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Management

g
ofreactionsto tuberculosis drugs
g

..

?
?
TB

cat. 1 5

?
?
Underlying HIV
Start GPO-vir 2 wks
OI
Bactrim 1 wk
pul TB
HRZE
1

?
?
anti-TB HRZE
1

?
?
anti-TB HRZE
1

?
?


50
.45
45 kg

anti-TB drugs (H 300, R 450, Z 1250, E


800 OD hs
1



SGOT/SGPT 229/ 195 U/L, TB/DB 3.2/1.7 mg/dl, ALP
220 U/L

ADR anti-TB

TB

TB underlying
d l
d
dz





ADR
TB

ADR

1st line drug





ADR

ADR

ADR anti-TB

anti-TB


anti-TB
i TB

ADR
----- > ADR & TB

(single agent)
(fixed dose combination: FDC)




monotherapy



ADR

1st line drug

Isoniazid

I or H

Tab 100 mg

5 mg/kg/day (max 300 mg)

Rifampicin

Cap 300, 600 mg


Tab 450 mg
Syr 100 mg/5 ml

>50 kg: 600mg/day


<50 kg: 450 mg/day

Pyrazinamide

Tab 500 mg

20-30 mg/kg/day (max 2 gm)

Ethambutol

Tab 400, 500 mg

15-25 mg/kg/day (max 2.5 gm)

Streptomycin

Inj 1 gm

> 50 kg: 1 gm/day


<50 kg: 750 mg/day
60 :

: 750 mg/day


1st line drug

2nd line drug

Kanamycin

Inj 1 gm

15 mg/kg/day
IM 1

Ofloxacin

Tab 100,
100 200,
200 300
mg

7.5
7
5-15
15 mg/kg/day
1-2

Ethionamide

Ethi

Tab 250 mg

10-20 mg/kg/day

2-3
2 3

Cycloserine

Cs

Tab 250mg

10-20 mg/kg/day
2-3

Para-Amino Salicylic P
acid

Tab 1 gm

200 mg/kg/day
2

Amikacin

Inj 250,
250 500 mg

15 mg/kg/day
IM 1

Fixed dose combination: FDC

Trade name

Generic name

Tablets for patient >


50 kg

Rifinah150
Rifinah300

Rifam150/INH100
Rifam300/INH150

3-4 tabs
2 tabs

Rimactazid300/150
Rimactazid150/75

Rifam300/INH150
Rifam150/INH75

2 tabs
4 tabs

Rifampyzid
Rifater

Rifam120/INH80/PZA250mg
Rifam120/INH80/PZA250mg

Rifafour ee-275
275

Rifam150/INH75/PZA400/ ETB275 mg

4 tabs

Rimstar4-FDC

Rifam150/INH75/PZA400/ ETB275 mg

4 tabs

4 tabs
tabs+(ETB
(ETB 2)

ADR

ADR
1

48
cat 1 (2HRZE/4 HR) dose



3

?
.

. rechallenge
.

. domperidone

ADR


5.5-20% cat.1
pyrazinamide (5.8%)


rifampicin
ethionamide
para-aminosalicylic acid (PAS)
fluoroquinolones

ADR

split dose

domperidone

PZA 1500 mg OD 500 mg TID + domperidone


1 tab TID

1

ADR ADR

2547; 25(1): 29-33

ADR
1

48
cat 1 (2HRZE/4 HR) dose


3


?
.

. rechallenge
.

. domperidone

ADR
2


45


cat 1 (2HRZE/4
HR) 5

ADR
2

ADR





13.8-40%




mucous membrane involved
1.3%


mucous membrane
b
involved
i
l d

ADR




exclude

anti
antihistamine CPM, hydroxyzine
anti-histamine 3
prednisolone 5 mg BID 5
continue anti-TB drug




ADR




oral antihistamine
topical corticosteroids


rechallenge
SJS, TEN, exfoliative dermasitis
systemic corticosteroids

ADR

rechallenge








2-3
2 3

rifampicin


INH,

INH ethambutol PZA

3
4

: ATS, CDC, IDSA 2003

ADR
Reintroduction of anti-TB
anti TB drugs following drug rash
Drug

Challenge dose
Day 1

Day 2

Day 3

INH

50

300

300

RMP

75

300

Full dose

PZA

2 0
250

1 gm

Fullll dose
d

EMB

100

500

Full dose

SM

125

500

Full dose

: WHO. TB/HIV a clinical manual, 2nd edition.

