Training on Tuberculosis & Its Treatment

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Training on Tuberculosis & Its Treatment

  1. 1. Dr Anshu P Gokarn
  2. 2. Mycobacteria Three major groups • Tubercular complex: Causes TB e.g. M.tuberculosis, M.bovis. M.africanum, M.microti • Non tubercular or atypical mycobacteria e.g.: MAC (Mycobacterium Avium Complex) • M.leprae : Causes leprosy Haas W D et al.Mycobacterium Tuberculosis.In:Mandell LG and Bennett EJ,editors.Principles and practice of infectious Diseases.4th Ed.New York:Churchill Livingstone;1995.Dr Anshu P Gokarn
  3. 3. Mycobacterium tuberculosisDr Anshu P Gokarn
  4. 4. Properties of Mycobacteria • Acid fast bacilli • Gram positive • Obligate Aerobe ( organisms that strictly require oxygen for survival) • Non-spore forming • Nonmotile bacillus • Unique Cell wall content-Mycolic acids (high molecular weight lipids) • Generation time: 15-20 hours Haas W D et al.Mycobacterium Tuberculosis.In:Mandell LG and Bennett EJ,editors.Principles and practice of infectious Diseases.4th Ed.New York:Churchill Livingstone;1995.Dr Anshu P Gokarn
  5. 5. Morphology of M.tuberculosis • Very slender • Occur singly,in pairs joined at an angle • Clumps with individual cells Haas W D et al.Mycobacterium Tuberculosis.In:Mandell LG and Bennett EJ,editors.Principles and practice of infectious Diseases.4th Ed.New York:Churchill Livingstone;1995.Dr Anshu P Gokarn
  6. 6. Nontuberculous or atypical mycobacteria (NTM ) • Mycobacterial species that may cause human disease but not tuberculosis. • NTM infections are not contagious unlike tuberculosis. • Risk groups:People with emphysema, bronchiectasis or previous tuberculosis infection,AIDS. E.g: Mycobacterium kansasii Mycobacterium avium Haas W D et al.Mycobacterium Tuberculosis.In:Mandell LG and Bennett EJ,editors.Principles and practice of infectious Diseases.4th Ed.New York:Churchill Livingstone;1995.Dr Anshu P Gokarn
  7. 7. Tuberculosis  A chronic, contagious bacterial infection caused by Mycobacterium tuberculosis.  Primararily affects the LUNGS  In one –third of cases it spreads to other organs like lymph nodes, kidneys, pleura, bones and joints genitourinary tract by the bloodstream or lymphatic system.  Granulomatous lesions characteristic of active disease.  Dissemination of bacilli takes place to many organs and tissues.  With appearance of immunity ,delayed hypersensitivity (DTH) develops to M.tuberculosis. Raviglione CM et al.Tuberculosis.In: Braunwald E et al.,editors.Harrison’s Principles of Internal Medicine.15th ed.New York:McGraw Hill;2001.Dr Anshu P Gokarn
  8. 8. Types of Tuberculosis Pulmonary Extrapulmonary • Braunwald E et al. HArrisons Principles of Internal Medicine Vol.1, 15 th ed. Mc Graw Hill: New York, 2001: 1027-1029 • WeatherHall DJ et al. Oxford Text Book of Medicine, vol 1 3 rd ed; Oxford University Press: Oxford,1996: 652-654 • Tuberculosis- Types- Pulmonology. http://www.pulmonologychannel.com/tuberculosis/types.shtmlDr Anshu P Gokarn
  9. 9. Pulmonary Tuberculosis • Primary Tuberculosis Pneumonia • Tuberculosis Pleurisy • Cavitary Tuberculosis • Miliary TB • Laryngeal Tuberculosis• Braunwald E et al. HArrisons Principles of Internal Medicine Vol.1, 15th ed. Mc Graw Hill: New York, 2001: 1027-1029• WeatherHall DJ et al. Oxford Text Book of Medicine, vol 1 3rd ed; Oxford University Press: Oxford,1996: 652-654• Tuberculosis- Types- Pulmonology. http://www.pulmonologychannel.com/tuberculosis/types.shtmlDr Anshu P Gokarn
  10. 10. Extrapulmonary Tuberculosis Occurs primarily in immunocompromised patients • Lymph Node Disease • Renal Tuberculosis • Adrenal Tuberculosis • Tuberculosis Peritonitis • Tuberculosis • Tuberculosis Pericarditis Meningitis • Osteal Tuberculosis• Braunwald E et al. HArrisons Principles of Internal Medicine Vol.1, 15th ed. Mc Graw Hill: New York, 2001: 1027-1029• WeatherHall DJ et al. Oxford Text Book of Medicine, vol 1 3rd ed; Oxford University Press: Oxford,1996: 652-654• Tuberculosis- Types- Pulmonology. http://www.pulmonologychannel.com/tuberculosis/types.shtmlDr Anshu P Gokarn
  11. 11. Pulmonary TuberculosisDr Anshu P Gokarn
  12. 12. Primary Tuberculosis Pneumonia • This uncommon type of TB presents as pneumonia and is very infectious. • Patients have a high fever and productive cough. • It occurs most often in extremely young children and the elderly. • It is also seen in patients with immunosuppression, such as HIV-infected and AIDS patients, and in patients on long term corticosteroid therapy.• Braunwald E et al. Harrisons Principles of Internal Medicine Vol.1, 15 th ed. Mc Graw Hill: New York, 2001: 1027-1029• WeatherHall DJ et al. Oxford Text Book of Medicine, vol 1 3 rd ed; Oxford University Press: Oxford,1996: 652-654• Tuberculosis- Types- Pulmonology. http://www.pulmonologychannel.com/tuberculosis/types.shtmlDr Anshu P Gokarn
  13. 13. Tuberculosis pleurisy • This usually develops soon after initial infection. • A granuloma located at the edge of the lung ruptures into the pleural space, the space between the lungs and the chest wall • Once the bacteria invade the space, the amount of fluid increases dramatically and compresses the lung, causing shortness of breath (dyspnea) and sharp chest pain that worsens with a deep breath (pleurisy). • Mild- or low-grade fever commonly is present. • Generally resolves without treatment • 2/3rd patients with tuberculosis pleurisy develop active pulmonary TB within 5 years.• Braunwald E et al. Harrisons Principles of Internal Medicine Vol.1, 15th ed. Mc Graw Hill: New York, 2001: 1027-1029• WeatherHall DJ et al. Oxford Text Book of Medicine, vol 1 3rd ed; Oxford University Press: Oxford,1996: 652-654• Tuberculosis- Types- Pulmonology. http://www.pulmonologychannel.com/tuberculosis/types.shtmlDr Anshu P Gokarn
