Pediatric TB Management Training

Module 6

Treatment
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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The fall and rise phenomenon

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Number of bacilli per ml of sputum

107 106
Smear + Culture +

Sensitive organisms

Resistant organisms

105 104 103 102 101 Smear 100 0 3 6 9 12 15 18

WHO 78351

Smear Culture +

Culture -

Start of treatment 12/11/2008 (isoniazid alone)

Weeks of treatment

Toman K, Tuberculosis, WHO, 1979

Hypothetical model of TB therapy

Pop A = rapidly multiplying (cavity)

A
B
C
D

Pop B = slowly multiplying (acidic) Pop C = sporadically multiplying (caseum) Pop D = dormant, not multiplying

3
Months of therapy

Bacteridal activity & sterilizing effect

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TB bacilli population
Location
TB population No of TB bacilli metabolism & replication acidity (pH) most effective drug (conscly)
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cavity, extra cell

Intra cell (macrophage)

caseous mass

A
107 - 109 active / rapidly neutral / base INH, RIF, ETB

B
105 - 106 slowly acid PZA, RIF, INH

C
103 104 sporadic / intermittent neutral RIF, INH
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Dosage of antituberculosis drug

Drugs Isoniazid (INH) Rifampicin (RIF) Pyrazinamide (PZA) Ethambutol (EMB) Streptomycin (SM)
Daily dose (mg/Kg/day) 2 Time/week dose (mg/Kg/dose))

Adverse reactions
Hepatitis, peripheral neuritis, hypersensitivity
Gastrointestinal upset,skin reaction, hepatitis, thrombocytopenia, hepatic enzymes, including orange discolouraution of secretions Hepatotoxicity, hyperuricamia, arthralgia, gastrointestinal upset Optic neuritis, decreased visual acuity, decreased red-green colour discrimination, hypersensitivity, gastrointestinal upset

5-15 (300 mg)) 10-15 (600 mg)) 15 - 40 (2 g) 15-25 (1,5 g) 15 - 40 (1 g)

15-40 (900 mg)) 10-20 (600 mg) 50-70 (4 g) 50 (1,5 g) 25-40 (1,5 g)

Ototoxicity nephrotoxicity

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

Note : twice weekly treatment not recommended anymore

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National consensus of tuberculosis in children, 8 2001 Int J Tuberc Lung Dis 2007; 11:1345-51

TB therapy regimen
2 mo 6 mo 9 mo 12mo

INH RIF PZA ETB SM PRED DOT.S !

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Corticosteroid
Anti inflammation prednisone : oral, 1-2mg/kgBW/day, tid 2-4 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 therapy failure

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drug resistance

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Therapeutic problems scheme

interrupted adherence discontinuation doctor mono therapy patient therapy failure MDR TB

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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)

monosubstance

combi-packs Pyrazinamide (Z) Ethambutol (E) fixed dose comb

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Combipack drugs
two or more separate tablet put in one pack

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fixed 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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FDCs advantages
single tablet supply simple management NTP success

FDC

simple treatment

increase adherence

prevent monotherapy

MDR chance

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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) <7 8-9 10-14 15-19 20-24 25-29

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Intensive, 2 mo (tablet) 1 1,5 2 3 4 5

Continuation, 4 mo (tablet) 1 1,5 2 3 4 5

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

BW (kg) 5-9 10-14 15-19 20-33 Intensive, 2 mo (tablet) 1 2 3 4

& H/R:50/75) Continuation, 4 mo (tablet) 1 2 3 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) <7 8-9 10-14 15-19 20-24 25-29
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Initial Cont (2mo) (4mo) 1 1,5 2 3 4 5 1 1,5 2 3 4 5

Dosage range R:9-20mg,H:4-10mg,Z:21-50mg R:8-9mg,H:5-5,6mg,Z:19-22mg R:11-12mg,H:4,3-6mg,Z:21-30mg R:9,4-12mg,H:4,3-6mg,Z:16-30mg R:10-12mg,H:5-6mg,Z:25-30mg R:10,3-12mg,H:5-6mg,Z:15-30mg

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IDAI FDC dosage range (75/50/150)

BW (Kg)
5-9

Initial (2 mo)
1

Cont (4 mo)
1

Dosage range
R:8,3-15mg H:5-10 mg Z:15-30 R:7,9-15mg H:5-10mg Z:15-30mg R:9-15mg H:6,7-10mg Z:18-30mg
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10-19

20-33

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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)

adult TB patient
AFB(-) culture(+) culture(-) CXR (+)

AFB(+)

65%
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26%

17%
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TB tracing
Adult TB patient
centrifugal

centripetal

Child TB patient
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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 2 3
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+ + +

+ +

proph I proph II? 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: 612 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
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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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The dream of a vaccine against tuberculosis; New vaccines improving or replacing BCG ?
Eur Respir J 2005; 26:162-7

Thank you
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