DRUG-INDUCED LEUKOPENIA - Kampus Kesihatan · OBJECTIVES To describe a case on drug-induced...
Transcript of DRUG-INDUCED LEUKOPENIA - Kampus Kesihatan · OBJECTIVES To describe a case on drug-induced...
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
Predictable
Pharmacologic side effect
Secondary pharmacologic side effect
Drug toxicity
Drug-drug interaction
Drug Overdose
Unpredictable
Pseudoallergic
Idiosynchratic
Intolerance
Immunolgic
Unpredictable
(I) IGE-mediated
(II) Cytotoxic
(III) Immune-complex
(IV) Delayed, cell
mediated
Specific T-cell activation
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
Occurs with 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
VISA development -- Prolong Vancomycin exposure11
MIC
(µg/mL) VSSA VISA VRSA
<2
4-8
>16
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
Anemia T. Vitamin B complex 1/1 OD
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
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
• 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.
8/12
• 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 • 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
• Haemotypsis and bruises (INR 2.55, aPTT 71.5s)– Warfarin withold, 6 unit FFP was transfused, target INR 1.5-2
24/12
• 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
25/12
• Hyperkalaemia (6.6mmol/L) – Lytic cocktail stat.
• Condition improving
28/12
• Reducing trend of TWBC – Drug related ? (Vancomycin / Linezolid / Rifampicin / Azathioprine)
• 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 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
ANCA +ve Vasculitis
30/11-7/12
IV Hydrocortisone 100mg BD 7/12-15/12
T. Prednisolone 35mg OD 15/12-2/1
T. Azathioprine 50mg OD 30/11, 9/12-13/12
IV Pantoprazole 40mg stat & BD Gastric Pain
30/11-30/12
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 Pain
1/12, 4/12, 8/12
C. Tramadol 50mg TDS 9/12-21/12, 25/12-cont
T. Vitamin B complex 1/1 OD
Anemia
1/12-cont
T. Folic acid 1/1 OD 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 Phosphate binder
5/12-28/12
T. Calcium Carbonate 500mg TDS 28/12-cont
T. Rocaltriol 0.25mg OD Supplement for
Calcium absorbtion
5/12-27/12
T. Rocaltriol 0.5mg OD 28/12-cont
T. Potassium Chloride 1200mg BD x
3/7 Hypokalaemia 7/12-10/12, 18/12-22/22
Lytic Cocktail stat
Hyperkalaemia
20/12
Ca Polysterene Sulfonate powder
10g TDS 24/12-26/12
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
DVT treatment and
prophylaxis
7/12-8/12
S/C Enoxaparin 20mg stat & OD 8/12-16/12
T. Warfarin 5mg OD 9/12-13/12
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 (
mm
Hg)
BPsystolic
BPdiastolic
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
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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
(b
eats
/min
)
HR
VITAL SIGNS T. Prazocin OD
VITAL SIGNS
36.5
37
37.5
38
38.5
39
39.530
-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
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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
Tem
pera
ture
oC
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
MRSA NIL Ciprofloxacin, Gentamicin, PenG,
Cloxacillin, Rifampicin, Co-
trimaxazole, EES, Fusidic acid
18/9 Blood-peripheral,
Central
MRSA NIL NIL
25/9 Blood-peripheral,
Central
MRSA NIL NIL
27/9 Blood-peripheral,
Central
MRSA Vancomycin NIL
3/10 Blood-peripheral,
Central
MRSA 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
sa
Amikacin, Fortum,
Genta, Tazocin,
Ciprofloxacin
Cloxacillin, EES, Fusidic acid, PenG,
Bactrim
BLOOD CULTURE & SENSITIVITY
Date Samples Organism Sensitive Resistant
8/12 Blood-peripheral,
Central
SFNG NIL NIL
16/12 Blood-peripheral,
Central
SFNG NIL NIL
20/12 Blood-peripheral,
Central
SFNG NIL NIL
6.67
4.26
3.42
7.58
7.89
7.05
6.73
5.62
3.66
3.42
3.85
3.62
4.29
5.22
4.23
3.6
3.05
2.72
2.48
3.49
4.09 4.06
3.97
4.92
8.95
12.83
0
2
4
6
8
10
12
14
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
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13
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14
-Dis
15
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16
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17
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18
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19
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20
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21
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22
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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 c
ount (x
10^
9 c
ell/m
L)
LAB RESULT - WBC
ANC: 1.49 x 109
