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

No estimate

0–24

50–99

100–299

300 or more

25–49

Estimated new TB cases (all forms) per 100 000 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 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

• 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.

STATUS OF TB IN PUNJAB

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.

Source: Zoonotic Tuberculosis in Developing Countries. EID - CDC.

AGRICULTURAL HEALTH IS NOT PREPARED TO FACE RE-EMERGING ZOONOSIS

In 22/34 countries of Latin America and the Caribbean

Tuberculosis

MilkAerosols

MilkAerosolsFoodWater

Source: Promed

TRADE AND TOURISM CHALLENGE AGRICULTURAL AND PUBLIC HEALTH

West Nile Virus New York, 1999

4,324 bird cases 57 equine cases

19 human cases4 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, reportexact 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

AFB X 3

Broad-spectrum antibiotic 10-14 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:

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. 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.

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 ImpairmentDrug 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.

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

Resistant mutants

Secondary (multiple)Drug-resistant tuberculosis

Primary (multiple)Drug-resistant tuberculosis

More Primary (multiple)Drug-resistant tuberculosis

Natural mutations

Selection of resistant strains by inadequate

treatment

Transmissionin droplets

HIV InfectionInadequate infection control

Diagnostic delay

Further transmission

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 Resistance1976-80 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 P-Value

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.

Drug resistance in North West Frontier Province, Pakistan, 1994

Drug

Primary resistance

(%)

Acquired resistance

(%)

Streptomycin 10 46

Isoniazid 1 57

Rifampicin 3 50

Pyrazinamide 3 57

Ethambutol 11 50

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 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 Primary Acquired P Value

N=228 Cases N=123 Cases N=105

Percent

resistant

Isoniazid + 15.78% (36) 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 16%• Rifampicin 07%• Ethambutol 02%• Streptomycin 03%• MDR 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 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)

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, LahoreFrom 01 July 2004 to 31th June, 2005.

• Isolates of Mycobacterium TB 116• Resistant to Rif & INH(MDR) 27

(23.27 %)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%

Management of MDR - T.B.

1. Detailed evaluation regarding history, clinical examination and previous

treatment

2. 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)

Gastrointestinal intolerance hepatitis, Hypersensitivity

Ciprofloxacin Ofloxacin

Levo Floxacin

500 – 1000 mg P.O. 400 – 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

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 3 HRZES** 5 HREretreatment (susceptibilitytesting 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.

Regimen for the Treatment of MDR tuberculosis

Resistance to Initial phase Continuation phaseMinimum

Drugs duration Drugs Durationin months 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

TB Register

Political commitmentDiagnosis by

microscopyAdequate supply of

the right drugsDirectly observed

treatmentAccountability