DRUG-INDUCED LEUKOPENIA

kck.usm.my

DRUG-INDUCED LEUKOPENIA

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 worldwide 2

• Most common cause of iatrogenic illness. 3

• Accounts for approximately 10% of the hospital admission

in some countries. 4

1) Requirements for adverse reaction reporting. Geneva, Switzerland: World Health Organization; 1975

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

3) Ditto AM. Drug allergy. In: Grammer LC, Greenberger PA, eds. Patterson's Allergic diseases. 6th ed. Philadelphia: Lippincott Williams & Wilkins, 2002:295.

4) 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 Reaction 2

Non-Immunologic

Immunolgic

Predictable

Pharmacologic side

effect

Secondary

pharmacologic side

effect

Drug toxicity

Drug-drug

interaction

Drug Overdose

Unpredictable

Pseudoallergic

Idiosynchratic

Intolerance

Unpredictable

(I) IGE-mediated

(II) Cytotoxic

(III) Immune-complex

(IV) Delayed, cell

mediated

Specific T-cell

activation

Fas/Fas ligandinduced

apoptosis

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


INTRODUCTION

Leukopenia

Definition:

• A reduction of the circulating WBC count to less than

4000/µl 5 (


INTRODUCTION

Drug-induced Leukopenia/Neutropenia 9

Occurs with various drugs

Mechanism 10

• Immune-mediated

• Hapten (Penicillin-group)

• Apoptosis (Clozapine)

• Immune complex

• Complement-mediated mechanism (PTU)

• Dose-dependent-inhibition of granulopoiesis

• Β-lactams antibiotics, Carbamazepine, Valproic acid

• Direct 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

(µg/mL)

VSSA VISA VRSA

16

VISA development -- Prolong Vancomycin exposure 11

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 to ANCA vasculitis

Right Lower Limb DVT

• On T. Warfarin 3mg OD

Recurrent MRSA infection

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

Anemia

Hypertension?


PAST MEDICATION HISTORY

DRUGS

T. Prednisolone 35mg OD

T. Azathioprine 50mg OD

INDICATION

ANCA vasculitis

T. Warfarin 3mg OD DVT prophylaxis

T. Felodipine 10mg OD

T. Prazocin 1mg BD

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

Anemia

T. Folate 5mg OD


SOCIAL HISTORY

Non Smoker

Non Alcohol drinker


SYSTEM REVIEW (ON ARRIVAL)

BP

HR

T

CVS

Lungs

132/82 mmHg

111 beats/min

37 o C

DRNM, JVP equal

Coarse Crepts, up to Midzone bilaterally

Per-Abdominal Soft non-tender

Non-organomegally

CXR

Others

Patchy opasity @ bilateral lower zone

Minimal Pleural Effusion

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

6/12

8/12

• 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

• 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 (5mg—4.5mg—

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


PROGRESS

9/12

• High BP (191/99mmHg) – restart prazocin

13/12

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

• KIV MMF.

18/12

• Hypotension (103/64 mmHg) – withold Prazocin

19/12

• Hypotension,

• Completed linezolid. Vancomycin and rifampicin combination was

started (VISA treatment)


PROGRESS

23/12

24/12

25/12

28/12

• 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.

• Respiratory failure (I) precipated by fluid overload and anemia.

• Oral candiasis – Syr Nystatin was given

• Hyperkalaemia (6.6mmol/L) – Lytic cocktail stat.

• Condition improving

• Reducing trend of TWBC – Drug related ? (Vancomycin / Linezolid /

Rifampicin / Azathioprine)

• Off Vancomycin and rifampicin, restart linezolid.


PROGRESS

1/1

3/1

• Condition improving, comfortable

• Blocked permanent cathether, not agree for IVL – Off linezolid,

change to C. Rifampicin and T. Fusidic acid.

