A rare case report of linezolid induced thrombocytopenia

 Ashish Karn a, *, Mausam Jain b, Bhavya Modi a, Riki Patel a

a Pharm D Intern, Department of Pharmacy, Sumandeep Vidyapeeth Deemed to be University, Piparia, Waghodia, Vadodara- 391760, India.

b Senior Resident, Department of General Medicine SBKS Medical Institute & Research Centre Dhiraj Hospital, Sumandeep Vidyapeeth Deemed to be University Waghodia, Vadodara- 391760, India

 

A R T I C L E  I N F O  

A B S T R A C T  

 

Received 15 December 2021;

Revised 29 January 2022;

Accepted 19 February 2022.

 

Introduction: Oxazolidinone like linezolid are widely used antibiotics because of the growing prevalence of resistant gram-positive infections. Because of its unique mode of action by inhibiting protein synthesis, it is widely effective against various resistant strains like penicillin-resistant and vancomycin-resistant strains of various gram-positive bacteria. It is widely used in the treatment of skin and soft tissue infection including MRSA and MSSA, also used in community-acquired pneumonia, and the combination is used in extensively drug-resistant tuberculosis. 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.

Case Presentation: Here we report a case of progressive but reversible thrombocytopenia in 75 years old male patient after receiving linezolid therapy for severe sepsis with multi-organ dysfunction with AKI on CKD with hepatic encephalopathy, severe hyponatremia with aspiration pneumonia. On the 9th day of linezolid, therapy thrombocytopenia was noted and immediately linezolid was stopped. After the 12th day, his platelet count went up which might be suggestive of linezolid induced thrombocytopenia.

Conclusion: Physicians 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 so that adverse reactions can be prevented.

 

Keywords:

Linezolid, oxazolidinone, thrombocytopenia, adverse drug reaction.

An official publication of Global Pharmacovigilance Society.


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


 

 

 

 

 

Laboratory data:

Table 2: laboratory data

 

Day

1

Day

2

Day

3

Day

4

Day

5

Day

6

Day

7

Day

8

Day

9

Day

10

Day

11

Day

12

Hb(g/dL)

10.1

10.2

10.5

10.9

11.3

10.7

10.6

10.7

10.8

10.9

10.9

11.1

Tc(103cells/mm3)

48000

50000

38000

35500

30500

36000

3500

3300

3325

3125

3100

4000

Dc(%)(Neutrophil/Monocyte)

 

93/2

88/3

90/2

92/2

90/3

91/2

90/2

91/2

90/2

91/2

92/3

92/3

Eosinophils/ Basophils (%)

2/3

5/4

4/4

3/3

3/3

3/4

3/4

3/4

2/3

2/3

2/3

2/3

ESR(mm/h)

114

 

 

 

112

 

 

 

 

 

 

 

Platelets(103/ mm3)

1.57

1.59

1.52

1.4

1.4

1.2

1.19

1

60000

50000

50000

1.5

Na (mEq/L)

112

106

109

117

124

127

130

131

132

130

132

132

K(mEq/L)

4.0

3.6

3.8

3.5

3.7

3.3

3.1

3.0

3.1

3.1

3.1

3.2

C(mEq/L)

81

78

79

89

92

96

97

98

98

99

99

99

Urea(mg/dL)

75

 

84

80

67

50

 

45

44

40

36

38

Creatinine (mg/dL)

4.2

 

3.9

3.0

1.8

1.4

 

1.3

1.2

1.2

1.2

1.2

Billirubin(mg/dL)

0.8

 

 

 

0.5

 

 

 

 

 

 

 

SGOT (units/L)

125

 

 

 

57

 

 

 

 

 

 

 

SGPT(units/L)

55

 

 

 

27

 

 

 

 

 

 

 

CRP(mg/L)

103.59

 

 

 

48.03

 

 

 

 

 

 

 

D-Dimer(ng/mL)

 

 

 

 

 

2990

 

 

 

 

 

 

PCV(%)

28.9

28.6

31.2

29.4

30.3

29.7

30.1

30.2

31.2

31.4

31.4

31.5

MCV (µm3)

29.4

29.8

29.8

29.4

29.6

29.9

30

29.9

29.9

30.1

30.2

30

MCH(pg)

35.7

35.8

34.8

35.2

35.4

35.6

35.7

35.6

35.5

35.8

35.6

35.9

MCHC(g/dL)

35.7

35.8

34.8

36.2

36.1

35.8

36.7

36.8

36.2

37.3

36.8

36.4

RBC(106/mm3)

3.41

3.43

3.76

3.56

3.78

3.78

3.70

3.79

3.76

3.78

3.77

3.70

RDW(%)

13.2

13.2

13.6

13.1

13.5

13.6

13.5

13.7

13.9

13.5

13.6

13.7


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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