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INTERNATIONAL SCENARIO
• ONE-THIRD OF THE WORLD POP I.E. 1.9B IS
INFECTED WITH M.TUBERCULOSIS
• GLOBAL PRAVELANCE 1S 16-20M
• 9M NEW CASES ADDED EVERY YEAR (INC.
136/100000)
• 1.82M DEATHS FROM TB
• 12% OF HIV DEATHS ATTRIBUTABLE TO TB
• 95% OF NEW CASES AND DEATHS OCCUR
IN DEVELOPING COUNTRIES
22 HIGHBURDEN DISEASE
COUNTRIES
•
•
•
•
•
•
•
INDIA
CHINA
INDONESIA
NIGERIA
BANGLADESH
ETHIOPIA
PHILIPPINES
• PAKISTAN
• SOUTH AFRICA
• CONGO
• RUSSIAN FEDERATION
•
•
•
•
•
•
•
•
•
•
•
KENYA
VIET NAM
UR TANZANIA
BRAZIL
UGANDA
ZIMBAVAA
MOZAMBIQUE
THAILAND
AFGHANISTAN
CAMBODIA
MYANMAR
Estimated TB incidence rate, 2005
Estimated new TB cases
(all forms) per 100 000
population
No estimate
0–24
25–49
50–99
100–299
300 or more
The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health
Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries.
Dotted lines on maps represent approximate border lines for which there may not yet be full agreement.
 WHO 2006. All rights reserved
STATUS OF TB IN PAKISTAN
• RANK: 8TH AMONGST 22 HBD COUNTRIES
• PAKISTAN CONTRIBUTES 43% OF THE
TUBERCULOSIS BURDEN IN THE EMRO
REGION
• PREVALANCE OF TB 1.5 M
• INCIDENCE: 181/100000 POPULATION
250000 NEW CASES EVERY YEAR
• 3 OUT OF 4 PATIENTS ARE ADULTS (15-59)
ECONOMICALLY PRODUCTIVE AGE GROUP
STATUS OF TB IN PUNJAB
• Punjab Accounts for > 50 % of disease burden
in country I.E.1.5 million cases.
• Fifty percent of patients are females.
• 60000 new smear positive cases every year.
Tuberculosis - 2 main types
1. Mycobacterium tuberculosis - most common
infection in humans.
2. Mycobacterium bovis (animal form) is
responsible for an increasing proportion of
human TB cases.
3. More recently, M. tuberculosis has been
documented in a free-ranging animal, the
banded mongoose.
Banded Mongoose
Possible Implications
Expansion of ecotourism,
excalating human populations, and
changes in land-use practices have
increased the possible disease
threat humans pose to wildlife.
AGRICULTURAL HEALTH IS NOT PREPARED
TO FACE RE-EMERGING ZOONOSIS
In 22/34 countries of Latin America
and the Caribbean
Tuberculosis
Milk
Aerosols
Milk
Aerosols
Food
Water
Source: Zoonotic Tuberculosis in Developing Countries. EID - CDC.
TRADE AND TOURISM CHALLENGE
AGRICULTURAL AND PUBLIC HEALTH
West Nile Virus
Source: Promed
4,324 bird cases
57 equine cases
New York, 1999
19 human cases
4 dead
AFB smear
AFB (shown in red) are tubercle bacilli
Reporting on AFB Microscopy
Number of bacilli seen
Result reported
None per 100 oil immersion fields Negative
1-9 per 100 oil immersion fields
Scanty, report
exact number
10-99 per 100 oil immersion fields 1+
1-10 per oil immersion field
2+
> 10 per oil immersion field
3+
Diagnosis of Pulmonary TB
Cough 3 weeks
If 1 positive,
X-ray and
evaluation
AFB X 3
If 2/3 positive:
Anti-TB Rx
If negative:
Broad-spectrum antibiotic 10-14 days
If symptoms persist, repeat AFB smears, X-ray
If consistent with TB
Anti-TB Treatment
Chemotherapy Era
Streptomycin (s) – 1940
INH (H) – 1952
PAS - 1949
Standard chemotherapy was effective but
unpleasant.
 Initially H.S.PAS 3 months, continuation
phase H + PAS – 15 months.




