UNIT KAJIAN DAN MAKLUMAT

DRUG (UKMD), HUSM.

ADR CASE REPORT:

DRUG-INDUCED LEUKOPENIA
PRECEPTORS:
PN NOOR SHUFIZA
PN NOORHASLIZA

KHOR KAH LOONG

HUSM PRP 2011/12

Presentation Outline
Objectives
Introduction
Case Report
Pharmaceutical Care Issues /
Discussion

Conclusion

OBJECTIVES

OBJECTIVES

To describe a case on drug-induced leukopenia.

To discuss the possible drug that causes of
leukopenia.
To discuss on management of drug-induced
neutropenia.

INTRODUCTION

INTRODUCTION
Adverse Drug Reaction (ADR)
Definition (WHO):
Any

response to a drug which is noxious and unintended,

and which occurs at doses normally used in man for
prophylaxis, diagnosis, or therapy of disease, or for the
modification of physiological function .1

Major cause of Morbidity and Mortality worldwide2

common cause of iatrogenic illness.3
Accounts for approximately 10% of the hospital admission
in some countries.4
Most

1)
2)
3)
4)

Requirements for adverse reaction reporting. Geneva, Switzerland: World Health Organization; 1975
Rield MA, Casillas AM. Adverse drug reactions: types and treatment options. Am Fam Physician. 2003 Nov 1;68(9):1781-90.
Ditto AM. Drug allergy. In: Grammer LC, Greenberger PA, eds. Patterson's Allergic diseases. 6th ed. Philadelphia: Lippincott Williams & Wilkins, 2002:295.
WHO. Safety of Medicines. WHO/EDM/QSM/2002.2 [Online]; Available from: URL:http://whqlibdoc.who.int/hq/2002/WHO_EDM_QSM_2002.2.pdf

Adverse Drug Reaction2

Non-Immunologic
Predictable
Pharmacologic side
effect
Secondary
pharmacologic side
effect
Drug toxicity
Drug-drug
interaction
Drug Overdose

Unpredictable
Pseudoallergic
Idiosynchratic
Intolerance

Rield MA, Casillas AM. Adverse drug reactions: types and treatment options. Am Fam Physician. 2003 Nov 1;68(9):1781-90.

Immunolgic
Unpredictable
(I) IGE-mediated
(II) Cytotoxic
(III) Immune-complex
(IV) Delayed, cell
mediated
Specific T-cell
activation
Fas/Fas ligandinduced apoptosis

INTRODUCTION
Leukopenia
Definition:
A

reduction of the circulating WBC count to less than

4000/l5 (<4.0 x 109/L)

Causes6,7:
Bone

marrow deficiency / failure

Sepsis

Collagen-vascular

disease

Sytemic Lupus Erythromatous8

Chemotherapy

/ Drug therapy
Radiation therapy/exposure
5) The Merck Manual for healthcare professional. Definition of Neutropenia and Leukopenia. [online] 2008 [cited on 2012 Jun]; Available from: URL:http://www.merckmanuals.com/professional/hematology_and_oncology
/neutropenia_and_lymphocytopenia/definition_of_neutropenia_and_leukopenia.html
6) MedlinePlus. WBC count. [online] 2011 Feb [cited on 2012 Jan]; Available from: URL:http://www.nlm.nih.gov/medlineplus/ency/article/003643.htm
7) Godwin JE. Neutropenia. [online] 2011 May [cited 2012 Jan]; Available from: URL:http://emedicine.medscape.com/article/204821-overview#a0104
8) Bartels CM. Systemic Lupus Erythematosus clinical presentation. [Online] 2011 Nov [cited on 2012 Jan]; Available from: URL:http://emedicine.medscape.com/article/332244-clinical

INTRODUCTION
Drug-induced Leukopenia/Neutropenia9
Occurs

with various drugs

Mechanism10
Immune-mediated

Hapten (Penicillin-group)
Apoptosis (Clozapine)
Immune complex
Complement-mediated mechanism (PTU)

Dose-dependent-inhibition

-lactams antibiotics, Carbamazepine, Valproic acid

Direct

of granulopoiesis

toxicity to myeloid precursor

Ticlopidine, Methimazole, Chemotherapy

9) Mintzer DM, Billet SN, Chmielewski L. Drug-Induced Hematologic Syndromes. Advances in Hematology. 2009;2009.
10) Bhatt V, Saleem A. Drug-induced neutropenia Pathophysiology, clinical features, and management. Annals of Clinical and Laboratory Science. 2004;34(2):131-7.

