Introduction
The growing prevalence of
resistant gram-positive infection in the world leads to recognition of
Oxazolidinone-like linezolid. It also gains popularity because of its
distinguish pharmacokinetic profile. It works by inhibiting protein synthesis
by binding to the P site of 23S ribosomal RNA of the 50S subunit and further
preventing the formation of the larger ribosomal-fMet-tRNA complex which is
useful in initiating the protein synthesis. It is widely effective against
gram-positive bacteria like staphylococcus, streptococcus, enterococcus, etc.
It is poorly active against most gram-negative bacteria. Because of their
distinctive mode of action, they are very effective against various resistant
strains like penicillin-resistant and vancomycin-resistant strains of various
gram-positive bacteria (Tsuji
et al., 2017).
It is well tolerated orally
with 100% bioavailability and can be taken irrespective of food. Generally, the
dosing regimen is the same for both oral and intravenous administration. It is
usually 30 % protein-bound and widely distributed to well-perfused tissues (Manfredi et al., 2006). No dose adjustment is required in renal
insufficiency. It is widely used in the treatment of skin and soft tissue
infection including MRSA and MSSA, also used in community-acquired pneumonia,
and in combination used also used in extensively drug-resistant tuberculosis (French et al., 2003).
The most common side effect of
linezolid includes gastrointestinal disturbances like nausea and vomiting.
Serious adverse effects include Myelosuppression including thrombocytopenia,
anemia, pancytopenia, and leukopenia. Peripheral neuropathy, optic neuritis,
and lactic acidosis are also reported. Here we report a case of progressive but
reversible thrombocytopenia in an elderly patient after receiving linezolid
therapy for severe sepsis with multi-organ dysfunction with AKI on CKD with
hepatitis encephalopathy, severe hyponatremia with aspiration pneumonia (French et al., 2003).
Case report
A 75-year-old male patient
came with complaints of altered sensorium for 2 days, loss of appetite, and
decreased urine output for 3 days along with headache in the parietal region,
dull aching, and continuous not associated with photophobia and phonophobia. He
also had a diabetic foot ulcer. He was known for cases of type 2 Diabetes
Mellitus and hypertension for 10 years and was irregular on medication. His CT
scan brain revealed extradural hemorrhage along with right parietal convexity
with the maximum thickness (11 mm). There is mild prominence of sulci and gyri
with mild dilation of bilateral ventricle suggestive of cerebral cortical
atrophy. It also revealed chronic small vessel ischemic changes. He was
diagnosed with severe sepsis with multi-organ dysfunction with AKI on CKD with
hepatitic encephalopathy, severe hyponatremia with aspiration pneumonia. He was
prescribed with Inj. Meropenem (500 mg) IV 12 hourly, Inj. Levofloxacin (250mg)
IV 24 hourly, Tab Linezolid (600 mg) BD. On the ninth day, his platelet count
decreased to 60,000. After which Tab. Linezolid (600 mg) was kept on hold after
three days of discontinuation i.e. on the twelfth day his platelet count went
up to 1.5 lakh, which might be suggestive of linezolid induced
thrombocytopenia. After that linezolid was stopped completely. No re-challenge
was done. Laboratory data and Medication charts are mentioned in Table 1 and Table 2 respectively.
