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5/11/2014

Pediatric TB treatment Darmawan B Setyanto Respirology WG Indonesian Pediatric Society
Pediatric TB
treatment
Darmawan B Setyanto
Respirology WG
Indonesian Pediatric Society
Management of pediatric TB Diagnosis Treatment Prevention Pediatric TB-HIV Ped drug resistant TB National TB
Management of pediatric TB
Diagnosis
Treatment
Prevention
Pediatric TB-HIV
Ped drug resistant TB
National TB program
Why TB is so strong? 5/11/2014 5
Why TB is so strong?
5/11/2014
5
Darmawan Budi Setyanto, MD Born: 11 April 1961 Education:  Medical Doctor, Faculty of Medicine,
Darmawan Budi Setyanto, MD
Born: 11 April 1961
Education:
 Medical Doctor, Faculty of Medicine, University of Indonesia, 1986
 Pediatrician, Faculty of Medicine, University of Indonesia, 1997
 Respirology Consultant, 2005
Current position :
Head of Respirology Division, Dept of Child Health, Faculty of
Medicine, University of Indonesia
Organization:
Chairman of Respirology Coordination Working Unit, Indonesian
Pediatric Society
TB, how old?
TB, how old?
TB, strong & robust  Nature of the bacilli  Very complex & special pathogenesis
TB, strong & robust
 Nature of the bacilli
 Very complex & special pathogenesis
 Very effective & efficient transmission
 Difficult diagnosis, especially in children
 Complicated therapy: multiple drug, long term
 Drug side effect, no better new drug yet
 Only clinical cure but not bacteriological cure,
 No effective prevention - immunization
 Sub-standard management
 MDR, XDR, HIV, … etc
 Not medical problem only
 …

5/11/2014

Treatment, basic concept
Treatment,
basic concept
M tuberculosis Unique characteristics :  live in weeks in dry condition  no endotoxins,
M tuberculosis
Unique characteristics :
 live in weeks in dry condition
 no endotoxins, no exotoxins
 hematogenic spread
 grows slowly
 non specific clinical manifestation
 aerob, organ predilection - lung
 wide spectrum of replication: dormant
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9
Ped TB therapy principles
Multi drug, should NOT single drug
(monotherapy)
 each TB drug has specific action to certain
TB bacilli population
 to prevent drug resistance through the
fall and rise phenomenon
Long term, continue, uninterrupted 
problem of adherence (compliance)
 The drug is taken daily and regularly
5/11/2014
11
Tuberculosis symptomatology pathophysiology granuloma pathogenesis CMI source M tb Diagnosis & Treatment
Tuberculosis
symptomatology
pathophysiology
granuloma
pathogenesis
CMI
source
M tb
Diagnosis & Treatment
Objectives To know and understand:  The basic concept of TB therapy  The mechanism
Objectives
To know and understand:
 The basic concept of TB therapy
 The mechanism & the danger of drug
resistant TB
 The fixed dose combination drug, the quality
control, the advantages and disadvantages
Hypothetical model of TB therapy Pop A = rapidly multiplying (caseum) A Pop B =
Hypothetical model of TB therapy
Pop A = rapidly multiplying (caseum)
A
Pop B = slowly multiplying (acidic)
Pop C = sporadically multiplying
B
Pop D = dormant, not multiplying
C
D
0
1
2
3
4
5
6
Months of therapy
Bacteridal activity & ‘sterilizing’ effect
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12

