2. Prof. Shamshad Rasul Awan
MBBS, MCPS, FCPS, FCCP
Prof. of Pulmonology
Head Institute of chest Medicine
King Edward Medical University
Mayo Hospital Lahore - Pakistan

3. 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

4. 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

5. Estimated TB incidence rate, 2005
No estimate
0–24
50–99
100–299
300 or more
25–49
Estimated new TB cases (all forms) per population
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 All rights reserved 5

6. 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/ POPULATION NEW CASES EVERY YEAR
3 OUT OF 4 PATIENTS ARE ADULTS (15-59) ECONOMICALLY PRODUCTIVE AGE GROUP

7. 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.

8. Tuberculosis - 2 main types
Mycobacterium tuberculosis - most common infection in humans.
Mycobacterium bovis (animal form) is responsible for an increasing proportion of human TB cases.
More recently, M. tuberculosis has been documented in a free-ranging animal, the banded mongoose.

9. Banded Mongoose

10. Possible Implications
Expansion of ecotourism, excalating human populations, and changes in land-use practices have increased the possible disease threat humans pose to wildlife.

11. 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.

12. LOSSES DUE TO TUBERCULOSIS
Argentina suffers US$63 million in losses annually
30 million deaths in the world from
Source: Zoonotic Tuberculosis in Developing Countries. EID - CDC

13. TRADE AND TOURISM CHALLENGE AGRICULTURAL AND PUBLIC HEALTH
West Nile Virus
New York, 1999
19 human cases
4 dead
4,324 bird cases
57 equine cases
Source: Promed

14. 14

15. 15

16. 16

17. 17

18. 18

19. AFB smear
AFB (shown in red) are tubercle bacilli

20. 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+

21. 21

22. 22

23. 23

24. Diagnosis of Pulmonary TB
Cough 3 weeks
AFB X 3
Broad-spectrum antibiotic days
If symptoms persist, repeat AFB smears, X-ray
If consistent with TB
Anti-TB Treatment
If 1 positive,
X-ray and
evaluation
If 2/3 positive:
Anti-TB Rx
If negative:

25. 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.

26. 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.

27. 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.

28. Collapse Therapy Artificial Pneumothorax Pneumoperitoneum
Phrenic Crush
Thoracoplasty
Plombage

29. 29

30. 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.

31. 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

33. Anti Tuberculosis Treatment and Diabetic Control
1. 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
2. High incidence of peripheral neuropathy with INH, Ethambutol and Ethionamide. So pyridoxine must be advised with ATT.
3. Ethionamide causes hypoglycemia so critical control of blood glucose level.

34. 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.

35. 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 Anti-tuberculosis treatment. Annals KEMC, June- Dec. 1996;49 – 51)
 Drug induced Hepatitis – stop the regimen .
Start- Ethambutol, Streptomycin and ofloxacin.

36. 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.

37. 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.

38. 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.

39. 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.

40. MULTI DRUG RESISTANCE (MDR)
Defined as resistance to both isoniazed and rifampicin with or without the presence of resistance to another drug.

41. 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)

42. Factors contributing to MDR TB (Contd.)
Asian origin.
Homelessness.
Drug abuse.
HIV.
Adverse reaction to anti T.B. drugs.

43. 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
HIV Infection Inadequate infection control Diagnostic delay
Transmission in droplets
Primary (multiple) Drug-resistant tuberculosis
Further transmission
More Primary (multiple) Drug-resistant tuberculosis

44. 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
% 57%
% 52.6% %
% 53%
Recommendations:- Initial phase 3 HRZE (S)
Continuation phase 6 HRE

45. Primary and secondary resistance to individual drugs
Case with Resistance
Primary Resistance
Secondary Resistance
Unknown
P-Value 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 4
4.7 - E 2.
4.4. S 25
16.7
2.2 23
27.0
PAS 19
12.75
8.9 14
16.5
<.05 TH
3.3 3
3.5
ETH
5.3
NS = NOT SIGNIFICANT, N = NUMBER
Biomedica Vo. 11 (Jul, Dec 1995)

46. Drug resistance in North West Frontier Province, Pakistan, 1994
Primary resistance (%)
Acquired resistance (%)
Streptomycin 10 46
Isoniazid 1 57
Rifampicin 3 50
Pyrazinamide
Ethambutol 11
Thiacetazone 2 30
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
Source, Tuberculosis in Pakistan A. Javaid and M. Amjad in clinical tuberculosis ed.. P.D.O.Davies. 2nd ed. 1998