Medication chart
Table 1: Drugs therapy prescribed
|
Drug
(Brand Name)
|
Generic Name
|
Dose
|
Frequency
|
|
Inj. Syscan
|
Fluconazole
|
200 mg
|
24 hourly
|
|
Inj. Meropenem
|
Meropenem
|
1 g
|
8 hourly
|
|
Inj.Levoflox
|
levofloxacin
|
500 mg
|
12 hourly
|
|
Tab. linezolid
|
Linezolid
|
600 mg
|
BID**
|
|
Inj Emset
|
Ondansetron
|
4 mg
|
SOS****
|
|
Inj Pan
|
Pantoprazole
|
40 mg
|
BID
|
|
Tab Sobsis
|
Sodium bicarbonate
|
500 mg
|
TID***
|
|
IVF NS
|
Normal saline
|
0.9% (60 cc/h)
|
2pint/day
|
|
Syp. Potklor
|
Potassium chloride
|
15mL with _ glass water
|
TID
|
|
Tab. Moxonidine
|
Moxonidine
|
0.3 mg
|
BID
|
|
Tab. Telma
|
Telmisartan
|
40 mg
|
OD*
|
|
Tab Amlo
|
Amlodipine
|
10 mg
|
OD
|
|
Inj. HAI
|
Human Actrapid insulin
|
2U-2U-4U
|
TID
|
*OD- once daily, **BID- twice daily,
***TID- thrice daily, ****SOS- as and when required
His HbA1C was 8.8 %,
Urine osmolality was 165.2 mOsm/kg, Urine sodium, potassium, and chloride was
16 mEq/mL, 17 mEq/mL and 40 mEq/mL respectively. His creatinine clearance was
17 mL/min and BUN/Cr. ratio was 8.9 mg/dL.
Peripheral smear:
RBC:
Normocytic Normochromic
WBC:
leukocytosis with shift to right
Toxic
changes in neutrophil in form of vacuoles and granules
Causality
assessment
Causality and severity
assessment has been done with the help of five different scales and results as
mentioned in Table 3.
Table 3: Causality assessment
|
ScaleÕs name
|
Result
|
|
NaranjoÕs algorithm
|
Probable
|
|
Hartwig and siegel
|
Moderate (Level 4)
|
|
Karch and lasagna
|
Probable
|
|
Who-Umc Scale
|
Probable
|
Discussion
Our case report is consistent
with previously documented linezolid induced thrombocytopenia which is a
serious adverse drug reaction (Waldrep
et al., 2002; Sakka et al., 2009; Halpem et al., 2002; Cossu et al., 2014). On the 9th day of linezolid
treatment, progressive thrombocytopenia was observed and linezolid was kept on
hold. Even after discontinuation of linezolid therapy platelet count continued
to decrease. Only after the 12th day (3rd day of holding
linezolid therapy) its platelet count goes up. Meropenem and levofloxacin are
also known to cause thrombocytopenia, but the adverse event resolved after
discontinuation of linezolid therapy suggestive of linezolid induced
thrombocytopenia. NaranjoÕs scale was used for causality assessment and
categorized as possible adverse drug reaction (Naranjo et al.,
1981).
The mechanism behind
linezolid-induced thrombocytopenia is still unclear. It has been documented
that drug-induced myelosuppression can occur by two major mechanisms:
immune-mediated and direct toxic effects to hematopoietic cells. It is believed
that linezolid-induced thrombocytopenia is immune-mediated rather than bone
marrow suppression (Brenstein
et al., 2003).
Risk factor for linezolid
induced thrombocytopenia includes: Creatinine clearance < 30 mL/min ,
baseline Hb < 10.5 g/dl, baseline platelet count < 200*103 /mm3
, prior /present treatment with antibiotics, immunosuppression therapy (Choi et al., 2019; Han et al.,
2021). In our case baseline platelet count was < 200*103
/mm3, Creatinine clearance < 30 mLmin, baseline Hb < 10.5
g/dLand antibiotics therapy of meropenem and levofloxacin was given which may
be the risk factor for thrombocytopenia.
Conclusion
Linezolid-induced
thrombocytopenia is reversible after discontinuation of the drug. The physician
should be more vigilant in monitoring complete blood count, especially in
elderly patients who are receiving linezolid for more than two weeks. They
should also make a risk assessment based on creatinine clearance, baseline
platelet count, immunosuppression therapy, baseline hemoglobin, and
prior/present antibiotics therapy.
Declaration of patient consent
The authors certify that they
have obtained all appropriate patient consent forms. The patients understand that their names
and initials will not be published and due efforts will be made to conceal
their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of
interest
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Ashish Karn a, *, Mausam Jain b, Bhavya Modi a, Riki
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