INTRODUCTION
Vancomycin-Intermediate Staphylococcus Aureus (VISA)
Under

MRSA group
Based on Breakpoint in Mean Inhibitory Concentration
(MIC)11
MIC
(g/mL)

VSSA

VISA

VRSA

<2
4-8

>16

VISA

development -- Prolong Vancomycin exposure11

11) Hageman JC, Patel JB, Carey RC, Tenover FC, McDonald LC. Investigation and control of vancomycin-intermediate and resistant Staphylococcus Aureus: A guide for health departments and infection control personnel.
[Online] 2006 [cited on 2012 Jan]; Available from: URL:www.cdc.gov/ncidod/dhqp/ar_visavrsa_prevention.html

CASE PRESENTATION

PATIENT DETAILS

Admission Date: 30/11/2011

39/Malay/Female
Complains upon admission:
Coughing
Sputum

with blood
Chest pain upon coughing
Tiredness / lethargy
Breathlessness

HISTORY OF CURRENT ILLNESS

Productive Cough x 1/52

Sputum Whitish to Blood-stained (x 2/7)
Hx of SOB x 3/12
Severe lethargy & pale looking
Lower limb oedema
Orthopnea, Paroxymal Nocturnal Dyspnea
Low effort tolerance

PAST MEDICAL HISTORY

ANCA (+ve) vasculitis

Under

Rheumato team follow-up in HRPZ II

End-stage Renal Failure

Secondary

Right Lower Limb DVT

On

T. Warfarin 3mg OD

Recurrent MRSA infection

On

to ANCA vasculitis

Vancomycin 1g OD (last dose 24/11/11)

Anemia
Hypertension?

PAST MEDICATION HISTORY

DRUGS
T. Prednisolone 35mg OD
T. Azathioprine 50mg OD

T. Warfarin 3mg OD
T. Felodipine 10mg OD
T. Prazocin 1mg BD

INDICATION
ANCA vasculitis
DVT prophylaxis
Hypertension?

C. Tramadol 50mg prn

Pain

T. Frusemide 60mg TDS

ESRF, promote urination

T. Esomeprazole 40mg OD

Gastric pain

Ravin Enema 1/1 prn

Constipation

T. Ferrous Sulphate 400mg TDS

T. Vitamin B complex 1/1 OD

T. Folate 5mg OD

Anemia

SOCIAL HISTORY

Non Smoker
Non Alcohol drinker

SYSTEM REVIEW (ON ARRIVAL)

BP

132/82 mmHg

HR

111 beats/min

37oC

CVS

DRNM, JVP equal

Lungs

Coarse Crepts, up to Midzone bilaterally

Per-Abdominal Soft non-tender

Non-organomegally
CXR

Patchy opasity @ bilateral lower zone

Minimal Pleural Effusion

Others

Alert and Conscious

Lethargic / Pale
Mildly dehydrated
Pedal Oedema

DIAGNOSIS

Symptomatic Anaemia
Cathether related blood stream infection (CRBSI)
MRSA

/ VISA

Chest Infection
Atypical

Pneumonia?

HCAP

ANCA (+ve) vasculitis

Not

in active disease state.

Lower Limbs DVT

ESRF on HD

PROGRESS
1/12

No evidence of atypical pneumonia Off Azithromycin, start

Meropenem.
ESRF, fluid overload restrict fluid 1-1.5L/d, strict I/O chart.

4/12

VISA, Off Vanco, Start 2 weeks IV Linezolid, completed on 19/12

Mild depression started Escitalopram, but discontinue on 10/12 due
to drug-drug interaction with Linezolid

6/12

8/12

Thrombosis start SC Heparin on 7/12, then change to enoxaparin

(8/12) before restart warfarin (9/12). However, INR fluactuation
(target 1.5-2) and haemotypsis forces dose reduction (5mg4.5mg
3mg) and on-off in dose-witholding.
Rheumato: To restart Azathioprine in view of patient underlying ANCA
(+ve) vasculitis. However, Off on 13/12 as patient TWBC <4 x 106/L
Back pain Tramadol was given.

PROGRESS
9/12

13/12

18/12

19/12

High BP (191/99mmHg) restart prazocin

Reducing trend of TWBC (3.66). Azathioprine was off.

KIV MMF.

Hypotension (103/64 mmHg) withold Prazocin

Hypotension,
Completed linezolid. Vancomycin and rifampicin combination was
started (VISA treatment)

PROGRESS
23/12

Haemotypsis and bruises (INR 2.55, aPTT 71.5s) Warfarin withold, 6

unit FFP was transfused, target INR 1.5-2

SOB, Sudden onset of desaturation secondary to pulmonary

haemorrhage, diagnose pulmonary embolism KIV intubation if
worsening.
24/12 Respiratory failure (I) precipated by fluid overload and anemia.
Oral candiasis Syr Nystatin was given
Hyperkalaemia (6.6mmol/L) Lytic cocktail stat.
25/12 Condition improving
Reducing trend of TWBC Drug related ? (Vancomycin / Linezolid /
Rifampicin / Azathioprine)
28/12 Off Vancomycin and rifampicin, restart linezolid.

