TUBERCULOSIS

TUBERCULOSIS
&&
Its
Its
management
management
R.VINOEDH NAIDU @ PRP U41
HSB (2014/2015)
PRECEPTOR : PUAN NADIA

LEARNING
OBJECTIVES
To learn about the definition & diagnosis of TB
To learn about the investigations & algorithm of
investigations of TB
To learn about the treatment target groups &
treatment regimens of TB
To understand different treatment aspects
involved in tuberculosis treatment management
2

INTRODUCTION
Tuberculosis , a multisystemic disease with numerous
presentations and manifestations, is the most common
cause of infectious diseaserelated mortality.
Mycobacterium tubeculosis @ Tubercle Bacilli (TB)
Number of TB cases in the country continues to
increase. *
High rates of morbidity & mortality due to:
Delayed presentation
Advanced HIV
3

EPIDEMIOLOGY
Top 3 causes of death for women aged 15 to 44
years
One quarter of all deaths in people living with HIV
TB death rate dropped 41% between 1990 & 2011
4000
3500
3000
2500
2000
1500
Number
1000 of cases (n)
500
0

TEN LEADING CAUSES OF DEATH

(WHO Factsheet, 2008)

World
Ischaemic heart disease
Stroke & other
cerebrovascular disease
Lower respiratory infections
Chronic obstructive
pulmonary disease
Diarrhoeal diseases
HIV/AIDS
Trachea, bronchus, lung
cancers
Tuberculosis
Diabetes mellitus
Road traffic accidents

Deaths in
millions
7.25

% of
deaths
12.8%

6.15

10.8%

3.46

6.1%

3.28

5.8%

2.46
1.78

4.3%
3.1%

1.39

2.4%

1.34
1.26
1.21

2.4%
2.2%
2.1%

ESTIMATED TB INCIDENCE RATE,

2011

TB Transmission

Dots in air represent droplet nuclei containing

M. tuberculosis

TB Pathogenesis

Symptoms associated with TB

Cough
Cough up
blood
Chest pains
Fever
Night sweats
Weak and
tired
Weight loss
Loss of

DIAGNOSIS
Detection of acid fast bacilli (AFB) on smears
& culture of M. tuberculosis from clinical
specimens.
SPUTUM

Acid fast bacilli

CULTURE & SENSITIVITY

11

12

CHEST X-RAY
IMAGING may assist in:
identifying the lesion
characterising the lesion
assessing the extent/severity
assisting in intervention
Findings may mimic other diseases.

EDUCATION
Nature of disease
Adherence with prolonged
treatment
Risks of defaulting treatment
Side effects of medication
Risks of transmission & need for
respiratory hygiene*
14

NEW CASES PTB

6-month
consisting of :

regimen

INTENSENSIFICATION
2
months
of
EHRZ
2 EHRZ + 4 HR
2 EHRZ + 4 H3R3
(2EHRZ)
2 E3H3R3Z3 + 4
H3R3

MAINTENANCE

15

RECOMMENDED ANTI-TB
DRUGS
DRUG

RECOMMENDED DOSES
Daily
3X a week
Dose
Max in Dose
Max in mg
(range) in
mg
(range) in
mg/kg
mg/kg
body weight
body weight
5 (4 - 6)
300
10 (8 - 12)
900
10 (8 - 12)
600
10 (8 - 12)
600
25 (20 - 30)
2000 35 (30 40)*
3000*

Isoniazid (H)
Rifampicin (R)
Pyrazinamide
(Z)
Ethambutol (E) 15 (15 - 20)
1600 30 (25 35)*
2400*
Streptomycin
15 (12 - 18)
1000 15 (12 18)*
1500*
Pyridoxine 10 - 50 mg daily needs to be added if Isoniazid is
(S)
prescribed*

16

WHO. Treatment of Tuberculosis Guidelines (4th Ed.), 201

IMPORTANT POINTS
Rifampicin
*should be used for the whole duration of
treatment.
*Rifampicin dosage should not be lower than
recommended dosage (10 - 12 mg/kg).

Pyrazinamide beyond 2 months during the

intensive phase does not confer further
advantage if the organism is fully
susceptible.
17

MAINTENANCE PHASE
In new patients with PTB, WHO
recommends daily dosing throughout the
course of antiTB treatment.
However, a daily intensive phase followed
by thrice weekly maintenance phase is an
option provided that each dose is directly
observed & patient has improved clinically.
.
18

FIXED-DOSE COMBINATION
(FDC) IN MALAYSIA
Forecox-Trac Film Coated Tab: isoniazid, rifampicin,
ethambutol & pyrazinamide
Rimactazid 300 Sugar Coated Tab: isoniazid, & rifampicin
Rimcure 3-FDC Film Coated Tab: isoniazid, rifampicin &
pyrazinamide
Akurit-Z Tab: isoniazid, rifampin (rifampicin) &
pyrazinamide
Akurit Tab: isoniazid & rifampin (rifampicin)
Akurit-Z Kid Dispersible Tab: isoniazid, rifampin
(rifampicin) & pyrazinamide
Akurit-4: ethambutol, isoniazid, rifampin (rifampicin) &
pyrazinamide
19

