Incidence and Management of Antituberculosis Drug-Induced

Cutaneous Adverse Drug Reactions

Chanida Kanjanapradit

A Thesis Submitted in Partial Fulfillment of the Requirements for the Degree of
Master of Pharmacy in Clinical Pharmacy
Prince of Songkla University
2555

(1)


.
(. ) ( . )

..................
( . )

..................
( . ) (. )

.
( . )

(2)


______________________
. )

______________________
( )

(3)


______________________
( )

(4)



2554

1 isoniazid (H), rifampicin (R), pyrazinamide
(Z) ethambutol (E)
17 2554 2555

2
58
( 21.6) 539
10.8/100 person-months ( 95
8.2 13.9) 47
( 17.5) 11 ( 4.1)
maculopapular rash 7 ( 2.6) urticaria 3 ( 1.1) Stevens-
Johnson syndrome 1 ( 0.4)
12.7 + 15.8 8 ( 0-88 ) 58

47 ( 81.0) 10 (
17.3) 1 ( 1.7)
52 ( 89.6) 3 (
5.2) 3 ( 5.2) 6
1 (16.7%) ofloxacin
43 ( 74.1)

(5)
 15.3 + 14.9 10 ( 0-
50 ) 6
4 ( 66.7) 4
(sequential re-challenge) isoniazid 3 ethambutol
1 225
(successful) 195 ( 86.7)
(unsuccessful) 30 ( 13.3)

(6)
Thesis Title Incidence and management of antituberculosis drug-induced
cutaneous adverse drug reactions
Author Mrs. Chanida Kanjanapradit
Major Program Clinical Pharmacy
Academic Year 2011

ABSTRACT

This prospective study aimed to determine incidence of antituberculosis drug-

induced cutaneous adverse drug reactions (anti-TB CADRs), clinical characteristics (type,
severity and onset) of anti-TB CADRs, types of anti-TB CADRs management, result of anti-TB
CADRs management and patient treatment outcome at the end of intensive phase. This study
included new cases of adult tuberculosis patients treated with first-line anti-TB drugs, including
isoniazid (H), rifampicin (R), pyrazinamide (Z) and ethambutol (E). It was conducted in 17
hospitals of southern Thailand. New cases of adult tuberculosis (TB) patients treated during June
2011 to March 2012 were included. Patients who had abnormal skin conditions before treatment
indication were excluded. Anti-TB CADRs was defined as a skin reaction such as rash and/or
itching that occurred during the treatment without other causes. Patients were followed-up
through telephone calls everyday within the first two weeks, then every week until the end of the
intensive phase.
Of the 269 TB patients included, 58 (21.6%) experienced CADRs. The total
follow up time was 539 months. The incidence rate of anti-TB CADRs was 10.8 per 100 person-
months (95% CI 8.2-13.9). Forty-seven patients (17.5%) had itching without rash and 11 patients
(4.1%) had both itching and rash. Types of rash were maculopapular rash (n=7, 2.6%), urticaria
(n=3, 1.1%) and Stevens-Johnson syndrome (n=1, 0.4%). The mean duration of time since the
patient started the treatment until CADRs occurred was 12.7 + 15.8 days (median = 8 days, range
1-88 days). Of 58 patients with anti-TB CADRs, 47 (81.0%) were mild, 10 (17.3%) were
moderate, and 1 (1.7%) were severe CADRs.
Among 58 patients experienced anti-TB CADRs, 52 (89.6%) continued the
treatment regimens, 3 (5.2%) discontinued some anti-TB drugs and 3 (5.2%) ceased all anti-TB.

(7)
Of the 6 patients discontinued some or all anti-TB drugs, 1 (16.7%) had ofloxacin as the
supplementary anti-TB drugs. Forty three patients (74.1%) resolved their CADRs. The mean
duration of anti-TB CADRs was 15.3 + 14.9 days (median = 10 days, range 0-50 days).
Anti-TB drugs were sequential re-challenge in 4 patients (66.7%) who ceased
their treatment. Isoniazid and ethambutol were the first agents for reintroduction in 3 patients and
1 patient, respectively. The treatment outcomes at the end of intensive phase of 225 patients were
successful 195 patients (86.7%) and unsuccessful 30 patients (13.3%).

(8)


.......(5)
Abstract......(7)
.. ....(9)
....(10)
.......(14)
.(15)
.......(16)
1 ... ..1
1.1 .2
1.2 ...2
1.3 ..2
2 . ..3
2.1 ..3
2.2 .4
2.3
( ) ..5
2.4 . ..6
2.4.1 (Guideline) ...7
2.4.2 (case report)....9
2.5 ...12
3 ...17
3.1 .....17
3.2 .. ..............17
3.3 ..17
3.3.1 .17
3.3.2 ...18

(10)
 ( )

3.4 .18
3.5 .....19
3.6 ..20
3.6.1 ............20
3.6.2 ...20
3.7 .23
3.8 ..24
3.9 ...24
3.10 ..24
4 ...26
4.1 .29
4.2
..31
4.3
..................34
4.3.1 ..34
4.3.2 ...34
4.3.3 .36
4.4 ...37
4.5
....37
4.5.1
.41
4.5.2 ...46
4.6 .................48

(11)
 ( )

4.7 . ..50
4.8 11 ..
52
5 ....61
5.1 ...61
5.2 ....63
5.2.1
....... ...63
5.2.2
..67
5.2.3
....73
5.3 .......74
5.4 ..74
5.5 .. 74
.76
..84
1
()...85
2
().87
3
( ). ...90

.. ...92
... ..99
100
...102
(12)
 ( )

1 ( ).. .103
.108
2 ( ).. .113
3 ( )....116

(WHO criteria)..117
.....118

(13)


3.1 ...22
3.2
...23
4.1 .28
4.2 ...30
4.3
..33

(14)


3.1 phase ..21
4.1 .....27
4.2
....35
4.3 .36
4.4 ...38
4.5 ..40
4.6 1...43
4.7 2...44
4.8 3...45
4.9 4...46
4.10
. .49
4.11 .51
4.12 Stevens-Johnson syndrome 8.58

(15)


ACE = Angiotensin-converting enzyme

AGEP = Acute Generalized Exanthematous Pustulosis
ASA = Acetylsalicylic acid
ATS = American Thoracic Society
BMI = Body mass index
CADR = Cutaneous Adverse Drug Reaction
CBC = Complete blood count
CD4 = Cluster of differentiation 4
CDC = Center for Disease Control and prevention
CI = Confidence Interval
COX = Cyclooxygenase
CPM = Chlorpheniramine maleate
Cr = Creatinine
CS = Cycloserine
DIHS = Drug-induced hypersensitivity syndrome
DRESS = Drug Reaction with Eosinophilia and Systemic Symptoms
E = Ethambutol
EMM = Erythema multiforme majus
Et = Ethionamide
FDE = Fixed drug eruption
FasL = Fas ligand
H = Isoniazid
HIV = Human Immunodeficiency Virus
5-HT = 5-Hydroxytryptamine
IL = Interleukin
LFT = Liver function test
MP = Maculopapular
NSAID = Non-steroidal anti-inflammatory drug

(16)
 ()

O = Ofloxacin
OR = Odd Ratio
PAS = Para-aminosalicylic acid
Pt = Prothionamide
R = Rifampicin
RNA = Ribonucleic acid
R/O = Rule out
S = Streptomycin
SJS = Stevens-Johnson Syndrome
SLE = Systemic Lupus Erythematosus
TA = Triamcinolone acetonide
TB = Tuberculosis
TEN = Toxic Epidermal Necrolysis
TNF = Tumor necrotic factor
UA = Urinalysis
WHO = World Health Organization
Z = Pyrazinamide

(17)
 1

1.1
1.2
1.3

1.1

2009
9.27 18 22 high burden country
(estimated incidence)
142 1

(Standard Short Course
Chemotherapy) 2 isoniazid
(H), rifampicin (R), pyrazinamide (Z), ethambutol (E) streptomycin (S)


3-5 6-7

29-74 3,8-13

1
 2

( )
15-45 1 3,8-13
1-43 1-4
14-24

1.2

1. (cumulative incidence incidence density)

( )
2. ( , ,
)
3.

