Modul 6 Treatment TB Anak

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Module 6

Treatment

Pediatric TB Management Training

Respirology Coordination Working Unit

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Objectives

• TB therapy

• TB tracing

• TB prophylaxis

• TB prevention – BCG

• Other aspects

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Goals of TB therapy

• Rapid reduction of the bacilli number, to cure the patient (esp. adult)

• ‘Sterilization’ to prevent relapses

• Two phases of therapy� Initial phase (2 months) – intensive, bacilli eradication

� Maintenance phase (4 months / more) – ‘sterilizing’effect, prevent relapse

• Prevention of acquired drug resistance

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Ped TB therapy principles

• Multi drug, NOT single drug (monotherapy)• to prevent drug resistance

• risk of fall and rise phenomenon

• each TB drug has specific action to certain TB bacilli population

• Long term, continue, uninterrupted �problem of adherence (compliance)

• The drug should be taken daily and regularly

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Smear +Culture +

Smear -Culture +

Smear -Culture -

108

107

106

105

104

103

102

101

100

Start of treatment(isoniazid alone)

Weeks of treatment0 3 6 9 12 15 18 WHO 78351

Sensitive organisms Resistant organisms

Nu

mb

er o

f b

acill

i per

ml o

f sp

utu

m

Toman K, Tuberculosis, WHO, 1979

The ‘fall and rise’ phenomenon

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Hypothetical model of TB therapy

A

B

C

Bacteridal activity & ‘sterilizing’ effect

0 1 2 3 4 5 6

Pop A = rapidly multiplying (cavity)

Pop B = slowly multiplying (acidic)

Pop C = sporadically multiplying (caseum)

Pop D = dormant, not multiplying

Months of therapy

D

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TB bacilli population

Location cavity,extra cell

Intra cell (macrophage)

caseous mass

TB population A B C

No of TB bacilli

107 - 109 105 - 106 103 – 104

metabolism & replication

active / rapidly

slowly sporadic / intermittent

acidity (pH) neutral / base

acid neutral

most effective drug (consc’ly)

INH, RIF,ETB

PZA, RIF, INH RIF, INH

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Drugs Daily dose(mg/Kg/day) Adverse reactions

2 Time/weekdose

(mg/Kg/dose))

Isoniazid(INH)

5-15(300 mg))

Hepatitis, peripheral neuritis,hypersensitivity

15-40(900 mg))

Rifampicin(RIF)

10-15(600 mg))

Gastrointestinal upset,skin reaction,hepatitis, thrombocytopenia,

hepatic enzymes, including orangediscolouraution of secretions

10-20(600 mg)

Pyrazinamide(PZA)

15 - 40(2 g)

Hepatotoxicity, hyperuricamia,arthralgia, gastrointestinal upset

50-70(4 g)

Ethambutol(EMB)

15-25(1,5 g)

Optic neuritis, decreased visualacuity, decreased red-green colour

discrimination, hypersensitivity,gastrointestinal upset

50(1,5 g)

Streptomycin(SM)

15 - 40(1 g)

Ototoxicity nephrotoxicity25-40(1,5 g)

When INH and RIF are used concurrently, the daily doses of the drugs are reduced

National consensus of tuberculosis in children, 2001Int J Tuberc Lung Dis 2007; 11:1345-51

Dosage of antituberculosis drug

Note : twice weekly treatment not recommended anymore

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TB therapy regimen

2 mo 6 mo 9 mo 12mo

INHRIFPZA

ETBSM

PREDDOT.S !

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Corticosteroid

• Anti inflammation

• prednisone : oral, 1-2mg/kgBW/day, tid2-4 weeks, tap off

• Indications :

– Miliary TB

– Meningitis TB

– Pleuritis TB with effusion

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Therapeutic problems (1)

• The main problem: adherence / compliance

• The factors :– Long term treatment

– Many drugs (tablets, powders, syrups)

– Costly

– Drug side effects

– Initial improvement – misinterpreted by parents

– Inconvenient health service

– Socio-economic-cultural factors

• Lead to interrupted therapy or discontinuation � drug resistance � therapeutic failure

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Therapeutic problems (2)

• The other problem: monotherapy

• the doctor factor:– misuse of TB drug: other indications

• the patient factor:– too many drugs form (tablets, powders, syrups)

– limited fund

– drug side effects

• Lead to mono-therapy � drug resistance �therapy failure

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Therapeutic problems scheme

adherence��

interrupted

discontinuation

patient

mono therapy

doctor

MDR TB

therapy failure

NTP failure

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Therapeutic problem solutions

• DOTS : Directly Observe Treatment Short-course

• FDC : Fixed Dose Combination i.e. >2 drugs in one tablet / capsule in a fixed dose formulation

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TB drugs & pharmaceutical formulation

Isoniazid (H)

Rifampicin (R)

Pyrazinamide (Z)

Ethambutol (E)

monosubstance

combi-packs

fixed dose comb

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Combipack drugstwo or more separate tablet put in one pack

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fixed dose combinationfixed dose combination

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FDC with IDAI formulation

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Fixed Dose Combination

FDC: >2 drugs in one tablet in a fixed dose formulation

• simple dosing

• patient friendly, doctor friendly

• increase adherence

• reduce MDR

• easier drug supplying

• easier drug monitoring

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FDC’s advantages

���� NTP success

����MDR chanceprevent

monotherapy

FDC

simple management

increase adherence

simple treatment

single tablet supply

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FDC tablet formulation

WHO

• H : 30 mg

• R : 60 mg

• Z : 150 mg

IDAI

• H : 50 mg

• R : 75 mg

• Z : 150 mg

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WHO/GDF FDC(H/R/Z:30/60/150 & H/R:30/60)