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TB bacilli population & drug activities INH Pop A Active, rapid RIF replication Pop B
TB bacilli population & drug activities
INH
Pop A
Active, rapid
RIF
replication
Pop B
Less active, slow
replication
PZA
Pop C
Not active, sporadic
replication
Pop D
Dormant, no
replication
Metabolism activities
2014
2014
Pop D Dormant, no replication Metabolism activities 2014 TB drugs & TB therapy  First line
TB drugs & TB therapy  First line drugs, the drug used for first time
TB drugs & TB therapy
 First line drugs, the drug used for first time
therapy; H, R, Z, E, S
 Second line drugs, for patients that already
resistance to the first line drugs
 TB therapy: relatively long period, minimal 6 mo
 Two phases:
o Initial, intensive: the first 2 months
o Continuation , maintenance: 4 months or
more
 Intial phase in children: 3 drugs - paucibacillary,
less tolerance to numbers
Treatment of Tuberculosis. Am J Respir Crit Care Med 2003
Background  The majority of the organisms in adult-type disease are found in the cavities
Background
 The majority of the organisms in adult-type
disease are found in the cavities
 Children usually have paucibacillary pulmonary
disease (low organism numbers)
 Cavitating disease is relatively rare (about 6% of
cases or fewer) in those <12 years of age
 In contrast, children develop extrapulmonary
TB more often than adults do
 Severe & disseminated TB (e.g. TB meningitis
and miliary TB) occur especially in young
children (<3 years old).
Management of TB in children . WHO 2006
Drug combination  Clinical evidences -- the initial therapy >1 drug, (3-4 drugs) -- greatly
Drug combination
 Clinical evidences -- the initial therapy >1 drug,
(3-4 drugs) -- greatly improves the efficacy of
treatment
 intensive phase -- continuation phase with
fewer drugs -- have a successful outcome
 At least 2 bactericidal drugs, such as H & R or
H & S, are required in the initial phase
Toman’s tuberculosis, 2004

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5/11/2014 Treatment response & follow up  Treatment outcomes in children are generally good – starts
5/11/2014 Treatment response & follow up  Treatment outcomes in children are generally good – starts
Treatment response & follow up  Treatment outcomes in children are generally good – starts
Treatment response & follow up
 Treatment outcomes in children are generally
good – starts promptly and adherence is
maintained until completion.
 The risk of serious adverse events in children
associated with use of the recommended
treatment regimens is very low.
with use of the recommended treatment regimens is very low. Ped TB therapy regimen 2 mo
Ped TB therapy regimen 2 mo 6 mo 9 mo 12mo INH RMP PZA ETB
Ped TB therapy regimen
2 mo
6 mo
9 mo
12mo
INH
RMP
PZA
ETB
SM
PREDNISON
DOTS !
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22

Treatment response & follow up

Treatment response & follow up  Ideally, at least at the following intervals: 2 wks after
Treatment response & follow up  Ideally, at least at the following intervals: 2 wks after
Treatment response & follow up  Ideally, at least at the following intervals: 2 wks after
Treatment response & follow up  Ideally, at least at the following intervals: 2 wks after
Treatment response & follow up  Ideally, at least at the following intervals: 2 wks after
Treatment response & follow up  Ideally, at least at the following intervals: 2 wks after
Treatment response & follow up  Ideally, at least at the following intervals: 2 wks after
Treatment response & follow up  Ideally, at least at the following intervals: 2 wks after
Treatment response & follow up  Ideally, at least at the following intervals: 2 wks after
Treatment response & follow up  Ideally, at least at the following intervals: 2 wks after
Treatment response & follow up  Ideally, at least at the following intervals: 2 wks after
Treatment response & follow up  Ideally, at least at the following intervals: 2 wks after
Treatment response & follow up  Ideally, at least at the following intervals: 2 wks after

Ideally, at least at the following intervals: 2 wks after the start of treatment, at the end of the

intensive phase, and every 2 months until completion of treatment.

2 wks after the start of treatment, at the end of the intensive phase, and every
2 wks after the start of treatment, at the end of the intensive phase, and every
2 wks after the start of treatment, at the end of the intensive phase, and every
2 wks after the start of treatment, at the end of the intensive phase, and every
2 wks after the start of treatment, at the end of the intensive phase, and every
2 wks after the start of treatment, at the end of the intensive phase, and every
2 wks after the start of treatment, at the end of the intensive phase, and every
2 wks after the start of treatment, at the end of the intensive phase, and every
2 wks after the start of treatment, at the end of the intensive phase, and every
2 wks after the start of treatment, at the end of the intensive phase, and every
2 wks after the start of treatment, at the end of the intensive phase, and every
2 wks after the start of treatment, at the end of the intensive phase, and every
2 wks after the start of treatment, at the end of the intensive phase, and every