1.3

6
2.1
2.2
2.3 ( )

2.4
2.5

2.1

Mycobacterium
tuberculosis



2 (pulmonary tuberculosis)
(extrapulmonary tuberculosis)
2-3

2
1. 1 (First-line drugs)
isoniazid (H), rifampicin (R), pyrazinamide (Z), ethambutol (E),
streptomycin (S)
2. 2 (Second-line drugs) cycloserine (Cs), ethionamide
(Et), para-aminosalicylic acid (PAS), prothionamide (Pt) fluoroquinolones,

3
 4

aminoglycosides 1


2 4-6
4-5 6-24 25

2HRZE(S)/4HR 2
4 H, R, Z, E ( S E) 2 H, R 4
(relapse) 2HRZES/1HRZE/5HRE 2
5 H, R, Z, E, S 4 H, R, Z, E 1
3 H, R, E 5
2 4 1
6

2.2

26-28
1 (First-line drugs) 2 1) Minor Adverse
Reactions 2) Major Adverse Reactions25

2.2.1 Minor Adverse Reactions

 5

2.2.2 Major Adverse Reactions

25
(ototoxicity) (visual impairment)
(liver and biliary system disorder)
(severe skin reaction)

2.3 ( )

4
1 isoniazid (H), rifampicin (R), pyrazinamide (Z), ethambutol (E),
streptomycin (S)
(re-challenge)

H, R (treatment of latent
tuberculosis infection)29-33 2

isoniazid 0.6-5.629-31
16.730
rifampicin 2.1-6.0
5.032-33

18 7 11


3
13-14,20
() ()
15-453,8-13
 6

() 1 1-4314-24 ()
1-4


(challenge test)







rash, maculopapular rash,
erythema multiforme, exfoliative dermatitis, morbiliform rash, urticaria, lichenoid eruption
(case report)
exfoliative dermatitis, leukocytoclastic vasculitis
2
13,20
21 2
2

2.4

(Guideline) 7 (case report)
7


 7

2.4.1 (Guideline) 2,25,41-48

(practice guidelines) 7
1 25 6
2,41-45
1
.. 255125
2 Guidelines for the Management of Adverse Drug Effects of
Antimycobacterial agents, Philadelphia Tuberculosis Control Program, 199841
3 Treatment of Tuberculosis, American Thoracic Society (ATS)/Centers for
Disease Control (CDC) and Prevention/ Infectious Disease Society of America, 200342
4 TB/HIV A clinical manual, 2nd edition, WHO, 200443
5 TomansTuberculosis:Case detection, treatment, and monitoring-questions
and answers, 2nd edition, WHO, Geneva, 200444
6 Treatment of tuberculosis guidelines, 4th edition, World Health Organization;
WHO), 20092
7 National Tuberculosis Management Guidelines, Republic of South African,
200945

4

( )




2
3

/
 8

chlorpheniramine maleate (CPM),
diphenhydramine prednisolone
hydrocortisone triamcinolone acetonide (TA)

3
25,41,43
2
1
ATS 200342 2 3 1
aminoglycoside 2
(Re-challenge)

re-challenge


H 2 R Z E 1
ATS 2003 R 2 H E Z
E 2 R
H Z
3 4

2 - 3 re-challenge

 9

2.4.2 (case report)

7 2 5

re-challenge
3

(2551)49
1 isoniazid, rifampicin, pyrazinamide, ethambutol
streptomycin 3 1
exfoliative dermatitis
dexamethasone chlorpheniramine maleate prednisolone 30
17
( streptomycin)
rifampicin 600 isoniazid 300
3 ethambutol 1,200
ethambutol hydroxyzine 30
betamethasone cream pyrazinamide ofloxacin 3
rifampicin, isoniazid,
pyrazinamide ofloxacin ethambutol 1
(2553)50
1 isoniazid, rifampicin, pyrazinamide ethambutol
1 maculopapular rash chlorpheniramine
maleate 4 3

hydroxyzine 10 3


Kishore (2007) 51 57
1 isoniazid, rifampicin,
 10

pyrazinamide ethambutol 11



2003
3
()
isoniazid, rifampicin ethambutol
pyrazinamide pyrazinamide ofloxacin

Garg (2007) 52 18
1 isoniazid, rifampicin,
pyrazinamide ethambutol 2
exfoliative dermatitis
7
2003

3
isoniazid rifampicin
7 ethambutol 6
ethambutol ethambutol
pyrazinamide
exfoliative dermatitis ethambutol pyrazinamide
15
isoniazid rifampicin 1
Kim (2010) 53 38
1 isoniazid rifampicin pyrazinamide
ethambutol 1
leukocytoclastic vasculitis prednisolone 20
3
 11

levofloxacin 500 10
ethambutol 400 2 800
3 isoniazid 100 3 4 isoniazid 300
6 rifampicin 150
rifampicin 300 2
prednisolone 20 3
rifampicin 4 pyrazinamide
1,500 pyrazinamide 3
isoniazid ethambutol levofloxacin kanamycin

Dua (2010) 54
1 isoniazid, rifampicin, pyrazinamide ethambutol
8 exfoliative
dermatitis corticosteroids
1
2004 (Tomans tuberculosis)44 isoniazid
2-3 rifampicin, pyrazinamide
ethambutol isoniazid 50
isoniazid rifampicin 150
rifampicin ethambutol pyrazinamide
streptomycin ofloxacin
streptomycin ofloxacin

exfoliative dermatitis, maculopapular rash, leukocytoclastic vasculitis

chlorpheniramine
maleate hydroxyzine corticosteroid prednisolone
dexamethasone

2003
 12

3

1
maculopapular rash

2.5

maculopapular rash ,
pruritus, urticaria, exfoliative dermatitis, erythema multiforme, StevensJohnson syndrome (SJS),
toxic epidermal necrolysis (TEN) 55-66

1.
European Academy of Allergy and Clinical Immunology (EAACI)
67-68
Immediate reaction
1
IgE-mediated
generalized urticaria, angioedema, rhinitis, conjunctivitis, bronchospasm
anaphylaxis anaphylaxis shock
Nonimmediate reaction
1 1
T-cell mediated
delayed urticaria, maculopapular eruptions, fixed
drug eruptions, vasculitis, toxic epidermal necrolysis, Stevens-Johnson syndrome drug
reaction with eosinophilia and systemic symptoms (DRESS)
 13

2. Gell and Coombs

classification 4 69-70
Type I reaction (IgE mediated) IgE mast cell mediators
histamine inflammatory mediators urticaria, angioedema,
bronchospasm, pruritus, vomiting, diarrhea anaphylaxis
1
Type II reaction (cytotoxic) IgG IgM antibodies
heamolytic anemia, neutropenia thrombocytopenia

Type III reaction (immune complex) antibody

drug-antibody complexs tissue serum sickness,
fever, rash, arthralgias, lymphadenopathy, urticaria, glomerulonephritis, erythema nultiforme
vasculitis 1-3
Type IV reaction (delayed, cell-mediated) T-lymphocytes
allergic contact dermatitis, fixed drug eruption maculopapular rash
2-7

Maculopapular rash (MP rash) 58
MP rash 40
1 3
(previous sensitization) MP rash 2
macule ( ) papule ()


1 2
cytotoxic T-cell-
mediation reactions
(papillary dermis)
(inflammatory cell) lymphocytes, macropharges, mast cells, eosinoplils
 14

maculopapular rash
Pruritus itching59
Pruritus ()
4
cutaneous itching, neuropathic itching, neurogenic itching psychogenic itching
cutaneous itching
itch-mediated C fiber fiber

, serotonin (5-HT),
acetylcholine, prostaglandins
Urticaria/ Angioedema 58,60-62



mast cells
( histamine)


(dermis) ( Urticaria)
(Angioedema)
Exfoliative dermatitis 63
(erythroderma)
90

ectropion


 15

Erythema Multiforme 64
EM
maculopapular rash
( target lesion iris lesion ) ( bulls
eye ) Erythema multiforme
3
1-2 EM
EM , Mycoplasma neumoniae
herpes virus
EM cell
mediated immune reaction lymphocyte

Stevens - Johnson syndrome (SJS) Toxic Epidermal Necrolysis (TEN) 55, 65-67
Stevens-Johnson syndrome toxic epidermal necrolysis
mucosa
Stevens-Johnson syndrome
10 toxic epidermal necrolysis
30
Stevens - Johnson syndrome Toxic Epidermal Necrolysis


Mycoplasma pneumoniae, herpes simplex virus 1
2 , Streptococcus species, Histoplasma capsulatum, influenza virus adenovirus,
systemic lupus ( sulfa, penicillin ),
NSAIDs, Allopurinol, (phenytoin, carbamazepine, barbiturates) Sullivan
Shear SJS epoxide hydrolase
arean oxide
arean oxide messenger RNA
autoantibodies deamoplakin I and II SJS autoantibodies
deamosome
 16

TEN Intermediate metabolite

T-cell Interleukin (IL-
6) Tumor necrotic factor (TNF-) Fas ligand (FasL) TNF FasL
death receptor FasL Fas receptor

HLA-B12
 3

3.1
3.2
3.3
3.4
3.5
3.6
3.7
3.8
3.9
3.10

3.1

observational prospective study

3.2

(
) 12
17

3.3

3.3.1.
(inclusion criteria)
17
 18

1. 20
2.