47. Resistance pattern of 228 culture positive cases to various antituberculosis drugs.
DRUG All Patients Primary Acquired P Value
N= Cases N= Cases N=105
Percent
resistant
Isoniazid % (36) 7.31% (9) 25.71% (27) <. 001
Rifampicin (MDR)
Isoniazid % (58) 21.13% (26) 30.47% (32) .10
Rifampicin 25.00% (57) 15.44% (19) 36.19% (38) <.001
Streptomycin % (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

48. Primary Drug Resistance At JPMC Karachi
INH %
Rifampicin %
Ethambutol %
Streptomycin %
MDR %
Rano Mal,Nadeem Rizvi,Shahina Qayyum
SAARC JTB,L DIS&HIV/AIDS (1)20-23

49. Pattern of drugs resistance among mycobacterium tuberculosis isolates (1998 to 2002)
Year
No of patients
(MDR) H + R
Isoniazid
Rifampicin
Pyrazinamide
Streptomycin
Ethambutol
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)
2002
15.35% (35)
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,

50. Gulab Devi Chest Hospital, Lahore From 01 July 2004 to 31th June, 2005.
Isolates of Mycobacterium TB 116
Resistant to Rif & INH(MDR) 27 ( %)
Resistant Pattern of individual drugs
Resistant to Rifampicin 38.79%
Resistant to Isoniazid 42.42%
Resistant to Streptomycin 37.06%
Resistant to Ethambutol 18.96%
Resistant to Thiacetazone 21.55%
Resistant to Pyrazinamide 58.62%

51. Management of MDR - T.B.
1. Detailed evaluation regarding history, clinical examination and previous treatment
2. Culture and sensitivity pattern.

52. 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.

53. Second Line Antituberculosis drugs
Daily Dose
Adverse Effects
Ethionamide
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

54. Second Line Antituberculosis drugs (Contd.)
Daily Dose
Adverse Effects
Para – AminoSalicylic Acid
10-20 g P.O. (In divided doses)
Gastrointestinal intolerance hepatitis, Hypersensitivity
Ciprofloxacin Ofloxacin
Levo Floxacin
500 – 1000 mg P.O – 800 mg p.o.
500 mg P.O.
Gastrointestinal intolerance headache, Restlessness, Hypersensitivity, Drug interactions
Clofazimine
100 – 300 mg q.d.s. P.O.
Abdominal pain, Skin Discoloration (both dose related) photosensitivity

55. Recommended Regimens for the Treatment of Tuberculosis in problem cases
Initial Phase Continuation Phase
Indication Duration, Drugs Duration Drugs
Months Months
Failure and relapse*
Standard HRZES** HRE
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
* 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.

56. Regimen for the Treatment of MDR tuberculosis
Resistance to Initial phase Continuation phase
Minimum
Drugs duration Drugs Duration
in months in months
Isoniazid 1. Aminoglycoside ethionamide
rifampicin and 2. Pyrazinamide Ofloxacin;
streptomycin 3. Ethionamide ethambutol; Ofloxacin
5. Ethambutol
Isoniazid 1. aminoglycoside ethionamide
rifampicin, 2. ethionamide Ofloxacin;
streptomycin and 3. pyrazinamide Cycloserine;
ethambutol 4. ofloxacin
5. cycloserine

57. 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.

58. 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.

59. 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.

60. 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).

61. Renal Impairment Ethambutol
If renal clearance ml/min, 25mg/kg three times a week.
If renal clearance 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.

62. Renal Impairment Thiacetazone, PAS
Partly excreted through kidney unchanged partly metabolized through liver.
Therapeutic index for thiacetazone is low, generally not recommended.

63. 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

64. TB Control: The 5 components of DOTS Political commitment
Diagnosis by microscopy
Adequate supply of the right drugs
Directly observed treatment
DOTS is a systematic strategy for tuberculosis control. The five components of DOTS are political and administrative commitment, diagnosis primarily by microscopy of patients attending health facilities, regular supply of good quality anti-TB drugs, direct observation of treatment, and systematic monitoring and evaluation.
Source: WHO. Framework for effective tuberculosis control. WHO/TB/
TB Register
Accountability

66. Thank you