5/11/2014

Assessement  symptom assessment  treatment adherence  enquiry about any adverse events  weight
Assessement
 symptom assessment
 treatment adherence
 enquiry about any adverse events
 weight measurement, dosages should be
adjusted to any weight gain
 follow-up chest X-rays are not routinely
required in children who are improving with
treatment, particularly as many children will
have a slow radiographic response to treatment
Treatment failure On assessment at 2 months after the start of treatment, the possibility of
Treatment failure
On assessment at 2 months after the start of
treatment, the possibility of treatment failure
should be considered if a child who is receiving
anti-TB treatment:
 has no symptom resolution or
 has worsening symptoms;
 shows continued weight loss;
 is sputum smear-positive
Treatment problems (2)  The other : monotherapy  the doctor factor: o mis-use of
Treatment problems (2)
 The other : monotherapy
 the doctor factor:
o
mis-use of TB drug: other indications
 the patient factor:
o
too many drugs (tablets, powders, syrups)
o
limited fund
o
drug side effects
 Lead to monotherapy  fall & rise phenomenon
 drug resistance  treatment failure
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29
Adherence  Whenever possible, FDCs of drugs should be used to simplify drug administ &
Adherence
 Whenever possible, FDCs of drugs should be
used to simplify drug administ & adherence.
 Adherence to the full course of therapy is
frequently a challenge, especially as clinical
improvement can be rapid; most children with
TB will start to show signs of improvement after
2-4 weeks of anti-TB treatment.
Treatment problems (1)  The main : adherence / compliance  The factors : o
Treatment problems (1)
 The main : adherence / compliance
 The factors :
o
Long term treatment
o
Many drugs (tablets, powders, syrups)
o
Costly
o
Drug side effects
o
Initial improvement – misinterpreted by parents
o
Inconvenient health service
o
Socio-economic-cultural factors
 Lead to interrupted therapy or treatment
discontinuation  drug resistance  failure
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TB drug resistance, mechanism
TB drug resistance,
mechanism

5/11/2014

Objectives To know and understand:  The basic concept of TB therapy  The mechanism
Objectives
To know and understand:
The basic concept of TB therapy
 The mechanism & the danger of drug
resistant TB
The fixed dose combination drug, the quality
control, the advantages and disadvantages
Drug resistant TB  TB organisms resistant to the antibiotics used in its treatment 
Drug resistant TB
 TB organisms resistant to the antibiotics used in
its treatment
 Multidrug-resistant TB (MDR-TB) is caused by
organisms that are resistant to at least the 2
most effective anti-TB drugs (H & R).
 Extensively drug-resistant TB (XDR-TB) is a form
of TB caused by organisms that are resistant to
H & R (i.e. MDR-TB) as well as any
fluoroquinolone & any of the 2nd line anti-TB inj
drugs (amikacin, kanamycin or capreomycin)
Treatment problems scheme interrupted adherence treatment discontinuation failure doctor adverse DR
Treatment problems scheme
interrupted
adherence
treatment
discontinuation
failure
doctor
adverse DR
monotherapy
MDR TB
patient
NTP failure
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The ‘fall & rise’ phenomenon 10 8 10 7 Sensitive Resistant organisms organisms 10 6
The ‘fall & rise’ phenomenon
10
8
10
7
Sensitive
Resistant
organisms
organisms
10
6
Smear
FALL
RISE
+
Culture +
10
5
10
4
Smear
-
Culture +
10
3
10
2
Smear
-
10
1
Culture -
10
0
0
3
6
9
12
15
18
WHO 78351
Start of treatment
(isoniazid alone)
Weeks of treatment
Toman K, Tuberculosis, WHO, 2004
Number of bacilli per ml of sputum
MDR-TB  Drug resistant TB, especially Multi-drug resistant (MDR-TB) will be very difficult to manage:
MDR-TB
 Drug resistant TB, especially Multi-drug resistant
(MDR-TB) will be very difficult to manage:
 For the patient, the family, health care provider,
& government:
o
Need numerous second line drugs (>8 drugs)
o
Very-very high cost (ten – hundreds fold)
o
Longer treatment periode (>2 years)
o
More adverse reaction (more toxic)
o
Less adherence
o
Less succesfull result
Doctors Struggling to Fight TDR-TB 'Totally Drug-Resistant' in South Africa TB kills more people annually
Doctors Struggling to Fight TDR-TB
'Totally Drug-Resistant' in South Africa
TB kills more people annually than any other
infectious disease besides HIV
By Jason Koebler
February 11, 2013

