huttenbach ED.  Linezolid and reversible myelosuppression.  JAMA  2001;285:1291.        
    3. Waldrep TW, Skiest DJ.  Linezolid-induced anemia and thrombocytopenia.  Pharmacotherapy  2002;22:109-12.        
    4. Bernstein WB, Trotta RF, Rector JT et al.  Mechanisms for linezolid-induced anemia and thrombocytopenia.  Ann Pharmacother  2003;37:517-20.       
    5. Tavil B, Balci YI, Yildirim I et al.  Linezolid-indcued reversible bicytopenia in a 4-year old boy with methicillin-resistant Staphylococcus aureus bacteremia.  Pediatr Hematol Oncol  2008;25:67-71.  
    6. Grau S, Morales-Molina JA, Mateu-de Antonio J et al.  Linezolid: low pre-treatment platelet values could increase the risk for thrombocytopenia.  J Antimicrob Chemother    2005;56:440-1.               
    7. Chong BH, Du XP, Berndt MC et al.  Characterization of the binding domains on platelet glycoproteins 1b-IX and IIb/IIIa complexes for the quinine/quinidine-dependent antibodies.  Bood  1991;77:2190-9.        
    8. Kaufman DW, Kelly JP, Johannes CB et al.  Acute thrombocytopenic purpura in relation to the use of drugs.  Blood  1993;82:2714-8.  
    9. Nasraway SA, Shorr AF, Kuter DJ et al.  Linezolid does not increase the risk of thrombocytopenia in patients with nosocomial pneumonia: comparative analysis of linezolid and vancomycin use.  Clin Infect Dis  2003;37:1609-16. 
    10. Grim SA, Rene L, Gupta S et al.  Safety of linezolid in patients with baseline thrombocytopenia.  J Antimicrob Chemother 2008;62:850-1.

MESH Terms & Keywords

  • Linezolid, Zyvox, Thrombocytopenia, Linezolid Induced Thrombocytopenia