Tuberculosis

An Old Disease New Twists

A Continuing Public Health

Challenge

Tuberculosis Old
Disease
May have evolved from M bovis; acquired by
humans from domesticated animals ~15,000 years
ago
Endemic in humans when stable networks of 200440 people established (villages) ~ 10,000 years
ago; Epidemic in Europe after 1600 (cities)
354-322 BC - Aristotle When one comes near
consumptives one does contract their disease
The reason is that the breath is bad and heavyIn
approaching the consumptive, one breathes this
pernicious air. One takes the disease because in
this air there is something disease producing.

Tuberculosis
1882 Robert Koch one seventh of
all human beings die of tuberculosis
and if one considers only the
productive middle-age groups,
tuberculosis carries away one-third
and often more of these

M tuberculosis as causative
agent for tuberculosis

Robert Koch

1886

TRANSMISI TB
Terbanyak : pasien TB dewasa dengan BTA (+)
> 90 % ditularkan melalui
udara (airborne), melalui
droplet nuclei 1-5 m

Lainnya : oral (susu segar, luka kulit,

kongenital)

I. Kontak TB
Bicara : 0-210 partikel

Batuk : 0-3500
partikel

Bersin : 4500 1 juta

partikel

Location of primary focus

in 2,114 cases, 19091928
Location

Lung 95.93
Intestine
1.14
Skin 0.14
Nose 0.09
Tonsil 0.09
Middle ear (Eustachian tube)
Parotid
0.05
Conjunctiva 0.05
Undetermined
2.41

0.09

TB pathogenesis
lymphadenitis

lymphangitis

primary focus

TB can occur in every organ

How can TB occur in every

organ ?

M. tuberculosis inhalation

TB
pathogenesi
s

phagocytosis by PAM
live bacilli
multiplies

bacilli dead

incubation period
(2-12 weeks)

primary focus formation

lymphogenic spread
hematogenic spread1)
Primary complex2)

TST (+)

Cell mediated immunity (+)

P
r
i
m
a
r
y

TB disease

TB infection

T
B

primary complex complication

hematogenic spread complication
lymphogenic complication

Optimal immunity

3)

Dead
immunity
reactivation/reinfection

Cured

TB disease4)

Incubation period
first implantation primary focus
4-6 weeks (2-12 weeks) incubation
period
first weeks: logaritmic growth, : 10 3-104
elicit cellular response
end of incubation period:
primary complex formation
cell mediated immunity
tuberculin sensitivity

PrimaryTB infection has established

TB infection & TB disease

TB infection: CMI can control
infection
primary complex
cell mediated immunity (CMI)
tuberculin hypersensitivity (DTH)
no clinical or radiological manifestation

TB disease: CMI failed to control TB

infection
TB infection + clinical
and/or radiological manifestation

Tidak semua orang yang kontak

dengan pasien TB paru akan
terinfeksi
Faktor yang mempengaruhi penularan:
1.Pasien TB paru (sumber penularan)
Derajat BTA pasien TB
Ada tidaknya kavitas pada Rontgen dada

2.Lingkungan :
Rumah padat penghuni
Rumah lembab
Daerah endemis TB

Tidak semua orang yang kontak

dengan pasien TB paru akan
terinfeksi
3. Intensitas kontak (lamanya &
kedekatan kontak)
tinggal serumah
tidur satu kamar
sering kontak/bertemu
4. Virulensi kuman TB

TB infection

TB

CMI

TB disease

CMI
TB

Antimicrobials used for

pulmonary tuberculosis

First line drugs

Isoniazid (H)
Rifampicin (R)
Pyrazinamide (Z)
Streptomycin (S)
Ethambutol (E)
Note: These drugs are available in single
entity and in fixed dose combination
(FDC) as well

Second line drugs

Kanamycin
Amikacin
Fluoroquinolones
Macrolides and co-amoxiclav
Miscellaneous (not available in Indonesia):

Capreomycin
Cycloserine
Para-amino salicylic acid (PAS)
Rifabutin
Thionamides: ethionamide, prothionamide

Dose of antituberculosis
drugs (ATD)
Drug
R

Recommended dose
(mg/kgBW)
10

Maximal dose
(mg)
600

300

25

15

15

1000

The combination of ATDs

Category

Case

Combination

New lung TB, smear positive, wide

lesion or severe EPTB

2RHZE / 4RH or 6 HE daily

II

Previously treated patients, smear

positive which include: relapse,
interrupted treatment, failure cases

2RHZES / 1RHZE / 5RHE

III

New lung TB, smear negative,

minimal lesion or less severe EPTB

2RHZE / 4RH or 6HE daily

IV

Chronic and Multi-drug resistant TB

Specially designed standardized

or individualized regimens

EPTB = extra pulmonary

tuberculosis

(WHO, 2003)