• 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 2 o 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 MRSA infection 24/11, 3/12

T. Azithromycin 500mg stat & OD 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

ANCA +ve Vasculitis

T. Prednisolone 35mg OD 15/12-2/1

T. Azathioprine 50mg OD 30/11, 9/12-13/12

IV Pantoprazole 40mg stat & BD

30/11-30/12

Gastric Pain

T. Pantoprazole 40mg BD 31/12-cont

Ravin Enema 1/1 stat & PRN Constipation 30/11, 28/12

T. Bromhexine 8mg stat & TDS Cough with sputum 1/12-14/12

C. Tramadol 50mg stat & PRN

1/12, 4/12, 8/12

Pain

C. Tramadol 50mg TDS 9/12-21/12, 25/12-cont

T. Vitamin B complex 1/1 OD

1/12-cont

T. Folic acid 1/1 OD Anemia 1/12-cont

T. Ferrous Fumarate 400mg TDS 30/11-cont


MEDICATIONS - OTHERS

DRUGS INDICATIONS DURATION

T. Paracetamol 1g stat Fever 30/11

Thymol gargle LA Oral Pain 2/12-cont

T. Escitalopram 10mg OD Depression 4/12-10/12

T. Calcium Carbonate 500mg BD

5/12-28/12

Phosphate binder

T. Calcium Carbonate 500mg TDS 28/12-cont

T. Rocaltriol 0.25mg OD

Supplement for 5/12-27/12

T. Rocaltriol 0.5mg OD Calcium absorbtion 28/12-cont

T. Potassium Chloride 1200mg BD x

3/7

Hypokalaemia

7/12-10/12, 18/12-22/22

Lytic Cocktail stat

20/12

Ca Polysterene Sulfonate powder Hyperkalaemia

24/12-26/12

10g TDS

T. Multivitamin 1/1 OD Supplement 9/12-cont

IV Metoclopramide 10mg Vomiting 9/12-10/12


MEDICATIONS - OTHERS

DRUGS INDICATIONS DURATION

T. Prazocin 1mg OD High Blood Pressure 9/12-18/12

S/C Heparin 5000iu BD

7/12-8/12

S/C Enoxaparin 20mg stat & OD 8/12-16/12

T. Warfarin 5mg OD DVT treatment and

9/12-13/12

prophylaxis

T. Warfarin 4.5mg OD 20/12-23/12

T. Warfarin 3mg OD 28/12-31/12


20

40

60

80

100

120

140

160

180

200

BP (mmHg)

BP

systolic

BP

diastolic

60

70

80

90

100

110

120

130

140

30-Nov

01-Dis

02-Dis

03-Dis

04-Dis

05-Dis

06-Dis

07-Dis

08-Dis

09-Dis

10-Dis

11-Dis

12-Dis

13-Dis

14-Dis

15-Dis

16-Dis

17-Dis

18-Dis

19-Dis

20-Dis

21-Dis

22-Dis

23-Dis

24-Dis

25-Dis

26-Dis

27-Dis

28-Dis

29-Dis

30-Dis

31-Dis

01-Jan

02-Jan

03-Jan

04-Jan

HR (beats/min)

HR

VITAL SIGNS

T. Prazocin OD


Temperature o C

30-Nov

01-Dis

02-Dis

03-Dis

04-Dis

05-Dis

06-Dis

07-Dis

08-Dis

09-Dis

10-Dis

VITAL SIGNS

11-Dis

12-Dis

13-Dis

14-Dis

15-Dis

16-Dis

17-Dis

18-Dis

19-Dis

20-Dis

21-Dis

22-Dis

23-Dis

24-Dis

25-Dis

26-Dis

27-Dis

28-Dis

29-Dis

30-Dis

31-Dis

01-Jan

02-Jan

03-Jan

04-Jan

39.5

39

38.5

38

37.5

37

36.5

Vanco 1 1 1 1

Linez 2 2 2 2 0 2 1 2 1 1 1 2 2 1 2 2

Rifam 1 1 1 1 1 1 1 1 1 1

Aza 1 1 1 1 1


BLOOD CULTURE & SENSITIVITY

Date Samples Organism Sensitive Resistant

14/9 Blood-peripheral,

Central

18/9 Blood-peripheral,

Central

25/9 Blood-peripheral,

Central

27/9 Blood-peripheral,

Central

3/10 Blood-peripheral,

Central

10/10 Blood (on

Vancomycin)

17/10 Blood (on

Teicoplanin)

MRSA NIL Ciprofloxacin, Gentamicin, PenG,

Cloxacillin, Rifampicin, Cotrimaxazole,

EES, Fusidic acid

MRSA NIL NIL

MRSA NIL NIL

MRSA Vancomycin NIL

MRSA NIL Cloxacillin, EES, Bactrim, PenG, Fusidic

Acid.