  14. 14. Cavitary TB • Cavitary TB involves the upper lobes of the lung. • Progressive lung destruction by forming cavities, or enlarged air spaces. • Symptoms include productive cough, night sweats, fever, weight loss, and weakness. There may be hemoptysis (coughing up blood). • Highly contagious. • Occasionally, disease spreads into the pleural space and causes TB empyema (pus in the pleural fluid).• Braunwald E et al. Harrisons Principles of Internal Medicine Vol.1, 15th ed. Mc Graw Hill: New York, 2001: 1027-1029• WeatherHall DJ et al. Oxford Text Book of Medicine, vol 1 3rd ed; Oxford University Press: Oxford,1996: 652-654• Tuberculosis- Types- Pulmonology. http://www.pulmonologychannel.com/tuberculosis/types.shtmlDr Anshu P Gokarn
  15. 15. Miliary TB • Miliary TB is disseminated TB. • "Miliary" describes the appearance on chest x-ray of very small nodules throughout the lungs that look like millet seeds. • Miliary TB can occur shortly after primary infection. • The patient becomes acutely ill with high fever and is in danger of dying. The disease also may lead to chronic illness and slow decline. • Symptoms may include fever, night sweats, and weight loss. • Patients who are immunosuppressed and children who have been exposed to the bacteria are at high risk for developing miliary TB.• Braunwald E et al. Harrisons Principles of Internal Medicine Vol.1, 15th ed. Mc Graw Hill: New York, 2001: 1027-1029• WeatherHall DJ et al. Oxford Text Book of Medicine, vol 1 3rd ed; Oxford University Press: Oxford,1996: 652-654• Tuberculosis- Types- Pulmonology. http://www.pulmonologychannel.com/tuberculosis/types.shtmlDr Anshu P Gokarn
  16. 16. Miliary tuberculosisDr Anshu P Gokarn
  17. 17. Laryngeal TB • TB can infect the larynx, or the vocal chord area. • It is extremely infectious.• Braunwald E et al. Harrisons Principles of Internal Medicine Vol.1, 15 th ed. Mc Graw Hill: New York, 2001: 1027-1029• WeatherHall DJ et al. Oxford Text Book of Medicine, vol 1 3 rd ed; Oxford University Press: Oxford,1996: 652-654• Tuberculosis- Types- Pulmonology. http://www.pulmonologychannel.com/tuberculosis/types.shtmlDr Anshu P Gokarn
  18. 18. Dr Anshu P Gokarn
  19. 19. Lymph node disease • Lymph nodes contain macrophages that capture the bacteria. • Any lymph node can harbor uncontrolled replication of bacteria, causing the lymph node to become enlarged. • The infection can develop a fistula (passageway) from the lymph node to the skin.• Braunwald E et al. Harrisons Principles of Internal Medicine Vol.1, 15th ed. Mc Graw Hill: New York, 2001: 1027-1029• WeatherHall DJ et al. Oxford Text Book of Medicine, vol 1 3rd ed; Oxford University Press: Oxford,1996: 652-654• Tuberculosis- Types- Pulmonology. http://www.pulmonologychannel.com/tuberculosis/types.shtmlDr Anshu P Gokarn
  20. 20. Tuberculosis peritonitis • M. tuberculosis can involve the outer linings of the intestines and the linings inside the abdominal wall, producing increased fluid, as in tuberculosis pleuritis. • Increased fluid leads to abdominal distention and pain. • Patients are moderately ill and have fever.• Braunwald E et al. Harrisons Principles of Internal Medicine Vol.1, 15 th ed. Mc Graw Hill: New York, 2001: 1027-1029• WeatherHall DJ et al. Oxford Text Book of Medicine, vol 1 3 rd ed; Oxford University Press: Oxford,1996: 652-654• Tuberculosis- Types- Pulmonology. http://www.pulmonologychannel.com/tuberculosis/types.shtmlDr Anshu P Gokarn
  21. 21. Tuberculosis pericarditis • The membrane surrounding the heart (the pericardium) is affected in this condition. • This causes the space between the pericardium and the heart to fill with fluid, impeding the hearts ability to fill with blood and beat efficiently.• Braunwald E et al. Harrisons Principles of Internal Medicine Vol.1, 15 th ed. Mc Graw Hill: New York, 2001: 1027-1029• WeatherHall DJ et al. Oxford Text Book of Medicine, vol 1 3 rd ed; Oxford University Press: Oxford,1996: 652-654• Tuberculosis- Types- Pulmonology. http://www.pulmonologychannel.com/tuberculosis/types.shtmlDr Anshu P Gokarn
  22. 22. Osteal Tuberculosis • Infection of any bone can occur, but one of the most common sites is the spine. • Spinal infection can lead to compression fractures and deformity of the back.• Braunwald E et al. Harrisons Principles of Internal Medicine Vol.1, 15 th ed. Mc Graw Hill: New York, 2001: 1027-1029• WeatherHall DJ et al. Oxford Text Book of Medicine, vol 1 3 rd ed; Oxford University Press: Oxford,1996: 652-654• Tuberculosis- Types- Pulmonology. http://www.pulmonologychannel.com/tuberculosis/types.shtmlDr Anshu P Gokarn
  23. 23. Renal Tuberculosis• This can cause asymptomatic pyuria (white blood cells in the urine) and can spread to the reproductive organs and affect reproduction.• In men, epididymitis (inflammation of the epididymis) may occur.• Braunwald E et al. Harrisons Principles of Internal Medicine Vol.1, 15 th ed. Mc Graw Hill: New York, 2001: 1027-1029• WeatherHall DJ et al. Oxford Text Book of Medicine, vol 1 3 rd ed; Oxford University Press: Oxford,1996: 652-654• Tuberculosis- Types- Pulmonology. http://www.pulmonologychannel.com/tuberculosis/types.shtmlDr Anshu P Gokarn
  24. 24. Gastrointestinal tuberculosis• Manifestation of primary tuberculosis• Caused by consuming unpastuerized milk containing M.bovis• Occurs in patients with post primary pulmonary tuberculosis who have swallowed infected sputum.• Symptoms: Recurrent abdominal pain and constipation with weight loss• Clinical finding: Non healing ulcers of the tongue, oropharynx, esophageal disease and duodenal disease• Standard chemotherapy is used•Haas W D et al.Mycobacterium Tuberculosis.In:Mandell LG and Bennett EJ,editors.Principles and practice of infectious Diseases.4th Ed.NewYork:Churchill Livingstone;1995.•WeatherHall DJ et al. Oxford Text Book of Medicine, vol 1 3rd ed; Oxford University Press: Oxford,1996: 652-654Dr Anshu P Gokarn
