Treatment of Tuberculosis | Jindal Chest Clinic

Tuberculosis is an infectious lung disease caused by bacteria that spreads through the air through coughing, sneezing, or spitting. In this presentation "Treatment of Tuberculsois (TB)" has been described including their causes, therapy, Principles, diagnosis, symptoms, management, etc. For more information, please contact us: 9779030507.

1. Treatment of TB

2. Historical landmarks Magical and supernatural treatments Tubercle bacillus (Mycobacterium tuberculosis): Discovered on March 24, 1882 by Robert Koch (Awarded Nobel Prize in 1905) Air, Diet, Fish-oils, Minerals etc Sanatoria treatment Chemotherapy: Streptomycin (1944), P.A.S., Isoniazid (1952) Ethambutal , Rifampicin (1960s-70s) Other new drugs (1980s onwards) Regimens and Strategies (SCC, Intermittent, DOTS)

3. Treatment: Issues Principles of therapy Goals Scientific Rationale – Bacterial Populations Drugs and Regimens: Efficacy, toxicity , costs Strategies: Efficacy, compliance Surgical Options Relapses and sequelae Specific situations: Comorbidities Multi and Extreme Drug Resistance (MDR/XDR) TB & HIV infection

4. Objectives of TB treatment To decrease mortality and long term morbidity by Ensuring care Minimizing relapses Preventing development of drug resistance To decrease and break the chain of transmission of infection To achieve the above whilst minimizing side effects due to drugs

5. Treatment Principles Most effective therapy to achieve early negative status Adequate period of time to ensure complete sterilization Most effective utilization of available resources Ensuring compliance Looking after social aspects

6. Why is the TB Therapy Long? Nature of the disease pathology High Load Poor drug penetration Phenotypic resistance in persisters Non-growing mycobacteria Stationary phase bacteria Residual survivors or persisters not killed during antibiotic exposure Dormant bacilli 3. Poor host immune system for residual bacteria (not killed by drugs)

7. Bacterial Populations and Chemotherapy A. Active growing T.b . INH Metabolic B. Bacilli with spurts Activity of metabolism RIF C. Bacilli in acid pH PZA D. Persisters

8. Classification of Anti-TB drugs Bacteristatic Ist line vs Vs bactericidal Second line Anti TB Drugs TB specific drugs vs Broad spectrum antibiotics

9. Anti TB drugs (Stop TB Deptt ., WHO) Group Drugs I Oral H,R,Z,E New generation rifamycin-rifabutin and rifapentine ( For HIV-TB) II Injectables Kana , Amika , Capreo , Strepto III Fluoroquinolones Moxi , Gati , Levo, Ofloxacin IV Oral bacteriostatic, 2 nd line drugs – thioamides , cycloserine , RAS, Terizidone V Unclear efficacy Clofazimine , Linezolid , High dose H; antibiotics

10. Drug side-effects/ Toxicities ( Ist line drugs) INH: Neuropathy, skin reactions, hepatitis, fever RIF: Hepatitis, Flu like syndrome, Nephritis ETM: Retrobulbar / Optic neuritis, Skin rashes PZN: Hyperuricaemia , hepatotoxicity, skin rashes STM: Ototoxicity, vestibular toxicity, skin rashes PAS: GI upset, hypersensitivity, fever, rashes Allergic reactions, skin rashes and GI intolerance can occur with almost any drug

11. Hepatotoxic anti- tuberculous agents Hepatotoxic Non-hepatotoxic* Isoniazid Ethambutol Rifampicin Streptomycin Pyrazinamide Kanamycin Ethionamide Amikacin Para-aminosalicylic acid Cycloserine Capreomycin Fluoroquinolones *Rare hepatotoxic reactions may occur

12. Treatment strategies (Short Course Chemotherapy Use of multiple drugs Most effective drugs Intensive followed by maintenance phase Ensuring compliance and completion 4 (Intensive phase) 2-3 (Maintenance) R , H, Z 2 + 4 months DOTS

13. Drugs and Regimens Daily Intensive Phase: RHZE (2 mths ) Maintenance: RH (4 mths ) RHE (HIV + ve Pts ) Intermittent (Always supervised) RNTCP Regimen: Category I 2 R 3 H 3 Z 3 E 3 (24 doses) 4 R 3 H 3 (54 doses)

14. Tmt for EPTB Duration ( Mth ) Lymph node 6 Bone & joint 6-9 Pleural disease 6 Pericarditis 6 CNS 9-12 Disseminated 6 Genitourinary 6 Peritoneal 6