(exclusion criteria)
1.
3.3.2.
(inclusion criteria)
1.
2. 1
3. 18
4.
(exclusion criteria)
1.
2.
3.

3.4

(sample size for estimate)
(unpublished data)13
1 (P) 18 (P = 0.18 )

n = Z2 /2 P (1-P)
d2
n = , = 0.05, (d) = 0.05
n = (1.96) (1.96) (0.18) (1 0.18)
(0.05)(0.05)
= 227
227
 19

3.5

3
1.
2. maculopapular rash,
urticaria
3. maculopapular
rash, urticaria, angioedema , exfoliative dermatitis, erythema
multiforme, Stevens-johnson syndrome, toxic epidermal necrolysis, acute generalized
exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms
(DRESS)

1. sputum convert

2. sputum not convert

3. sputum not examine

 20

4. complete

5. failure

6. successful 1)
2)

7. unsuccessful 1)
2)

3.6

2
3.6.1
1.

2. ,
3. ( )
4. /

5.



6.

3.6.2


 21

3 phase 3.1
3.1 3.2

3.1 phase
Phase 1
(inclusion criteria)
1.
2. 1
3. 18
4.
(exclusion criteria)
1.
2.
3.

Phase 2

-
7 -
3 -

Phase 3

 22

3.1

1 /

2 /
( )
3 /
( )
4 /
( : 1)
5 /

6 /

7 /
(

)
2
1
(2 )
(intensive phase)
 23

3.2

1
()

()
2
()
( : )
()
3
( : 2)
4
( : 3)
WHO criteria
( )
5 7
3

3.7

3


1 ( )


 24

2 ( )


3 ( )

3.8

Epidata version 3.1

R-program version 2.0 descriptive statistics [
(mean) (median) ]

3.9

3.10

1.

2.



 25

3.

4.
6
 26

1
isoniazid (H), rifampicin (R), pyrazinamide (Z) ethambutol (E)
(
) 12 17
2554
2555 345 18 2
2 58 10
4 ( 4.1)
269 4.1
4
1.
2.
3.

4.

26
 27

4.1

(n = 345)

(n = 76) (n = 269)
- 18 2
-
2
- 58
- 10
- 4
 28

4.1

a
1 73 56
2 7 7
3 31 25

4 17 17
5 18 13
6 9 6
7 11 5
8 15 13
9 25 16
10 8 6
11 18 11
12 10 10
13 20 15
14 12 2 2
15 5 5
16 54 40
17 22 22
345 269
a
2554 2555
 29

4.1

269
4.2 185 ( 68.8)
238 ( 88.5) 28 ( 10.4)
3 ( 1.1) (
241 ) 173 ( 64.3)
16 ( 6.0) 8
( 3.0) 3 ( 1.1) 2
( 0.7) 2 ( 0.7)
94 ( 34.9) HIV 34 ( 12.6)
23 ( 8.6) 20 ( 7.4)
8 ( 3.0) 6 ( 2.2) 4
( 1.5) 3 ( 1.1) 3 ( 1.1)
3 ( 1.1) Systemic lupus erythematosus 2 ( 0.7)
1 ( 0.4)
15 ( 5.6) 12
( 4.4)

145 ( 53.9) 124 ( 46.1)
 30

4.2
(n=269)
185 68.8

238 88.5
28 10.4
3 1.1
( )
173 64.3
68 25.3

16 6.0
8 3.0
3 1.1
2 0.7
2 0.7

175 65.1
a 94 34.9
HIVb 34 12.6
23 8.6
20 7.4
8 3.0
6 2.2
4 1.5
3 1.1
3 1.1
3 1.1
Systemic lupus erythematosus (SLE) 2 0.7
1 0.4
 31

4.2 ()

(n=269)
15 5.6
12 4.4
6 2.2
3 1.1
3 1.1
4 1.4
2 0.7
2 0.7

145 53.9
124 46.1
a
1
b
HIV = Human Immunodeficiency Virus

4.2

269
58 ( 21.6)
12.7 + 15.8 8 ( 0-88 )
44 ( 16.4)
12 ( 4.5), ( loss follow up)
8 ( 3.0) 8 ( 3.0)
6 ( 2.2) 6
( 2.2) 3 ( 1.1)
1 ( 0.4) 539
 32

10.8/100 person-months (
95 8.2 13.9) 2.0/100
person-months ( 95 1.0 3.7)

58 47 ( 17.5)
11 ( 4.1) 3 maculopapular rash 7
( 2.6) urticaria 3 ( 1.1) Stevens-Johnson syndrome 1
( 0.4)

12.7 + 15.8 8 ( 0-88 ) 11
15.8 + 18.8 10 ( 1-61 )

47 ( 81.0)
10 ( 17.3) maculopapular rash urticaria
1 ( 1.7) Stevens-
Johnson syndrome
4.3
 33

4.3
(n = 269)

211 78.4
58 21.6
47 17.5
a
/ 30 11.2
21 7.8
19 7.1
2 0.7
(), mean (SD), [median] 12.7 (15.8), [8]
11 4.1
a
/ 6 2.2
4 1.5
3 1.1

Maculopapular rash 7 2.6
Urticaria 3 1.1
Stevens-Johnson syndrome (SJS) 1 0.4
(), mean (SD), [median] 15.8 (18.8), [10]
(n = 58)
47 81.0
10 17.3
1 1.7
a
1
 34

4.3

4.3.1
58
4.2 52 ( 89.6)
44 ( 75.9) 8 ( 13.8)
maculopapular rash 6 ( 10.4) urticaria 2
( 3.4)
6 ( 10.4) 3
( 5.2)
1 maculopapular rash 1 SJS 1
3 ( 5.2)
2 ( H 1 ,
Z 1 ) urticaria 1 ( RZ)
4.3.2

3
RZE
H HRE Z
HEO RZ 6
5 ( 83.3)
1 1 ofloxacin
( 4.2)
 35

4.2

(n = 58)

(n = 52) (n = 6)

(n = 3) (n = 3)

H Z RZ
(n = 1) (n = 1) (n = 1)

RZE HRE HEO

(n=3) (n=1) (n=1) (n=1)

: H = isoniazid, R = rifampicin, Z = pyrazinamide, E = ethambutol, O = ofloxacin

 36

4.3.3
58
32 ( 55.2) 26
( 44.8)
4.3

4.3

(n = 58)

a
(n = 32, 55.2%) (n = 26, 44.8%)

(n=44)b (n=20)c

Oral antihistamine Oral corticosteroid Calamine lotion (n = 7)

CPMd (n = 13) Prednisolone (n = 2) Topical steroid (n = 13)
Hydroxyzine (n = 24) (Triamcinolone acetonide,
Cetirizine (n = 3) Betamethasone)
Loratadine (n = 2)

a
1 1
b
1 1
c
1 1
d
Chlorpheniramine maleate
 37

4.4

58 43
( 74.1) 15 ( 25.9)
12 ( 20.7)
2 ( 3.4)
1 ( 1.7) 4.4
58 (
) 43 ( 74.1)
15 ( 25.9) 4.4
15.3 + 14.9 10 ( 0-50 )
11
16.4 + 13.2 14 ( 0-37
)

4.5

6
(re-challenge) 4 ( 66.7)
2 maculopapular rash
1 SJS 1
( sequential re-challenge) 2 ( 33.3)
1 urticaria
1 4.5
 37

4.4

(n = 58)

(n = 47) (n = 11)

(n = 44) (n = 1) (n = 2)

(n = 23) (n = 21) (n = 1) (n = 2)

(n = 18) (n = 12) (n = 2)

(n = 2) (n = 9) (n = 1)
39
(n = 2)

(n = 1)

38
 38

4.4 ()

(n = 58)

38 (n = 11)

Maculopapular rash (n=7) Urticaria (n=3) Stevens-Johnson syndrome (n=1)

(n = 6) (n =1) (n = 2) (n =1) (n =1)

