5/11/2014

Darmawan Budi Setyanto, MD

Pediatric TB Born: 11 April 1961

treatment Education:
 Medical Doctor, Faculty of Medicine, University of Indonesia, 1986
 Pediatrician, Faculty of Medicine, University of Indonesia, 1997
 Respirology Consultant, 2005

Darmawan B Setyanto Current position :

 Head of Respirology Division, Dept of Child Health, Faculty of
Respirology WG Medicine, University of Indonesia

Indonesian Pediatric Society Organization:

 Chairman of Respirology Coordination Working Unit, Indonesian
Pediatric Society

Management of pediatric TB TB, how old?

Diagnosis
Treatment
Prevention
Pediatric TB-HIV
Ped drug resistant TB
National TB program

TB, strong & robust

Why TB is so strong?  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
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 …

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Tuberculosis

Diagnosis & Treatment

symptomatology

Treatment, pathophysiology
basic concept granuloma
pathogenesis
CMI

source M tb

M tuberculosis Objectives
Unique characteristics : To know and understand:
 live in weeks in dry condition  The basic concept of TB therapy
 no endotoxins, no exotoxins
 hematogenic spread  The mechanism & the danger of drug
 grows slowly resistant TB
 non specific clinical manifestation
 aerob, organ predilection - lung  The fixed dose combination drug, the quality
 wide spectrum of replication: dormant
control, the advantages and disadvantages

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Ped TB therapy principles Hypothetical model of TB therapy

 Multi drug,
should NOT single drug Pop A = rapidly multiplying (caseum)
(monotherapy)
 each TB drug has specific action to certain A Pop B = slowly multiplying (acidic)
TB bacilli population Pop C = sporadically multiplying
 to prevent drug resistance through the B
fall and rise phenomenon C Pop D = dormant, not multiplying
 Long term, continue, uninterrupted  D
problem of adherence (compliance) 0 1 2 3 4 5 6
Months of therapy
 The drug is taken daily and regularly
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Bacteridal activity & ‘sterilizing’ effect
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TB bacilli population & drug activities TB drugs & TB therapy

INH  First line drugs, the drug used for first time
therapy; H, R, Z, E, S
Pop A
 Second line drugs, for patients that already
Metabolism activities

Active, rapid RIF

replication
Pop B resistance to the first line drugs
Less active, slow  TB therapy: relatively long period, minimal 6 mo
replication
PZA  Two phases:
Pop C
o Initial, intensive: the first 2 months
Not active, sporadic o Continuation , maintenance: 4 months or
Pop D
replication more
Dormant, no  Intial phase in children: 3 drugs - paucibacillary,
replication 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
 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
2014 children (<3 years old).
Management of TB in children. WHO 2006

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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Ped TB therapy regimen

2 mo 6 mo 9 mo 12mo

INH
RMP
PZA

ETB
SM

PREDNISON
DOTS !

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Treatment response & follow up 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
 Ideally, at least at the following intervals: 2 wks
associated with use of the recommended
after the start of treatment, at the end of the
treatment regimens is very low.
intensive phase, and every 2 months until
completion of treatment.

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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
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 failure Treatment problems (1)

 The main : adherence / compliance
On assessment at 2 months after the start of
 The factors :
treatment, the possibility of treatment failure
o Long term treatment
should be considered if a child who is receiving
o Many drugs (tablets, powders, syrups)
anti-TB treatment: o Costly
 has no symptom resolution or o Drug side effects
 has worsening symptoms; o Initial improvement – misinterpreted by parents
o Inconvenient health service
 shows continued weight loss;
o Socio-economic-cultural factors
 is sputum smear-positive
 Lead to interrupted therapy or treatment
discontinuation  drug resistance  failure

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Treatment problems (2)

 The other : monotherapy
 the doctor factor:
o mis-use of TB drug: other indications
 the patient factor: TB drug resistance,
o too many drugs (tablets, powders, syrups) mechanism
o limited fund
o drug side effects

 Lead to monotherapy  fall & rise phenomenon

 drug resistance  treatment failure
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The ‘fall & rise’ phenomenon

Objectives
108

Number of bacilli per ml of sputum

To know and understand: 107
Sensitive Resistant
organisms organisms
 The basic concept of TB therapy 106
Smear + FALL RISE
Culture +
105