Current Standard Chemotherapy
 (WHO/IUATLD RECOMMENDATIONS)
 Rich countries
– Initial phase
2 HRZE/S
– Continuation phase
4 HR
 Poor countries
– Initial phase
2 HRZE
– Continuation phase
6 H.T./H.E.
Tuberculosis is a disease of
great antiquity
 Evidence in Egyptian and precolumbian
mummies.
 Before the availability of drugs, diagnosis
of T.B. – a life time sentence.
 Bed Rest, good diet, sanatoria on
hillsides – only available treatment.
Collapse Therapy

Artificial Pneumothorax

Pneumoperitoneum

Phrenic Crush

Thoracoplasty

Plombage
Tuberculosis & Diabetes
Mellitus
BOTH T.B. & DIABETES MELLITUS COMMON CLINICAL PROBLEM IN
DEVELOPING COUNTRIES LIKE
PAKISTAN.
DIABETICS HAVE A HIGHER RATE OF
T.B. BY A FACTOR OF THREE.
REASONS FOR HIGH INCIDENCE
OF T.B. IN DIABETICS
NOT CERTAIN
MAY BE DUE TO: POOR GLYCEMIC CONTROL
 DUE TO DEFECT IN T. CELL
ALVEOLAR MACROPHAGES
ACTIVATION IN DIABETICS
Anti Tuberculosis Treatment
and Diabetic Control
1.
2.
3.
Rifampicin - causes hyperglycemia due to:*
increased metabolism of oral
hypoglycemic agents - as a liver
microsomal enzyme inducer.
*
Initial hyperglycemia - unknown
mechanism.
Patients needs high dose of oral
hypoglycemic agents
High incidence of peripheral neuropathy
with INH, Ethambutol and Ethionamide. So
pyridoxine must be advised with ATT.
Ethionamide causes hypoglycemia so critical
control of blood glucose level.
Relapse of Tuberculosis
 Relapse should be less than 1%
 Resistance studies should be obtained.
 If previous treatment adequate: 1/3 rd patients
have drug resistance.
 If previous treatment inadequate: Resistance in
2/3 rd of patients, initial therapy should be for
presumed drug resistance.
Liver Impairment
Drug induced hepatotoxicity 3-5% in the
population.In our population it is around
9% (Haq M.U, Rasul S*, Iqbal Z.H. Ch. MK, Bhatti A.H, Anwar
N, Nasir
Incidence of Hepatitis in patients taking Antituberculosis treatment. Annals KEMC, June- Dec. 1996;49 – 51)
Drug induced Hepatitis – stop the
regimen .
Start- Ethambutol, Streptomycin and
ofloxacin.
Pregnancy
Primary TB drugs are safe- no evidence of
teratogenecity.
Rifampicin, INH, Ethambutol, PZA – all
safe.
Streptomycin: may produce ototoxicity of fetus
not recommended.
Preferable :-Female married patients avoid
pregnancy during treatment course.
Pregnancy
Rifampicin baby:
Rifampicin
decreases
the
efficacy
of
oral
contraceptives. Pregnancy may occur while taking
contraceptive pill.
Hence dose of pill should be doubled or alternative
methods used.
If pregnancy occurs – then treat with ATT.
First time diagnosis of TB during pregnancy give ATT.
Dot not advise termination of pregnancy.
HIV Infection
The normal regimen is as effective
as in HIV negative patients.
Adverse reactions to thiacetazone
are common.
Higher relapse rates are found, so
that treatment may be prolonged.
Silicosis
•
•
•
•
•
•
•
More prone to active pulmonary tuberculosis
Difficult to treat
i) Function of alveolar macrophages is impaired.
ii) Massive fibrosis may prevent penetration of
drugs to the site.
Forty percent of silicosis patients had active TB in
Hong Kong.
More relapse.
Prolonged treatment required.
MULTI DRUG RESISTANCE (MDR)
Defined
as
resistance
to
both
isoniazed and rifampicin with or
without the presence of resistance
to another drug.
Factors contributing to MDR TB