PROGRESS
1/1

Condition improving, comfortable

Blocked permanent cathether, not agree for IVL Off linezolid,
change to C. Rifampicin and T. Fusidic acid.

3/1

Hallucination - Delirium secondary to multiple medical problem.

Low BP, New spike T and rise in TWBC & HR treat as CRI Start IV
Ceftazidime

4/1

Conscious, restlessness, talking incoherently

Diagnosis: HAP with sepsis, Hypotension, delirium 2o sepsis
Off IV Ceftazidime, start IV Meropenem, transfer to acute cubicle
To correct anemia Transfer antibody-free blood.

MEDICATIONS - ANTIBIOTIC
DRUGS

INDICATIONS

DURATION

Vancomycin 1g stat
T. Azithromycin 500mg stat & OD

MRSA infection

24/11, 3/12

Atypical Pneumonia

30/11-1/12

IV Ceftazidime 1g stat & OD

Pneumonia

30/11-1/12

IV Meropenem 500mg BD

HCAP

1/12-19/12

IV Linezolid 600mg BD x 14/7

VISA infection

4/12-19/12

IV Vancomycin 1g EOD

VISA infection

20/12-28/12

C. Rifampicin 600mg OD

VISA infection

20/12-29/12

Syr. Nystatin 50000iu QID

Oral Candidiasis

25/12-cont

IV Linezolid 600mg BD

VISA infection

29/12

Rifampicin 600mg stat & OD

VISA infection

1/1/12-cont

Fusidic acid 500mg stat & TDS

VISA infection

1/1/12-cont

MEDICATIONS - OTHERS
DRUGS

INDICATIONS

DURATION

IV Hydrocortisone 100mg TDS

30/11-7/12

IV Hydrocortisone 100mg BD

7/12-15/12

T. Prednisolone 35mg OD

ANCA +ve Vasculitis

15/12-2/1

T. Azathioprine 50mg OD

30/11, 9/12-13/12

IV Pantoprazole 40mg stat & BD

30/11-30/12

T. Pantoprazole 40mg BD

Gastric Pain

Ravin Enema 1/1 stat & PRN

Constipation

T. Bromhexine 8mg stat & TDS

Cough with sputum

C. Tramadol 50mg stat & PRN

C. Tramadol 50mg TDS

Pain

T. Ferrous Fumarate 400mg TDS

30/11, 28/12
1/12-14/12
1/12, 4/12, 8/12
9/12-21/12, 25/12-cont
1/12-cont

T. Vitamin B complex 1/1 OD

T. Folic acid 1/1 OD

31/12-cont

Anemia

1/12-cont
30/11-cont

MEDICATIONS - OTHERS
DRUGS

INDICATIONS

DURATION

T. Paracetamol 1g stat
Thymol gargle LA

Oral Pain

2/12-cont

T. Escitalopram 10mg OD

Depression

4/12-10/12

T. Calcium Carbonate 500mg BD

T. Calcium Carbonate 500mg TDS

T. Rocaltriol 0.25mg OD
T. Rocaltriol 0.5mg OD
T. Potassium Chloride 1200mg BD x
3/7
Lytic Cocktail stat
Ca Polysterene Sulfonate powder
10g TDS
T. Multivitamin 1/1 OD
IV Metoclopramide 10mg

Fever

Phosphate binder
Supplement for
Calcium absorbtion

Hypokalaemia

30/11

5/12-28/12
28/12-cont

5/12-27/12
28/12-cont
7/12-10/12, 18/12-22/22
20/12

Hyperkalaemia

Supplement
Vomiting

24/12-26/12
9/12-cont
9/12-10/12

MEDICATIONS - OTHERS
DRUGS
T. Prazocin 1mg OD
S/C Heparin 5000iu BD

INDICATIONS
High Blood Pressure

T. Warfarin 4.5mg OD
T. Warfarin 3mg OD

9/12-18/12
7/12-8/12

S/C Enoxaparin 20mg stat & OD

T. Warfarin 5mg OD

DURATION

DVT treatment and

prophylaxis

8/12-16/12
9/12-13/12
20/12-23/12

28/12-31/12

04-Jan

03-Jan

02-Jan

01-Jan

31-Dis

30-Dis

29-Dis

28-Dis

27-Dis

26-Dis

25-Dis

24-Dis

23-Dis

22-Dis

21-Dis

20-Dis

19-Dis

18-Dis

17-Dis

16-Dis

15-Dis

14-Dis

13-Dis

12-Dis

11-Dis

10-Dis

09-Dis

08-Dis

BP (mmHg)
200

07-Dis

06-Dis

05-Dis

04-Dis

03-Dis

02-Dis

01-Dis

30-Nov

HR (beats/min)