15. Paradoxical Reactions Worsening during ATT (e.g. LN, Pl. effusion) ? Ongoing inflammation/fibrosis ? Immune reconstitution (esp. HIV) ? Release of toxins Treatment Anti-inflammatory drugs ? Corticosteroids No need for ATT prolongation / 2 nd line

16. Revised National TB Control Programme (RNTCP)

17. WHY “REVISED” ? National Tuberculosis Programme Started in 1962 Domiciliary treatment at District TB centers Over dependence on chest X-ray for diagnosis Self administered drug regimens Poor funding Poor treatment completion rates RNTCP Started in 1997 Presently covers the entire country

18. Directly Observed Treatment, Short course (DOTS) Principle strategy of RNTCP Components Sustained political commitment Access to quality-assured TB sputum microscopy Standardized short-course chemotherapy Uninterrupted supply of quality assured drugs Recording and reporting system enabling outcome assessment

19. Diagnosis of pulmonary tuberculosis Patients with TB feel ill and seek care promptly Active case finding is unnecessary and unproductive Microscopy is appropriate technology, indicating infectiousness, risk of death, and priority for treatment X-ray is non-specific for TB diagnosis Serological and amplification technologies (PCR, etc.) currently of no proven value in TB control

20. Diagnosis of Pulmonary Tuberculosis Two specimens optimal Spot specimen on first visit; sputum container given to patient Early morning collection by patient on next day Spot specimen during second visit

21. Patient categorization New patients (Cat. I and III merged) Previously treated / Retreatment cases/ Defaulters (Cat. II) Other specific categories Multi-drug resistant TB (Cat IV) TB and HIV

22. What is DOTS ? A strategy ( D irectly O bserved T herapy, S hort Course) to ensure treatment completion in which Treatment observer (DOT provider) must be accessible and acceptable to the patient and accountable to the health system DOT provider administers the drugs in intensive phase. Ensures that the patient takes medicines correctly in continuation phase. Provides the necessary information and encouragement for completion of treatment. Direct observation ensures treatment for the entire course with the right drugs in the right doses at the right intervals

23. Why DOTS? To ensure compliance To render early non-infectiousness To standardize treatment regimen and avoid drug resistance Provide free and affordable treatment Control TB – nationally and globally

24. Treatment schedules (RNTCP) New cases 2 H 3 R 3 Z 3 E 3 / 4 H 3 R 3 Previously treated 2 H 3 R 3 Z 3 E 3 S 3 / 1 H 3 R 3 Z 3 E 3 / 5 H 3 R 3 E 3 Treatment under Direct Supervision (DOTS)

25. RNTCP: What should be the duration? New patients should receive a 6 month regimen 2HRZE / 4HR ( Thrice weekly) Intensive Phase 2 months Maintenance Phase 4 months

26. Can steroids help early resolution? No. Steroids have proven benefit in only TB Meninigitis TB Pericarditis Other uses of steroids in TB. ( Tuberculous ) Addison’s disease Acute hypersensitivity reaction to ATT Severe, unresolving IRS (Immune Reconstitution Syndrome)

27. Do anti TB drugs have interactions with other drugs? Yes. Rifampicin induces pathways that metabolize other drugs. It reduces the concentrations and effects of following drugs: Anti infective ( macrolides , doxicycline , azole antifungals , mefloquine , antiretroviral) Hormones ( tamoxifen , levothyroxine , ethinylestradiol , norethindrone ) Cardiovascular agents – digoxin , nifedipine , diltiazem , propranolol , hypo lipidaemics , etc. Others: Methadone, warfarin , cyclosporin , corticosteroids, anti convulsants , theophylline , sulphoxylurla

28. Can ATT be used safely during pregnancy? Yes, except streptomycin ( Ototoxic to the fetus) Breast feeding should continue on ATT Treatment / Chemoprophylaxis for the babies of mothers with active TB

29. ATT in patients with liver disease? No chronic liver disease; Hepatitis virus carriers; Past H/o hepatitis; Excessive alcohol use Usual TB regimens More common hepatotoxic reactions Unstable / Advanced liver disease LFT before starting tmt . (ALT > 3 times) Two hepatotoxic drugs 9 RHE 2 RHES 6 HR 6-9 RZE One hepatotoxic drug – 2HES 10 HE No hepatotoxic drug – 18-24 SE Flouro

30. Latent MTB Infection A. Diagnosis Positive tuberculin test Exclude active disease B. Regimens INH for 12 mths : For both HIV – and + cases R + Z for 2 mths : For HIV + ve H + R for 3 mths : HIV – ve R for 4 mths : HIV – ve