Non compliant patient
– Multifactorial (Interruption,
Selection of Drugs, Premature
cessation of treatment)
Inadequate regimen.
Prolonged treatment.
Exposure to an MDR TB patient
(Lack of facilities to isolate the
patient)
Factors contributing to MDR TB
(Contd.)

Asian origin.

Homelessness.

Drug abuse.

HIV.

Adverse reaction to anti T.B. drugs.
Development and spread of drug-resistant
tuberculosis
Colony of mycobacterium
tuberculosis
Natural mutations
Resistant mutants
Selection of resistant
strains by inadequate
treatment
Secondary (multiple)
Drug-resistant tuberculosis
Transmission
in droplets
Primary (multiple)
Drug-resistant tuberculosis
Further transmission
More Primary (multiple)
Drug-resistant tuberculosis
HIV Infection
Inadequate infection control
Diagnostic delay
Drug Resistance Status in Pakistan

In 1967: 87% of isolates from treated patients
resistant to one or more drugs.

In 1989: 31.6% in treated patients

Resistance to H:
Primary
Secondary
Resistance
Resistance
1976-80
24.5%
57%
1981-82
25.8%
52.6%
1993
53%
1995
29%
53%
Recommendations:- Initial phase 3 HRZE (S)
Continuation phase 6 HRE
Primary and secondary resistance to individual drugs
Drug
Case with
Resistance
Primary
Resistance
Secondary
Resistance
Unknown
N
%
N
%
N
%
N
%
H
65
43.6
13
28.9
45
52.9
7
36.
8
<0.001
R
8
5.4
2
4.4
5
5.9
1
5.2
NS
Z
6
4.0
2
4.4
4
4.7
-
-
NS
E
6
4.0
2.
4.4.
4
4.7
-
-
NS
S
25
16.7
1
2.2
23
27.0
1
5.2
<0.001
PAS
19
12.75 4
8.9
14
16.5
1
5.2
<.05
TH
5
3.3
1
2.2
3
3.5
1
5.2
NS
ETH
8
5.3
2
4.4
5
5.9
1
5.2
NS
NS = NOT SIGNIFICANT, N = NUMBER
Biomedica Vo. 11 (Jul, Dec 1995) 54-57.
P-Value
Drug resistance in North West
Frontier Province, Pakistan, 1994
Primary
resistance
(%)
Acquired
resistance
(%)
Streptomycin
10
46
Isoniazid
1
57
Rifampicin
3
50
Pyrazinamide
3
57
Ethambutol
11
50
Thiacetazone
2
30
Drug
Percentage resistant to one drug
8.8
Percentage resistant to two to four drug
12.7
Percentage resistant to five drugs
20.0
Percentage resistant to six drugs
8.8
Source, Tuberculosis in Pakistan A. Javaid and M. Amjad in
clinical tuberculosis ed.. P.D.O.Davies. 2nd ed. 1998
