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
 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 Reaction2
Non-Immunologic Immunolgic
Predictable Unpredictable Unpredictable

Pharmacologic side Pseudoallergic (I) IGE-mediated

effect Idiosynchratic (II) Cytotoxic
Secondary Intolerance (III) Immune-complex
pharmacologic side
effect (IV) Delayed, cell
Drug toxicity mediated
Drug-drug Specific T-cell
interaction activation
Drug Overdose Fas/Fas ligand-
induced 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/µl5 (<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
 Occurswith various drugs
 Mechanism10
 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
VSSA VISA VRSA
(µg/mL)
<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 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 INDICATION
T. Prednisolone 35mg OD
ANCA vasculitis
T. Azathioprine 50mg OD
T. Warfarin 3mg OD DVT prophylaxis
T. Felodipine 10mg OD
Hypertension?
T. Prazocin 1mg BD
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 132/82 mmHg
HR 111 beats/min
T 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
• No evidence of atypical pneumonia – Off Azithromycin, start
Meropenem.
1/12 • ESRF, fluid overload – restrict fluid 1-1.5L/d, strict I/O chart.

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

• Mild depression – started Escitalopram, but discontinue on 10/12 due
4/12 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
6/12 (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 <4 x 106/L
8/12 • Back pain – Tramadol was given.
PROGRESS

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

9/12

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

• KIV MMF.
13/12

• Hypotension (103/64 mmHg) – withold Prazocin

18/12

• Hypotension,
• Completed linezolid. Vancomycin and rifampicin combination was
19/12 started (VISA treatment)
PROGRESS
• Haemotypsis and bruises (INR 2.55, aPTT 71.5s)– Warfarin withold, 6
unit FFP was transfused, target INR 1.5-2
23/12

• 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
• Condition improving, comfortable
• Blocked permanent cathether, not agree for IVL – Off linezolid,
1/1 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
3/1 Ceftazidime

• Conscious, restlessness, talking incoherently

• Diagnosis: HAP with sepsis, Hypotension, delirium 2o sepsis
4/1 • 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 7/12-10/12, 18/12-22/22
Hypokalaemia
3/7
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
 HR (beats/min) BP (mmHg)

60
70
80
90
100
110
120
130
140
20
40
60
80
120
140
160
180
200

100
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
T. Prazocin OD

13-Dis
14-Dis
15-Dis
16-Dis
17-Dis
18-Dis
19-Dis
20-Dis
21-Dis
22-Dis
23-Dis
VITAL SIGNS

24-Dis
25-Dis
26-Dis
27-Dis
28-Dis
29-Dis
30-Dis
31-Dis
01-Jan
02-Jan
03-Jan
04-Jan
BP
BP
systolic