VITAL SIGNS

T. Prazocin OD

180

160

140

120
BP
systolic

100

80
BP
diastolic

60

40

20
140

130

120

110

100

90
HR

80

70

60

Vanco

Linez

Aza

Rifam

11111

1
1
1
1

2222021211122122
1111111111

04-Jan

03-Jan

02-Jan

01-Jan

31-Dis

30-Dis

29-Dis

28-Dis

27-Dis

26-Dis

25-Dis

24-Dis

23-Dis

22-Dis

21-Dis

20-Dis

19-Dis

18-Dis

17-Dis

16-Dis

15-Dis

14-Dis

13-Dis

12-Dis

11-Dis

10-Dis

09-Dis

08-Dis

07-Dis

06-Dis

05-Dis

04-Dis

03-Dis

02-Dis

01-Dis

30-Nov

Temperature oC

VITAL SIGNS

39.5

39

38.5

38

37.5

37

36.5

BLOOD CULTURE & SENSITIVITY

Date

Samples

Organism Sensitive

Resistant

14/9

Blood-peripheral, MRSA
Central

NIL

Ciprofloxacin, Gentamicin, PenG,

Cloxacillin, Rifampicin, Cotrimaxazole, EES, Fusidic acid

18/9

Blood-peripheral, MRSA
Central

NIL

NIL

25/9

Blood-peripheral, MRSA
Central

NIL

NIL

27/9

Blood-peripheral, MRSA
Central

Vancomycin

NIL

3/10

Blood-peripheral, MRSA
Central

NIL

Cloxacillin, EES, Bactrim, PenG, Fusidic

Acid.

10/10 Blood (on

Vancomycin)

MRSA,
MIC=1

NIL

NIL

17/10 Blood (on

Teicoplanin)

MRSA

Teicoplanin
Linezolid

Ciprofloxacin, Cloxacillin, Bactrim, EES,

Fusidic acid, Genta, PenG, Rifampicin

BLOOD CULTURE & SENSITIVITY

Date

Samples

Organism Sensitive

Resistant

20/10 Blood-Peripheral

MRSA

NIL

NIL

26/10 Blood-Peripheral

MRSA,
mixed

NIL

NIL

10/11 Blood

MRSA,
VISA

Teicoplanin,
Linezolid

NIL

15/11 Blood

MRSA,
VISA

Teicoplanin,
Linezolid

NIL

20/11

Blood

MRSA,
VISA

NIL

NIL

23/11

Blood-central,
Peripheral

MRSA,
VISA,
MIC = 3

NIL

NIL

30/11

Blood peripheral

P.Aerogino Amikacin, Fortum,

sa
Genta, Tazocin,
Ciprofloxacin

Cloxacillin, EES, Fusidic acid, PenG,

Bactrim

BLOOD CULTURE & SENSITIVITY

Date

Samples

Organism Sensitive

Resistant

8/12

Blood-peripheral, SFNG
Central

NIL

NIL

16/12 Blood-peripheral, SFNG

Central

NIL

NIL

20/12 Blood-peripheral, SFNG

Central

NIL

NIL

05-Jan

04-Jan

4.06

03-Jan

ANC: 1.49 x 109

cells/L
(MILD NEUTROPENIA)

02-Jan

3.49

01-Jan

4.09

31-Dis

3.05

30-Dis

4.23

29-Dis

3.6

28-Dis

27-Dis

26-Dis

3.62

25-Dis

7.89

24-Dis

10

23-Dis

3.85

22-Dis

4.29

21-Dis

20-Dis

5.62

19-Dis

18-Dis

3.42

17-Dis

3.42

16-Dis

3.66

15-Dis

14-Dis

4.26

13-Dis

12-Dis

11-Dis

10-Dis

6.67

09-Dis

7.58

08-Dis

07-Dis

06-Dis

05-Dis

04-Dis

03-Dis

02-Dis

01-Dis

30-Nov

Cell count (x 10^9 cell/mL)