  25. 25. Adrenal Tuberculosis • TB of the adrenal glands can lead to adrenal insufficiency. • Adrenal insufficiency is the inability to increase steroid production in times of stress, causing weakness and collapse.• Braunwald E et al. Harrisons Principles of Internal Medicine Vol.1, 15th ed. Mc Graw Hill: New York, 2001: 1027-1029• WeatherHall DJ et al. Oxford Text Book of Medicine, vol 1 3rd ed; Oxford University Press: Oxford,1996: 652-654• Tuberculosis- Types- Pulmonology. http://www.pulmonologychannel.com/tuberculosis/types.shtmlDr Anshu P Gokarn
  26. 26. TB meningitis • M. tuberculosis can infect the meninges (the main membrane surrounding the brain and spinal cord). • This can be devastating, leading to permanent impairment and death. • TB can be difficult to discern from a brain tumor because it may present as a focal mass in the brain with focal neurological signs. • Headache, sleepiness, and coma are typical symptoms. • The patient may appear to have had a stroke.• Braunwald E et al. Harrisons Principles of Internal Medicine Vol.1, 15th ed. Mc Graw Hill: New York, 2001: 1027-1029• WeatherHall DJ et al. Oxford Text Book of Medicine, vol 1 3rd ed; Oxford University Press: Oxford,1996: 652-654• Tuberculosis- Types- Pulmonology. http://www.pulmonologychannel.com/tuberculosis/types.shtmlDr Anshu P Gokarn
  27. 27. Symptoms of Tuberculosis • Coughing, general fatigue, loss of appetite, chest pain, night sweats, and low-grade fever. • The cough is at first not too productive, but later increasing amounts of phlegm are coughed up. • The person loses weight and the sputum becomes bloody.• Braunwald E et al. Harrisons Principles of Internal Medicine Vol.1, 15th ed. Mc Graw Hill: New York, 2001: 1027-1029• WeatherHall DJ et al. Oxford Text Book of Medicine, vol 1 3rd ed; Oxford University Press: Oxford,1996: 652-654• Tuberculosis- Types- Pulmonology. http://www.pulmonologychannel.com/tuberculosis/types.shtmlDr Anshu P Gokarn
  28. 28. MDR -TB • A form of tuberculosis that is resistant to two or more of the primary drugs used for the treatment of tuberculosis. • Resistance to one or several forms of treatment occurs when the bacteria develops the ability to withstand antibiotic attack and relay that ability to their progeny. • Since that entire strain of bacteria inherits this capacity to resist the effects of the various treatments, resistance can spread from one person to another. • On an individual basis, however, inadequate treatment or improper use of the anti-tuberculosis medications remains an important cause of drug-resistant tuberculosis. Braunwald E et al. HArrisons Principles of Internal Medicine Vol.1, 15th ed. Mc Graw Hill: New York, 2001: 1027-1029 WeatherHall DJ et al. Oxford Text Book of Medicine, vol 1 3rd ed; Oxford University Press: Oxford,1996: 652-654Dr Anshu P Gokarn
  29. 29. MDRTB: Treatment • Standardized regimens cannot be developed for MDRTB, and good data are lacking on the efficacy of non-standard regimens. • If a person has MDRTB, a longer course of treatment (up to 2 years) with more drugs is necessary. • Some drugs used include aminoglycosides (e.g., amikacin, capreomycin, kanamycin), fluoroquinolones (e.g., ciprofloxacin, ofloxacin), cycloserine, and ethionamide. • In some advanced, treatment-resistant cases, surgery may be done to remove infected lung tissue. Rrecommendations on treatment of patients with MDRTB, NYC Department of Health, TB Control Program, Clinical Policies and Protocols, 3rd edition, 1999.Dr Anshu P Gokarn
  30. 30. General rules of MDRTB treatment • Program of daily DOT (directly observed therapy) to ensure adherence. • At least two -- and preferably three to five -- medications to which the mycobacterial strain is reported to be susceptible should be used. Rrecommendations on treatment of patients with MDRTB, NYC Department of Health, TB Control Program, Clinical Policies and Protocols, 3rd edition, 1999.Dr Anshu P Gokarn
  31. 31. General rules of MDRTB treatment contd… • Treatment to be continued for a minimum of 18 months after culture conversion to negative • Patients with HIV infection or cavitary disease : treatment to be continued for 24 months after culture conversion. • Treatment must be daily, not intermittent. • An aminoglycoside (e.g., streptomycin, kanamycin, amikacin) or capreomycin should be prescribed from the start of therapy and for at least 6 months after cultures convert to negative. Rrecommendations on treatment of patients with MDRTB, NYC Department of Health, TB Control Program, Clinical Policies and Protocols, 3rd edition, 1999.Dr Anshu P Gokarn
  32. 32. Dr Anshu P Gokarn
  33. 33. Risk of progression from Infection to active disease • 5-15% of infected individuals will develop active tuberculosis. • Likelihood of developing active disease varies with the intensity and duration of exposure. • Strongest risk factor- AIDS • Other factors: malnutrition,renal failure,immunosuppressed. 1. Raviglione CM et al.Tuberculosis.In: Braunwald E et al.,editors.Harrison’s Principles of Internal Medicine.15th ed.New York:McGraw Hill;2001. 2. Haas W D et al.Mycobacterium Tuberculosis.In:Mandell LG and Bennett EJ,editors.Principles and practice of infectious Diseases.4th Ed.New York:Churchill Livingstone;1995.Dr Anshu P Gokarn