BW

(kg)

Intensive, 2 mo

(tablet)

Continuation, 4 mo

(tablet)

<7 1 1

8-9 1,5 1,5

10-14 2 2

15-19 3 3

20-24 4 4

25-29 5 5

IDAI FDC (H/R/Z:50/75/150 & H/R:50/75)

23

BW

(kg)

Intensive,

2 mo (tablet)

Continuation,

4 mo (tablet)

5-9 1 1

10-14 2 2

15-19 3 3

20-33 4 4

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

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WHO vs IDAI FDC formulation

• WHO:

– INH: 4-6 mg/kgBW

– BW grouping: too many

– not practical

– hard to remember

– a gap for BW 30-33 kg

• IDAI

– INH: 5-10 mg/kgBW

– simple BW grouping

– Child friendly and doctor friendly

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WHO FDC dosage range (60/30/150)

BW

(kg)

Initial (2mo)

Cont (4mo)

Dosage range

<7 1 1 R:9-20mg,H:4-10mg,Z:21-50mg

8-9 1,5 1,5 R:8-9mg,H:5-5,6mg,Z:19-22mg

10-14 2 2 R:11-12mg,H:4,3-6mg,Z:21-30mg

15-19 3 3 R:9,4-12mg,H:4,3-6mg,Z:16-30mg

20-24 4 4 R:10-12mg,H:5-6mg,Z:25-30mg

25-29 5 5 R:10,3-12mg,H:5-6mg,Z:15-30mg

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IDAI FDC dosage range (75/50/150)

BW

(Kg)

Initial

(2 mo)

Cont (4 mo) Dosagerange

5-9 1 1 R:8,3-15mg

H:5-10 mg

Z:15-30

10-19 2 2 R:7,9-15mg

H:5-10mg

Z:15-30mg

20-33 4 4 R:9-15mg

H:6,7-10mg

Z:18-30mg

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Therapeutic evaluation

• Obvious improvement in clinical and supporting examination, especially in the first 2 months

• Mainly : clinical

• Other supporting exam may be useful

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Therapeutic evaluation

• Clinical improvement :– Increased body weight

– Increased appetite

– Diminished / reduced symptoms (fever, cough, etc)

• Supporting examination : – Chest X rays : 2 or 6 months (on indication)

– Blood : ESR

– Tuberculin test : once positive, should not be repeated

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Therapeutic failure

• Inadequate response, despite adequate therapy :

– Review the diagnosis, not a TB case ?

– Review other aspects : nutrition, other disease

– MDR – rare in children

• Treatment discontinuation

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TB treatment outline

• TB therapy

• TB tracing

• TB prophylaxis

• TB prevention – BCG

• Other aspects

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Transmission rate (Shaw 1954)

adultTB patient

AFB(+)AFB(-)

culture(+)culture(-)CXR (+)

65% 26% 17%

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TB tracing

Child TBpatient

Adult TB patient

centri-petal

centri-fugal

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TB tracing (case finding)

centripetal

• trace the source

• adult

• close contact

• by sputum and chest X ray

centrifugal

• trace other ‘victims’

• children

• close contact

• by tuberculin

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TB treatment outline

• TB therapy

• TB tracing

• TB prophylaxis

• TB prevention – BCG

• Other aspects

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TB classification (ATS/CDC modified)

Class Contact Infection Disease Treatment

0 - - - -

1 + - - proph I

2 + + - proph II?

3 + + + therapy

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Primary prophylaxis

• to prevent TB infection in TB Class 1 person

• exposure (+), infection (-) � tuberculin negative

• drug: INH 5 - 10 mg/kgBW/day

• as long as contact take place, the source should be treated

• at least for 3 months

• repeat TST:– negative: success, stop INH

– positive: fail, become TB Class 2 continue as 2nd

proph

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Secondary prophylaxis

• to prevent TB disease in TB Class 2 person (exposure (+), infection (+), disease (-)

• and person with tuberculin conversion

• certain high risk population

– under five, puberty

– long term use of steroid

– malignancy

– certain infection: morbili, pertussis

• drug: INH 5 - 10 mg/kgBW/day

• during the higher risk of TB disease development: 6-12 month

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Secondary prophylaxis

• Longer duration of prophylaxis better in reducing risk of disease

– 3 months : reduce risk 21%

– 6 months : reduce risk 65%

– 12 months : reduce risk 70-90%

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TB treatment outline

• TB therapy

• TB tracing

• TB prophylaxis

• TB prevention – BCG

• Other aspects

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Prevention

• socio-economic improvement

• BCG immunization

• chemoprophylaxis (1st & 2nd)

• ‘therapy’

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BCG immunization

• Bacille Calmette Guerin (BCG) an attenuated bovine mycobacterium

• BCG vaccination give a susceptible/uninfected child a non pathogenic primary infection using a measured dose of BCG (artificial infection) � induce tuberculin sensitivity and increase defence mechanism� induce or prevent dissemination after primary complex.

• Ideally TST should be done before BCG immunization

BCG immunization

• Mass BCG immunization:

– Direct BCG immunization without prior TST

– Given at 0-2 months old

• Acceleration BCG reaction: suspect TB infection

• BCG in HIV infected children

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TB treatment outline

• TB therapy

• TB tracing

• TB prophylaxis

• TB prevention – BCG

•Other aspects

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Other aspects

• improve nutrition•prevent / search & treat other disease(s)

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Thank you

The dream of a vaccine against tuberculosis; New vaccines improving or replacing BCG ?

Eur Respir J 2005; 26:162-7