5/11/2014

Fixed dose combination, FDC
Fixed dose combination,
FDC
TB drugs & pharmaceutical formulation isoniazid (H) monosubstance rifampicin (R) combi-packs pyrazinamide (Z)
TB drugs & pharmaceutical formulation
isoniazid (H)
monosubstance
rifampicin (R)
combi-packs
pyrazinamide (Z)
ethambutol (E)
fixed dose comb
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Quality control  1980’s – 1990’s FDC quality -- a big concern -- substandard quality
Quality control
 1980’s – 1990’s FDC quality -- a big concern --
substandard quality & low bioavailabilty FDC found
in global market
 Bioavailability is the amount of drug absorbed from
the GI tract and found in the blood
 Rifampicin is the most ‘vulnerable’ drug, esp if it is
mixed with other TB drugs
 Isoniazid has the stability problem esp in syrup
formulation
 FDC should be produce according to GMP – Good
Manufacturing practice
 WHO already make regulations of quality control
Objectives To know and understand:  The basic concept of TB therapy  The mechanism
Objectives
To know and understand:
 The basic concept of TB therapy
 The mechanism & the danger of drug resistant
TB
 The fixed dose combination drug (FDC),
the quality control, the advantages and
disadvantages
>2 drugs in one tablet / capsule in a fixed dose formulation fixedfixed dosedose combinationcombination
>2 drugs in one tablet / capsule
in a fixed dose formulation
fixedfixed dosedose combinationcombination
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40
drugs in one tablet / capsule in a fixed dose formulation fixedfixed dosedose combinationcombination 5/11/2014 40

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5/11/2014 Pediatric FDC formulation WHO IDAI  H : 30 mg  50 mg H :
Pediatric FDC formulation WHO IDAI  H : 30 mg  50 mg H :
Pediatric FDC formulation
WHO
IDAI
 H
:
30 mg
 50 mg
H
:
 R
:
60 mg
 75
R
:
mg
 : 150 mg
Z
 : 150 mg
Z
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FDC with IDAI formulation 5/11/2014 47
FDC with IDAI formulation
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47
Z 5/11/2014 45 FDC with IDAI formulation 5/11/2014 47 IDAI FDC ( H 50 R 75

IDAI FDC (H50R75Z150 & H50R75)

Body

Intensive

Continuation

weight

2 month

4 month

(kg)

(tablet)

(tablet)

5-9

1

1

10-14

2

2

15-19

3

3

20-30

4

4

Note: BW < 5kg should be referred and need tailored dosing

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46

3 3 20-30 4 4 Note: BW < 5kg should be referred and need tailored dosing

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5/11/2014 FDC advantage medical perspective Qualified FDC program perspective simple prevent treatment simple
FDC advantage medical perspective Qualified FDC program perspective simple prevent treatment simple drug
FDC advantage
medical
perspective
Qualified FDC
program
perspective
simple
prevent
treatment
simple drug
monotherapy
logistic
patient
doctor
friendly
friendly
easier drug
easier drug
supply
monitoring
 adherence
prevent
misprescr
 MDR
 NTP
success
complete
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treatment
51
Issues specific to adolescents  The treatment of TB in adolescents follows the same guidelines
Issues specific to adolescents
 The treatment of TB in adolescents follows the
same guidelines as for adults:
o
regards dosage requirements,
o
risk of MDR-TB, and
o
drug tolerance,
adolescents show greater similarity to adults
than to young children.
 Thus, it is recommended that adolescents &
older children (BW >25 kg) be treated at adult
dosages
Concl & recommendation  existing formulations were not optimal  ideal formln: H 100mg +
Concl & recommendation
 existing formulations were not optimal
 ideal formln: H 100mg + R 200mg + Z 350mg
+ (E 200 mg).
 biopharmaceutical perspective:
o readily dispersible and
o scored to a sufficient depth to allow
accurate splitting of the tablet
 ½ tab -- 5 kg child;
1 tab -- 10 kg child,
1½ tab -- 20 kg child, & 2 tab -- 30 kg child
FDC disadvantage  Drug interaction possibility – every FDC product & production should be controlled
FDC disadvantage
 Drug interaction possibility – every FDC product
& production should be controlled strictly &
regularly
 Mass dosing, not exactly accurate – acceptable ,
still in dosage range
 Adverse drug reaction – should be stopped, and
changed to loose / separate drugs
 Price, high technology, big investment
– worthed, wider use reduce price
Adverse events  much less common in children than in adults  the most important
Adverse events
 much less common in children than in adults
 the most important AE is hepatotoxicity, (H, R, or Z)
 serum liver enzyme levels do not need to be monitored
routinely, as asymptomatic mild elevation (<5x N
values) is not an indication to stop treatment
 liver tenderness, hepatomegaly or jaundice should
prompt investigation of serum liver enzyme levels and
 the immediate stopping of all potentially hepatotoxic
drugs.
 patients should be screened for other causes of
hepatitis,
 and no attempt to reintroduce these drugs until liver
functions have normalized