FDC IN MOH
4-Drug combination: isoniazid 75 mg,
rifampicin 150 mg, pyrazinamide 400 mg &
ethambutol 275 mg tab
3-Drug combination: isoniazid 75 mg,
rifampicin 150 mg & pyrazinamide 400 mg
tablet

30 - 37 kg body weight: 2 tablets daily

38 - 54 kg body weight: 3 tablets daily
55 - 70 kg body weight: 4 tablets daily
More than 70 kg body weight: 5 tablets
daily
20

FIRST LINE TREATMENT

DRUG
ISONIAZID

MECHANISM
Inhibits bacteria
cell division

PYRAZINAMID Kills bacteria

E
RIFAMPICIN
Kills bacteria,
metabolized via
bile and body
fluids

ETHAMBUTOL

SIDE EFFECTS
Joints pain,
vitamin B6
deficiency
Uric acid
retention, gout
Red-colored
urine, nausea,
vomiting,
rashes, fever,
jaundice in
alcoholic
Reduced vision

Synergistic with
Rifampicin
STREPTOMYCI Inhibits bacterial Ototoxic,

DIRECTLY OBSERVED THERAPY

(DOT)
Direct observation of drug ingestion of the
DOTS component should not be the sole
emphasis in TB control programmes.
Enhanced DOTS can reduce incidence of TB
within a community (p=0.04)
Cavalcante SC et al., Int J Tuberc & Lung Dis. 2010

22

DOT during office hour only by

trained personnel
No take away
Can DOT at any KK or KD

LIVER IMPAIRMENT
Baseline LFT prior to treatment
Regular monitoring at weekly &
intervals during the initial 2 months

biweekly

If LFTs are more than 3X upper limit of normal

before
initiation
of
therapy,
a
regimen
containing fewer hepatotoxic drugs can be
considered
The likelihood of drug induced hepatitis is
greater & is potentially life threatening
Fluoroquinolones

&

24
aminoglycosides

can

be

ANTITB DRUGS IN LIVER IMPAIRMENT

Drugs
Isoniazid & rifampicin,
plus ethambutol

Progressive
ly more
severe liver
disease

Duration
9 months Ethambutol given
until isoniazid
susceptibility is
documented
2 months

Isoniazid, rifampicin,
streptomycin &
ethambutol,
followed by isoniazid &
6 months
rifampicin
Rifampicin, pyrazinamide
6-9
& ethambuthol
months
Isoniazid, ethambutol &
2 months
streptomycin,
followed by
isoniazid & ethambutol
10 months
Streptomycin,
18 - 24
ethambutol &
months

25

RENAL IMPAIRMENT
2 months of isoniazid, rifampicin, pyrazinamide
& ethambutol followed by 4 months of isoniazid
& rifampicin
Significant renal excretion of ethambutol &
metabolites of pyrazinamide occurs, hence
doses must be adjusted to intermittent dosing
Pyrazinamide should be administered after
hemodialysis to avoid premature drug removal
All 4 antiTB drugs can be administered after
hemodialysis to facilitate DOT
Avoid streptomycin

26

ANTITB DRUGS IN RENAL IMPAIRMENT

Drug
Isoniazid
Rifampicin
Pyrazinamid
e
Ethambutol

Change in
frequency?

Recommended
dose & frequency

No change

Max 300 mg PO once

daily

No change

Max 600 mg PO once

daily

Yes

25 - 30 mg/kg per
dose PO 3 times per
week

Yes

15 - 25 mg/kg per
dose PO 3 times per
week
27

ADVERSE DRUG REACTION

(ADR)
A response to a medicine which is unintended or
harm which occurs at a normal dosage during
normal use.

ONSET OF ADR FOR ANTITB

ADRs occur within early stage of the
treatment compared to the later stage.
28

CLASSIFICATION OF ADR FOR

ANTITB
Troublesome but NOT SERIOUS

Treat
symptomatica
lly WITHOUT
treatment
interruption

29

RISK FACTORS OF ADR FOR

ANTITB
Age >40 years
Overweight/obesity
Smoking
Alcoholism
Anaemia
Baseline ALT more than
twice upper limit of
normal
Baseline aspartate
aminotransferase more
than twice upper limit of
normal

*
Renal

EPTB
MDR-TB medication
HIV infection
CD4 count <350
cells/mm3
Hepatitis B virus
infection
Hepatitis C virus
infection
Concomitant use of
other hepatotoxic
drugs
Hepatobiliary, Skin Gastrointestinal tract, Skeletal system,

30

DRUG-INDUCED RASHES
Pyrazinamide
(MOST)

Drug-Induced
Algorithm
Severe Cutaneous ADRs

Discontinue antiTB until the rashes subside

Reintroduce individual drug sequentially to identify the offending
drug
Provide suitable regimen when an offending drug is identified
(If possible, regimen should include 2 most potent drugs namely
isoniazid & rifampicin )
31