31. TB and HIV Co-infection

32. Mechanisms of Coinfection Impairment of immune response Progressive depletion & dysfunction of CD 4 lymphocytes Impaired macrophage function Invasion of inflamed bronchial walls – the breeding sites

33. Augmented Effects HIV on TB Rapid progression Active disease (40%) Higher morbidity Mortality: 4 times higher (than HIV – ve ), 20-35% Increased ADRs to ATT Increased drug resistance (MDR and XDR) TB on HIV Increased viral replication, load, immune suppression, infections, morbidity and mortality

34. How does TB occur? Endogenous reactivation HIV is most potent risk factor Exogenous (Re) infection Increased chances of TB exposure in hospitals

35. Clinical Features Early stage (CD 4 > 200/mm 3 ) Typical reactivation TB (Upper lobes infiltrates/cavities) Advanced stage (CD 4 < 200/mm 3 ) Atypical disease Disseminated/ extrapulmonary TB

36. Clinical Presentation, Symptoms Fever, cough, chest pain, weight loss Chronic diarrhoea Generalized lymphadenopathy Organ specific symptoms and signs

37. Atypical Manifestations (Pulmonary) Lower lobe/diffuse involvement Absence of cavity formation Endobronchial involvement Prominent hilar / mediastinal Pleural effusion – common Miliary TB Chest wall abscess/cutaneous sinuses

38. Extra Pulmonary TB LYMPH NODE - Commonest EP site - Peripheral - Intrathoracic -Intra-abdominal (accompanying visceral involvement) DISSEMINATED - Miliary or more than - one XP site - Mycobacteremia SKIN - May co-exist with pulmonary TB Erythematous papules, purpura , subcutaneous nodules, pustules Biopsy- little granuloma, AFB+ HEPATOSPLENIC Round , hypoechoic , multiple lesions <1 cm TB MENINGITIS CSF findings may be normal LARYNGEAL

39. Tuberculin skin testing Tuberculin reactivity four fold less in HIV infection Reactivity declines with increasing immune suppression early HIV 40-70 % advanced HIV 10-30% Annual tuberculin testing for HIV infection to detect latent infection Tuberculin anergy assoc. with risk of active TB is controversial

40. Treatment of HIV-TB dual infection Both ATT and ART (Anti retroviral treatment) HAART (Highly Active Anti-Retroviral Therapy) At least 3 drugs from amongst: - Protease inhibitors - Reverse transcriptase inhibitors - Viral integrase enzyme inhibitors - Viral entry inhibitors Combined ATT and ATT is more toxic; drug-drug interaction (Rif causes decrease in conc. o f ARV), Rifabutin is an alternate choice.

41. Tuberculosis and ARV Therapy Status When to Start ARV Therapy CD4 less than 200/mm 3 Start TB Therapy Start ARV as soon as TB therapy can be tolerated CD4 between 200 and 350/mm 3 Start TB therapy Start ARV therapy after 2 mo. Of TB therapy with EFV CD4 greater than 350/mm 3 Treat TB, start ARV therapy according to general indications

42. Why MDR / XDR TB in HIV? Poor immune response leads to increased rapidly dividing bacilli and spontaneous mutations Noncompliance due to frequent ADR Large pill burden Malabsorption of ATT

43. Adverse drug reactions More frequently in HIV infected, 20-25% Related to level of immune activation and immune suppression Thiacetazone induced exfoliative dermatitis, TEN, Steven Johnson syndrome can be fatal (contraindicated with HIV) ATT induced hepatitis four fold higher than in seronegative patient Risk factors- anergy , lymphopenia , Elevated Neopterin levels

44. Do anti TB drugs have interactions with other drugs? Yes. Rifampicin induces pathways that metabolize other drugs. It reduces the concentrations and effects of following drugs: Anti infective ( macrolides , doxicycline , azole antifungals , mefloquine , antiretroviral) Hormones ( tamoxifen , levothyroxine , ethinylestradiol , norethindrone ) Cardiovascular agents – digoxin , nifedipine , diltiazem , propranolol , hypo lipidaemics , etc. Others: Methadone, warfarin , cyclosporin , corticosteroids, anti convulsants , theophylline , sulphoxylurla

45. Paradoxical reaction Defined as temporary worsening of clinical condition, appearance of new radiologic manifestations after initiation of Tt ,and are not due to Tt failure or a second process Due to recovery of immunological Th 1 response to mycobacterial antigen Heightened granulomatous response may clear the organism but itself may cause tissue damage

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