(n = 2) (n = 4) (n = 1) (n = 2) (n = 1) (n = 1)

(n = 2) (n = 4) (n = 1) (n = 2) (n = 1) (n = 1)

39
 40

4.5

(n = 6)

(n = 3) (n = 3)

re-challenge re-challenge
(n = 4) (n = 2)

Sequential re-challenge Simultaneous re-challenge

(n = 4) (n = 0)

Start with H Start with E

(n = 3) (n = 1)

re-challenge E
- HRE (n = 1)
- HRE Z (n = 1)
-H (n = 1)
 41

4.5.1

1
10 maculopapular rash
1
H
2 R 2
R 1 R
oral antihistamine topical steroid R
E
Z
2HEOS/16HE
4.6

2
38
oral antihistamine 4

Stevens-Johnson syndrome
2 oral antihistamine oral
corticosteroid topical steroid
E 2

oral antihistamine, oral corticosteroid topical steroid
re-challenge
2SEO/16EO
4.7
 42

3
3

oral antihistamine topical steroid 2
H R
2 E 3 Z
re-challenge oral antihistamine
topical steroid
2HRZE/4HR

4.8

4
14
oral antihistamine
topical steroid 3
H H RZE
H H

2HRZE/4HR
4.9
 43

4.6 1
30 2554
10

maculopapular rash
10 2554
oral antihistamine
4
14 2554
1

15 2554 re-challenge H 100 mg.

2

17 2554 H 200 mg.

2

19 2554 H 300 mg.

3

22 2554 H 300 mg.+ R 300 mg. R R

3

25 2554 H 300 mg.+ E 400 mg.

2

27 2554 H 300 mg.+ E 800 mg.

3
30 2554 H 300 mg.+ E 1,200 mg.

2HEOS/16HE
 44

4.7 2

19 2554
38

26 2554
oral antihistamine
4

SJS
30 2554 oral antihistamine,
oral topical corticosteroid

15

15 2554 re-challenge E 400 mg.

17 2554 E 800 mg.

19 2554 E 1,200 mg.

2
22 2554 2SEO/16EO
 45

4.8 3

19 2554
3

22 2554
oral antihistamine topical corticosteroid

23 2554
14

6 2555 re-challenge H 300 mg.

4

10 2555 H 300 mg. + R 600 mg.

7

17 2555 H 300 mg. + R 600 mg. + E 800 mg.

14

31 2555 H 300 mg. + R 600 mg. + E 800 mg. + Z 1,500 mg.

2HRZE/4HR
 46

4.9 4

4 2554
14

17 2554
oral antihistamine topical corticosteroid

21 2554 ( H)

25 2554 re-challenge H 300 mg.

2HRZE/4HR

4
4 (H, R, Z, E)

4.5.2

WHO criteria 4 ( certain)
(probable) (possible) (unlikely)
WHO criteria

 47

1
maculopapula rash
H
R E Z re-challenge 2 R
R
WHO criteria
R
certain Z possible

2
Stevens-Johnson syndrome
Stevens-Johnson syndrome

E
H, R Z
H, R Z

possible

4

H RZE
H
 48

HRZE


3 isoniazid,
rifampicin pyrazinamide

4.6

58
44
8
2HRZE/4HR
6 3

2HRZE/4HR 1 2
2SEO/16EO 1 2HEOS/16HE 1
3
2HRZE/4HR 1
2 2HRE/1HREO/7HR 1 18HEO 1
4.10

2HRZE/4HR 54 4
2SEO/16EO, 2HEOS/16HE, 2HRE/1HREO/7HR 18HEO
 48

4.10

(n = 58)

(n = 47) (n = 11)

(n = 44) (n = 1) (n = 2) (n = 8) (n = 2) (n = 1)

H (n=1) Z (n=1) RZ (n=1)

re-challenge HREZ re-challenge H re-challenge re-challenge E (n=1) re-challenge HRE (n=1) re-challenge

2HRZE/4HR 2HRZE/4HR 2HRZE/4HR 2HRE/1HREO/7HR 2HRZE/4HR 2SEO/16EO 2HEOS/16HE 18HEO

49
 50

4.7

( 2) 225
150
53 22
150 (sputum convert)
118 ( 52.5) (sputum not convert) 27 ( 12.0)
(sputum not examine) 5 ( 2.2)
53 (complete) 50 (
22.2) ( failure) 3 ( 1.3)
22 ( complete) 22
( 9.8) 4.11
225
(successful) 195 (
86.7) (unsuccessful) 30 ( 13.3)
 51

4.11

(n = 269)

(n = 225) (n = 44)

(n = 150) (n = 53) (n = 22)

Sputum convert Complete Complete

(n = 118) (n = 50) (n = 22)

Sputum not convert Failure

(n = 27) (n = 3)

Sputum not examine

(n = 5)
 52

4.8 11

1 (patient ID 08005)
54

2HRZE/4HR 10 2554 1 (11
2554) 2

1-2
vitamin B6, bromhexine brown mixture
maculopapular rash

1
( 18 2554)

2 (patient ID 09006)
44

2HRZE/4HR 13 2554 13 (26
2554) 2

1
vitamin B6 maculopapular rash


1. Hydroxyzine (10 mg) 1
2. Loratadine (10 mg) 1 1
3. Calamine lotion
 53

3 14 ( 10 2554)

3 (patient ID 09007)
39

2HRZE/4HR 14 2554 61 (14
2554)

1
vitamin B6
urticaria

betamethasone cream
35 ( 19 2554)

4 (patient ID 09009)
36
Systemic lupus erythematosus
(SLE) 2HRZE/4HR 19 2554
26 (14 2554)

1
vitamin B6 urticaria

 54

rifampicin pyrazinamide
isoniazid ethambutol 2
ofloxacin 1
12 (28 2554)

18HEO
2 rifampicin
pyrazinamide
(causality assessment)
rifampicin pyrazinamide possible

5 (patient ID 12009)
47

2HRZE/4HR 26 2554
2 (28 2554) 2
calamine lotion 3 (31 2554)


1 vitamin
B6 urticaria

hydroxyzine (10 mg) 1 3
rifampicin
isoniazid, pyrazinamide ethambutol
rifampicin
3 (3 2554)
hydroxyzine (10 mg) 1 3
2
1 (4 2554)
 55

6 (patient ID 19009)
42
( allergic rhinitis)
2HRZE/4HR 30 2554
10 (10 2554)

3
vitamin B6
maculopapular rash


1. Chlorpheniramine maleate (4 mg) 1 3
2. Calamine lotion
2 4 (14 2554)
(H, R, Z, E)

1. Chlorpheniramine maleate (4 mg) 1 3
2. 0.1% triamcinolone acetonide lotion
1 ( 15
2554) ( re-challenge)
( sequential re-challenge)
isoniazid 100 mg (2 ), 200 mg
(2 ) 300 mg (3 ) rifampicin 300 mg rifampicin
3
rifampicin isoniazid 300 mg
1. Chlorpheniramine maleate (4 mg) 1 3
2. 0.1% triamcinolone acetonide lotion
 56

3 (25 2554) ethambutol

ethambutol 400 mg (2 ), 800 mg (3 ), 1,200 mg (1 )
pyrazinamide
2 ofloxacin 1
aminoglycoside streptomycin 1 isoniazid

2HEOS/16HE
2 rifampicin
pyrazinamide rifampicin
( causality assessment)
certain pyrazinamide
causality assessment possible

7 (patient ID 20006)
61

2HRZE/4HR 6 2554 3 (9
2554)

1
vitamin B1-6-12, bromhexine, theophylline brown mixture
maculopapular rash
16 (25 2554)

1. Chlorpheniramine maleate (4 mg) 1 2
2. Hydroxyzine (10 mg) 1 2
2 66 (30 2554)

 57

8 (patient ID 20011)
64

2HRZE/4HR 19 2554
38 (26 2554)

1-2
vitamin B1-6-12, doxazosin, theophylline,
folic acid, ferrous fumarate bromhexine


1. Chlorpheniramine maleate (4 mg) 1 2
2. 0.1% triamcinolone acetonide lotion
2 4 (30 2554)

( 4.12) (H, R, Z, E)

1. Chlorpheniramine maleate (4 mg) 1 2
2. 0.1% triamcinolone acetonide cream
3. 0.1% triamcinolone acetonide paste
7 (6
2554)
1. Hydroxyzine (10 mg) 1 2
2. Prednisolone (5 mg) 1 3
3. 0.1% triamcinolone acetonide lotion
4. 0.1% triamcinolone acetonide paste
4 4 (10 2554)