cells/L
(MILD NEUTROPENIA)
ANC: 1.69 x 109 cells/L
ANC: 5.72 x 109 cells/L
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/1
00m
L
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 1
00/L
No thrombocytopenia
COAGULATION - INR
3.47
2.10
1.80
1.46
1.11
1.13
1.01 1.05
1.53
2.47
3.26
2.41
2.55
1.29
1.50
1.14
1.17
1.15
1.15
1.09
1.40
1.13
0
0.5
1
1.5
2
2.5
3
3.5
4
INR
T. Warfarin 5mg OD T. Warfarin 4.5mg OD T. Warfarin 3mg OD
105
52.8
50.3
38.6
42
40.7
54.7
42.3
48.9
68.7
86.7
66.7
71.5
65.2
81.3
47.2
53.2
44.5
56.6
45.6
39.6
34.9 23.5
20.8 17.6
14.2 14.4 13.2
13.6
18.3
26.7
33.2
26.2
27.4
16
18
14.5
14.8
14.6
14.6
14
17.1
14.4
0
20
40
60
80
100
120
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
aPTT
PT
COAGULATION – PT/aPTT
aPTT: 30s – 45.8s PT: 12.6s – 15.7s aPTT control : 37.9s
Heparin
Enoxaparin
0
1
2
3
4
5
6
7
8
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
K
Ca
PO4
ELECTROLYTES – K / Ca / PO
K+: 3.5-4.5mmol/L Ca2+: 2.1-2.6mmol/L PO4-: 0.8-1.4mmol/L
Lytic
cocktail Ca Polysterene Sulphonate
Tab KCL
Tab KCL
0
1
2
3
4
5
6
7
8
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
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14
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15
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16
-Dis
17
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18
-Dis
19
-Dis
20
-Dis
21
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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
K
Ca
PO4
ELECTROLYTES – K / Ca / PO
K+: 3.5-4.5mmol/L Ca2+: 2.1-2.6mmol/L PO4-: 0.8-1.4mmol/L
CaCO3 500mg BD
Vit D 0.25mcg OD
CaCO3 500mg TDS
Vit D 0.5mcg OD
CURRENT DIAGNOSIS (as of 4/1/2012)
Active Problem
Haemotypsis
VISA
Delirium d/t Sepsis
Hypotension
Inactive Problem
ANCA (+ve) vasculitis
ESRF
DISCUSSION
PHARMACEUTICAL CARE ISSUES
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
6.67
4.26
3.42
7.58
7.89
7.05
6.73
5.62
3.66
3.42
3.85
3.62
4.29
5.22
4.23
3.6
3.05
2.72
2.48
3.49
4.09 4.06
3.97
4.92
8.95
12.83
0
2
4
6
8
10
12
14
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 c
ount (x
10^
9 c
ell/m
L)
LAB RESULT - WBC
Vancomycin
1g stat
(24/11)
IV Linezolid 600mg BD Vancomycin
1g EOD
T. Azathioprine 50mg OD
C. Rifampicin 600mg OD
Vancomycin
1g stat
6.67
4.26
3.42
7.58
7.89
7.05
6.73
5.62
3.66
3.42
3.85
3.62
4.29
5.22
4.23
3.6
3.05
2.72
2.48
3.49
4.09 4.06
3.97
4.92
8.95
12.83
0
2
4
6
8
10
12
14
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 c
ount (x
10^
9 c
ell/m
L)
LAB RESULT - WBC
Vancomycin
1g stat IV Linezolid 600mg BD
Vancomycin
1g EOD
T. Azathioprine 50mg OD
C. Rifampicin 600mg OD
IV Linezolid 600mg BD
Vancomycin
1g stat
(24/11)
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? +2 -1 0 +2 +2 +2 +2
Did the adverse reaction improve when the drug was
discontinued, or a specific antagonists was administered? +1 0 0 +1 0 +1 0
Did the adverse reaction reappear when the drug was
readministered? +2 -1 0 +2 +2 +2 -1
Are there alternatives causes (other than the drug) that could
on their own have caused that reaction? -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? +1 0 0 0 0 0 0
Was the reaction more severe when the dose was increased,
or less severe when the dose was decreased? +1 0 0 +1 0 0 0
Did the patient have a similar reaction to the same or similar
drug in any previous reaction? +1 0 0 0 0 0 0
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
NARANJO ADR PROBABILITY SCALE
INCIDENCES
(LEUKOPENIA/NEUTROPENIA)
Drugs
Micromedex12 Lexi-comp13
Incidence Onset Recovery Incidence Onset Recovery
Linezolid 1.1% (adult) >14 days
Upon
Discont’ 1%-10% >14 day N/A
Vancomycin
rare
>7 days
or total
dose
>25g
Promptly
reversed
when
discont’
1%-10%
>7 days or
total dose
>25g
Promptly
reversed
when
discont’
Rifampicin
N/A N/A N/A Not defined,
Dose related N/A 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. 19th 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.
Gorchynski et
al.
2007
2008
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 drug-
exposure 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;35:275–7
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
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
AZATHIOPRINE13
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. 19th ed. Ohio: Lexi-Comp Inc.; 2010.
LITERATURE REVIEW
STUDIES YEARS STUDIES DESIGN OUTCOME
Gisbert et al. 2008 Systematic
review, meta-
analysis
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, meta-
analysis
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
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. 19th 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.