 The mechanism & the danger of drug 104

resistant TB Smear -
Culture +
103

102
 The fixed dose combination drug, the quality
control, the advantages and disadvantages Smear -
101 Culture -

100
0 3 6 9 12 15 18 WHO 78351
Start of treatment Weeks of treatment
(isoniazid alone) Toman K, Tuberculosis, WHO, 2004

Drug resistant TB MDR-TB

 TB organisms resistant to the antibiotics used in  Drug resistant TB, especially Multi-drug resistant
its treatment (MDR-TB) will be very difficult to manage:
 Multidrug-resistant TB (MDR-TB) is caused by  For the patient, the family, health care provider,
organisms that are resistant to at least the 2 & government:
most effective anti-TB drugs (H & R). o Need numerous second line drugs (>8 drugs)
 Extensively drug-resistant TB (XDR-TB) is a form o Very-very high cost (ten – hundreds fold)
of TB caused by organisms that are resistant to o Longer treatment periode (>2 years)
H & R (i.e. MDR-TB) as well as any o More adverse reaction (more toxic)
fluoroquinolone & any of the 2nd line anti-TB inj o Less adherence
drugs (amikacin, kanamycin or capreomycin) o Less succesfull result

Treatment problems scheme Doctors Struggling to Fight TDR-TB

'Totally Drug-Resistant' in South Africa
interrupted TB kills more people annually than any other
infectious disease besides HIV
adherence By Jason Koebler
treatment February 11, 2013
discontinuation
failure
doctor
adverse DR monotherapy MDR TB

patient

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Objectives
To know and understand:
 The basic concept of TB therapy

Fixed dose combination,

 The mechanism & the danger of drug resistant
FDC TB

 The fixed dose combination drug (FDC),

the quality control, the advantages and
disadvantages

TB drugs & pharmaceutical formulation

isoniazid (H) monosubstance

rifampicin (R)
combi-packs >2 drugs in one tablet / capsule
pyrazinamide (Z) in a fixed dose formulation

ethambutol (E) fixed dose comb

fixed dose combination
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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

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IDAI FDC (H50R75Z150 & H50R75)

Pediatric FDC formulation
Body Intensive Continuation
WHO IDAI weight 2 month 4 month
 H : 30 mg  H : 50 mg (kg) (tablet) (tablet)
 R : 60 mg  R : 75 mg
5-9 1 1
10-14 2 2
 Z : 150 mg  Z : 150 mg
15-19 3 3
20-30 4 4
Note: BW < 5kg should be referred and need tailored dosing
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FDC with IDAI formulation

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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 advantage FDC disadvantage

medical
perspective
program Qualified FDC
perspective
 Drug interaction possibility – every FDC product
& production should be controlled strictly &
simple regularly
prevent
simple drug treatment
monotherapy
logistic  Mass dosing, not exactly accurate – acceptable ,
patient doctor still in dosage range
friendly friendly
easier drug easier drug  Adverse drug reaction – should be stopped, and
supply monitoring changed to loose / separate drugs
 adherence prevent
misprescr  Price, high technology, big investment
– worthed, wider use reduce price
 MDR
 NTP
success complete
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Issues specific to adolescents Adverse events

 much less common in children than in adults
 The treatment of TB in adolescents follows the  the most important AE is hepatotoxicity, (H, R, or Z)
same guidelines as for adults:  serum liver enzyme levels do not need to be monitored
o regards dosage requirements, routinely, as asymptomatic mild elevation (<5x N
values) is not an indication to stop treatment
o risk of MDR-TB, and
 liver tenderness, hepatomegaly or jaundice should
o drug tolerance, prompt investigation of serum liver enzyme levels and
adolescents show greater similarity to adults  the immediate stopping of all potentially hepatotoxic
than to young children. drugs.
 Thus, it is recommended that adolescents &  patients should be screened for other causes of
hepatitis,
older children (BW >25 kg) be treated at adult
 and no attempt to reintroduce these drugs until liver
dosages functions have normalized

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I’m
still
here
Yes,, but ...
Thank you

Ped FDC based on BW (new) Ped FDC dose calculation

Ped BW Ped BW Dosage range
Body weight
FDC (kg) (mg)
FDC (kg) (kg) H 10.0 – 07.1
1 tab 05 - 07 R 15.0 – 10.7
1 tab 05 - 07 5, 6, 7 (3 BW) Z 30.0 – 21.4
H 12.5 – 09.0