  34. 34. Transmission of the tubercle bacilli Transmission is by airborne droplet infection: Coughing, sneezing, speaking can transmit TB. Contrary to popular myth, fomites (ie countertops) do not spread TB 50% of those exposed are usually infected 10-15 % of those who are infected after exposure go on to develop disease 1. Raviglione CM et al.Tuberculosis.In: Braunwald E et al.,editors.Harrison’s Principles of Internal Medicine.15th ed.New York:McGraw Hill;2001. 2. Haas W D et al.Mycobacterium Tuberculosis.In:Mandell LG and Bennett EJ,editors.Principles and practice of infectious Diseases.4th Ed.New York:Churchill Livingstone;1995.Dr Anshu P Gokarn
  35. 35. How Tuberculosis Develops Inhalation of M.tuberculosis Pulmonary Tuberculosis Dormant inside Infected macrophages are macrophages for carried by years or get activated lyphatics,,spreads to cause infection Extrapulmonary throughoout the body bvia Tuberculosis bloodstream Pathogen reaches lungs where multiplication Destroys alveolar begins macrophages,monocytes 1. Raviglione CM et al.Tuberculosis.In: Braunwald E et al.,editors.Harrison’s Principles of Internal Medicine.15th ed.New York:McGraw Hill;2001. 2. Haas W D et al.Mycobacterium Tuberculosis.In:Mandell LG and Bennett EJ,editors.Principles and practice of infectious Diseases.4th Ed.New York:Churchill Livingstone;1995.Dr Anshu P Gokarn
  36. 36. Granulomatous Lesions: Typical of TuberculosisDr Anshu P Gokarn
  37. 37. Complications of Tuberculosis Toxicity of drugs – Rifampin and isoniazid may both cause a non-infectious hepatitis. Other complications include: – drug resistance – relapse of the disease – tuberculous meningitis – respiratory failure – adult respiratory distress syndrome (ARDS) 1. Raviglione CM et al.Tuberculosis.In: Braunwald E et al.,editors.Harrison’s Principles of Internal Medicine.15th ed.New York:McGraw Hill;2001. 2. Haas W D et al.Mycobacterium Tuberculosis.In:Mandell LG and Bennett EJ,editors.Principles and practice of infectious Diseases.4th Ed.New York:Churchill Livingstone;1995.Dr Anshu P Gokarn
  38. 38. Secondary or Reactivated Tuberculosis • Secondary tuberculosis is usually due to the reactivation of old lesions or gradual progression of primary tuberculosis into chronic form • The characteristics of secondary tuberculosis include extensive tissue damages due to immunologic reactions of the host to tubercle bacilli and their products. 1. Raviglione CM et al.Tuberculosis.In: Braunwald E et al.,editors.Harrison’s Principles of Internal Medicine.15th ed.New York:McGraw Hill;2001. 2. Haas W D et al.Mycobacterium Tuberculosis.In:Mandell LG and Bennett EJ,editors.Principles and practice of infectious Diseases.4th Ed.New York:Churchill Livingstone;1995.Dr Anshu P Gokarn
  39. 39. TB and HIV infection TB is an opportunistic infection in HIV-infected patients. HIV patients show increased susceptibility to tuberculosis due to weakened immune system In early HIV infection,pulmonary tuberculosis is most common infection. In advanced HIV infection, the following diseases are most common  Extrapulmonary tuberculosis- disseminated,lymphatic,pleural and pericardial  Mycobacteremmia.  Meningitis• Haas W D et al.Mycobacterium Tuberculosis.In:Mandell LG and Bennett EJ,editors.Principles and practice of infectious Diseases.4th Ed.New York:Churchill Livingstone;1995.Dr Anshu P Gokarn
  40. 40. Diagnosis of tuberculosis  Microscopy (Ziehl Neelson Method)  Culture o Identification of cultural properties  Animal inoculation  Typing o to trace the source of infection  Tuberculin tests  Chest X-rays  Lung biopsy 1. Raviglione CM et al.Tuberculosis.In: Braunwald E et al.,editors.Harrison’s Principles of Internal Medicine.15th ed.New York:McGraw Hill;2001. 2. Haas W D et al.Mycobacterium Tuberculosis.In:Mandell LG and Bennett EJ,editors.Principles and practice of infectious Diseases.4th Ed.New York:Churchill Livingstone;1995.Dr Anshu P Gokarn
  41. 41. Microscopy Films of sputum ,pus can be stained by • Ziehl Neelson • Fluorescent (Auramine – Rhodamine) method. 1. Raviglione CM et al.Tuberculosis.In: Braunwald E et al.,editors.Harrison’s Principles of Internal Medicine.15th ed.New York:McGraw Hill;2001. 2. Haas W D et al.Mycobacterium Tuberculosis.In:Mandell LG and Bennett EJ,editors.Principles and practice of infectious Diseases.4th Ed.New York:Churchill Livingstone;1995.Dr Anshu P Gokarn
  42. 42. Acid fastness of mycobacteria • A distinguishing feature • Acid fastness is due to high molecular weight lipids- Mycolic acids • Since mycobacteria grow slowly ,acid fast smear play an important role in early diagnosis of mycobacterial infections. 1. Raviglione CM et al.Tuberculosis.In: Braunwald E et al.,editors.Harrison’s Principles of Internal Medicine.15th ed.New York:McGraw Hill;2001. 2. Haas W D et al.Mycobacterium Tuberculosis.In:Mandell LG and Bennett EJ,editors.Principles and practice of infectious Diseases.4th Ed.New York:Churchill Livingstone;1995.Dr Anshu P Gokarn
  43. 43. Importance of Acid fast Stained Smears  It provides a presumptive diagnosis of mycobacterial disease.  Most infectious cases are rapidly identified.  Used to follow-up the success of chemotherapy of tuberculosis patients.  Vitally important to the patients discharge from the hospital, or return to employment.  It can confirm that cultures growing on media are indeed acid-fast. 1. Raviglione CM et al.Tuberculosis.In: Braunwald E et al.,editors.Harrison’s Principles of Internal Medicine.15th ed.New York:McGraw Hill;2001. 2. Haas W D et al.Mycobacterium Tuberculosis.In:Mandell LG and Bennett EJ,editors.Principles and practice of infectious Diseases.4th Ed.New York:Churchill Livingstone;1995.Dr Anshu P Gokarn