HR
diastolic
Aza
Linez
Rifam
Temperature oC

Vanco
36.5
37.5
38.5
39.5

37
39

38
30-Nov
01-Dis
02-Dis
03-Dis

1
04-Dis
05-Dis
06-Dis
07-Dis
08-Dis
09-Dis
10-Dis
11-Dis
12-Dis
13-Dis

11111
14-Dis
15-Dis
16-Dis
17-Dis
18-Dis
19-Dis
2222021211122122

20-Dis
1

21-Dis
VITAL SIGNS

22-Dis
1

23-Dis
24-Dis
25-Dis
26-Dis
27-Dis
1

28-Dis
29-Dis
1111111111

30-Dis
31-Dis
01-Jan
02-Jan
03-Jan
04-Jan
 BLOOD CULTURE & SENSITIVITY
Date Samples Organism Sensitive Resistant
14/9 Blood-peripheral, MRSA NIL Ciprofloxacin, Gentamicin, PenG,
Central Cloxacillin, Rifampicin, Co-
trimaxazole, EES, Fusidic acid
18/9 Blood-peripheral, MRSA NIL NIL
Central
25/9 Blood-peripheral, MRSA NIL NIL
Central
27/9 Blood-peripheral, MRSA Vancomycin NIL
Central
3/10 Blood-peripheral, MRSA NIL Cloxacillin, EES, Bactrim, PenG, Fusidic
Central Acid.
10/10 Blood (on MRSA, NIL NIL
Vancomycin) MIC=1
17/10 Blood (on MRSA Teicoplanin Ciprofloxacin, Cloxacillin, Bactrim, EES,
Teicoplanin) Linezolid 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, NIL NIL
mixed
10/11 Blood MRSA, Teicoplanin, NIL
VISA Linezolid
15/11 Blood MRSA, Teicoplanin, NIL
VISA Linezolid
20/11 Blood MRSA, NIL NIL
VISA
23/11 Blood-central, MRSA, NIL NIL
Peripheral VISA,
MIC = 3
30/11 Blood peripheral P.Aerogino Amikacin, Fortum, Cloxacillin, EES, Fusidic acid, PenG,
sa Genta, Tazocin, Bactrim
Ciprofloxacin
 BLOOD CULTURE & SENSITIVITY
Date Samples Organism Sensitive Resistant
8/12 Blood-peripheral, SFNG NIL NIL
Central
16/12 Blood-peripheral, SFNG NIL NIL
Central
20/12 Blood-peripheral, SFNG NIL NIL
Central
 Cell count (x 10^9 cell/mL)

0
4
6
8
10
12
14

2
30-Nov

6.67
01-Dis

4.26
02-Dis

3.42
03-Dis
04-Dis

7.58
05-Dis
06-Dis

7.89
07-Dis
08-Dis

7.05
09-Dis
10-Dis

6.73
ANC: 5.72 x 109 cells/L
11-Dis

5.62
12-Dis
13-Dis

3.66
14-Dis

3.42
15-Dis

3.85
16-Dis

3.62
17-Dis
4.29
18-Dis
LAB RESULT - WBC

19-Dis
5.22

20-Dis
21-Dis
4.23

3.6

22-Dis
23-Dis
3.05

24-Dis
2.72

25-Dis
26-Dis
27-Dis
28-Dis
cells/L

3.49

2.48

29-Dis
4.09

30-Dis
ANC: 1.49 x 109

31-Dis
(MILD NEUTROPENIA)

4.06

01-Jan
3.97

02-Jan
8.95

03-Jan
4.92

04-Jan
ANC: 1.69 x 109 cells/L

05-Jan
12.83
 g/100mL

10
12

0
2
4
6
8
30-Nov

4.0
9.1
01-Dis
02-Dis

7.3
03-Dis
04-Dis

7.0
05-Dis

8.3
06-Dis
07-Dis

8.2
08-Dis
09-Dis
9.0

10-Dis 8.0
11-Dis
12-Dis
8.5

13-Dis
14-Dis
8.0

7.1

15-Dis
16-Dis
9.4

7.5

17-Dis
18-Dis
19-Dis
Anemia
10.0

20-Dis
7.9

21-Dis
6.8

22-Dis
6.7

23-Dis
HAEMATOLOGICAL- Hb

(Normal range: 11.5-16.5g/dL)

