Tuesday, February 7, 2017

Linezolid-induced thrombocytopenia

Thrombocytopenia is a notable adverse effect of linezolid.  Some of the evidence behind the onset, duration, and the extent of platelet decrease will briefly be described here and summarized in bullets at the bottom of the discussion.  For a discussion of linezolid's mechanism of action and some other notable features, see a prior post here.

Mechanism of thrombocytopenia

Linezolid-induced thrombocytopenia is suspected to occur via immune-mediated platelet destruction. This first involves the drug or metabolites binding to a platelet membrane glycoprotein (ie. IIb/IIIa) which forms a complex.  This complex can be immunogenic to immunoglobulin G (IgG) antibodies which bind it with the Fab portion.  Then, the free Fc portion of that bound IgG antibody is bound to a macrophage and the whole platelet-linezolid-IgG complex is processed by the reticuloendothelial system.  This mechanism is also known as the quinine/quinidine mechanism and is different from heparin-induced thrombocytopenia (more about the diagnosis and treatment if HIT).

Under the warnings and precautions section of the linezolid prescribing information, it is stated that
"myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) has been reported in patients receiving linezolid.  In cases where the outcome is known, when linezolid was discontinued, the affected hematologic parameters have risen toward pretreatment levels. Complete blood counts should be monitored weekly in patients who receive linezolid, particularly in those who receive linezolid for longer than two weeks, those with pre-existing myelosuppression, those receiving concomitant drugs that produce bone marrow suppression, or those with a chronic infection who have received previous or concomitant antibiotic therapy. Discontinuation of therapy with linezolid should be considered in patients who develop or have worsening myelosuppression." 
The prescribing information also claims that thrombocytopenia generally occurs after 2 weeks of therapy, and states that in Phase 3 trials, only 2.4% of adult patients developed a substantially low platelet count.

Some more evidence

In a study of 19 patients, thrombocytopenia was observed in 6 (32%) patients (who experienced a 47% decrease in platelets) after 10 days of therapy. In all cases, platelets continued to decrease after discontinuation of therapy, but increased to >100,000 platelets/mm3 4-13 days after discontinuation.  Three patients died while receiving or shortly after discontinuing linezolid therapy. The rate of thrombocytopenia and complications following discontinuation of therapy in this trial vastly differ from what was found during clinical trials.

A retrospective analysis of 47 Japanese patients receiving linezolid therapy resulted in similar results -  thrombocytopenia was observed in 53.2% of patients within an average of 11.4 days. The risk factors associated with thrombocytopenia in this study were:
  • Prolonged treatment
  • Renal insufficiency
  • Dose escalation (at a weight based dose of ≥22mg/kg for some reason)
  • Increased WBC count (>12,000/mcL)
  • Chronic liver disease
  • Increased plasma linezolid trough concentration and area under the curve value

Take home points

  • Rates of thrombocytopenia vary widely from single digit percentage up near 50% in some post-market studies
    • Risk factors are listed above
  • Onset seems to be duration dependent - 10-14 days is fairly consistently reported
  • Platelet recovery can take a few days to two weeks and may initially continue to fall

Attassi K, Hershberger E, Alam R, et al.  Thrombocytopenia associated with linezolid therapy. Clin Infect Dis 2002;34:695-8.
Bernstein WB, Trotta RF, Rector JT, et al.  Mechanisms for linezolid-induced anemia and thrombocytopenia.  Ann Pharmcother  2003;37:517-20.
Gerson, Stanton L., Sheldon L. et al.  Hematologic effects of linezolid: Summary of clinical experience.  Antimicrobial Agents and Chemotherapy 2002.
Ichie, T, Suzuki D, Yasui K, et al.  The association between risk factors and time of onset for thrombocytopenia in Japanese patients receiving linezolid therapy: a retrospective analysis.  J Clin Pharm Ther 2015;40(3):279-84.
Zyvox(R) [package insert] N.p., 2000. Web. 06 Oct. 2016.

image by Yohan

Thanks to Eesha Khan for her contribution to this post


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