(re-challenge) ethambutol
 58

ethambutol 400 mg (2 ), 800 mg (2 )

1,200 mg (2 )
ethambutol 2
ofloxacin 1 aminoglycoside streptomycin
1
2SEO/16EO
3 isoniazid,
rifampicin pyrazinamide 3
( causality assessment)
possible

4.12 Stevens-Johnson syndrome 8

 59

9 (patient ID 20014)
57

2HRZE/4HR 17 2554 11 (28
2554) 2

1-2
vitamin B 1-6-12 maculopapular rash

4
(25 2554)

10 (patient ID 20015)
46

2HRZE/4HR 18 2554 1
(19 2554) 2

1
glibenclamide vitamin B1-6-12
maculopapular rash

2 (21 2554)
1. Hydroxyzine (10 mg) 1
2. Cetirizine (10 mg) 1 1
3. 0.1% triamcinolone acetonide lotion
 60

3 41 (25 2554)

11 (patient ID 20019)
36

2HRZE/4HR 8 2554 5 (13
2554)

1
vitamin B1-6-12
maculopapular rash


1. Hydroxyzine (10 mg) 1 2
2. 0.1% triamcinolone acetonide lotion
2 10 (23 2554)

5.1
5.2
5.2.1

5.2.2
5.2.3
5.3
5.4
5.5

5.1

1
269
21.6 225
539
10.8/100 person-months ( 95 8.2 13.9)
2.0/100 person-months ( 95 1.0
3.7)

17.5 4.1 maculopapular rash, urticaria
Stevens-Johnson syndrome
12.7 8 ( 0-88 )
3 81.0

61
 62

17.3 maculopapular rash urticaria

1.7 Stevens-Johnson syndrome

89.6 10.4
3

RZE H
HRE Z HEO RZ
55.2 44.8
oral antihistamine, oral
corticosteroid topical corticosteroid
43 ( 74.1)
15 ( 25.9) 15.3 +
14.9 10 ( 0-50 )
16.4 + 13.2 14 ( 0-37 )
6
4 ( re-challenge)
4 sequential re-challenge
isoniazid 3 ethambutol 1 re-challenge
4 (H, R, Z, E)

3 isoniazid,
rifampicin pyrazinamide

2HRZE/4HR 54
4 2SEO/16EO, 2HEOS/16HE,
2HRE/1HREO/7HR 18HEO
225
(successful) 195 ( 86.7)
(unsuccessful) 30 ( 13.3)
 63

5.2

5.2.1

1
isoniazid (H), rifampicin (R), pyrazinamide (Z) ethambutol (E)

21.6

15-453,8-12 1-4314-24 -

2-614,20 incidence density
10.8/100 person-months ( 95 8.2 13.9)
2 Yee
(2003)16 0.25/100 person-months ( 95
0.20 0.30) Marra ( 2007)21 4.1/100
person-months ( 95 4.0 4.3)






( , )
2
4 HRZE
34-40
17.5
Marra ( 2007)21
2.1
 64

Vieira (2008)23
6.0

Koju (2005)17
H, R, Z, E S 38.6
4
H, R, Z E

4.1 Koju (2005)17
4.3 Marra
(2007)21 Vieira (2008)23
7.5 10.8
( continuation phase)



urticaria, maculopapular rash Stevens-
Johnson syndrome
14,17,20-24,49-50,52-54
generalized rash, papulosquaous rash , macular and vesiculobullous rash, morbiliform rash,
erythema multiforme, urticaria, angioedema, exfoliative dermatitis, lichenoid eruption,
leukocytoclastic vasculitis, maculopapular rash, acneiform, papulaosquamous rash,
erythematous/macular rash skin hyperpigmentation


1

13
 65

( intensive phase) 8,10,12,15-16,19,20-21,23
4
21 4
HRZE

21



rash generalized rash22 exanthema
rash23 erythematous/macular rash24



3
2
( intensive phase) 8,10,12,15-
16,19,20-21,23
69-70


4 isoniazid, rifampicin, pyrazinamide, ethambutol
( polypharmacy) 26-28
2

3

81.0
17.3 maculopapular rash, urticaria
 66

1.7 Stevens-Johnson syndrome

25 minor adverse effect major adverse effect
Hartwig SC Siegel J.71
3 (mild reaction)
( moderate reaction)

1 ( severe reaction)

1
20 mild reaction
10 moderate reaction
10 30
severe reaction 30
( guideline)
2
25

Philadelphia 199841 flushing /
/ hives (raised, itchy rash)
ATS 200342
generalized erythematous rash
( ) ( WHO 2009)2

South Africa45
maculopapular rash
( guideline)



 67

2,21,41-45 /
calamine2,21

1
2,21,41-45,70

5.2.2


antihistamine

/
1

70,71,72

3


3
1



10
8
maculopapular rash urticaria

1
Stevens-Johnson syndrome
 68

Stevens-Johnson
syndrome 1-573-74

25




55-57,60-
65,70-71
75-76 antihistamine
histamine
(H1- receotor) histamine
histamine
histamine first-generation antihistamine
(sedative antihistamine) chlorpheniramine maleate, diphenhydramine, hydroxyzine
second-generation antihistamine (non-sedative antihistamine) cetirizine, loratadine
antihistamine 2
1
antihistamine
2 H1-receptor
1
corticosteroid
76
dexamethasone, prednisolone, hydrocortisone, triamcinolone acetonide,
betamethasone type III
(immune complex hypersensitivity reactions) type IV (delayed hypersensitivity reactions)
IgE-mediated immediated hypersensitivity reactions ( type I )

exfoliative dermatitis63, Stevens-Johnson syndrome73-74
 69

calamine lotion
25,41-43,44,47
antihistamine, corticosteroid calamine lotion
42




antihistamine corticostaroid


3-5




/
3 aminoglycoside 1 2 25,42-43

3 1 1 1

3-7 3
3
2 ( H
RZE, Z HRE) 1 RZ
HEO ( bactericidal activity)
(HRZE)77

( 2 ) bactericidal activity
SHRZ ( 95) SHRE ( 81)
 70

3 SHR SHZ
80 1-2
50 ( HRZE)
3 2
1 streptomycin 25
ATS 20032003 fluoroquinolone
78-82 ciprofloxacin, levofloxacacin,
moxifloxacin, ofloxacin (O) sparfloxacin
82
ofloxacin ciprofloxacin78
1 81
ofloxacin 1 H R
1 H R Z E
278
fluoroquinolone (Multidrug-resistant tuberculosis;
MDR-TB)
178,81
3 RZE, HRE
HEO streptomycin


74.1
/




50
15 ( 0 - 50 ) 1
2
 71

1 14
urticaria angioedema


( urticaria)
(angioedema)
24 60-62 Stevens-Johnson syndrome toxic epidermal necrolysis
2-6
55,65



urticaria angioedema
Stevens-Johnson syndrome
urticaria angioedema maculopapular rash
Stevens-Johnson syndrome toxic epidermal necrolysis





51-52,54 200348
( sequential re-challenge)
isoniazid rifampicin

ethambutol15,20,24,83 isoniazid rifampicin
14,16
pyrazinamide15,20,24

 72

desensitization 1 10
41,46

re-challenge

4 H, R, Z, E S
2


6 4 4
sequential re-challenge
isoniazid
3 ethambutol 1 isoniazid
Philadelphia Tuberculosis control program
199841, TB/HIV A clinical manual 200443, Tomans Tuberculosis 200444
South Africa 200945
ethambutol
isoniazid
isoniazid 1
2 ethambutol
25

(de-challenge)
(re-challenge)56-57 4
 73

25

4





WHO
criteria

5.2.3

94.1
2 4 2SEO/16EO, 18HEO, 2HEOS/16HE
2HRE/1HREO/7HR Vasankari (2007)5

HRE HRS (failure, death, default,
physician's decision to stop early transfer out) HRZ (adjusted OR 5.97, 95%
CI 2.92-12.20) Szklo (2007)84
3SEO/9EO
85
fluoroquinolone