MRSA,

MIC=1

MRSA

NIL

Teicoplanin

Linezolid

NIL

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

10/11 Blood MRSA,

VISA

15/11 Blood MRSA,

VISA

20/11 Blood MRSA,

VISA

23/11 Blood-central,

Peripheral

MRSA,

VISA,

MIC = 3

30/11 Blood peripheral P.Aerogino

sa

NIL

Teicoplanin,

Linezolid

Teicoplanin,

Linezolid

NIL

NIL

Amikacin, Fortum,

Genta, Tazocin,

Ciprofloxacin

NIL

NIL

NIL

NIL

NIL

Cloxacillin, EES, Fusidic acid, PenG,

Bactrim


BLOOD CULTURE & SENSITIVITY

Date Samples Organism Sensitive Resistant

8/12 Blood-peripheral,

Central

16/12 Blood-peripheral,

Central

20/12 Blood-peripheral,

Central

SFNG NIL NIL

SFNG NIL NIL

SFNG NIL NIL


Cell count (x 10^9 cell/mL)

30-Nov

01-Dis

02-Dis

03-Dis

04-Dis

05-Dis

06-Dis

07-Dis

08-Dis

09-Dis

10-Dis

11-Dis

12-Dis

13-Dis

14-Dis

15-Dis

16-Dis

17-Dis

18-Dis

19-Dis

20-Dis

21-Dis

22-Dis

23-Dis

24-Dis

25-Dis

26-Dis

27-Dis

28-Dis

29-Dis

30-Dis

31-Dis

01-Jan

02-Jan

03-Jan

04-Jan

05-Jan

LAB RESULT - WBC

14

12.83

12

10

8

6.67

ANC: 5.72 x 10 9 cells/L

7.89

7.58

7.05

6.73

ANC: 1.49 x 10 9

cells/L

(MILD NEUTROPENIA)

8.95

6

5.62

5.22

4

2

4.26

3.42

3.66

3.42

3.85

4.29

3.62

4.23

3.6

3.05

2.72

4.09 4.06 4.92

3.49

3.97

2.48

ANC: 1.69 x 10 9 cells/L

0


HAEMATOLOGICAL- Hb

4.0

9.1

7.3

7.0

8.3

8.2

9.0

8.0

8.5

8.0

7.1

7.5

9.4

10.0

7.9

6.8

6.7

6.8

5.8

4.7

6.4

6.9

5.2

6.1

6.3

5.3

0

2

4

6

8

10

12

30-Nov

01-Dis

02-Dis

03-Dis

04-Dis

05-Dis

06-Dis

07-Dis

08-Dis

09-Dis

10-Dis

11-Dis

12-Dis

13-Dis

14-Dis

15-Dis

16-Dis

17-Dis

18-Dis

19-Dis

20-Dis

21-Dis

22-Dis

23-Dis

24-Dis

25-Dis

26-Dis

27-Dis

28-Dis

29-Dis

30-Dis

31-Dis

01-Jan

02-Jan

03-Jan

04-Jan

05-Jan

g/100mL

Anemia

(Normal range: 11.5-16.5g/dL)


