2 Prof. Shamshad Rasul Awan MBBS, MCPS, FCPS, FCCPProf. of PulmonologyHead Institute of chest MedicineKing Edward Medical UniversityMayo Hospital Lahore - Pakistan
3 INTERNATIONAL SCENARIO ONE-THIRD OF THE WORLD POP I.E. 1.9B IS INFECTED WITH M.TUBERCULOSISGLOBAL PRAVELANCE 1S 16-20M9M NEW CASES ADDED EVERY YEAR (INC. 136/100000)1.82M DEATHS FROM TB12% OF HIV DEATHS ATTRIBUTABLE TO TB95% OF NEW CASES AND DEATHS OCCUR IN DEVELOPING COUNTRIES
4 22 HIGHBURDEN DISEASE COUNTRIES INDIACHINAINDONESIANIGERIABANGLADESHETHIOPIAPHILIPPINESPAKISTANSOUTH AFRICACONGORUSSIAN FEDERATIONKENYAVIET NAMUR TANZANIABRAZILUGANDAZIMBAVAAMOZAMBIQUETHAILANDAFGHANISTANCAMBODIAMYANMAR
5 Estimated TB incidence rate, 2005 No estimate0–2450–99100–299300 or more25–49Estimated new TB cases (all forms) per populationThe 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 reserved5
6 STATUS OF TB IN PAKISTAN RANK: 8TH AMONGST 22 HBD COUNTRIESPAKISTAN CONTRIBUTES 43% OF THE TUBERCULOSIS BURDEN IN THE EMRO REGIONPREVALANCE OF TB 1.5 MINCIDENCE: 181/ POPULATION NEW CASES EVERY YEAR3 OUT OF 4 PATIENTS ARE ADULTS (15-59) ECONOMICALLY PRODUCTIVE AGE GROUP
7 STATUS OF TB IN PUNJABPunjab 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.
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 CaribbeanTuberculosisMilkAerosolsMilkAerosolsFoodWaterSource: Zoonotic Tuberculosis in Developing Countries. EID - CDC.
12 LOSSES DUE TO TUBERCULOSIS Argentina suffers US$63 million in losses annually30 million deaths in the world fromSource: Zoonotic Tuberculosis in Developing Countries. EID - CDC
13 TRADE AND TOURISM CHALLENGE AGRICULTURAL AND PUBLIC HEALTH West Nile VirusNew York, 199919 human cases4 dead4,324 bird cases57 equine casesSource: Promed
19 AFB smearAFB (shown in red) are tubercle bacilli
20 Reporting on AFB Microscopy Number of bacilli seenResult reportedNone per 100 oil immersion fieldsNegative1-9 per 100 oil immersion fieldsScanty, reportexact number10-99 per 100 oil immersion fields1+1-10 per oil immersion field2+> 10 per oil immersion field3+
24 Diagnosis of Pulmonary TB Cough 3 weeksAFB X 3Broad-spectrum antibiotic daysIf symptoms persist, repeat AFB smears, X-rayIf consistent with TBAnti-TB TreatmentIf 1 positive,X-ray andevaluationIf 2/3 positive:Anti-TB RxIf 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 countriesInitial phase 2 HRZE/SContinuation phase 4 HRPoor countriesInitial phase 2 HRZEContinuation 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.
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 agents2. 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 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.
