Upload
moch-rizki-destiantoro
View
18
Download
0
Embed Size (px)
Citation preview
12/11/2008 1
Module 6
Treatment
Pediatric TB Management Training
Respirology Coordination Working Unit
12/11/2008 2
Objectives
• TB therapy
• TB tracing
• TB prophylaxis
• TB prevention – BCG
• Other aspects
12/11/2008 3
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
12/11/2008 4
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
12/11/2008 5
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
12/11/2008 6
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
12/11/2008 7
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
12/11/2008 8
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
12/11/2008 9
TB therapy regimen
2 mo 6 mo 9 mo 12mo
INHRIFPZA
ETBSM
PREDDOT.S !
12/11/2008 10
Corticosteroid
• Anti inflammation
• prednisone : oral, 1-2mg/kgBW/day, tid2-4 weeks, tap off
• Indications :
– Miliary TB
– Meningitis TB
– Pleuritis TB with effusion
12/11/2008 11
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
12/11/2008 12
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
12/11/2008 13
Therapeutic problems scheme
adherence��
interrupted
discontinuation
patient
mono therapy
doctor
MDR TB
therapy failure
NTP failure
12/11/2008 14
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
12/11/2008 15
TB drugs & pharmaceutical formulation
Isoniazid (H)
Rifampicin (R)
Pyrazinamide (Z)
Ethambutol (E)
monosubstance
combi-packs
fixed dose comb
12/11/2008 16
Combipack drugstwo or more separate tablet put in one pack
12/11/2008 17
fixed dose combinationfixed dose combination
12/11/2008 18
FDC with IDAI formulation
12/11/2008 19
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
12/11/2008 20
FDC’s advantages
���� NTP success
����MDR chanceprevent
monotherapy
FDC
simple management
increase adherence
simple treatment
single tablet supply
12/11/2008 21
FDC tablet formulation
WHO
• H : 30 mg
• R : 60 mg
• Z : 150 mg
IDAI
• H : 50 mg
• R : 75 mg
• Z : 150 mg
12/11/2008 22
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
12/11/2008 24
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
12/11/2008 25
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
12/11/2008 26
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
12/11/2008 27
Therapeutic evaluation
• Obvious improvement in clinical and supporting examination, especially in the first 2 months
• Mainly : clinical
• Other supporting exam may be useful
12/11/2008
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
12/11/2008 29
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
12/11/2008 30
TB treatment outline
• TB therapy
• TB tracing
• TB prophylaxis
• TB prevention – BCG
• Other aspects
12/11/2008 31
Transmission rate (Shaw 1954)
adultTB patient
AFB(+)AFB(-)
culture(+)culture(-)CXR (+)
65% 26% 17%
12/11/2008 32
TB tracing
Child TBpatient
Adult TB patient
centri-petal
centri-fugal
12/11/2008 33
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
12/11/2008 34
TB treatment outline
• TB therapy
• TB tracing
• TB prophylaxis
• TB prevention – BCG
• Other aspects
12/11/2008 35
TB classification (ATS/CDC modified)
Class Contact Infection Disease Treatment
0 - - - -
1 + - - proph I
2 + + - proph II?
3 + + + therapy
12/11/2008 36
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
12/11/2008 37
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
12/11/2008 38
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%
12/11/2008 39
TB treatment outline
• TB therapy
• TB tracing
• TB prophylaxis
• TB prevention – BCG
• Other aspects
12/11/2008 40
Prevention
• socio-economic improvement
• BCG immunization
• chemoprophylaxis (1st & 2nd)
• ‘therapy’
12/11/2008 41
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
12/11/2008 42
12/11/2008 43
TB treatment outline
• TB therapy
• TB tracing
• TB prophylaxis
• TB prevention – BCG
•Other aspects
12/11/2008 44
Other aspects
• improve nutrition•prevent / search & treat other disease(s)
12/11/2008 45
Thank you
The dream of a vaccine against tuberculosis; New vaccines improving or replacing BCG ?
Eur Respir J 2005; 26:162-7