24-Dis
25-Dis
6.8

26-Dis
5.8

27-Dis
28-Dis
4.7
6.4

29-Dis
30-Dis
6.9

31-Dis
5.2

01-Jan
6.1

02-Jan
03-Jan
6.3

04-Jan
05-Jan
5.3
 X 100/L

50

0
100
150
200
250
300
350
400
450
500
30-Nov
01-Dis

319
02-Dis

201
03-Dis

181
04-Dis
05-Dis
06-Dis

288
07-Dis
08-Dis

358
09-Dis 376

10-Dis
11-Dis 326

282
12-Dis
13-Dis
272

14-Dis
15-Dis 247
260

16-Dis
250

17-Dis
18-Dis
335

19-Dis
20-Dis
344

21-Dis
248

22-Dis
23-Dis
229

No thrombocytopenia

24-Dis
239

25-Dis
26-Dis
315

27-Dis
28-Dis
29-Dis
290
HAEMATOLOGICAL - PLATELET

30-Dis
342

31-Dis
375

01-Jan
440

02-Jan
370

03-Jan
384

04-Jan
427

05-Jan
342
 COAGULATION - INR
4

3.5 3.47
3.26

2.55
2.5
2.47
2.41
2.10
INR

2
1.80

1.46 1.53 1.50 1.40

1.5

1.17
1.13 1.29 1.15
1 1.11 1.14 1.15
1.01 1.05 1.09 1.13

0.5
T. Warfarin 5mg OD T. Warfarin 4.5mg OD T. Warfarin 3mg OD

0
 COAGULATION – PT/aPTT
120

105
100

86.7
81.3
80
71.5

68.7
66.7
60 54.7 65.2
52.8 53.2 56.6 aPTT
50.3
PT
42 48.9 47.2 45.6

40 42.3 39.6
44.5
38.6 40.7 27.4
34.9 23.5
20.8
17.6 Enoxaparin 26.7
33.2
18
17.1
26.2
20 14.8 14.6
18.3 16
14.4
14.2 14.4 13.6 14.5 14.6 14
13.2
Heparin
0
05-Dis

22-Dis
30-Nov

01-Jan
02-Jan
01-Dis
02-Dis
03-Dis
04-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

23-Dis
24-Dis
25-Dis
26-Dis
27-Dis
28-Dis
29-Dis
30-Dis
31-Dis
aPTT: 30s – 45.8s aPTT control : 37.9s PT: 12.6s – 15.7s
 1
2
3
4
5
6
7
8

0
30-Nov
01-Dis
02-Dis
03-Dis
04-Dis
05-Dis
06-Dis

K+: 3.5-4.5mmol/L
07-Dis
08-Dis
09-Dis
10-Dis
Tab KCL

11-Dis
12-Dis
13-Dis
14-Dis
15-Dis
16-Dis

Ca2+: 2.1-2.6mmol/L
17-Dis
Tab KCL

18-Dis
Lytic

19-Dis
cocktail

20-Dis
21-Dis
22-Dis
23-Dis
24-Dis
25-Dis
26-Dis

PO4-: 0.8-1.4mmol/L
27-Dis
28-Dis
29-Dis
30-Dis
ELECTROLYTES – K / Ca / PO

31-Dis
01-Jan
02-Jan
Ca Polysterene Sulphonate

03-Jan
K
Ca
PO4
 1
2
3
4
5
6
7
8

0
30-Nov
01-Dis
02-Dis
03-Dis
04-Dis
05-Dis
06-Dis

K+: 3.5-4.5mmol/L
07-Dis
08-Dis
09-Dis
10-Dis
11-Dis
12-Dis
13-Dis
14-Dis
15-Dis
16-Dis

Ca2+: 2.1-2.6mmol/L
17-Dis
18-Dis
19-Dis
Vit D 0.25mcg OD
CaCO3 500mg BD

20-Dis
21-Dis
22-Dis
23-Dis
24-Dis
25-Dis
26-Dis

PO4-: 0.8-1.4mmol/L
27-Dis
28-Dis
29-Dis
30-Dis
ELECTROLYTES – K / Ca / PO

31-Dis
01-Jan
02-Jan
03-Jan
Vit D 0.5mcg OD
K
CaCO3 500mg TDS

Ca
PO4
CURRENT DIAGNOSIS (as of 4/1/2012)

Active Problem Inactive Problem

Haemotypsis ANCA (+ve)
VISA vasculitis
Delirium d/t ESRF
Sepsis
Hypotension
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
Vancomycin 12.83
1g stat
12 (24/11)

10 T. Azathioprine 50mg OD

C. Rifampicin 600mg OD 8.95

Cell count (x 10^9 cell/mL)

7.89
8
7.58
7.05
6.67
6.73
6
5.62
5.22
4.29 4.92
4.26 4.23 4.09 4.06
3.66 3.85
4
3.05 3.97
3.49
3.62 3.6
3.42 3.42
2.72
2 2.48
Vancomycin Vancomycin
IV Linezolid 600mg BD
1g stat 1g EOD
0
03-Dis

23-Dis
30-Nov

01-Jan
02-Jan
03-Jan
04-Jan
05-Jan
01-Dis
02-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