ADR
Desensitization of anti
anti-TB
TB drugs following drug rash
1 10
1 10
10
desensitization
desensitization anti-TB drugs


desensitization
INH --- > EMB --- > RMP

: WHO. TB/HIV a clinical manual, 2nd edition.

ADR
2

ADR
3

36 55 kg underlying dz. HIV


10

INH (100) 3 tab hs + R (300) 2 cap hs + Z (500) 3 tab hs
+ E (400) 3 tab hs .

ADR
3

: mild jaundice
U/S: mild hepatosplenomegaly
:
Lab (normal)

Admission

Day 6

Day 12

AST (10-30 U/L)

142

119

88

ALT (9-43
(9 43 U/L)

60

72

80

ALP (35-110 U/L)

465

339

304

TB (0
(0.2
2-1
1.5
5 mg/dl)

22
2.2

45
4.5

62
6.2

DB (0.5-0.8 mg/dl)

1.3

2.47

3.45

immunology: Anti
Anti-HAV
HAV IgM,
IgM HBsAg,
HBsAg
HBeAg, Anti-Hbc, anti-HCV -----> negative

ADR

3
hepatotoxic TB
Liver enzyme function test > 5 upper normal limit
upper normal limit
Liver enzyme function test > 3


hepatitis



: 2551

ADR

3
hepatotoxic ?
Liver enzyme function test > 3 upper normal limit


hepatitis

Lab (normal)

Admission

Day 6

Day 12

AST (10-30 U/L)

142

119

88

ALT (9-43 U/L)

60

72

80

ALP (35-110 U/L)

465

339

304

TB (0.2-1.5
(0 2
mg/dl)
/dl)

22
2.2

4.5

62
6.2

DB (0.5-0.8 mg/dl)

1.3

2.47

3.45

ADR

3
hepatotoxic ?


j
:
--- > mild jaundice
lab
--- > AST 142/30
= > 4.73 ,
ALT 60/43
=> 1.39 ,
ALP 465/110
= > 4.23
4 23 ,

TB 2.2/1.5
= > 1.47 ,
DB 1.3/0.8
= > 1.63
immunology: Anti-HAV
Anti HAV IgM,
IgM HBsAg,
HBsAg HBeAg,
HBeAg
Anti-Hbc, anti-HCV -----> negative
U/S
--- > mild hepatosplenomegaly

--- >

ADR

3
hepatic injury ?

ADR

3
hepatic injury ?
R ratio = (ALT/ULN)
(ALP/ULN)

= 1.39/4.23 = 0.33

ADR
Fact about anti
anti-TB
TB drug
drug-induced
induced hepatotoxic
INH, Rifampicin PZA


eosinophil

--- >

INH
toxic metabolite
Rifam bilirubin reuptake
hepatocyte
INH+Rifam > INH alone
rifam enzyme inducer reactive
metabolite INH hepatoxic
PZA fulminant hepatic failure --- > doserelated

ADR
Risk Factors anti
anti-TB
TB drug
drug-induced
induced hepatotoxic

Advanced age
Alcoholism
Previous significant liver abnormalities
HBV HCV
HBV,
HCV, HIV infection
Malnourish

ADR
Fact about INH
INH-induced
induced hepatotoxic
onset ---- > 8-12

AST/ALT --- > 10-20%



N/V


~ 0.101
0.6%
INH


~ 0.023%

ADR
INH induced hepatotoxic
INH-induced
INH
acetylation
Acetyl-isoniazid
hydrolysis
Acetylhydrazine

acetylation

Oxidation (CYP 450)

Diacetylhydrazine

Reactive metabolite
(hepatotoxic)

ADR
Risk factors for INH
INH-induced
induced hepatotoxic

Acetylator phenotype
Age > 35 years
Alcoholism
Concurrent rifampicin use
female
pre-existing liver disease
pregnancy (>2-4
(>2 4 )
)
hepatotoxic

ADR
Fact about Rifampicin-induced
Rifampicin induced hepatotoxic
onset ---- > 2
liver injury
cholestasis
INH
20% earlier onset

ADR
Fact about Pyrazinamide-induced
Pyrazinamide induced hepatotoxic
most severe case 1
dose-dependent
1% standard dose 10-20% 40-50
mg/kg/dose
~20%

~ 10%

liver injury hepatocellular hepatitis

ADR
3

36 55 kg underlying dz. HIV 10


INH (100) 3 tab


t b hs
h + RMP
(300) 2 cap hs + PZA (500) 2 tab hs + ETB (400) 2 tab hs
.
2

?
.