  44. 44. Staining of Mycobacteria  Their lipid-rich cell walls of Mycobacteria are relatively impermeable to various basic dyes unless the dyes are combined with phenol.  Once stained the cells resist decolonization with acidified organic solvents and are therefore called ACID FAST. 1. Raviglione CM et al.Tuberculosis.In: Braunwald E et al.,editors.Harrison’s Principles of Internal Medicine.15th ed.New York:McGraw Hill;2001. 2. Haas W D et al.Mycobacterium Tuberculosis.In:Mandell LG and Bennett EJ,editors.Principles and practice of infectious Diseases.4th Ed.New York:Churchill Livingstone;1995.Dr Anshu P Gokarn
  45. 45. Fluorescent staining • Smears are flooded with Auramine Rhodamine stain. • Decolorize by 0.5% of Acid Alcohol. • Acceptable result: Orange to yellow flourescence1. Raviglione CM et al.Tuberculosis.In: Braunwald E et al.,editors.Harrison’s Principles of Internal Medicine.15th ed.New York:McGraw Hill;2001.2. Haas W D et al.Mycobacterium Tuberculosis.In:Mandell LG and Bennett EJ,editors.Principles and practice of infectious Diseases.4th Ed.New York:Churchill Livingstone;1995.Dr Anshu P Gokarn
  46. 46. Disadvantages of Fluorescent Staining • Dead, or organisms rendered non- cultivable by chemotherapy may still fluoresce positive (stained) • Therefore more bacilli are stained than by the Ziehl-Neelsen method – Count error in 1. microscopy. Raviglione CM et al.Tuberculosis.In: Braunwald E et al.,editors.Harrison’s Principles of Internal Medicine.15th ed.New York:McGraw Hill;2001. 2. Haas W D et al.Mycobacterium Tuberculosis.In:Mandell LG and Bennett EJ,editors.Principles and practice of infectious Diseases.4th Ed.New York:Churchill Livingstone;1995.Dr Anshu P Gokarn
  47. 47. Ziehl Neelson Method • Requires 105 AFB per mL of sputum for recognition. • Heat fixed Smears are flooded with Carbol fuchsin and steamed for 5 minutes. • Decolorized with 3% acid-alcohol Acceptable result: Red • Counterstained with bacilli against blue methylene blue background 1. Raviglione CM et al.Tuberculosis.In: Braunwald E et al.,editors.Harrison’s Principles of Internal Medicine.15th ed.New York:McGraw Hill;2001. 2. Haas W D et al.Mycobacterium Tuberculosis.In:Mandell LG and Bennett EJ,editors.Principles and practice of infectious Diseases.4th Ed.New York:Churchill Livingstone;1995.Dr Anshu P Gokarn
  48. 48. Mycobacterial Culture • Definitive diagnosis depends on isolation and identification of M.tuberculosis from diagnostic specimen. • Culture detects as few as 10 to 100 CFU/mL of sputum • Cultured on Lowenstein-Jenson media • Media Selective for M.tuberculosis and M.bovis • Colonies confirmed by Ziehl Neelson staining and biochemical identification tests. 1. Raviglione CM et al.Tuberculosis.In: Braunwald E et al.,editors.Harrison’s Principles of Internal Medicine.15th ed.New York:McGraw Hill;2001. 2. Haas W D et al.Mycobacterium Tuberculosis.In:Mandell LG and Bennett EJ,editors.Principles and practice of infectious Diseases.4th Ed.New York:Churchill Livingstone;1995.Dr Anshu P Gokarn
  49. 49. Tuberculin Skin test (PPD Testing)  Used to measure hypersensitivity.  Tuberculin, a protein extracted from M. tuberculosis, is injected into an individual.  A localized immune reaction elicited within 1-3 days:- tuberculin-positive.  Indurations (hardening) and edema :- Previous exposure but may not have the disease.  For most individuals, immune protection gained from previous exposure is lifelong. 1. Raviglione CM et al.Tuberculosis.In: Braunwald E et al.,editors.Harrison’s Principles of Internal Medicine.15th ed.New York:McGraw Hill;2001. 2. Haas W D et al.Mycobacterium Tuberculosis.In:Mandell LG and Bennett EJ,editors.Principles and practice of infectious Diseases.4th Ed.New York:Churchill Livingstone;1995.Dr Anshu P Gokarn
  50. 50. Nucleic acid amplification:Rapid diagnosis PCR, DNA probes specific against 16S ribosomal RNA of mycobacterial species can  Facilitates rapid detection of mycobacteria in culture media  Rapid differentiaton of pathogenic  M.tuberculosis from other mycobacteria from a positive culture. 1. Raviglione CM et al.Tuberculosis.In: Braunwald E et al.,editors.Harrison’s Principles of Internal Medicine.15th ed.New York:McGraw Hill;2001. 2. Haas W D et al.Mycobacterium Tuberculosis.In:Mandell LG and Bennett EJ,editors.Principles and practice of infectious Diseases.4th Ed.New York:Churchill Livingstone;1995.Dr Anshu P Gokarn
  51. 51. Dr Anshu P Gokarn
  52. 52. History Until the late 1940s no drugs were available to treat tuberculosis. Treatment was directed toward lessening the symptoms, identifying environmental factors, and enhancing general physical health. Many prescribed substances to be taken were actually lethal, such as a kerosene and whiskey concoction. Shikes, R.H. (1986) Rocky Mountain Medicine: Doctors, Drugs, and Disease in Early Colorado. Boulder, Johnson Books. http://www.uccs.edu/~cragmor/tuber.htmlDr Anshu P Gokarn
  53. 53. Need for Sanatoriums??• Sanatorias are essentially large treatment centres that specialized in the diagnosis and recovery of patients with tuberculosis• Demonstrate the value of rest, fresh air, good nutrition and isolation to prevent the spread of Simple Bed Rest infection.Dr Anshu P Gokarn
  54. 54. Anti tuberculosis drugs • Three key first line drugs used for previously untreated patients are:  Isoniazid  Rifampicin  Pyrazinamide • Ethambutol and streptomycin are valuable additional drugs. • In some countries thiacetazone and p- aminosalicylic acid are still used Oxford textbook of medicine. Third edition. Vol 1. Oxford medical publications, page no.655Dr Anshu P Gokarn
  55. 55. • Reserve drugs which may be used when first line drugs have failed are:  Ethionamide  Prothionamide  Amikacin  Kanamycin  Capreomycin  Viomycin  Cycloserine  Quinolones (ofloxacin, ciprofloxacin, sparfloxacin) Oxford textbook of medicine. Third edition. Vol 1. Oxford medical publications, page no.655Dr Anshu P Gokarn