HAEMATOLOGICAL - PLATELET

319

201

181

288

358

376

326

282 272

247

260

250

335

344

248

229 239 315

290

342

375

440

370

384

427

342

0

50

100

150

200

250

300

350

400

450

500

30-Nov

01-Dis

02-Dis

03-Dis

04-Dis

05-Dis

06-Dis

07-Dis

08-Dis

09-Dis

10-Dis

11-Dis

12-Dis

13-Dis

14-Dis

15-Dis

16-Dis

17-Dis

18-Dis

19-Dis

20-Dis

21-Dis

22-Dis

23-Dis

24-Dis

25-Dis

26-Dis

27-Dis

28-Dis

29-Dis

30-Dis

31-Dis

01-Jan

02-Jan

03-Jan

04-Jan

05-Jan

X 100/L

No thrombocytopenia


INR

COAGULATION - INR

4

3.5

3.47

3.26

3

2.5

2

2.10

1.80

2.47

2.41

2.55

1.5

1.46

1.53

1.50

1.40

1

1.11

1.13

1.01 1.05

1.29

1.17

1.15

1.14 1.15

1.09

1.13

0.5

T. Warfarin 5mg OD T. Warfarin 4.5mg OD T. Warfarin 3mg OD

0


30-Nov

01-Dis

02-Dis

03-Dis

04-Dis

05-Dis

06-Dis

07-Dis

08-Dis

09-Dis

10-Dis

11-Dis

aPTT: 30s – 45.8s aPTT control : 37.9s PT: 12.6s – 15.7s

12-Dis

13-Dis

14-Dis

15-Dis

16-Dis

17-Dis

18-Dis

19-Dis

20-Dis

21-Dis

22-Dis

23-Dis

24-Dis

25-Dis

26-Dis

27-Dis

28-Dis

29-Dis

30-Dis

31-Dis

01-Jan

02-Jan

COAGULATION – PT/aPTT

120

100

105

80

86.7

71.5

81.3

60

52.8

50.3

42

54.7

48.9

68.7

66.7

65.2

47.2

53.2

56.6

45.6

aPTT

PT

40

20

34.9

23.5

20.8

Heparin

42.3

38.6 40.7

17.6

Enoxaparin

14.2 14.4

13.6

13.2

26.7

18.3

33.2

26.2

27.4

16

44.5

18

14.8 14.6

14.5 14.6 14

17.1

39.6

14.4

0


30-Nov

01-Dis

02-Dis

03-Dis

04-Dis

05-Dis

06-Dis

07-Dis

08-Dis

09-Dis

10-Dis

11-Dis

12-Dis

13-Dis

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

14-Dis

15-Dis

16-Dis

17-Dis

18-Dis

19-Dis

20-Dis

21-Dis

22-Dis

23-Dis

24-Dis

25-Dis

26-Dis

27-Dis

28-Dis

29-Dis

30-Dis

31-Dis

01-Jan

02-Jan

03-Jan

ELECTROLYTES – K / Ca / PO

8

7

Tab KCL

Lytic

cocktail

Ca Polysterene Sulphonate

6

5

Tab KCL

4

3

K

Ca

PO4

2

1

0


30-Nov

01-Dis

02-Dis

03-Dis

04-Dis

05-Dis

06-Dis

07-Dis

08-Dis

09-Dis

10-Dis

11-Dis

12-Dis

13-Dis

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

14-Dis

15-Dis

16-Dis

17-Dis

18-Dis

19-Dis

20-Dis

21-Dis

22-Dis

23-Dis

24-Dis

25-Dis

26-Dis

27-Dis

28-Dis

29-Dis

30-Dis

31-Dis

01-Jan

02-Jan

03-Jan

ELECTROLYTES – K / Ca / PO

8

7

6

5

4

3

CaCO3 500mg BD

Vit D 0.25mcg OD

CaCO3 500mg TDS

Vit D 0.5mcg OD

K

Ca

PO4

2

1

0


CURRENT DIAGNOSIS (as of 4/1/2012)

Active Problem

Inactive Problem

Haemotypsis

VISA

Delirium d/t

Sepsis

Hypotension

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


30-Nov

01-Dis

02-Dis

03-Dis

04-Dis

05-Dis

06-Dis

07-Dis

08-Dis

09-Dis

10-Dis

11-Dis

12-Dis

13-Dis

14-Dis

15-Dis

16-Dis

17-Dis

18-Dis

19-Dis

20-Dis

21-Dis

22-Dis

23-Dis

24-Dis

25-Dis

26-Dis

27-Dis

28-Dis

29-Dis

30-Dis

31-Dis

01-Jan

02-Jan

03-Jan

04-Jan

05-Jan

Cell count (x 10^9 cell/mL)

LAB RESULT - WBC

14

12

Vancomycin

1g stat

(24/11)

12.83

10

T. Azathioprine 50mg OD

8

6.67

7.58

7.89

7.05

6.73

C. Rifampicin 600mg OD

8.95

6

4

2

4.26

3.42

Vancomycin

1g stat

5.62

3.66 3.85

3.42

IV Linezolid 600mg BD

4.29

3.62

5.22

4.23

3.6

3.05

Vancomycin

1g EOD

2.72

3.49

2.48

4.09 4.06

3.97

4.92

0


30-Nov

01-Dis

02-Dis

03-Dis

04-Dis

05-Dis

06-Dis

07-Dis

08-Dis

09-Dis

10-Dis

11-Dis

12-Dis

13-Dis

14-Dis

15-Dis

16-Dis

17-Dis

18-Dis

19-Dis

20-Dis

21-Dis

22-Dis

23-Dis

24-Dis

25-Dis

26-Dis

27-Dis

28-Dis

29-Dis

30-Dis

31-Dis

01-Jan

02-Jan

03-Jan

04-Jan

05-Jan

Cell count (x 10^9 cell/mL)