0.4-2.185-86
2,42,78,81
 74

5.3

5.3.1





5.3.2

5.3.3

5.4

5.5

 75

 76

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48. World Health Organization. Treatment of tuberculosis: guidelines for national
programmes. WHO/CDS/TB/2002.313. Geneva, Switzerland : WHO, 2003.
49. . Ethambutol induced Exfoliative Dermatitis.
. 2551;10(3):25-6.
50. . Maculopapular rash due to anti-
tuberculosis drug allergy. . 2553;13(1):12-6.
51. Kishore PV, Palaian S, Prabhu S, Prabhu M, Mishra M. Drug induced maculopapular rash
with the commonly used first line antitubercular drug, Pyrazinamide. The Internet Journal
of Dermatology. 2007; 5(1): Available:http://www.ispub.com/ostia/index.php?
xmlPrinter=true&xmlFilePath =journals/ijd/vol5n1/rash.xml. (Accessed: 2010, May 4).
52. Garg R, Verma AK, Mahajan V, Prasad R. Exfolative dermatitis secondary to Ethambutol
and Pyrazinamide. The Internet Journal of Pulmonary Medicine. 2007;9(1): Available:
http://www.ispub.com/ostia/index.php?xmlFilePath=journals/ijpm/vol9n1/ dermatitis.xml.
(Accessed: 2010, May 4).
 81

53. Kim JH, Moon JI, Kim JE, Choi GS, Park HS, Ye YM, Yim H. Cutaneous leukocytoclastic
vasculitis due to anti-tuberculosis medications, rifampin and pyrazinamide. Allergy Asthma
Immunol Res. 2010;2(1):55-8.
54. Dua R, Sindhwani G, Rawat J. Exfoliative dermatitis to all four first line oral anti-
tubercular drugs. Indian J Tuberc. 2010;57(1):53-6.
55. . :
(skin disorder) . 3 . :
; 2550.
1-19.
56. , . Adverse drug reaction.
: .2550.
57. , . Adverse drug reaction
2. :.2551.
58. Weedon D, Strutton D. Skin pathology/David Weedon.Churchill Livingstone. USA. 1997.
59. Tivoli Y.A, Rubenstein R.M. Pruritus: An update look at an old problem. J Clin Aesthet
Dermatol. 2009;2(7):306.
60. Poonawalla T, Kelly B. Urticaria - A Review. Am J Clin Dermatol. 2009;10(1): 9-21.
61. Urticaria. Avalilable: http://en.wikipedia.org/wiki/Urticaria. (Accessed: 2010, November
3).
62. Limsuwan T, Demoly P. Acute Symptoms of Drug Hypersensitivity (Urticaria,
Angioedema, Anaphylaxis, Anaphylactic shock. Med Clin N Am. 2010; 94: 691710.
63. CPG for Exfoliative Dermatitis. Institutue of Dermatology. Available at: URL:
http://www.inderm.go.th/inderm_th/Research/CPG/3.Exfoliative.pdf. (Accessed: 2010,
November 3).
64. Lamoreux M, Sternbach MR, HSU WT. Erythema Multiforme. Am Fam Physician. 2006;
74(11):1883-8.
65. French LE. Toxic epidermal necrolysis and Stevens Johnson syndrome: our current
understanding. Allergol Int. 2006;55(1):9-16.
66. Martin T, Li H. Severe cutaneous adverse drug reactions: a review on epidemiology,
etiology, clinical manifestation and pathogenesis. Chin Med J (Engl). 2008;121(8):756-61.
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67. Sullivan JR, Shear NH. Drug eruptions and other adverse drug effects in aged skin. Clin
Geriatr Med. 2002;18(1):21-42.
68. Johansson SG, Hourihane JO, Bousquet J, Bruijnzeel-Koomen C, Dreborg S, Haahtela T,
et al. A revised nomenclature for allergy. An EAACI position statement from the EAACI
nomenclature task force. Allergy. 2001;56(9):813-24.
69. Demoly P. Anaphylactic reactions-value of skin and provocation tests. Toxicology.
2005;209(2):221-3.
70. Riedl MA, Casillas AM. Adverse drug reactions: types and treatment options. Am Fam
Physician. 2003;68(9):1781-90.
71. Hartwig SC, Siegel J, Schneider PJ. Preventability and severity assessment in reporting
adverse drug reactions. Am J Hosp Pharm. 1992;49(9):2229-32.
72. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE)
version 4.02. Bethesda, MD, USA:National Institutes of Health, 2009.
73. Harr T, French LE. Toxic epidermal necrolysis and Stevens-Johnson syndrome. Orphanet
Journal of Rare Diseases. 2010;5(39):1-11.
74. French LE. Toxic epidermal necrolysis and Stevens Johnson syndrome: our current
understanding. Allergol Int. 2006;55(1):9-16.
75. del Cuvillo A, Mullol J, Bartra J, Dvila I, Juregui I, Montoro J, et al. Comparative
pharmacology of the H1 antihistamines. J Investig Allergol Clin Immunol. 2006;16(S1):3-
12.
76. Heasman SJ, Giles KM, Ward C, Rossi AG, Haslett C, Dransfield I. Glucocorticoid-
mediated regulation of granulocyte apoptosis and macrophage phagocytosis of apoptotic
cells: implications for the resolution of inflammation. J Endocrinol. 2003;178(1):29-36.
77. Jawahar MS. Current trends in chemotherapy of tuberculosis. Indian J Med Res.
2004;120(4):398-417.
78. Alangaden GJ, Lerner SA. The clinical use of fluoroquinolones for the treatment of
mycobacterial diseases. Clin Infect Dis. 1997;25(5):1213-21.
79. Vacher S, Pellegrin JL, Leblanc F, Fourche J, Maugein J. Comparative antimycobacterial
activities of ofloxacin, ciprofloxacin and grepafloxacin. J Antimicrob Chemother.
1999;44(5):647-52.
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80. Berning SE. The role of fluoroquinolones in tuberculosis today. Drugs. 2001;61(1):9-18.
81. Manika K, Kioumis L. The role of fluoroquinolones in the treatment of Tuberculosis.
pneumon. 2008;4(21):395-401.
82. Ziganshina LE, Squire SB. Fluoroquinolones for treating tuberculosis (Review). The
Cochrane Library (1) 2009. Chichester, UK: John Wiley & Sons,Ltd.
83. Lehloenya RJ, Todd G, Badri M, Dheda K. Outcomes of reintroducing anti-tuberculosis
drugs following cutaneous adverse drug reactions. Int J Tuberc Lung Dis.
2011;15(12):1649-57.
84. Szklo A, Mello FC, Guerra RL, Dorman SE, Muzy-de-Souza GR, Conde MB. Alternative
anti-tuberculosis regimen including ofloxacin for the treatment of patients with hepatic
injury. Int J Tuberc Lung Dis. 2007;11(7):775-80.
85. Mandell L, Tillotson G. Safety of fluoroquinolones: An update. Can J Infect Dis.
2002;13(1):54-61.
86. Stahlmann R. Safety profile of the quinolones. J Antimicrob Chemother. 1990;26 Suppl
D:31-44.
 84

 75

1 ()

, / , /
() () CADR ( ) ADR
1 308 Prospective study 128 ( 41.6) 2
, 2536 () ( ( ) (All ADR) /
)
2 160 Prospective study 71 ( 44.4) 1-2 /
, 2537 () ( ( ) (All ADR)
)
3 226 Prospective study 36 ( 15.9) 1 /
, 2539 () () ( ) (All ADR)
4 138 Retrospective study 24 ( 17.4) / pyrazinamide
, 2543 () (review record) ( )
5 200 Prospective study 34 ( 17.0) 2 /
, 2545 () () ( ) (All ADR)

*
CADR = Cutaneous adverse drug reaction

85
 76

, / , /
() () CADR ( ) ADR
6 500 Retrospective study 77 ( 15.4) /
, 2552 () (review record) ( )
7 673 Retrospective study 132 ( 19.6) 37.5 ( 86.8
, 2553a () (review record) ( 88.8, ( 21 ,
61.2, 1-274 ) HRZE)
erythematous papule
22.8, maculopapular
rash 18.9,
urticaria/angioedema
9.5, erythema
multiforme 2.7,

43.2)
a

86
 77

2 ( )
, / , /
() () CADR ( ) ADR
1 Kothari et ala , 1989 1008 Prospective study/ 18 ( 1.8) Challenge testb/
() fortnightly interval (papulaosquamous rash, H 5 (27.8)
followed up acneiform, macular and E 4 (22.2)
vesiculobullous rash) R 2 (11.1)
S 1 (5.6)
2 Ormerod et al (1996) 1317 retrospective study 31 87 Challenge test/
() and prospective study ( 2.4) 4 Z = 26
( ) ADR R = 4
9 E = 1
3 Yee D et al, 2003 430 Prospective study 21 (4.9) 2 Challenge test/
() ( ) (All ADR) H 4 (1)
R 10 (2)
Z 9 (2)