  56. 56. Principles of anti tuberculosis therapy.• Large number of actively multiplying bacilli must be killed : isoniazid achieves this.• Treat semi dormant bacilli that metabolizes slowly or intermittently: rifampicin and pyrazinamide are the most efficacious.• Prevent emergence of resistance by multiple therapy to suppress drug-resistant mutants : isoniazid and rifampicin are best.• Combined formulations are used to ensure that poor compliance does not result in monotherapy with consequent drug resistance.Laurence DR, Bennett PN, Brown MJ, Clinical pharmacology. 8 th edition. Churchill Livingstone publications. Page 225-27Dr Anshu P Gokarn
  57. 57. Older treatment regimens All TB cases or suspects were started on a 4 drug treatment regimen of isoniazid, rifampicin, pyrazinamide, ethambutol. This can be given in three ways: Daily Bi-weekly :4-drug therapy-daily for 2 weeks and 2 times a week for 6 weeks. Thrice weekly 4 drug therapy –6 months World health organization. Essential drugs. WHO Model List (revised in December 1997). WHO Drug information 1998; 12:22-25Dr Anshu P Gokarn
  58. 58. Classification of agents. Drugs used in the treatment of tuberculosis can be divided into two major categories. First line agents Second line agents Goodman and Gilman’s The pharmacological basis of therapeutics. Ninth edition, page:1155-1174.Dr Anshu P Gokarn
  59. 59. First line drugs These combine the greatest level of efficacy with an acceptable degree of toxicity. These include: Isoniazid Rifampin / Rifampicin Ethambutol Streptomycin Pyrazinamide A large majority of patients can be treated successfully these agents. Goodman and Gilman’s The pharmacological basis of therapeutics. Ninth edition, page:1155-1174.Dr Anshu P Gokarn
  60. 60. Second line drugs Because of microbial resistance or factors such as HIV infection or AIDS, it may be necessary to resort to second-line drugs in addition, so that treatment may be initiated with 5-6 drugs. Goodman and Gilman’s The pharmacological basis of therapeutics. Ninth edition, page:1155-1174.Dr Anshu P Gokarn
  61. 61. Second line drugs The drugs in this class include: Ofloxacin Ciprofloxacin Ethionamide Aminosalicylic acid Cycloserine Amikacin Kanamycin Capreomycin Goodman and Gilman’s The pharmacological basis of therapeutics. Ninth edition, page:1155-1174.Dr Anshu P Gokarn
  62. 62. Isoniazid Group- Tuberculocidal (Antimycobacterial agent ) Synonyms - INH; INAH; Isoniazidium; Isonicotinic acid hydrazide; Isonicotinyl hydrazide; Isonicotino- hydrazide; Pycazide; Tubazid Origin-. synthetic pyridine derivative of nicotinamide Chemical name- isonicotinic acid hydrazide Molecular formula- C6H7N3O Molecular weight - 137.14 Goodman and Gilman’s The pharmacological basis of therapeutics. Ninth edition, page:1155-1174.Dr Anshu P Gokarn
  63. 63. Mechanism of action (MOA) • Inhibitory action on the biosynthesis of mycolic Porin acid, an important INH Mycolic constituent of the acid mycobacterial cell wall. • High degree of Lipid bilayer mycobacterial selectivity. Goodman and Gilman’s The pharmacological basis of therapeutics. Ninth edition, page:1155-1174.Dr Anshu P Gokarn
  64. 64. Bacterial resistance Due to missense mutation within the mycobacterial inhA gene involved in mycolic acid biosynthesis. Cross-resistance between INH and other anti TB drugs (except ethionamide, which is structurally related to INH) does not occur. Shift from primary sensitive to mainly insensitive microorganisms occasionally occurs within a few weeks after therapy is started. The time of appearance of resistance may vary considerably from one case to another. Goodman and Gilman’s The pharmacological basis of therapeutics. Ninth edition, page:1155-1174.Dr Anshu P Gokarn
  65. 65. Pharmacokinetics Rapidly and completely (90-95%) absorbed both orally and parenterally. Cmax= 3 to 5µg/ml Tmax= 1 to 2 hours after oral administration. Diffuses readily into all body fluids and cells. Drug detected in the pleural and ascitic fluids. Concentration in the CSF similar to plasma. Goodman and Gilman’s The pharmacological basis of therapeutics. Ninth edition, page:1155-1174.Dr Anshu P Gokarn
  66. 66. Main biotransformation mechanisms involve acetylaytion and hydrolysis. Human populations show genetic heterogeneity with regard to rate of acetylation of INH. Based on that the two classes are: Fast acetylators (rapid metabolism-short half life) Slow acetylators (slow metabolism-longer half life) The half life of the drug may be prolonged in the presence of hepatic insufficiency. 75% to 95 % of drug is excreted in urine within 24 hours mostly as metabolites. Goodman and Gilman’s The pharmacological basis of therapeutics. Ninth edition, page:1155-1174.Dr Anshu P Gokarn
  67. 67. Dosage of Isoniazid Daily dose Twice daily dose Thrice weekly dose Children Adults Children Adults Children Adults 10-20 5 20-40 15 20-40 15 < 300mg < 300mg < 900mg < 900mg < 900mg <900mgDr Anshu P Gokarn
  68. 68. Rifampin Group- Antimycobacterial agent Synonyms - Rifampin Rifaldazine Rifamycin Origin-. semisynthetic derivative of rifamycin antibiotics Molecular formula- C43H58N4O12 Molecular weight – 822.96 Daily dose Twice daily dose Thrice weekly dose Children Adults Children Adults Children Adults 10-20 10 10-20 10 10-20 10 < 600mg < 600mg < 600mg < 600mg < 600mg <600mg Goodman and Gilman’s The pharmacological basis of therapeutics. Ninth edition, page:1155-1174.Dr Anshu P Gokarn