LAB RESULT - WBC

14
12.83

12

ANC: 5.72 x 109 cells/L

8.95

7.05
6.73

5.22
4.92

3.97

2.72
2.48

ANC: 1.69 x 109 cells/L

5.2

05-Jan

6.1

04-Jan

03-Jan

02-Jan

6.4

01-Jan

31-Dis

30-Dis

7.1

29-Dis

28-Dis

27-Dis

26-Dis

6.8

25-Dis

24-Dis

23-Dis

7.5

22-Dis

8.0

21-Dis

20-Dis

19-Dis

8.2

18-Dis

9.0

17-Dis

10

16-Dis

4.0

15-Dis

8.0

14-Dis

13-Dis

12-Dis

11-Dis

8.3

10-Dis

9.1

09-Dis

7.0

08-Dis

07-Dis

06-Dis

7.3

05-Dis

04-Dis

03-Dis

02-Dis

01-Dis

30-Nov

g/100mL

HAEMATOLOGICAL- Hb

12

10.0

9.4

8.5
7.9

6.8
6.9
6.3

6.7
5.8
5.3

4.7

Anemia

(Normal range: 11.5-16.5g/dL)

342

05-Jan

440

04-Jan

370

03-Jan

375

02-Jan

450

01-Jan

376

31-Dis

344

30-Dis

29-Dis

28-Dis

27-Dis

26-Dis

229

25-Dis

248

24-Dis

23-Dis

250

22-Dis

335

21-Dis

358

20-Dis

19-Dis

326

18-Dis

247

17-Dis

250

16-Dis

272

15-Dis

14-Dis

282

13-Dis

100

12-Dis

288

11-Dis

319

10-Dis

09-Dis

350

08-Dis

07-Dis

300

06-Dis

05-Dis

04-Dis

03-Dis

200

02-Dis

01-Dis

30-Nov

X 100/L

HAEMATOLOGICAL - PLATELET

500

427

400
384

342

315

260

290

239

201
181

150

No thrombocytopenia

50

COAGULATION - INR
4

3.5

3.47
3.26

3
2.55
2.5

2.47

INR

2.41
2.10
2

1.5

1.80
1.46
1.13

0.5

1.11

1.50

1.53

1.17

1.29

1.14
1.01

T. Warfarin 5mg OD

1.40
1.15

1.15
1.09

1.05

T. Warfarin 4.5mg OD

1.13

T. Warfarin 3mg OD

COAGULATION PT/aPTT
120

105
100

86.7

81.3

80
71.5
68.7
66.7
60

65.2

54.7

52.8

53.2

48.9

42
40
40.7

17.6

Enoxaparin

23.5

34.9

20.8

39.6

44.5
27.4
33.2
26.7

20
14.2 14.4

14.6

14.8
16

14.6

14.5

13.6

13.2

17.1

18

26.2

18.3

Heparin

PT

45.6

47.2

42.3
38.6

aPTT

56.6

50.3

14.4

14

aPTT: 30s 45.8s

aPTT control : 37.9s

PT: 12.6s 15.7s

02-Jan

01-Jan

31-Dis

30-Dis

29-Dis

28-Dis

27-Dis

26-Dis

25-Dis

24-Dis

23-Dis

22-Dis

21-Dis

20-Dis

19-Dis

18-Dis

17-Dis

16-Dis

15-Dis

14-Dis

13-Dis

12-Dis

11-Dis

10-Dis

09-Dis

08-Dis

07-Dis

06-Dis

05-Dis

04-Dis

03-Dis

02-Dis

01-Dis

30-Nov

K+: 3.5-4.5mmol/L
Ca2+: 2.1-2.6mmol/L
PO4-: 0.8-1.4mmol/L
03-Jan

02-Jan

01-Jan

31-Dis

30-Dis

29-Dis

28-Dis

27-Dis

26-Dis

25-Dis

24-Dis

Lytic
cocktail

23-Dis

22-Dis

21-Dis

20-Dis

19-Dis

Tab KCL

18-Dis

17-Dis

16-Dis

15-Dis

14-Dis

13-Dis

12-Dis

11-Dis

10-Dis

09-Dis

08-Dis

07-Dis

06-Dis

05-Dis

04-Dis

03-Dis

02-Dis

01-Dis

30-Nov

ELECTROLYTES K / Ca / PO
Ca Polysterene Sulphonate

Tab KCL

4
K

Ca

3
PO4

K+: 3.5-4.5mmol/L
Ca2+: 2.1-2.6mmol/L
PO4-: 0.8-1.4mmol/L
03-Jan

02-Jan

01-Jan

31-Dis

30-Dis

CaCO3 500mg BD
Vit D 0.25mcg OD

29-Dis

28-Dis

27-Dis

26-Dis

25-Dis

24-Dis

23-Dis

22-Dis

21-Dis

20-Dis

19-Dis

18-Dis

17-Dis

16-Dis

15-Dis

14-Dis

13-Dis

12-Dis

11-Dis

10-Dis

09-Dis

08-Dis

07-Dis

06-Dis

05-Dis

04-Dis

03-Dis

02-Dis

01-Dis

30-Nov

ELECTROLYTES K / Ca / PO

CaCO3 500mg TDS

Vit D 0.5mcg OD
K

Ca

3
PO4

CURRENT DIAGNOSIS (as of 4/1/2012)

Active Problem
Haemotypsis
VISA
Delirium d/t
Sepsis
Hypotension

Inactive Problem
ANCA (+ve)
vasculitis
ESRF

PHARMACEUTICAL CARE ISSUES

DISCUSSION

PHARMACEUTICAL CARE ISSUES

Leukopenia/neutropenia
Causes

?
Intervention ?
Outcomes ?