87
 78

, / , /
() () CADR ( ) ADR
4 Koju et al, 2005 70 Prospective cohort 30 ( 42.9) Challenge test/
() study (itching without rash 27
, rash 3 )
5 Nahar et al, 2006 34 Prospective study 3 ( 15.0) /
() ( )
6 Gholami et al, 2006 83 Prospective study 4 ( 4.8) 71.6 / R (
( ) ( ) 10 )
(All ADR)
7 Tan et ala , 2007 820 Retrospective study 47 ( 5.7) 97.0 Challenge test/
( ) 2 H 8 (0.98)
(Morbiliform rash 34 (ADR ) R 10 (1.23)
Erythema multiform 4 E 7 (1.44)
Urticaria 4 Z 18 (2.38)
exfoliative dermatitis S 4 (1.45)
lichenoid eruption 5 )

88
 79

, / , /
() () CADR ( ) ADR
8 Marra et al, 2007 1061 Prospective study 102 ( 9.6) 150 Challenge test/
() (rash 80 , pruritus 22 (All ADR)
)
9 Chhetri et al, 2008 137 Prospective study 29 ( 21.2) /
() () (Generalized
itching/itching rash)
10 Vieira et al , 2008 297 Retrospective study 50 ( 16.8) 58.4 Challenge test/
( ) (exanthema 19 , 2
pruritus 18 , acne 11 ADR
, alopecia 1 , skin 6
hyperpigmentation 1 ) (All ADR)
11 Kishore et al , 2008 326 Retrospective study/ 3 ( 0.9) - Challenge test /
() review record (erythematous/macular H 32 (32.32)
rash) Z 32 (32.32)
R 31 (31.31)
E 3 (3.030

89
a

b
challenge test (de-challenge) ( re-challenge)
 80

3 ()
,

1 Kishore, HRZE 11 - 1. pyrazinamide
2007 2.
3. WHO 2003
2 Garg R. et al, HRZE 1 20 Exfoliative dermatitis 1. ethambutol
2007 2. pyrazinamide
3. WHO 2003
3 , HRZES 1 Exfoliative dermatitis 1. ethambutol
2008 2.
- CPM 10 mg.
CPM 4 mg. 3 prednisolone 5
mg. 3
3.
4. HRZO (O=ofloxacin)

90
 81

,

4 ,2010 HRZE 1 Maculopapular rash 1. -
2. CPM 4 mg. X 3
hydroxyzine 10 mg. X 3
5 Kim JH. et al, HRZE 1 Leukocytoclastic 1. rifampicin
2010 vasculitis 2. prednisolone 20 mg. 3 pyrazinamide
3. levofloxacin 500 mg.
4.
HELK ( L= levofloxacin, K= kanamycin)
6 Dua R. et al, HRZE 8 Exfoliative dermatitis 1. HRZE
2010 2. corticosteroid 1 mg/kg
3.

WHO 2003

91
 82

4
1 2 3 4 5 6 7
(Thai NTP, 2551) (TB/HIV, 2004) (Philadelphia 1998) (ATS 2003) (WHO 2009) (Tomans, 2004) (South Africa, 2009)
1

1. 1. 1. 1. 1. 1. 1.
flushing /
2. 2. generalized 2. MP rash
2. 2. erythematous rash pruritus
/ ( 2. 2.
(generalized hives (raised,
erythematous rash) exfoliative dermatitis, itchy rash) )
toxic epidermal 3. Petichial rash
necrolysis, mucous
membrane thrombocytopenia
involvement, rifampicin

92
 83

1 2 3 4 5 6 7
(Thai NTP, 2551) (TB/HIV, 2004) (Philadelphia 1998) (ATS 2003) (WHO 2009) (Tomans, 2004) (South Africa, 2009)
2
2.1
1. 1. 1. 1. 1. 1.

2. 2. 2. 2. 2. 2. TB
3.
calamine 3. 3.

3. 4.

93
 84

1 2 3 4 5 6 7
(Thai NTP, 2551) (TB/HIV, 2004) (Philadelphia 1998) (ATS 2003) (WHO 2009) (Tomans, 2004) (South Africa, 2009)
2 ( )
2.2.

1. TB 1. TB 1. TB 1. generalized TB 1. TB TB
re- re- erythematous rash
challenge challenge TB 2. re-challenge
(re-challenge) 2. 2. corticosteroids
2. Petichial rash
(Ebstein-Barr
Herpes Simplex)
3. intravenous rifampicin
fluids

94
 85

1 2 3 4 5 6 7
(Thai NTP, 2551) (TB/HIV, 2004) (Philadelphia 1998) (ATS 2003) (WHO 2009) (Tomans, 2004) (South Africa, 2009)
3
1. 1. - 1.

Chlorpheniramine 2. diphenhydramine 25 2.Corticosteroid diphenhydramine
mg 4-6 ,
2. prednisolone 60 mg chlorpheniramine prednisolone 25-50 mg.
0.1% 4 mg 4-6 40-60 mg
TA cream 3.
3.
intravenous
prednisolone hydrocortisone 100-
2-3 200 mg

95
 86

1 2 3 4 5 6 7
(Thai NTP, 2551) (TB/HIV, 2004) (Philadelphia 1998) (ATS 2003) (WHO 2009) (Tomans, 2004) (South Africa, 2009)
4



2
2 3
() (
aminoglycoside
3
( 2 )
)

5 (rechallenge)
1 1 1 1 1 1 1

96
 87

1 2 3 4 5 6 7
(Thai NTP, 2551) (TB/HIV, 2004) (Philadelphia 1998) (ATS 2003) (WHO 2009) (Tomans, 2004) (South Africa, 2009)
6
1. E 1. 1. H 1. H R 1. H->R->Z->E->S
R->H->Z R->Z->E->S
H 3
2-3 R->Z->E->S ( 3 ) H
2. R->Z->E
2. 2. R H->E- 3 2.
>Z ( H 50 mg. 3
3 ( 1 2-3 ) 3 3.
H= 50 mg, 2 H 2.
3 3. re- = 300 mg, 3 (
challenge 2, 4 3
R 75 mg)
2 3. 3 )
4. 4.
1 10 4. 3

97
 88

1 2 3 4 5 6 7
(Thai NTP, 2551) (TB/HIV, 2004) (Philadelphia 1998) (ATS 2003) (WHO 2009) (Tomans, 2004) (South Africa, 2009)
6 ()

4
recurrence 4.
5.

98
 99

.............................................
..................................... 2554

..................................... ..
............................................................................

1.

2.

3.

4.

5.

.............................................
(.............................................................)
 100

-
, 12
. .
.

2
/











 101

250



2

90112 074-213057 074-212906, 074-282000 8909,
8934

(081-540-0399)
 102

..............................................................................................
( / ).
2 / (/ )..


/
(/ ) ....


2



,


074 213057

/
1

..... ... /
....
 103

1 ( )

A. // ......../............./.......

A1 Patient ID [ ] [ ] [ ] [ ] [ ] [ ][ ][ ][ ][ ]
A2 ............................... [ ][ ]
A3 ........................ [ ][ ]
A4 1. 2. [ ]
A5 // .........../............./............ [ ] [ ]/ [ ] [ ]/ [ ] [ ] [ ][ ]
A6 1. 2. 3. [ ]
A7 1. 2. [ ]
A8 [ ]
1.
2.
3.
4.
5.
6.
7.
8.
9. ...........................................................................................
A9
1. ................................... [ ]
2. 2.1 H .........................mg/ [ ]
2.2 R ........................mg/ [ ]
2.3 Z ........................mg/ [ ]
2.4 E ........................mg/ [ ]
2.5 S ........................mg/ [ ]

A10 [ ]
1. 2.
 104

A11
1. HIV [ ]
2. DM [ ]
3. Hypertension [ ]
4. Allergic rhinitis () [ ]
5. Dermatitis (eczema) () [ ]
6. asthma [ ]
7. SLE [ ]
8. Rheumatoid arthritis (RA) [ ]
9. (......................................) [ ]
A12 ( ) [ ]
1. ().............................................................................
2.
A13 [ ]
1. 1. ................................................................
2. .................................................................
3. .................................................................
2.
A14 , [ ]
1. /
2.
3.
4. .................................................................