5/11/2014

Thank you
Thank you

Ped FDC based on BW (new)

 

Ped

BW

Body weight

FDC

(kg)

(kg)

1

tab

05

- 07

5, 6, 7 (3 BW)

2

tab

08

- 11

8, 9, 10, 11 (4 BW)

3

tab

12

- 16

12, 13, 14, 15, 16 (5 BW)

4

tab

17

- 22

17, 18, 19, 20, 21, 22 (6 BW)

5

tab

23

- 30

24, 25, 26, 27, 28, 29, 30

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BW <5kg should be referred & need tailored dosing BW >30kg 6 ped FDC tablet, or use adult FDC tablet

57

Management of pediatric TB Diagnosis Treatment Prevention Pediatric TB-HIV Ped drug resistant TB National TB
Management of pediatric TB
Diagnosis
Treatment
Prevention
Pediatric TB-HIV
Ped drug resistant TB
National TB program
I’m still here Yes,, but
I’m
still
here
Yes,, but

Ped FDC dose calculation

Ped

BW

Dosage range

FDC

(kg)

 

(mg)

   

H

10.0 07.1

1

tab

05

- 07

R

15.0 10.7

   

Z

30.0 21.4

   

H

12.5 09.0

2 tab

08

- 11

R

18.8 13.6

 

Z

37.5 27.3

   

H

12.5 09.4

3

tab

12

- 16

R

18.8 14.0

 

Z

37.5 28.1

   

H

11.7 09.0

4

tab

17

- 22

R

17.6 13.6

 

Z

35.3 27.3

   

H

10.9 08.3

5

tab

23

- 30

R

16.3 12.5

 

Z

32.6 25.0

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58

TB management in Indonesia Healthcare provider Government Private Government , Private Private PHC hospital
TB management in Indonesia
Healthcare provider
Government
Private
Government ,
Private
Private
PHC
hospital
hospital
clinic
BKPM
Specialist,
assisted by GP
GP &
RSP
Specialist
GP
Pulm
60

5/11/2014

TB management guideline Healthcare provider Government Private Government , Private Private PHC hospital hospital
TB management guideline
Healthcare provider
Government
Private
Government ,
Private
Private
PHC
hospital
hospital
clinic
BKPM
Specialist,
GP &
dots
RSP
assisted by GP
Guidelines: PDPI, PAPDI,
Specialist
GP
IDAI: PNTA
strategy
Pulm
61
‘Separated’ TB management ‘public’ Healthcare provider mass, simple, Government optimal Private Government
‘Separated’ TB management
‘public’
Healthcare provider
mass, simple,
Government
optimal
Private
Government ,
Private
‘private’
Private
PHC
hospital
individual, complete,
hospital
clinic
high standard
BKPM
Specialist,
GP &
dots
RSP
assisted by GP
Guidelines: PDPI, PAPDI,
Specialist
GP
IDAI: PNTA
strategy
Pulm
63
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65
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65
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62
Incomplete National TB data ‘national data’ Healthcare provider included: recorded & reported Government
Incomplete National TB data
‘national data’
Healthcare provider
included:
recorded & reported
Government
Private
‘national data’
Government ,
Private
Private
PHC
NOT included:
hospital
hospital
clinic
NOT recorded & reported
BKPM
Specialist,
GP &
dots
RSP
assisted by GP
Guidelines: PDPI, PAPDI,
Specialist
GP
IDAI: PNTA
strategy
Pulm
64
TB management in Indonesia Healthcare provider Government Private Government , Private Private PHC hospital
TB management in Indonesia
Healthcare provider
Government
Private
Government ,
Private
Private
PHC
hospital
hospital
clinic
BKPM
Specialist,
GP &
dots
RSP
assisted by GP
Guidelines: PDPI, PAPDI,
Specialist
Sub-standardIDAI: PNTAmanagement
GP
strategy
Pulm
66