LEUKOPENIA - Causes

Possible causes of leukopenia

Disease
Sepsis

?
ANCA (+ve) vasculitis
Drugs

Possible drugs:
Azathioprine
Linezolid
Vancomycin
Rifampicin

LAB RESULT - WBC

14

12

Vancomycin
1g stat
(24/11)

12.83

T. Azathioprine 50mg OD
C. Rifampicin 600mg OD

7.89
8

7.58

8.95

7.05

6.67

6.73
6

5.62

5.22
4.29

4.26

3.66

3.62

3.42

3.42

4.92

4.09 4.06

4.23

3.85

3.05

3.97

3.49

3.6
2.72

Vancomycin
1g stat

2.48

Vancomycin
1g EOD

IV Linezolid 600mg BD

05-Jan

04-Jan

03-Jan

02-Jan

01-Jan

31-Dis

30-Dis

29-Dis

28-Dis

27-Dis

26-Dis

25-Dis

24-Dis

23-Dis

22-Dis

21-Dis

20-Dis

19-Dis

18-Dis

17-Dis

16-Dis

15-Dis

14-Dis

13-Dis

12-Dis

11-Dis

10-Dis

09-Dis

08-Dis

07-Dis

06-Dis

05-Dis

04-Dis

03-Dis

02-Dis

01-Dis

0
30-Nov

Cell count (x 10^9 cell/mL)

10

LAB RESULT - WBC

14

12

Vancomycin
1g stat
(24/11)

12.83

T. Azathioprine 50mg OD
C. Rifampicin 600mg OD

7.89
8

7.58

8.95

7.05

6.67

6.73
6

5.62

5.22
4.29

4.26

3.66

3.62

3.42

3.42

4.92

4.09 4.06

4.23

3.85

3.05

3.97

3.49

3.6
2.72

Vancomycin
1g stat

2.48

Vancomycin
1g EOD

IV Linezolid 600mg BD

IV Linezolid 600mg BD
05-Jan

04-Jan

03-Jan

02-Jan

01-Jan

31-Dis

30-Dis

29-Dis

28-Dis

27-Dis

26-Dis

25-Dis

24-Dis

23-Dis

22-Dis

21-Dis

20-Dis

19-Dis

18-Dis

17-Dis

16-Dis

15-Dis

14-Dis

13-Dis

12-Dis

11-Dis

10-Dis

09-Dis

08-Dis

07-Dis

06-Dis

05-Dis

04-Dis

03-Dis

02-Dis

01-Dis

0
30-Nov

Cell count (x 10^9 cell/mL)

10

NARANJO ADR PROBABILITY SCALE

Question

Yes No

Dont
know

Are there previous conclusive reports on this reaction?

+1

+1

+1

+1

+1

Did the adverse event appear after the suspected drug was
administered?

+2

-1

+2

+2

+2

+2

Did the adverse reaction improve when the drug was

discontinued, or a specific antagonists was administered?

+1

+1

+1

Did the adverse reaction reappear when the drug was

readministered?

+2

-1

+2

+2

+2

-1

Are there alternatives causes (other than the drug) that could
on their own have caused that reaction?

-1

+2

-1

-1

-1

-1

Did the reaction reappear when a placebo was given?

-1

+1

Was the drug detected in the blood (or other fluids) in

concentration known to be toxic?

+1

Was the reaction more severe when the dose was increased,
or less severe when the dose was decreased?

+1

+1

Did the patient have a similar reaction to the same or similar

drug in any previous reaction?

+1

Was the adverse event confirmed by any objective evidence?

+1

+1

+1

+1

+1

TOTAL
(<0 = doubtful, 1-4 = Possible 5-8 = Probable, >9 = Highly probable)

INCIDENCES
(LEUKOPENIA/NEUTROPENIA)
Micromedex12
Drugs
Linezolid

Lexi-comp13

Incidence

Onset

Recovery

Incidence

Onset

Recovery

1.1% (adult)

>14 days

Upon
Discont

1%-10%

>14 day

N/A

rare

>7 days
or total
dose
>25g

Promptly
reversed
when
discont

1%-10%

>7 days or
total dose
>25g

Promptly
reversed
when
discont

N/A

N/A

N/A

Not defined,
Dose related

N/A

N/A

Delay

reversed
discont or
reduce
dose

Not defined,
Dose related

Delay

N/A

Vancomycin

Rifampicin

Azathioprine
Dose
related

12) Micromedex Healthcare Series. 150 ed. US: Thomsom Reuther; 2011.
13) Lacy CF, Armstrong LL, Goldman MP, Lance LL. Drug information handbook with international trade names index. 19 th ed. Ohio: Lexi-Comp Inc.; 2010.

