treatment tb

Treatment TB In Children

HMS Chandra KusumaPediatric Departement Of Fac. Med.

Brawijaya Univ.Saiful Anwar General Hospital

TB treatment outline•TB therapy•TB tracking•TB prophylaxis•TB prevention – BCG•Other aspects

Objectives of TB therapy• Rapid reduction of the bacilli number, to

cure the patient• ‘Sterilization’ to prevent relapses

to achieve two phases: Initial phase (2 months) – intensive, bacilli

eradication Maintenance phase (4 months / more) – ‘sterilizing’

effect, prevent relaps

• Prevention of acquired drug resistance,to achieve: principles of therapy

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 is taken daily and regularly

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

acil

li p

er m

l o

f sp

utu

m

Toman K, Tuberculosis, WHO, 1979

The ‘fall and rise’ phenomenon

Hypothetical model of TB therapy

A

BC

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

TB bacilli populationLocation

cavity,extra cell

intra macrophag

e

caseous mass

TB population

A B CTB amount 107 - 109 105 - 106 103 – 104

metabolism & replication

active / rapidly

slowly sporadic / intermitte

nt acidity (pH) neutral /

baseacid neutral

most effective drug (consc’ly)

INH, RIF,ETB

PZA, RIF, INH RIF, INH

DrugsDaily dose

(mg/Kg/day) Adverse reactions2 Time/week

dose(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(2,5 g)

Optic neuritis, decreased visualacuity, decreased red-green colour

discrimination, hypersensitivity,gastrointestinal upset

50(2,5 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, 2001

Dosage of antituberculosis drug

TB therapy regimen 2 mo 6 mo 9 mo 12mo

INHRIFPZA

ETBSM

PREDDOT.S !

Corticosteroid

• Anti inflammation • prednison : oral, 1-2mg/kgBW/day, tid

2-4 weeks, tap off• Indications :

– Miliary TB– Meningitis TB– Pleuritis TB with effusion

Therapy problems (1)• The main : 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 therapy failure

Therapy problems (2)• The other : monotherapy • the doctor factor:

– misuse of TB drug: other indications

• the patient factor:– too many drugs (tablets, powders, syrups)– limited fund– drug side effects

• Lead to mono-therapy drug resistance therapy failure

Therapy problems scheme

adherence

interrupted

discontinuation

patient

mono therapy

doctor

MDR TB

therapy failure

NTP failure

Therapy 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

TB drugs & pharmaceutical formulation

Isoniazid (H)

Rifampicin (R)

Pyrazinamide (Z)

Ethambutol (E)

monosubstance

combi-packs

fixed dose comb

Combipack drugs two or more separate drugs put in one pack

FDC with IDAI formulation

fixed dose fixed dose combinationcombination

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

FDC tablet formulation

WHO• H : 30 mg• R : 60 mg• Z : 150 mg

IDAI• H : 50 mg• R : 75 mg• Z : 150 mg

WHO 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)

BW (kg)

Intensive, 2 mo

(tablet)

Continuation, 4 mo(tablet)

5-9 1 1

10-19 2 2

20-33 4 4

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

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 – more friendly both for doctor and patient

Therapy evaluation

•Clear improvement in clinical and supporting examination, especially in the first 2 month

•Main : clinical•supporting exam as

adjuvant

Therapy evaluation• Clinical improvement :

– Increased body weight – Increased appetite– Diminished / reduced symptoms (fever,

cough, etc)• Supporting examination :

– Chest X rays : 2 / 6 month (on indication)

– Blood : BSR – Tuberculin test : once positive, do not

needed to repeat !

Therapy failure

• Inadequate response, despite adequate therapy :– Review the diagnosis, not a TB case ?– Review other aspects : nutrition,

other disease– MDR – rarely in children

• Treatment discontinuation

TB treatment outline•TB therapy•TB tracking•TB prophylaxis•TB prevention – BCG•Other aspects

Transmission rate (Shaw ’54)

adultTB patient

AFB(+) AFB(-)culture(+)

culture(-)CXR (+)

65% 26% 17%

TB tracking

Child TBpatient

Adult TB patient

centri-petal

centri-fugal

TB tracking (case finding)

centripetal• trace the

source • adult people• close contact• by chest X ray

centrifugal• trace other

‘victims’• children• close contact• by tuberculin

TB treatment outline•TB therapy•TB tracking•TB prophylaxis•TB prevention – BCG•Other aspects

TB classification (ATS/CDC modified)

Class Contact Infection Disease Treatmen

t

0 - - - -

1 + - - proph I

2 + + - proph II?

3 + + + therapy

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

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

TB treatment outline•TB therapy•TB tracking•TB prophylaxis•TB prevention – BCG•Other aspects

Prevention

• socio-economic improvement

• BCG immunization• chemoprophylaxis (1st & 2nd)• ‘therapy’

BCG immunization• mimicking the TB pathogenesis with

attenuated TB bacilli • without hematogenic spread and/or

without establishment of remote foci• CMI (+) DTH (+) TST (+) • older neonate (>2 month not vaccinated)

TST first• mass immunization : BCG without TST first• accelerated BCG reaction: help the

screening

TB treatment outline•TB therapy•TB tracking•TB prophylaxis•TB prevention – BCG•Other aspects

Other aspects

nutrition improvementprevent / search & treat other disease(s)

Thank you

FDC’s advantages NTP

success

MDR chanceprevent

monotherapy

FDC

simple manageme

nt

increase adherence

simple treatmen

t

single drug supply

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

IDAI FDC dosage range (75/50/150)

BW (Kg)

Initial (2 mo)

Cont (4 mo)

Dosage range

5-9 1 1 R:8,3-15mgH:5-10 mgZ:15-30

10-19 2 2 R:7,9-15mgH:5-10mgZ:15-30mg

20-33 4 4 R:9-15mgH:6,7-10mgZ:18-30mg