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)