Resistance pattern of 228 culture positive cases
to various antituberculosis drugs.
DRUG
All Patients
N=228
Percent
resistant
Isoniazid +
15.78% (36)
Primary
Cases N=123
Acquired
Cases N=105
P Value
7.31% (9)
25.71% (27)
<. 001
Rifampicin (MDR)
Isoniazid
25.43% (58)
21.13% (26)
30.47% (32)
.10
Rifampicin
25.00% (57)
15.44% (19)
36.19% (38)
<.001
Streptomycin
24.12% (55)
16.26% (20)
33.30% (35)
<.01
Pyrazinamide
21.49% (49)
11.38% (14)
36.19% (38)
<.001
Ethambutol
10.00% (23)
04.87% (06)
16.19% (17)
<.01
Shamshad Rasul, Iffat Shabbir, Rizwan Iqbal et al: Trends in multidrug resistant
tuberculosis, Pakistan Journal of Chest Medicine, Volume 7, No. 3, 2001, 1-28
Primary Drug Resistance At
JPMC Karachi
•
•
•
•
•
INH
Rifampicin
Ethambutol
Streptomycin
MDR
16%
07%
02%
03%
01%
• Rano Mal,Nadeem Rizvi,Shahina Qayyum
SAARC JTB,L DIS&HIV/AIDS.2004-1(1)20-23
Pattern of drugs resistance among mycobacterium
tuberculosis isolates (1998 to 2002)
Year
No of
patients
(MDR)
H+R
Isoniazid
Rifamp
icin
Pyrazin
amide
Strepto
mycin
Ethamb
utol
1998
204
17.08%
(41)
22.91%
(55)
22.5%
(54)
29.16%
(70)
17.5%
(42)
10.41%
(25)
1999
228
15.78%
(36)
25.43%
(58)
25%
(57)
21.49%
(49)
24.12%
(55)
10.08%
(23)
2000
238
15.96%
(38)
26% (62)
28.15
% (67)
26.89%
(64)
25.21%
(60)
15.54%
(37)
2001
212
16.50%
(35)
27.35%
(58)
30.18
% (64)
31.13%
(66)
26.88%
(57)
16.50%
(35)
2002
228
15.35%
(35)
25% (57)
27.63
% (63)
29.38%
(67)
22.36%
(51)
14.47%
(33)
Rizwan Iqbal, Iffat Shabbir et al: TB drug resistance alarming challenge –
answer DOTS., Pakistan J. Med. Res. Vol. 42 No.3, 2003, 134-138.
Gulab Devi Chest Hospital, Lahore
From 01 July 2004 to 31th June, 2005.
• Isolates of Mycobacterium TB
• Resistant to Rif & INH(MDR)
116
27
(23.27 %)
Resistant Pattern of individual drugs
•
•
•
•
•
•
Resistant to Rifampicin
Resistant to Isoniazid
Resistant to Streptomycin
Resistant to Ethambutol
Resistant to Thiacetazone
Resistant to Pyrazinamide
38.79%
42.42%
37.06%
18.96%
21.55%
58.62%
Management of
MDR - T.B.
1.
2.
Detailed evaluation regarding
history, clinical
examination and previous
treatment
Culture and sensitivity
pattern.
Principles of MDR TB management