2 tab 08 - 11 8, 9, 10, 11 (4 BW) 2 tab 08 - 11 R 18.8 – 13.6

Z 37.5 – 27.3
H 12.5 – 09.4
3 tab 12 - 16 12, 13, 14, 15, 16 (5 BW) 3 tab 12 - 16 R 18.8 – 14.0
Z 37.5 – 28.1
H 11.7 – 09.0
4 tab 17 - 22 17, 18, 19, 20, 21, 22 (6 BW) 4 tab 17 - 22 R 17.6 – 13.6
Z 35.3 – 27.3
5 tab 23 - 30 24, 25, 26, 27, 28, 29, 30 H 10.9 – 08.3

BW <5kg should be referred & need tailored dosing

5 tab 23 - 30 R 16.3 – 12.5
Z 32.6 – 25.0
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BW >30kg 6 ped FDC tablet, or use adult FDC tablet

Management of pediatric TB TB management in Indonesia

Diagnosis Healthcare provider
Treatment Government Private
Prevention ,
PHC Government
hospital
Private
hospital
Private
clinic
Pediatric TB-HIV
Ped drug resistant TB BKPM Specialist, GP &
RSP
assisted by GP Specialist
National TB program GP
Pulm
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TB management guideline
Healthcare provider

Government Private
,
PHC Government
hospital
Private
hospital
Private
clinic

BKPM Specialist, GP &

dots
RSP
assisted by GP
Guidelines: Specialist
PDPI, PAPDI,
GP
strategy IDAI: PNTA
Pulm
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‘Separated’ TB management Incomplete National TB data

‘public’
Healthcare provider ‘national Healthcare
data’ provider
mass, simple, included:
optimal
Government Private recorded & reported
Government Private
,
‘private’ , ‘national data’
PHC Government
hospital
Private Private
hospital complete,
clinic
PHC Government
hospital
Private
hospital
Private
NOT included:
clinic
individual,
high standard NOT recorded & reported
BKPM Specialist, GP & BKPM Specialist, GP &
dots
RSP
assisted by GP
Guidelines: Specialist
PDPI, PAPDI, dots
RSP
assisted by GP
Guidelines: Specialist
PDPI, PAPDI,
GP
strategy IDAI: PNTA GP
strategy IDAI: PNTA
Pulm Pulm
63 64

TB management in Indonesia
Healthcare provider

Government Private
,
PHC Government
hospital
Private
hospital
Private
clinic

BKPM Specialist, GP &

dots
RSP
assisted by GP
Guidelines: Specialist
PDPI, PAPDI,
GP
strategy Sub-standard management
IDAI: PNTA
Pulm
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Sub-standard management TB management in Indonesia

Diagnosis Treatment Public Health
Healthcare provider
 Diagnosing adult Treat TB disease  Treat TB patient
TB without sputum using <3 drugs (adult) only, not
examination trace the ‘victim’
Government Private
 Under dosage
,
PHC Government Private Private
 Diagnosing ped TB  Treat TB patient
without TST  Treatment less than (ped) only, not
6 months trace the source hospital hospital clinic
 Diagnosing TB
based on PCR from
blood specimen

 etc ….
 Treat ped TB up to
5 years

 etc ….
 Not recording &
not reporting TB
appropriately
BKPM

dots
RSP

GP
strategy
ISTC
Specialist,
assisted by GP
Guidelines:
Sub-standard management
IDAI: PNTA
GP &
Specialist
PDPI, PAPDI,

Pulm
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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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Original ISTC 1st ed 2006 Standards for Diagnosis (6)

 Standard 1. All persons with otherwise unexplained
ISTC: 17 standards productive cough lasting two–three weeks or more
should be evaluated for TB.
 Standard 2. All patients (adults, adolescents, and
Diagnosis 6 standards children who are capable of producing sputum)
suspected of having pulmonary TB should have at
Treatment 9 standards least 2, and preferably 3, sputum specimens
obtained for microscopic xamination.
Public Health 2 standards  Standard 3. All patients (adults, adolescents, and
children) suspected of having extra-pulmonary TB,
appropriate specimens …
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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 …
5/11/2014
ISTC 2nd edition 2009
Presented at:
 Pediatric TB mini-training
 IDAI Banten
 Fame hotel
 Tangerang
 Sunday, 11 Jun 2014
5/11/2014
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 3rd edition 2014
13