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 InfectionThe 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 treati) 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 patientMultifactorial (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 tuberculosisNatural mutationsResistant mutantsSelection of resistant strains by inadequate treatmentSecondary (multiple) Drug-resistant tuberculosisHIV Infection Inadequate infection control Diagnostic delayTransmission in dropletsPrimary (multiple) Drug-resistant tuberculosisFurther transmissionMore 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 patientsResistance 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 ResistancePrimary ResistanceSecondary ResistanceUnknownP-ValueN%H6543.61328.94552.9736.8<0.001R85.424.455.915.2NSZ64.044.7-E2.4.4.S2516.72.22327.0PAS1912.758.91416.5<.05TH3.333.5ETH5.3NS = NOT SIGNIFICANT, N = NUMBERBiomedica Vo. 11 (Jul, Dec 1995)
46 Drug resistance in North West Frontier Province, Pakistan, 1994 Primary resistance (%)Acquired resistance (%)Streptomycin1046Isoniazid157Rifampicin350PyrazinamideEthambutol11Thiacetazone230Percentage resistant to one drug8.8Percentage resistant to two to four drug12.7Percentage resistant to five drugs20.0Percentage resistant to six drugsSource, 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 ValueN= Cases N= Cases N=105PercentresistantIsoniazid % (36) 7.31% (9) 25.71% (27) <. 001Rifampicin (MDR)Isoniazid % (58) 21.13% (26) 30.47% (32) .10Rifampicin 25.00% (57) 15.44% (19) 36.19% (38) <.001Streptomycin % (55) 16.26% (20) 33.30% (35) <.01Pyrazinamide 21.49% (49) 11.38% (14) 36.19% (38) <.001Ethambutol 10.00% (23) 04.87% (06) 16.19% (17) <.01Shamshad 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 QayyumSAARC JTB,L DIS&HIV/AIDS (1)20-23
49 Pattern of drugs resistance among mycobacterium tuberculosis isolates (1998 to 2002) YearNo of patients(MDR) H + RIsoniazidRifampicinPyrazinamideStreptomycinEthambutol199820417.08% (41)22.91% (55)22.5% (54)29.16% (70)17.5% (42)10.41% (25)199922815.78% (36)25.43% (58)25% (57)21.49% (49)24.12% (55)10.08% (23)200023815.96% (38)26% (62)28.15% (67)26.89% (64)25.21% (60)15.54% (37)200121216.50% (35)27.35% (58)30.18% (64)31.13% (66)26.88% (57)200215.35% (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 116Resistant to Rif & INH(MDR) 27 ( %)Resistant Pattern of individual drugsResistant 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 treatment2. 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 MustDuration of therapy 18 – 24 months.
53 Second Line Antituberculosis drugs Daily DoseAdverse EffectsEthionamidemg P.O. (In divided doses if necessary)Gastrointestinal intolerance hepatitis, endocrine disturbances, hypersensitivityCycloserine250 – 750 mg P.O. (In divided doses adjust for renal impairment)Neurological and Psychiatric DisturbancesCapreomycin15 mg / kg i.m.Hearing loss, VestibularAmikacin Kanamycin5 days a week (adjust for renal impairment)Renal toxicity Electrolyte disturbances
54 Second Line Antituberculosis drugs (Contd.) Daily DoseAdverse EffectsPara – AminoSalicylic Acid10-20 g P.O. (In divided doses)Gastrointestinal intolerance hepatitis, HypersensitivityCiprofloxacin OfloxacinLevo Floxacin500 – 1000 mg P.O – 800 mg p.o.500 mg P.O.Gastrointestinal intolerance headache, Restlessness, Hypersensitivity, Drug interactionsClofazimine100 – 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 PhaseIndication Duration, Drugs Duration DrugsMonths MonthsFailure and relapse*Standard HRZES** HREretreatment(susceptibilitytesting unavailable)Resistance to H + R Throughout (12-18) ZE + O + S (oranother injectableagent)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 phaseMinimumDrugs duration Drugs Durationin months in monthsIsoniazid 1. Aminoglycoside ethionamiderifampicin and 2. Pyrazinamide Ofloxacin;streptomycin 3. Ethionamide ethambutol; Ofloxacin5. EthambutolIsoniazid 1. aminoglycoside ethionamiderifampicin, 2. ethionamide Ofloxacin;streptomycin and 3. pyrazinamide Cycloserine;ethambutol 4. ofloxacin5. 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 ImpairmentRifampicin, INH, PZA, Eithionamide and Prothionamide eliminated almost entirely by normal routes – Hepatic metabolism or billiary excretion.In severe renal failure – INH dose be reduced to200 mg daily with pyridoxine supplementation.No adjustment required, if patient on hemodialysis.
60 Renal ImpairmentStreptomycin 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 / Kg4 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 allInappropriate diagnostic procedures and over reliance on x-rayLack of recording ,reporting and Evaluating systemUse of non standardized drug regimenNon existent supervision
64 TB Control: The 5 components of DOTS Political commitment Diagnosis by microscopyAdequate supply of the right drugsDirectly observed treatmentDOTS 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 RegisterAccountability