At least 4 drugs to be given never used
before.
An injectable should be used ___ one
of the aminoglycosides not used
earlier.
Never add a single drug to a failing
regimen ____ a minimum of 2 drugs be
added.
DOTS Plus Must
Duration of therapy 18 – 24 months.
Second Line Antituberculosis drugs
Drugs
Daily Dose
Adverse Effects
Ethionamide
500-1000 mg P.O.
(In divided doses if
necessary)
Gastrointestinal
intolerance hepatitis,
endocrine disturbances,
hypersensitivity
Cycloserine
250 – 750 mg P.O.
(In divided doses
adjust for renal
impairment)
Neurological and
Psychiatric Disturbances
Capreomycin
15 mg / kg i.m.
Hearing loss, Vestibular
Amikacin
Kanamycin
5 days a week
(adjust for renal
impairment)
Renal toxicity Electrolyte
disturbances
Second Line Antituberculosis drugs
(Contd.)
Drugs
Daily Dose
Adverse Effects
Para –
AminoSalicylic
Acid
10-20 g P.O. (In
divided doses)
Ciprofloxacin
Ofloxacin
Levo Floxacin
500 – 1000 mg P.O. Gastrointestinal
400 – 800 mg p.o. intolerance headache,
Restlessness,
500 mg P.O.
Hypersensitivity, Drug
interactions
Clofazimine
100 – 300 mg q.d.s. Abdominal pain, Skin
P.O.
Discoloration (both dose
related) photosensitivity
Gastrointestinal
intolerance hepatitis,
Hypersensitivity
Recommended Regimens for the Treatment of Tuberculosis in
problem cases
Initial Phase
Indication
Duration,
Months
Drugs
Continuation Phase
Duration
Months
Failure and relapse* Standard
3
HRZES**
retreatment
(susceptibility
testing unavailable)
Resistance to H + R Throughout (12-18) ZE + O + S (or
another injectable
agent)
Resistance to all first Throughout (24) 1 injectable agent*** + 3 of these 4:
ethionamide,
cycloserine, PAS, O
Drugs
-
-
5
HRE
-
-
* Regimen is tailored according to the results of drug susceptibility results.
** Streptomycin should be discontinued after 2 months
*** Amikacin, Kanamycin or Capreomycin. Treatment with all of these agents should be
discontinued after 2-6 months depending on patient’s response and tolerance.
Regimen for the Treatment of MDR
tuberculosis
Resistance to
Initial phase
Drugs
Continuation phase
Minimum
duration
in months
Drugs
Duration
in months
Isoniazid
1. Aminoglycoside
3
1. ethionamide
18
rifampicin and
2. Pyrazinamide
3
2. Ofloxacin;
18
streptomycin
3. Ethionamide
3
3. ethambutol;
18
4. Ofloxacin
3
5. Ethambutol
3
Isoniazid
1. aminoglycoside
3
1. ethionamide
18
rifampicin,
2. ethionamide
3
2. Ofloxacin;
18
streptomycin and
3. pyrazinamide
3
3. Cycloserine;
18
ethambutol
4. ofloxacin
3
5. cycloserine
3
Prevention for MDR TB




Proper management – DOTS.
Proper regimens.
Adequate dosage
(Fixed dose combination – A partial
solution)
Treatment should consider patient’s
needs, constraints, preferences
and confidentiality.
Prevention for MDR TB (Contd.)



Early case detection of primary MDR
cases.
Education of medical and
paramedical professionals in all
aspects to be maintained or
reemphasized.
Free treatment and other incentives
for the patients.
Renal Impairment
•Rifampicin, INH, PZA, Eithionamide and
Prothionamide eliminated almost entirely by normal
routes – Hepatic metabolism or billiary excretion.
•In severe renal failure – INH dose be reduced to
200 mg daily with pyridoxine supplementation.
• No adjustment required, if patient on hemodialysis.
Renal Impairment
Streptomycin and other amino glycosides –
need
dose
adjustment.
Streptomycin
injections should be spaced, so that trough
levels of the drugs does not exceed 4mg/L. In
patients on dialysis, streptomycin should be
given 6-8 hours prior to dialysis.
Ethambutol excreted predominantly by kidney.
The dose needs to be adjusted (decreased).
Renal Impairment
Ethambutol
If renal clearance 50-100 ml/min, 25mg/kg
three times a week.
If renal clearance 30-50 ml/min, above dose twice a
week.
If renal clearance <10-25 ml/min, a dose of 15 mg / Kg
at 36 to 48 hours interval.
Patients on thrice weekly hemodialysis, 25 mg / Kg
4 to 6 hours before the procedure.
Renal Impairment
Thiacetazone, PAS
Partly excreted through kidney unchanged
partly metabolized through liver.
Therapeutic index for thiacetazone is low,
generally not recommended.
PRE DOTS SCENARIO
 Low Priority by Policy makers
 Reliance on specialized units not
accessible to all
 Inappropriate diagnostic procedures and
over reliance on x-ray
 Lack of recording ,reporting and
Evaluating system
 Use of non standardized drug regimen
 Non existent supervision
TB Control:
The 5 components of DOTS
 Political
commitment
 Diagnosis by
microscopy
 Adequate supply of
the right drugs
 Directly observed
treatment
 Accountability
TB Register