  69. 69. Mechanism of action • It inhibits DNA-dependent RNA polymerase and mycobacteria and other microorganisms by forming a stable drug-enzyme complex , leading to suppression of initiation of chain formation (but not chain elongation) in RNA synthesis. • More specifically, the ß subunit of this complex enzyme is the site of action of the drug, although rifampin binds only to the holoenzyme. Goodman and Gilman’s The pharmacological basis of therapeutics. Ninth edition, page:1155-1174.Dr Anshu P Gokarn
  70. 70. Pharmacokinetics Readily absorbed from the GI tract (90%). Peak plasma concentration occurs at 1.5 to 4 hours after an oral dose. 89(+/- 1) % of rifampicin in circulation is bound to plasma proteins. When the meninges are inflamed, rifampicin enters the cerebrospinal fluid It reaches therapeutic levels in the lungs, bronchial secretions, pleural fluid, other cavity fluid, liver, bile, and urine. Goodman and Gilman’s The pharmacological basis of therapeutics. Ninth edition, page:1155-1174.Dr Anshu P Gokarn
  71. 71. Approximately 85% of rifampicin is metabolised by the liver microsomal enzymes to its main and active metabolite - deacetylrifampicin. Rifampicin undergoes enterohepatic recirculation but not the deacetylated form. Rifampicin metabolite deacetylrifampicin is excreted in the bile and also in the urine. Approximately 50% of the rifampicin dose is eliminated within 24 hours and 6 to 30% of the drug is excreted unchanged in the urine, while 15% is excreted as active metabolite. Goodman and Gilman’s The pharmacological basis of therapeutics. Ninth edition, page:1155-1174.Dr Anshu P Gokarn
  72. 72. Ethambutol Group- Antimycobacterial agent Origin-. synthetic oral antibiotic derivative of ethylenediamine which contains two imine radicals and two butanol radicals. Molecular formula- C10H24N2O2 Molecular weight – 204.3 Chemical structure: CH3CH2CH(CH2OH)NHCH2CH2NHCH(CH2OH)CH2CH3 Daily dose Twice daily dose Thrice weekly dose Children Adults Children Adults Children Adults 15-25 15-25 mg 50mg 50mg 25-30 25-30 mg mg mg Goodman and Gilman’s The pharmacological basis of therapeutics. Ninth edition, page:1155-1174.Dr Anshu P Gokarn
  73. 73. Mechanism of action Ethambutol is bacteriostatic and appears to inhibit the synthesis of one or more metabolites, thus causing impairment of cell metabolism, arrest of multiplication, and cell death. Goodman and Gilman’s The pharmacological basis of therapeutics. Ninth edition, page:1155-1174.Dr Anshu P Gokarn
  74. 74. Pharmacokinetics • Following a single oral dose of 25 mg/kg of body weight, attains a peak of up to 5 œg/mL in serum within 4 hours after administration and is less than 1 ug/ml by 24 hours. • About 80% of an oral dose of ethambutol is absorbed from the gastro-intestinal tract. • Ethambutol diffuses readily into red blood cells and into the cerebrospinal fluid when the meninges are inflamed. Goodman and Gilman’s The pharmacological basis of therapeutics. Ninth edition, page:1155-1174.Dr Anshu P Gokarn
  75. 75. • The main path of metabolism appears to be an initial oxidation of the alcohol to an aldehydic intermediate, followed by conversion to a dicarboxylic acid • During the 24-hour period following oral administration of ethambutol, approximately 50% of the initial dose is excreted unchanged in the urine, while an additional 8% to 15% appears in the form of metabolites. • From 20 to 22% of the initial dose is excreted in the faeces as unchanged drug basis of therapeutics. Ninth edition, page:1155-1174. Goodman and Gilman’s The pharmacologicalDr Anshu P Gokarn
  76. 76. Pyrazinamide • Synthetic pyrazine analog of nicotinamide. • Bactericidal • Well absorbed orally • Widely distributed. • Metabolized by hydroxylation • Primary excretion by glomerular filtration. Daily dose Twice daily dose Thrice weekly dose Children Adults Children Adults Children Adults 15-30 15-30 50-70 50-70 50-70 50-70 <2g <2g <4g <4g <3g <3g Goodman and Gilman’s The pharmacological basis of therapeutics. Ninth edition, page:1155-1174.Dr Anshu P Gokarn
  77. 77. Streptomycin • Aminoglycoside. • Not absorbed by mouth,is given by i.m. inj. • Serum half life may be prolonged during renal impairment. • Half life prolonged in new born babies and adults over 40 years, thereby increasing risk of toxicity. • Leads to ototoxicity. • Since it crosses placental barrier, should not be used in pregnant women. Daily dose Twice daily dose Thrice weekly dose Children Adults Children Adults Children Adults 20-40 15 25-30 25-30 25-30 25-30 < 1.0g < 1.0g < 1.5g < 1.5 g < 1.5g < 1.5g Oxford textbook of medicine. Third edition. Vol 1. Oxford medical publications, page no.638-64Dr Anshu P Gokarn
  78. 78. Thiacetazone • A thio semi carbazone • Bacteriostatic • Widely used in combination with other agents in developing countries due to cheapness • Should not be given to patients with liver disease due to hepatotoxic effects. Oxford textbook of medicine. Third edition. Vol 1. Oxford medical publications, page no.638-64Dr Anshu P Gokarn
  79. 79. Para-amino salicylic acid • Bacteriostatic • Either used in combination with isoniazid or as a reserve drug when it has not already been used. • Due to GI reactions it has been replaced by other drugs • Should not be given to patients with impaired renal function. Oxford textbook of medicine. Third edition. Vol 1. Oxford medical publications, page no.638-64Dr Anshu P Gokarn
  80. 80. Ethionamide and Prothionamide • Derivative of thioisonicotinamide • Secondary agent- to be used concurrently with other drugs only when therapy with primary agents is ineffective or contraindicated • It acts by inhibition of oxygen dependant of mycolic acid synthesis • Used limited by their adverse effects. • Adverse reactions less severe in children and with prothionamide. Oxford textbook of medicine. Third edition. Vol 1. Oxford medical publications, page no.638-64 Haas W D et al.Mycobacterium Tuberculosis.In:Mandell LG and Bennett EJ,editors.Principles and practice of infectious Diseases.4th Ed.New York:Churchill Livingstone;1995.Dr Anshu P Gokarn