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Sub-standard management Diagnosis Treatment Public Health  Diagnosing adult TB without sputum examination
Sub-standard management
Diagnosis
Treatment
Public Health
Diagnosing adult
TB without sputum
examination
Treat TB disease
using <3 drugs
Treat TB patient
(adult) only, not
trace the ‘victim’
Under dosage
Diagnosing ped TB
Treat TB patient
without TST
 Treatment less than
(ped) only, not
6
months
trace the source
Diagnosing TB
based on PCR from
blood specimen
Treat ped TB up to
Not recording &
5
years
not reporting TB
appropriately
etc ….
etc ….
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69
Original ISTC 1 st ed 2006 ISTC: 17 standards Diagnosis 6 standards Treatment 9 standards
Original ISTC 1 st ed 2006
ISTC: 17 standards
Diagnosis
6
standards
Treatment
9
standards
Public Health
2 standards
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71
TB management in Indonesia Healthcare provider Government Private Government , Private Private PHC hospital
TB management in Indonesia
Healthcare provider
Government
Private
Government ,
Private
Private
PHC
hospital
hospital
clinic
ISTC
BKPM
Specialist,
GP &
dots
RSP
assisted by GP
Guidelines: PDPI, PAPDI,
Specialist
Sub-standardIDAI: PNTAmanagement
GP
strategy
Pulm
68
ISTC  Not replace guideline but as complementary  Guideline – HOW to manage 
ISTC
 Not replace guideline but as complementary
 Guideline – HOW to manage
 Standards – WHAT should be done
 Standards do not provide specific guidance
on disease management but, present set of
principles that can be applied in nearly all
situations.
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Standards for Diagnosis (6)  Standard 1. All persons with otherwise unexplained productive cough lasting
Standards for Diagnosis (6)
Standard 1. All persons with otherwise unexplained
productive cough lasting two–three weeks or more
should be evaluated for TB.
Standard 2. All patients (adults, adolescents, and
children who are capable of producing sputum)
suspected of having pulmonary TB should have at
least 2, and preferably 3, sputum specimens
obtained for microscopic xamination.
 Standard 3. All patients (adults, adolescents, and
children) suspected of having extra-pulmonary TB,
appropriate specimens …
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72

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Standards for Treatment (9)  Standard 7. Any practitioner treating a patient for TB is
Standards for Treatment (9)
 Standard 7. Any practitioner treating a patient
for TB is assuming an important public health
responsibility. To fulfill this responsibility the
practitioner must not only prescribe an
appropriate regimen but, also, be capable of
assessing the adherence of the patient …
 Standard 8. All patients (incl those with HIV
infection) who have not been treated previously
should receive an internationally accepted …
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73
ISTC 2 nd edition 2009
ISTC 2 nd edition 2009
Presented at:  Pediatric TB mini-training  IDAI Banten  Fame hotel  Tangerang 
Presented at:
 Pediatric TB mini-training
 IDAI Banten
 Fame hotel
 Tangerang
 Sunday, 11 Jun 2014
Standards for Public Health (2)  Standard 16. All providers of care for patients with
Standards for Public Health (2)
 Standard 16. All providers of care for patients with
TB should ensure that persons (esp children <5
years of age & persons with HIV infection) who
are in close contact with patients who have
infectious TB are evaluated & managed in line with
international recommendations. Children<5 years
of age & persons with HIV infection …
 Standard 17. All providers must report both new
and retreatment TB cases …
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ISTC 3 rd edition 2014
ISTC 3 rd edition 2014