LINEZOLID

Target: Most Gram +ve bacteria14

Oxazolidinone derivatives15
Associated

with reversible Myelosuppresion14-16

Thrombocytopenia

(Most common), anemia, Leukopenia

Pancytopenia

Myelosuppresion

occurs:

course of treatment (~15days to 4 months)17

Pre-existing myelosuppression17
Receiving concomitant myelosuppresive drugs17
Long

14) Pfizer, Inc. Zyvox prescribing information. [Online] 2007 [cited on 2012 Jan];Available from: URL:www.zyvox.com/prescribingInfo.asp.
15) Moellering RC. Linezolid: the first oxazolidinone antimicrobial. Annals of Internal Medicine. 2003;138:13542.
16) Shaw KJ, Barbachyn MR. The oxazolidinones: past, present, and future. Annals of the New York Academy of Sciences.1241(1):48-70
17) Faguer S, Kamar N, Fillola G, Guitard J, Rostaing L. Linezolid-related pancytopenia in organ-transplant patients: Report of two cases. Infection. 2007;35:2757

LITERATURE REVIEW
STUDIES

YEARS STUDIES DESIGN OUTCOME

Faguer et al. 2007

Gorchynski et 2008
al.

Case Report

Case report of Linezolid-induced

pancytopenia in patient infected with
MRSA

Matsumoto et
al.

2010

PK study

Renal dysfunction increases linezolid

trough level and AUC. Higher drugexposure induces thrombocytopenia

Rao et al.

2004

Prospective,
Observational
study

Recent treatment with vancomycin

increased the risk (thrombocytopenia)
whose therapy was switched to linezolid
compare linezolid alone.

Soriano et al.

2007

Comparative
study

Haematological toxicity is directly related

to the degree of linezolid exposure

17) Faguer S, Kamar N, Fillola G, Guitard J, Rostaing L. Linezolid-related pancytopenia in organ-transplant patients: Report of two cases. Infection. 2007;35:2757
18) Gorchynski J, Rose J. Complications of MRSA treatment: Linezolid-induced myelosuppression Presenting with Pancytopenia. West J Emerg Med. 2008 August;9(3):1778
19) Matsumoto K, Takeshita A, Ikawa K, Shigemi A, Yaji K, Shimodozono Y, et al. Higher linezolid exposure and higher frequency of thrombocytopenia in patients with renal dysfunction. International Journal of Antimicrobial
Agents. 2010;36(2):179-81.
20) Rao N, Ziran BH, Wagener MM, Santa ER, Yu VL. Similar Hematologic Effects of Long-Term Linezolid and Vancomycin Therapy in a Prospective Observational Study of Patients with Orthopedic Infections. Clinical
Infectious Diseases. 2004 April 15, 2004;38(8):1058-64.
21) Soriano A, Ortega M, Garca S, Pearroja G, Bov A, Marcos M, et al. Comparative study of the effects of pyridoxine, rifampin, and renal function on hematological adverse events induced by linezolid. Antimicrob
Agents Chemother. 2007;51(7 ):2559-63

VANCOMYCIN

Glycopeptide antibiotic22
G+ve
Indication: MRSA (susceptible) infection.
Concentration-independent activity

Related Problems23:
Slow bactericidal activity
Resistant-development
Serious Toxicity

Ototoxicity
Nephrotoxicity
Neutropenia (rare)

22) Rybak MJ, Lomaestro BM, Rotschafer JC, Moellering RC, Craig WA, Billeter M, et al. Vancomycin therapeutic guidelines: a summary of consensus recommendations from the infectious diseases Society of America, the
American Society of Health-System Pharmacists, and the Society of Infectious Diseases Pharmacists. Clin Infect Dis. 2009;49(3):325-7.
23) Liu C, Bayer A, Cosgrove SE, Daum RS, Fridkin SK, et al. Clinical Practice Guidelines by the Infectious Diseases Society of America for the Treatment of Methicillin-Resistant StaphylococcusAureus Infections in Adults and
Children. [online] 2011 [cited 2012 Jan]; Available from: URL:http://cid.oxfordjournals.org/content/early/2011/01/04/cid.ciq146.full.pdf

LITERATURE REVIEW
STUDIES

YEARS STUDIES DESIGN OUTCOME

Black et al.