[ ]
1. (certain definite)
2. (probable)
3. (possible)
4. ..........................................................
A15 [ ]
1. 2. 3.
A16 ( 1 ) [ ]
1. 2. 3. / 4. 4. (................)
 105

A17 [ ]
1. 2.
A18 [ ]
2.1 ( ) [ ]
2.2 ( )
2.3 () ....................................................................................
2.4 () ..................................................................................
2.5 ............................................................................................
A 19 ( ) [ ]

1. ( 2) 2.
 106

B. ( )
Patient ID [ ] [ ] [ ] [ ] [ ]
B1 .............../............../................. [ ] [ ]/ [ ] [ ]/ [ ] [ ] [ ] [ ]
B2 // ............/.........../............. [ ] [ ]/ [ ] [ ]/ [ ] [ ] [ ] [ ]
B3 [ ]
1. sputum convert
2. sputum not convert
3. sputum not examined
4. died
5. default
6. transfer out (. ......................................................... )
7. others
B4 [ ]
1.
2.
3.
4.
5. > 2
6. (. ......................................................... )
 107

Patient ID [ ] [ ] [ ] [ ] [ ]

1:

 96

eczema, xerosis, seborrhaic dermatitis, acne,
fungal infection, HIV with PPE

< 1 hour > 1 hour

(immediate) (non-immediate)

2 4 :
* , a
(delayed urticaria, MPE ) * - Severe MPE
* (urticaria, angioedema) * 3 - MPE
* * Lab : CBC, LFT, Cr, UA - Vasculitis
* - - Exfoliative dermatitis
() 1 - - ..
(graded challenge)
Anaphylaxis * beta-lactam, ASA-NSAIDs ACE-inhibitor AGEP, SJS-TEN, DRESSa
1.
2 structure related
()3 2.
FDEa
1. structure related graded challenge
2. 1.
3. desensitization ( ) Structure related
2.

108
 109

:
1
anaphylaxis : Limsuwan T, Demoly P. Acute
Symptoms of Drug Hypersensitivity (Urticaria, Angioedema, Anaphylaxis, Anaphylactic shock).
Med Clin N Am. 2010; 94: 691710.
2
- beta-lactam ( )
graded challenge
- ASA/NSAIDs-urticaria, angioedema asthma pseudoallergy
COX enzyme conventional NSAIDs specific COX-2 inhibitor
1-3 NSAIDs

- ACE-inhibitor-induced angioedema pseudoallergy

ACE-inhibitor Angiotensin-II-receptor antagonist
3

a
FDE: Fixed drug eruption, SJS: Stevens-Johnson syndrome, TEN: Toxic epidermal necrolysis,
AGEP: Acute generalized exemthematous pustular, MPE : Maculopapular exanthema,
DRESS: Drug rash with eosinophilia and systemic symptoms
 110

Drug reaction with eosinophilia and systemic symptoms
(DRESS)

Diagnostic criteria for drug-induced hypersensitivity syndrome (DIHS) established by a

Japanese consensus group
1. Maculopapular rash developing > 3 weeks after start in with a limited number of drugs
2. Prolonged clinical symptoms 2 weeks after discontinuation of the causative drug
3. Fever (> 38 C)
4. Liver abnormalities (alanine aminotransferase > 100 U L- 1)a
5. Leucocyte abnormalities (at least one present)
a. Leucocytosis (> 11 X 109 L-1)
b. Atypical lymphocytosis (> 5%)
c. Eosinophilia (> 1.5 X 109 L-1)
6. Lymphadenopathy
7. Human herpesvirus 6 reactivation

The diagnosis is confirmed by the presence of the seven criteria above (typical DIHS) or of the
five (1~5) (atypical DIHS).
a
This can be replaced by other organ involvement, such as renal involvement.
Reference
1. Shiohara T., Iijima M., Ikezawa Z.and Hashimoto K. The diagnosis of a DRESS syndrome has
been sufficiently established on the basis of typical clinical features and viral reactivations. J
Cutan Pathol. 2001; 28:113-9.
 111

Acute generalized exanthematous pustulosis
(AGEP)

AGEP R/O infection

AGEP
1) an acute pustular eruption
2) fever above 38C
3) neutrophilia with or without a mild eosinophilia
4) subcorneal or intraepidermal pustules on skin biopsy
5) spontaneous resolution in less than 15 days
Reference
1. Sidoroff A., Halevy S., Bavinck JM and et al. Acute generalized exanthematous pustulosis a
clinical reaction pattern. J Cutan Pathol. 2001; 28:113-9.
 112

Stevens - Johnson syndrome (SJS)
Toxic epidermal necrolysis (TEN)

SJS TEN
3 pattern of individual skin lesions,
distribution of lesion, and maximum extent of detachment of the epidermis during the course of
the disease
Pattern of lesion Distribution Extent of blisters/
detachment,%
Erythema multiforme majus Typical targets, Localized (acral) < 10
(EMM) raised atypical targets
Stevens-Johnson syndrome Blisters on macule, Widespread < 10
(SJS) flat atypical targets
Overlap SJS-TEN Blisters on macule, Widespread 10-29
flat atypical targets
Toxic epidermal necrolysis Blisters on macule, Widespread > 30
(TEN) with spots flat atypical targets
TEN without spots No discrete lesion, Widespread > 10
large erythematous areas

Reference
1. Auquier-Dunant A., Mockenhaupt M., Naldi L. and et al. Correlations between
clinical patterns and causes of Erythema multiforme majus, Stevens-Johnson syndroeme, and
Toxic Epidermal Necrolysis. Arch Dermatol. 2002; 138: 1019-1024.
 113

2 ( )
C. Patient ID [ ][ ][ ][ ][ ]
C1 ( 1 ) [ ]
1. (// ......../............/..........)
2. (// ......../............/..........)
C2 , [ ]
1.
2. ( 3) [ ]
/ .....................
C3 , [ ]
1.
2. ( 3 4) [ ]
/ ......................
C4 , ( ) [ ]
immediate ( < 1 )
non-immediate ( > 1 )
C5 immediate type ............................. ................. [ ]
anaphylaxis
anaphylaxis [ ]
1. ////Oxygen sat.drop
2 . ///
3. ...................mmHg
C6 non-immediate type,
1. 1. 2. (...........C, // ......./. ......../.... .....) [ ]
2. 1. 2. (// .. ..../......../.... .....) [ ]
[ ]
C7 non-immediate type,
1. CBC
- WBC = ......( 5-10 x 103 /uL) 1. 2. [ ]
- Lymphocytes = ..( 20-50%) 1. 2. [ ]
- Eosinophil = ..........................( 1-3%) 1. 2. [ ]
 114

- Platelet count =...( 1.5-4 x 105 cell/mm3 ) 1. 2. [ ]

2. Liver function test
- AST (AST = .....; 0-40 U/L) 1. 2. [ ]
- ALT (ALT =. ; 0-35 U/L) 1. 2. [ ]
- ALP (ALP = .......; 35-110 U/L) 1. 2. [ ]
- Total bilirubin (Tol.bili = ............. ..; 0.1 - 1.0 mg%) 1. 2. [ ]
- Direct Bilirubin (Tol.bili = .......... ..; 0.1 0.3 mg%) 1. 2. [ ]
3.
- BUN (BUN =...; 12-20 mg/dl) 1. 2. [ ]
- Cr (Cr =...; 0.6-1.4 mg/dl) 1. 2.
- Urine analysis 1. 2. .. [ ]
4. [ ]
- Skin biopsy 1. 2. ..................................................
- ....................................................................................................................... [ ]

C8 [ ][ ]
1. Urticaria 2 angioedema 3. Maculopapular rash
4. Eczematous rash 5. Fixed Drug Eruption 6. Vasculitis
7. Erythema multiforme 8. Exfoliative dermatitis 9. Pethichial rash
10. Bullous drug eruption 11. Photosensitivity drug eruption
12. Stevens-Johnson Syndrome 13. Toxic Epidermal Necrolysis
14. Acute generalized exanthematous pustulosis (AGEP)
15. Drug Reaction with Eosinophilia and Systemic symptoms (DRESS) syndrome
16. ..
 115

Patient ID [ ] [ ] [ ] [ ] [ ]
2:

 116

3 ( )
. ..............
D. CADR (cutaneous ADRs) Patient ID [ ] [ ] [ ] [ ] [ ]
// (mg/) CADR,
H R Z E ( ,
CPM (4mg) 1X3 pc 14 /, / )

116
 117

(WHO criteria)

Certain ( ): (
)
1. ()
2.
3. ()

4.

Probable ( ): (
)
1. ()
2.
3. ()

4.
Possible ( ): (
)
1. ()
2.
3. ()
Unlikely ( ): (
)
1. ()
2.