Tuberclosis pharmacotherapy

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  • IntroductionTB remains one of the most common causes of death amongst infectious diseases worldwide.Despite the fact that Mycobacterium tuberculosis colonizes few hosts other than man and survives only briefly when isolated in the environment, efforts to eliminate the disease have failed to date.TB has staged a comeback in the US and other parts of the world because of shifts in the population considered endemic for TB, healthcare policies changes, in the number of immunocompromised individuals, and development of drug resistance.

  • TB Burden 20128.6 million people fell ill with TB in 2012, including 1.1 million cases among people living with HIVIn 2012, 1.3million people died from TB, including 320000 among people who were HIV-positive

  • Epidemiology of TB PakistanTuberculosis (TB) is a massive public health problem and according to World Health Organization, (WHO) Pakistan ranks 5th in the countries having high disease burden. It contributes 26% of avoidable deaths among adults and children in our country. The present annual incidence of open TB cases is estimated to be between 231/100,000 persons and subsequently about 361,000 new cases of TB are added every year in Pakistan

  • Epidemiology of TBFour out of 5 TB patients in Pakistan still remain undetected, untreated and inadequately managed. One untreated or poorly treated open case of TB can make 10-15 people more patients in a years time. Lack of proper diagnostic equipment and skills, irrational prescription and non-availability of essential anti TB drugs are among the major contributing factors of various complications including emerging resistance. Multi Drug Resistant TB is a contributing factor to increasing costs, mortality and duration of treatment. A simple TB case management incurs a cost of 6000 rupees for the treatment of 9 months while a MDR TB case, which requires treatment for 2 years, costs about 300,000 rupees

  • Etiology of TBTB is caused by M. tuberculosis, an aerobic, non-spore-forming bacillus. Also called Acid-fast bacillus (AFB).M. tuberculosis replicates slowly (q 24hrs) (20-40 minutes with other organisms).M. tuberculosis thrive well in environment where O2 tension is high such as renal parenchyma, growing ends of bones.

  • Mycobacterium species include:M. tuberculosis complex: M. tuberculosis, M. bovis, M. africanumMycobacteria other than tuberculosis: Around 15 are recognised as pathogenic to humans and some causepulmonary disease resembling TB. They have been foundin soil, milk and water. They are also referred to asatypical mycobacteria.Mycobacterium leprae: The cause of leprosy.

  • Pulmonary (respiratory) TBextrapulmonary (non-respiratory) TB.

    Sites of extrapulmonary disease include the pleura, lymph nodes, pericardium, kidneys,meninges, bones and joints, larynx, skin, intestines, peritoneum and eyes.

    Pulmonary TB may arise from exogenous reinfection or endogenous reactivation of a latent focus remaining from the initial infection.

  • TransmissionTubercle bacilli are transmitted through the air by aerosolized droplet nuclei that are produced when a person with pulmonary or laryngeal TB coughs, sneezes, speaks, or sings.

    Droplet nuclei may also be produced by other methods such as bronchoscopy, endotracheal intubation, processing of secretions in labs and hospitals.

    The nuclei, which contains one to 3 M. tuberculosis organisms, are small enough to remain airborne for long periods of time and to reach the alveoli within the lungs when inhaled.

  • TransmissionTubercle bacilli are not transmitted on inanimate objects such as dishes, clothing, or beddings, and organisms deposited on skin or intact mucosa do not invade tissues.

    Several factors influence the likelihood of transmission of M. tuberculosis, including the number of organisms expelled into the air, the length of time an exposed person breathes the contaminated air, and presumably the immune status of the exposed individual.

  • TransmissionFamily household contacts, especially children, and people working or living in an enclosed environment (hospitals, prisons, nursing homes) with an infected person are at increased risk.

    Individuals with impaired cell-mediated immunity are thought to be more likely to become infected with M. tuberculosis after exposure than persons with normal immune functions.

    Most effective means of reducing transmission is by treating infected patients with effective chemotherapy.

  • Pathophysiology of TBLatent Infection vs. Active Disease (TB).Upon inhalation, droplet nuclei settle into the bronchioles and alveoli of the lungs.Development of infection in the lungs will depend on virulence and other factors.Individuals with latent TB infections are not infectious and cannot transmit the organisms.

