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.