DRUG-INDUCED HEPATITIS

Risk Factors

Drug-Induced

Slow acetylators
Old age
Extensive TB disease
Malnutrition
Alcoholism
Chronic viral hepatitis B & C
infections
Pregnancy until 90 days
postpartum
HIV
Organ transplant recipients

Pyrazinamide (MOST)

Isoniazid
Rifampicin (LEAST)

Monitoring
At least for the first 2 - 4 weeks
is recommended among all
patients with antiTB treatment as
DIH usually occurs within the
initial 2 months of treatment.
32

TB DRUGS-RESISTANT *

CNS

MDR & Extensively drug-resistant

(XDR) incidence & prevalence are
increasing worldwide including
Malaysia
Rate of MDR-TB cultures had increased
from 0.3% in 2005 to 1.3% in 2011 of
all MTB cultures positive in Malaysia

High mortality & morbidity

In a study in Vietnam, mortality
during MDR-TB treatment was 8.7%
33

DEFINITION
Monodrug resistant
MTB resistant to any one of antiTB drugs

Polydrug resistant
MTB resistant to 2 or more antiTB drugs

Multidrug resistant
MTB resistant to both isoniazid & rifampicin
with or without resistance to other antiTB
drugs
HIV+
34

DEFINITION
Extensively drug-resistance
(XDR)
MDR TB with resistance to at least one
injectable second-line antiTB drugs & any
fluoroquinolone

Extremely/Total drug-resistant
TB
not well-defined
MTB resistant to all tested first-line & secondline antiTB drugs
35

SECOND-LINE ANTI-TB DRUGS

36

STANDARD MDR-TB REGIMEN

Consist of 4 second-line antiTB drugs that
are most likely to be effective in the
intensive phase
Regimens should include:
Secon
d-line
antiTB
drugs

Fluoroquinolone

Parenteral agent
(aminoglycosides)

Ethionamide &
Either cycloserine or PAS (if
cycloserine cannot be used) &

Pyrazinamide

later-generation fluoroquinolone (e.g.

37
levofloxacin & moxifloxacin) should be used

DURATION OF TREATMENT
Intensive phase
Defined by the duration of treatment with the
injectable agent

WHO recommends 8 months for most

patients
Duration of treatment
Newly MDR-TB (not previously treated for MDRTB), a total treatment duration is 20 months for
most patients

May be modified according to the response

to treatment based on patients 38
cultures,
smears, CXR & clinical status

 Maternal TB - increased risk of maternal

mortality and perinatal morbidity:
premature delivery
small-for-gestation age
low birth weight
Streptomycin
ototoxicity

(teratogenic)

foetal

Pyridoxine (25mg daily) with isoniazid

to prevent foetal neurotoxicity
First-line antiTB drugs are safe in breast
feeding.

 Once active TB in baby is ruled out, the baby

should
be
given
six
months
isoniazid
prophylaxis, followed by BCG vaccination.
Separation of the infant from the mother
should be considered if the mother has MDR-TB
or non-compliant to treatment.
Pyridoxine supplementation is recommended
for all pregnant or breastfeeding women taking
isoniazid.
rifampicin
and
rifabutin
reduce
the
contraceptive efficacy of oral contraceptive
pills.
Alternative contraceptive methods

for one

REFERENCES:
1.
2.
3.

4.
5.
6.

7.

8.

World Health Organization. Treatment of tuberculosis Guidelines. Fourth

ed. Geneva: WHO; 2010.
Sistem Maklumat Tibi Kementerian Kesihatan Malaysia. Fakta-Fakta
Utama Program Kawalan Tibi. 2011
Jetan C, Jamaiah I, Rohela M, et al. Tuberculosis: an eight year (20002007) retrospective study at the University of Malaya Medical Centre
(UMMC), Kuala Lumpur, Malaysia. Southeast Asian J Trop Med Public
Health. 2010 Mar;41(2):378-85.
Iyawoo K. Tuberculosis in Malaysia: problems and prospect of treatment
and control. Tuberculosis. 2004;84(1-2):4-7.
Dony JF, Ahmad J, Khen Tiong Y. Epidemiology of tuberculosis and
leprosy, Sabah, Malaysia.Tuberculosis. 2004;84(1-2):8-18.
Moran-Mendoza O, Marion SA, Elwood K, et al. Risk factors for
developing tuberculosis: a 12-year followup of contacts of tuberculosis
cases. Int J Tuberc Lung Dis. 2010 Sep;14(9):1112-9.
Jeon CY, Murray MB. Diabetes mellitus increases the risk of active
tuberculosis: a systematic review of 13 observational studies. PLoS Med.
2008 Jul 15;5(7):e152.
Lienhardt C, Fielding K, Sillah J S, et al. Investigation of the risk factors
for tuberculosis: a case-control study in three countries in West Africa. Int