LAB RESULT - WBC

14

12

Vancomycin

1g stat

(24/11)

12.83

10

T. Azathioprine 50mg OD

8

6.67

7.58

7.89

7.05

6.73

C. Rifampicin 600mg OD

8.95

6

4

2

4.26

3.42

Vancomycin

1g stat

5.62

3.66 3.85

3.42

IV Linezolid 600mg BD

4.29

3.62

5.22

4.23

3.6

3.05

Vancomycin

1g EOD

2.72

3.49

2.48

4.09 4.06 4.92

3.97

IV Linezolid 600mg BD

0


NARANJO ADR PROBABILITY SCALE

Question

Yes No

Don’t

know

V L A R

Are there previous conclusive reports on this reaction? +1 0 0 +1 +1 +1 +1

Did the adverse event appear after the suspected drug was

administered?

Did the adverse reaction improve when the drug was

discontinued, or a specific antagonists was administered?

Did the adverse reaction reappear when the drug was

readministered?

Are there alternatives causes (other than the drug) that could

on their own have caused that reaction?

+2 -1 0 +2 +2 +2 +2

+1 0 0 +1 0 +1 0

+2 -1 0 +2 +2 +2 -1

-1 +2 0 -1 -1 -1 -1

Did the reaction reappear when a placebo was given? -1 +1 0 0 0 0 0

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

concentration known to be toxic?

Was the reaction more severe when the dose was increased,

or less severe when the dose was decreased?

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

drug in any previous reaction?

+1 0 0 0 0 0 0

+1 0 0 +1 0 0 0

+1 0 0 0 0 0 0

Was the adverse event confirmed by any objective evidence? +1 0 0 +1 +1 +1 +1

TOTAL

(9 = Highly probable)

7 5 6 2


INCIDENCES

(LEUKOPENIA/NEUTROPENIA)

Drugs

Micromedex 12 Lexi-comp 13

Incidence Onset Recovery Incidence Onset Recovery

Linezolid

Vancomycin

Rifampicin

1.1% (adult) >14 days

rare

>7 days

or total

dose

>25g

Upon

Discont’

Promptly

reversed

when

discont’

N/A N/A N/A

1%-10% >14 day N/A

1%-10%

Not defined,

Dose related

>7 days or

total dose

>25g

N/A

Promptly

reversed

when

discont’

N/A

Azathioprine

Dose

related

Delay

reversed

discont’ or

reduce

dose

Not defined,

Dose related

Delay

N/A

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 bacteria 14

Oxazolidinone derivatives 15

Associated with reversible Myelosuppresion 14-16

• Thrombocytopenia (Most common), anemia, Leukopenia

• Pancytopenia

Myelosuppresion occurs:

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

• Pre-existing myelosuppression 17

• Receiving concomitant myelosuppresive drugs 17

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;138:135–42.

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;35:275–7


LITERATURE REVIEW

STUDIES

Faguer et al.

Gorchynski et

al.

Matsumoto et

al.

YEARS STUDIES DESIGN OUTCOME

2007

2008

Case Report

Case report of Linezolid-induced

pancytopenia in patient infected with

MRSA

2010 PK study Renal dysfunction increases linezolid

trough level and AUC. Higher drugexposure

induces thrombocytopenia

Rao et al. 2004 Prospective,

Observational

study

Soriano et al. 2007 Comparative

study

Recent treatment with vancomycin

increased the risk (thrombocytopenia)

whose therapy was switched to linezolid

compare linezolid alone.

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;35:275–7

18) Gorchynski J, Rose J. Complications of MRSA treatment: Linezolid-induced myelosuppression Presenting with Pancytopenia. West J Emerg Med. 2008 August;9(3):177–8

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, García S, Peñarroja G, Bové 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 antibiotic 22

G+ve

Indication: MRSA (susceptible) infection.

Concentration-independent activity

Related Problems 23 :

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.

Segarra-

Newnham 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


AZATHIOPRINE 13

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

Higgs et al. 2010 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.

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, Gomollón 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


MANAGEMENT 13,14




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.

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