Adverse drug reactions (1)

In the majority of the patients, the tuberculostatic agents are well tolerated. The
followings are the side effects of these drugs.
1. Isoniazid:
Peripheral neuropathy: can be
prevented by the administration of 10
mg of oral pyridoxine/day
Hepatitis:
more commonly occurs in the elderly
stop treatment and treat symptomatically

Adverse drug reactions (2)

2. Rifampicin:

Flu like syndrome

Gastrointestinal complaints
Hepatitis: stop treatment
Hemolytic anemia, purpura, and renal failure:
stop treatment
Red color of the urine (inform the patients in
advance, this is not harmful)
Strong enzyme inducer

Adverse drug reactions (3)

3. Pyrazinamide:

Hepatitis (contraindication: liver disease)

Gastrointestinal complaints
Arthralgia and hyperuricemia
Safety in pregnancy is not known

4. Ethambutol:

Retrobulbar neuritis loss of visual acuity and

red-green color blindness. Uncommonly occur if
the dose is 15-25 mg/kgBB/day
Usually reversible in several weeks
Not recommended for young children

Adverse drug reactions (4)

5. Streptomycin:

Ototoxic and vestibulotoxic

Dose- and age-related side effect
Tinnitus
Reversible if the treatment is stopped early
Predisposing factor: renal impairment
Other side effect: temporary numbness around
mouth and ear area
Contraindicated for pregnant women

Treatment for MDR tuberculosis

(1)
This term is applied for tuberculosis caused
by M. tuberculosis which is resistant to INH
and rifampicin with or without to other
agents
Caused by: the use of single drug,
inadequate combination for local resistance
pattern, patients incompliance
At least 4 drugs should be used: 2-3 of the
first line drugs plus 2 second line drugs
(e.g. ciprofloxacin or ofloxacin)
Treatment is given for at least 18 months,
but often for life

Treatment for MDR tuberculosis

(2)
All drugs used must be still effective
No standard regimen for MDR, the
combination must be tailored to the report
of the sensitivity test
Drugs commonly used for MDR:
aminoglycosides (streptomicin, kanamycin,
amikacin), thionamides, pyrazinamide,
ofloxacin, ethambutol, cycloserine, PAS
DOTS strategy may be helpful
Refer to specialist

Directly Observed Treatment

Short Course (DOTS)
The drug ingestion by the patients is
physically observed by a health care
worker, spouse, house mate, or other
person
Objectives of DOTS:

To achieve high cure rate

To reduce drop out
To overcome side effects
To prevent resistance

Fixed-dose Combination (FDC)

(1)
FDC is the combination of antituberculosis drugs
produced by the manufacturer
Advantages:
Reduction of prescribing error
Less tablets to swallow compliance
The patients cannot modify treatment regimen by
their own
Disadvantages:
Prescribing error
Trend to avoid DOTS
Decreased bioavailability of rifampicin

Fixed-dose Combination (FDC)

(2)
Examples of FDC for daily administration:

75 mg INH + 150 mg rifampicin

150 mg INH + 150 mg rifampicin

150 mg INH + 400 mg ethambutol

75 mg INH + 150 mg rifampicin + 400 mg

pyrazinamide

75 mg INH + 150 mg rifampicin + 400 mg

pyrazinamide + 275 mg ethambutol

Prophylaxis (1)
According to the American Thoracic Society,
prophylaxis is given to those who have:
contact with active cases, Mantoux (-)
Mantoux test (+), chest X-ray abnormality typical
for tuberculosis
a positive Mantoux conversion during the last 2
years
high risk for infection, eg., being on corticosteroid
or immunosuppresant therapy, leukemia, diabetes
mellitus, Hodgkin disease

Prophylaxis (2)
Prophylaxis for children is indicated for those who:
Have contact, appear healthy, and aged < 5 years
old
Are suckling to a mother with positive sputum
Prophylaxis (INH 5mg/BW) should be given for 6
months
Children aged > 5 years do not need prophylaxis, but
they should be monitored clinically

Hepatotoxicity induced by
antituberculosis drugs
If clinical symptoms (+) stop all drugs
If clinical symptoms (-), but serum bilirubin >2 mg/dL
and/or SGOT/SGPT 5 x stop all drugs
If clinical symptoms (-) and SGOT/SGPT 3 x
continue treatment but monitor closely
Recognize the potentially hepatotoxic drugs: R, H, Z
If clinical condition improves re-introduce H, then R,
but not Z
In the re-introduction, start with low dose and
increase gradually (desensitization). All should be
done with close monitoring

Thank you