24-Dis
25-Dis
26-Dis
27-Dis
28-Dis
29-Dis
30-Dis
31-Dis
 LAB RESULT - WBC
14
Vancomycin 12.83
1g stat
12 (24/11)

10 T. Azathioprine 50mg OD

C. Rifampicin 600mg OD 8.95

Cell count (x 10^9 cell/mL)

7.89
8
7.58
7.05
6.67
6.73
6
5.62
5.22
4.29 4.92
4.26 4.23 4.09 4.06
3.66 3.85
4
3.05 3.97
3.49
3.62 3.6
3.42 3.42
2.72
2 2.48
Vancomycin Vancomycin
IV Linezolid 600mg BD IV Linezolid 600mg BD
1g stat 1g EOD
0
03-Dis

23-Dis
30-Nov

01-Jan
02-Jan
03-Jan
04-Jan
05-Jan
01-Dis
02-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

24-Dis
25-Dis
26-Dis
27-Dis
28-Dis
29-Dis
30-Dis
31-Dis
 NARANJO ADR PROBABILITY SCALE
Don’t
Question Yes No V L A R
know
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
+2 -1 0 +2 +2 +2 +2
administered?
Did the adverse reaction improve when the drug was
+1 0 0 +1 0 +1 0
discontinued, or a specific antagonists was administered?
Did the adverse reaction reappear when the drug was
+2 -1 0 +2 +2 +2 -1
readministered?
Are there alternatives causes (other than the drug) that could
-1 +2 0 -1 -1 -1 -1
on their own have caused that reaction?
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
+1 0 0 0 0 0 0
concentration known to be toxic?
Was the reaction more severe when the dose was increased,
+1 0 0 +1 0 0 0
or less severe when the dose was decreased?
Did the patient have a similar reaction to the same or similar
+1 0 0 0 0 0 0
drug in any previous reaction?
Was the adverse event confirmed by any objective evidence? +1 0 0 +1 +1 +1 +1
TOTAL
(<0 = doubtful, 1-4 = Possible 5-8 = Probable, >9 = Highly probable)
7 5 6 2
 INCIDENCES
(LEUKOPENIA/NEUTROPENIA)
Micromedex12 Lexi-comp13
Drugs
Incidence Onset Recovery Incidence Onset Recovery

Linezolid Upon
1.1% (adult) >14 days 1%-10% >14 day N/A
Discont’
Vancomycin >7 days Promptly Promptly
>7 days or
or total reversed reversed
rare 1%-10% total dose
dose when when
>25g
>25g discont’ discont’
Rifampicin
Not defined,
N/A N/A N/A N/A N/A
Dose related

Azathioprine reversed
Dose discont’ or Not defined,
Delay Delay N/A
related reduce Dose related
dose
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:
 Long course of treatment (~15days to 4 months)17
 Pre-existing myelosuppression17
 Receiving concomitant myelosuppresive drugs17

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 YEARS STUDIES DESIGN OUTCOME
Faguer et al. 2007 Case Report Case report of Linezolid-induced
Gorchynski et 2008 pancytopenia in patient infected with
al. MRSA
Matsumoto et 2010 PK study Renal dysfunction increases linezolid
al. trough level and AUC. Higher drug-
exposure induces thrombocytopenia
Rao et al. 2004 Prospective, Recent treatment with vancomycin
Observational increased the risk (thrombocytopenia)
study whose therapy was switched to linezolid
compare linezolid alone.
Soriano et al. 2007 Comparative Haematological toxicity is directly related
study 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 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 Vancomycin-induced neutropenia is most
review 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- 2004 Review/case Prolong exposure leads to increase risk of
Newnham et report neutropenia. Mechanism most likely to be
al. 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
 AZATHIOPRINE13

 Immunosuppressant
 Imidazolyl of mercaptopurine
 Inhibitsynthesis 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 The incidence rate (per patient and year
review, meta- of treatment) of the drug-induced
analysis myelotoxicity was 3% in IBD patient. Bone
marrow toxicity occur more frequently
during first month.
Higgs et al. 2010 Systematic Individuals with both intermediate and
review, meta- absent Thiopurine-S-methyltransferase
analysis 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
 MANAGEMENT13,14

 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.