  81. 81. Cycloserine Acts by inhibiting cell wall synthesis One of the several alternatives for retreatment regimen or for the treatment primary drug resistant M. tuberculosis Low level of activity against MDR TB strains Used as a reserve drug Use limited by mental disturbances. Haas W D et al.Mycobacterium Tuberculosis.In:Mandell LG and Bennett EJ,editors.Principles and practice of infectious Diseases.4th Ed.New York:Churchill Livingstone;1995.Dr Anshu P Gokarn
  82. 82. Role of quinolones • Of the quinolones ciprofloxacin, ofloxacin, flerofloxacin, and sparfloxacin all have inhibitory activity against M. tuberculosis and MAC bacteria, in vitro. • Used in combination with second line agents in the treatment of MDR TB and in patients with HIV. Goodman and Gilman’s The pharmacological basis of therapeutics. Ninth edition, page:1155-1174.Dr Anshu P Gokarn
  83. 83. WHO recommended Alternative Treatment regimens(1997) • INH + RIF for 9 months • RIF + EMB for 12-18 months:Can be used in disease caused by INH –resistant organism. • RIF,EMB and PZA for 6-9 months. • INH + EMB for 18-24 months:Can be used in disease caused by RIF resistant organism World health organization. Essential drugs. WHO Model List (revised in December 1997). WHO Drug information 1998; 12:22-25Dr Anshu P Gokarn
  84. 84. Treatment regimen in Pregnancy-WHO recommended (1997) • 3 drug regimen with INH,RIF and EMB • PYZ not approved • No harm to the breast-fed infant due to anti- TB drugs. World health organization. Essential drugs. WHO Model List (revised in December 1997). WHO Drug information 1998; 12:22-25Dr Anshu P Gokarn
  85. 85. TUBERCULOSIS CONTROL - INDIA India now has the second-largest DOTS (Directly Observed Treatment, Short-course) programme in the world, placing about 40,000 patients on treatment every month. World health organization. Essential drugs. WHO Model List (revised in December 1997). WHO Drug information 1998; 12:22-25Dr Anshu P Gokarn
  86. 86. Short course treatment Prolonged therapy leads to poor patient compliance and hence short course regimens were developed. To be effective the therapy must continue for at least 6 months, or longer if isoniazid and rifampicin are not given throughout. Martindale-the extra pharmacology, 31st edition.Dr Anshu P Gokarn
  87. 87. Treatment of choice for pulmonary tuberculosis. Recommended by the International Union Against Tuberculosis and Lung Disease (IUAT- LD). Martindale-the extra pharmacology, 31st edition.Dr Anshu P Gokarn
  88. 88. The IUAT-LD regimens combine drugs with potent bactericidal activity (Isoniazid, Rifampicin) with sterilizing activity against semi dormant bacilli (Rifampicin, Pyrazinamide) with the ability to suppress drug resistant mutants (Isoniazid, Rifampicin) and which may be administered 2 or 3 times weekly (Isoniazid, rifampicin, pyrazimamide, ethambutol) Martindale-the extra pharmacology, 31st edition.Dr Anshu P Gokarn
  89. 89. The IUAT regimen for newly diagnosed adults and children with pulmonary and extra pulmonary disease consist of concurrent adninisteration of isoniazid and rifimpicin for 6 months with pyrazinamide given with isoniazid and rifampicin in the 8 week initial phase. Martindale-the extra pharmacology, 31st edition.Dr Anshu P Gokarn
  90. 90. Prevention and Control: BCG vaccination  Derived from attenuated strain of M.bovis.  Safe  Recommended for routine use at birth in high tuberculosis prevalence countries, healthcares workers.  WHO recommends vaccination in asymptomatic HIV-infected children from endemic areas. 1. Raviglione CM et al.Tuberculosis.In: Braunwald E et al.,editors.Harrison’s Principles of Internal Medicine.15th ed.New York:McGraw Hill;2001. 2. Haas W D et al.Mycobacterium Tuberculosis.In:Mandell LG and Bennett EJ,editors.Principles and practice of infectious Diseases.4th Ed.New York:Churchill Livingstone;1995.Dr Anshu P Gokarn
  91. 91. Treatment of Latent tuberculosis  Patients are identified by PPD testing from high risk groups.  INH at a dose of 15 mg/kg twice weekly for 6 months recommended in PPD positive –HIV negative patients  Alternative regimens for adults: – 2-months daily rifampin+ PYR – 4-months daily rifampin. 1. Raviglione CM et al.Tuberculosis.In: Braunwald E et al.,editors.Harrison’s Principles of Internal Medicine.15th ed.New York:McGraw Hill;2001. 2. Haas W D et al.Mycobacterium Tuberculosis.In:Mandell LG and Bennett EJ,editors.Principles and practice of infectious Diseases.4th Ed.New York:Churchill Livingstone;1995.Dr Anshu P Gokarn
  92. 92. Zucox Range• Zucox-2 Captabs: (R 450 mg+ H 300 mg)• Zucox-3 Kit (R 450 mg+ H 300 mg, E 800 mg)• Zucox-4 Kit (R 450 mg+ H 300 mg, E 800 mg, Z 1500 mg• Zucox Kit (R 450 + H 300, Z1500 mg)Dr Anshu P Gokarn
  93. 93. Recommended Daily Dosage Regimen for Adults (wt. 33-50 kg) Zucox Range Treatment Description Daily Regimen Category Initial phase Continuati on phase I New smear positive pulmonary TB New cases of smear negative Zucox -4 (For 2 months) Zucox-2 (For 4 severe Pulmonary/ months) Extrapulmonary TB II Smear Positive Relapse Zucox -4 (For 3 months) Zucox-3 (For 5 Treatment failure Streptomycin inj months) Treatment after interruption (for 2 months) III New smear negative Pulmonary TB other than Category I and less Zucox Kit (For 2 months) Zucox-2 (For 4 severe forms of Extrapulmonary months) TBDr Anshu P Gokarn
  94. 94. Dr Anshu P Gokarn

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