2011

Systematic
review

Vancomycin-induced neutropenia is most

likely associated with prolonged
vancomycin exposure (as early as > 7
days), not dose dependent.

Duff et al.

2011

Case Report

Delayed-neutropenia developed several

weeks after discontunation of prolong
course of vancomycin treatment.
Agranulocytosis was resulted due to
unintentional rechallenged.

SegarraNewnham et
al.

2004

Review/case
report

Prolong exposure leads to increase risk of

neutropenia. Mechanism most likely to be
immune-mediated. Reversible by
discontinuation.

24) Black E, Lau TTY, Ensom MHH. Vancomycin-induced neutropenia: Is it dose- or duration-related?. Ann Pharmacother 2011;45(5):629-38
25) Duff JM, Moreb JS, Muwalla F. Severe neutropenia following a prolonged course of vancomycin that progressed to agranulocytosis with drug reexposure (January). Ann Pharmacother [serial online] 2011 [cited 2012
Jan]; Available from: URL:http://www.ncbi.nlm.nih.gov/pubmed/22170976
26) Segarra-Newnham M, Tagoff SS. Probable vancomycin-induced neutropenia. Ann Pharmacother 2004;38:1855-9

13
AZATHIOPRINE

Immunosuppressant
Imidazolyl of mercaptopurine
Inhibit

synthesis of DNA, RNA & protein.

Interfere cellular metabolism and inhibit mitosis.

Adverse effect
Hepatotoxicity
Rash
Haematologic
Bleeding,

leukopenia, macrocytic anemia, thrombocytopenia,

pancytopenia

13) Lacy CF, Armstrong LL, Goldman MP, Lance LL. Drug information handbook with international trade names index. 19 th ed. Ohio: Lexi-Comp Inc.; 2010.

LITERATURE REVIEW
STUDIES

YEARS STUDIES DESIGN OUTCOME

Gisbert et al.

2008

Systematic
review, metaanalysis

The incidence rate (per patient and year

of treatment) of the drug-induced
myelotoxicity was 3% in IBD patient. Bone
marrow toxicity occur more frequently
during first month.

Higgs et al.

2010

Systematic
review, metaanalysis

Individuals with both intermediate and

absent Thiopurine-S-methyltransferase
activity have an increased risk of
developing thiopurine-induced
myelosuppression compared with
individuals with normal activity.

Hadda et al.

2009

Case Report

Azathioprine-induced pancytopenia was

suspected in patient treated for lupus
nephritis.

24) Gisbert JP, Gomolln F. Thiopurine-induced myelotoxicity in patients with inflammatory bowel disease: a review. Am J Gastroenterol. 2008;103(7):1783-800
25) Higgs JE, Payne K, Roberts C, Newman WG. Are patients with intermediate TPMT activity at increased risk of myelosuppression when taking thiopurine medications? Pharmacogenomics 2010;11:177-88
26) Hadda V, Pandey BD, Gupta R, Goel A. Azathioprine induced pancytopenia: A serious complication. J Postgrad Med [serial online] 2009 [cited 2012 Jan 9];55:139-40. Available from:
URL:http://www.jpgmonline.com/text.asp?2009/55/2/139/52849

MOST PROBABLE ?

By Naranjo Score:
Vancomycin

--- Azathioprine --- Linezolid

By TWBC Drug trend

Azathioprine

--- Vancomycin --- Linezolid

By Incidence / Onset / Recovery

Azathioprine

--- Linezolid --- Vancomycin

13,14
MANAGEMENT

To stop offending drugs

Administer G-CSF (if severe)
Close Monitor:

FBC
Coagulation Profile
S/S of infection

Temperature, Blood pressure, HR

To identify risk factors (prior myelosuppression,

concommitant myelosuppressive / leukopenic drugs) before
initiating treatments. To use in caution in case of concomittant
administration of myelosuppresive drugs. Discontinuation if
myelosuppresion / worsening of myelosuppresion occurs.

Linezolid

13) Micromedex Healthcare Series. 150 ed. US: Thomsom Reuther; 2011
14) Lacy CF, Armstrong LL, Goldman MP, Lance LL. Drug information handbook with international trade names index. 19 th ed. Ohio: Lexi-Comp Inc.; 2010.

CONCLUSION

A case on probable drug-related adverse reaction was

presented.
Involves multiple drugs of probable haematological toxicity
Concomittant / Follow-by multiple drugs administration
results in difficulties in identifying responsible drug.

Probable drugs responsible for leukopenia:

Azathioprine, Vancomycin, Linezolid

Complicated by underlying disease (ANCA vasculitis on

steroid and immunosuppresant)
ADR cases should be highlighted to provide better
information and precaution to other healthcare
providers.