. rechallenge
. INH
. rifampicin
monitor
LFT

. PZA 1500 mg 1000 mg/day

ADR
Anti-TB

Anti TB drugs induced liver injury







3-5

LFT

: 2551

ADR
Anti-TB

Anti TB drugs induced liver injury



TB


streptomycin + ethambutol

q
quinolone

: 2551

ADR
rechallenge anti

anti-TB
TB

rechallenge
LFT < 2
g/
TB < 1.5 mg/dl

Challenge dose
1

INH

100

200

300

RFP

150


10 MKD

PZA

500



25 MKD

3
monitor LFT
normall

LFT normal

+ add ETB

2HRZE(S)/4HR

: 2551

ADR

1
1-2
2
rechallenge
Alternative regimen

2SHRE/6HR
6RZE
2HRE/7HR
2HZE/10HE
9RE
2SH(R)E/10H(R)E
2SOE/16OE

: 2551

ADR
Management of symptomatic anti
anti-TB
TB drugs-induced
drugs induced hepatitis


PZA, INH
TB/DB RFP
hepatitis / AST/ALT <3
PZA


F/U clinical symptoms LFT

ADR

50

100

150

200

300

300

150

300

300

300

300

300

450

10

300

450

If success
No more PZA?

ADR
3

26 55 kg underlying dz. HIV 10


INH (100) 3 tab


t b hs
h + RMP
(300) 2 cap hs + PZA (500) 2 tab hs + ETB (400) 2 tab hs
.
2

?
.

. rechallenge
. INH
. rifampicin
monitor
LFT

. PZA 1000 mg 500 mg/day

ADR
Anti-TB

Anti TB drugs induced liver injury

baseline LFT

DI hepatotoxic

: 2551

ADR
Anti-TB

Anti TB drugs induced liver injury


2
1-2

aminoglycoside,
aminoglycoside ethambutol,
ethambutol quinolone

: 2551

(Peripheral Neuropathy)
Optic Neuritis

(joint pain & gouty arthritis)

(hearing loss, vertigo)

INH
ETB
PZA
Streptomycin

INH & N
Neuropathy
h

HIV-positive

DM
renal failure
alcoholism
malnourished or chronic liver disease
elderly
children
pregnancy


INH & N
Neuropathy
h

INH vitamin B6 cofactor
synaptic neurotransmitters
dose related neurological side effects
dose-related
peripheral
neuropathy, ataxia paresthesia


pyridoxine 10 mg/day

25-50 mg/day

1 risk high-risk
features


pyridoxine
id i

100 200 mg/day


100-200
/d

Optic
p neuritis & Ethambutol

Sudden blurred, "foggy" or dimmed vision.


Blind spots, particularly with central vision. Sudden loss of vision
(partial or complete).
complete)
Pain with eye movement in the affected eye. 92.2% of pts experienced pain,
which actually preceded the visual loss in 39.5% of cases.
Sudden color blindness (red-green
(red green color blindness)
Impaired night vision.
Impaired contrast sensitivity


Optic neuritis & Ethambutol

ethambutol
2

reversible process
p
dose-independent
18%
> 35 mg/kg/day
5-6% 25 mg/kg/day
<1%
1%



15 mg/kg/day
/k /d

Ototoxicity&Nephrotoxicity Streptomycin
Damage 8th cranial nerve
auditory
---- > hearing loss
g , ataxia
vestibular
---- > vertigo,
irreversible
Nephrotoxicity
less
l
frequent
f
t th
than other
th aminoglycosides
i
l
id
~2%
reversible

Hearing loss/ disturbed balance


Renal failure, shock or thrombocytopenia
Poor vision, and poor color perception
Hepatitis
SJS/ TEN/ Exfoliative dermatitis

-----------

>
>
>
>
>

SM
RMP
EMB
PZA
any drugs

ADR anti-TB

Major ADR

ADR

Minor ADR

ADR

Major Adverse Drug Reaction

ADR anti
anti-TB

TB
1.
2.
3.
4.

&ADR

&ADR
MDR-TB
guideline

5.

monitor educate

..

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