  • Pathophysiology of TBThe extent of the disease produced by M. tuberculosis in humans depends on the size of the inoculum of bacteria inhaled (most common route of acquisition) and the immune status of the host at the time of initial infection and at a later time.If the patient is immunocompromised at the time of initial infection, the disease will more likely progress into bacterial pneumonia at the site of implantation, known as primary progressive disease.In the remaining group whose immune system is competent, the infection will usually be halted after a brief period of bacillary dissemination.

  • Pathophysiology of TBIn individuals who inhale a massive inoculum of organisms, however, clinical disease may occur despite an intact immune system.In immunocompetent individuals, the 1 infection is held in check due to the development of T cell-mediated hypersensitivity that usually occurs 4-8 weeks after initial infection.At this time, the patient will demonstrate a positive reaction to a TST, and any remaining viable organisms within the body will be walled off in caseating granulomas.

  • Pathophysiology of TB1/10 persons with symptomatic 1 infection will at some later date develop active TB (reactivation disease) because the immune system fails to contain the organism.

    This most often presents as pulmonary tuberculosis (PTB), although extrapulmonary tuberculosis (CNS, renal, hepatic, GI, skeletal) is not uncommon.

  • Diagnosis of TuberculosisThe most common form of TB in adults is post-primary pulmonary tuberculosis (PTB).

    Has great epidemiological significance.

    Based on clinical, radiological and/or bacteriological evidence.

  • Signs & Symptoms of PTBPersistent cough (more than 2 weeks).Cough with blood-stained sputum (hemoptysis).Dyspnea, chest pain, hoarseness of voice.Fever with night sweats. Loss of weight and loss of appetite.

  • Signs & Symptoms of PTBConsolidation. Pulmonary fibrosis.Stony dullness caused by pleural effusion.

  • Signs & Symptoms of PTB

  • Laboratory InvestigationsSputum direct smear for AFB (3 specimens).C&S using egg-based media.Chest X-ray often reveals lesions in the apical and posterior segments of the upper lobes (soft, usually little or no fibrosis).Mantoux Test (Tuberculin PPD Skin Test) has some role in diagnosis.

  • Laboratory InvestigationsErythrocyte Sedimentation Rate (ESR) has little role and cannot be recommended for routine use in the diagnosis and follow-up evaluation of patients.Techniques utilizing PCR can give rapid results, but are expensive.

  • Diagnosis of Extra-pulmonary TBDue to lympho-hematogenous dissemination during 1 TB infection. Symptoms are often non-specific: anorexia, fever, weight loss.Specific features related to the organ involved.TB lymphadenitis, GU TB, TB of joints and bones, miliary TB.

  • High Risk GroupContacts of sputum positive TB cases. Persons with HIV infections.Immigrants from countries with high prevalence.Persons in institutions such as prison or drug rehabilitation centers. Persons with other risk factors (DM, silicosis, prolonged corticosteroids and immunosuppressive therapies).

  • Treatment of Active TBGOALS OF TREATMENTCure the individual to prevent morbidity and mortality.Prevent relapse of the disease.Minimize transmission of M. tuberculosis.Prevent emergence of MDR-TB.

  • Treatment of Active TBEssential First Line DrugsIsoniazid, INH (H)Rifampicin (R)Pyrazinamide (Z)Streptomycin (S)Ethambutol (E)

  • Reserve Second Line Drugs

  • Treatment of Active TBDOTS RegimenDirectly observed treatment (DOT) is an important element in the internationally recommended policy package for TB control.

    DOTS remains at the heart of the Stop TB Strategy.

  • Treatment of Active TBDOTS RegimenDirectly observed treatment means that an observer watches the patient swallowing their tablets, in a way that is sensitive and supportive to the patient's needs. This ensures that a TB patient takes the right antituberculosis drugs, in the right doses, at the right intervals.

  • Treatment of Active TBDOTS RegimenThe five elements of DOTS: Political commitment with increased and sustained financing.Case detection through quality-assured bacteriology.Standardized treatment, with supervision and patient support.An effective drug supply and management system. Monitoring and evaluation system, and impact measurement.

  • Treatment of Active TBTreatment RegimensEffective treatment of TB requires substantial period (minimum 6 months) of intensive drug therapy with at least two (2) bactericidal drugs that are active against the organism.

    The initial phase of treatment is crucial for preventing the emergence of resistance and for ultimat