Tuberculosis PDF by Dr-Mazin Al-Mubasher

Tuberculosis 10/16/2022 DR-Mazin M AL-Mubasher 1  Introduction.  Transmission.  Microbiology.  Epidemiology.  Immunity.  Progression to disease.  Risk factors for infection and disease.  Effect of HIV on the epidemiology of TB.  Clinical features 10/16/2022...

Tuberculosis 10/16/2022 DR-Mazin M AL-Mubasher 1  Introduction.  Transmission.  Microbiology.  Epidemiology.  Immunity.  Progression to disease.  Risk factors for infection and disease.  Effect of HIV on the epidemiology of TB.  Clinical features 10/16/2022 DR-Mazin M AL-Mubasher 2  Differential diagnosis.  Investigations.  Management.  Monitoring treatment.  TB in Special Situations.  The question of isolation.  Adjunctive corticosteroid therapy.  Prevention and public health aspects. 10/16/2022 DR-Mazin M AL-Mubasher 3  TB is an infectious disease caused by bacteria of the Mycobacterium tuberculosis complex, of which M. tuberculosis is the most common and important agent causing human disease. 10/16/2022 DR-Mazin M AL-Mubasher 4  In 1882, Robert Koch demonstrated that the tubercle bacillus was the true cause of TB, a discovery for which he received the Nobel Prize in 1905. 10/16/2022 DR-Mazin M AL-Mubasher 5  People who are sick with TB in their lungs (pulmonary TB) may be infectious and may transmit TB to others.  It only takes a small number of the TB bacilli to infect another person. 10/16/2022 DR-Mazin M AL-Mubasher 6  Transmission of the disease occurs when another person inhales air containing the droplet nuclei.  This generally occurs indoors, since ventilation removes droplet nuclei from a contaminated space and direct sunlight rapidly kills M. tuberculosis. 10/16/2022 DR-Mazin M AL-Mubasher 7 10/16/2022 DR-Mazin M AL-Mubasher 8  It occurs by droplet nuclei; infectious particles of respiratory secretions aerosolized by coughing, sneezing or talking, which are sufficiently small (around 10 μm, drying to less than 5 μm diameter while airborne) to remain suspended in the air for long periods and reach the terminal air spaces if inhaled. 10/16/2022 DR-Mazin M AL-Mubasher 9  Although transmission of M. bovis from cattle to humans may be important in some parts of the tropics, humans are the only reservoir of MTB infection and transmission is only possible from individuals with disease. 10/16/2022 DR-Mazin M AL-Mubasher 10 10/16/2022 DR-Mazin M AL-Mubasher 11 10/16/2022 DR-Mazin M AL-Mubasher 12 10/16/2022 DR-Mazin M AL-Mubasher 13  Of the mycobacteria, M. tuberculosis, M. bovis and M. africanum are now known to be genetically very similar, have the highest pathogenicity, and are together referred to as the M. tuberculosis (MTB) complex. 10/16/2022 DR-Mazin M AL-Mubasher 14  They are non-spore-forming, non-motile bacilli with a large cell wall content of high- molecular-weight lipids.  They are aerobic but exhibit complex metabolic responses in their latent state. 10/16/2022 DR-Mazin M AL-Mubasher 15  Growth is slow, the generation time being 15–20 h, as compared to well under 1 h for most common bacterial pathogens. 10/16/2022 DR-Mazin M AL-Mubasher 16  Visible growth of yellow colonies in culture, on egg-based solid Löwenstein–Jensen medium, takes between 4 and 12 weeks.  Growth in liquid media is faster. 10/16/2022 DR-Mazin M AL-Mubasher 17 10/16/2022 DR-Mazin M AL-Mubasher 18  Bacilli of the MTB complex are referred to as tubercle bacilli, acid-fast bacilli (AFB) or acid- and alcohol fast bacilli (AAFB) on the basis of the ability of their lipid-rich cell walls to retain the red carbol-fuchsin stain in the presence of acid and alcohol during the Ziehl– Neelsen (ZN) staining process. 10/16/2022 DR-Mazin M AL-Mubasher 19 10/16/2022 DR-Mazin M AL-Mubasher 20  Under oil-immersion light microscopy the stained bacilli appear as slightly bent rods, 2–4 mm long and 0.2–0.5 mm wide. 10/16/2022 DR-Mazin M AL-Mubasher 21 10/16/2022 DR-Mazin M AL-Mubasher 22 10/16/2022 DR-Mazin M AL-Mubasher 23  It is estimated that one-third of the global human population is infected with MTB and the microbe is thought to cause one-quarter of avoidable adult deaths in developing countries. 10/16/2022 DR-Mazin M AL-Mubasher 24 10/16/2022 DR-Mazin M AL-Mubasher 25 10/16/2022 DR-Mazin M AL-Mubasher 26  Once MTB droplet nuclei reach alveolar level within the lungs, the bacilli are taken up by phagocytosis into air-space macrophages. 10/16/2022 DR-Mazin M AL-Mubasher 27 10/16/2022 DR-Mazin M AL-Mubasher 28 10/16/2022 DR-Mazin M AL-Mubasher 29 10/16/2022 DR-Mazin M AL-Mubasher 30 10/16/2022 DR-Mazin M AL-Mubasher 31  Within these cells they are processed into phagosomes which fail to acidify.  In this way the bacilli avoid intracellular killing and may survive and multiply for long periods of time. 10/16/2022 DR-Mazin M AL-Mubasher 32 10/16/2022 DR-Mazin M AL-Mubasher 33 10/16/2022 DR-Mazin M AL-Mubasher 34  Infected macrophages may therefore carry viable bacilli in the lymphatics to regional lymph nodes or in the bloodstream to any part of the body. 10/16/2022 DR-Mazin M AL-Mubasher 35 10/16/2022 DR-Mazin M AL-Mubasher 36 10/16/2022 DR-Mazin M AL-Mubasher 37 10/16/2022 DR-Mazin M AL-Mubasher 38 10/16/2022 DR-Mazin M AL-Mubasher 39 10/16/2022 DR-Mazin M AL-Mubasher 40  Both humoral and cell-mediated immune responses are mounted against MTB and are correlated with the development of detectable delayed-type hypersensitivity (DTH) reactions.  Rarely, these are manifested clinically in the form of erythema nodosum or conjunctivitis. 10/16/2022 DR-Mazin M AL-Mubasher 41  More usually, DTH to MTB is detected by intradermal injection of mycobacterial tuberculin or purified protein derivatives (PPD) – the basis of the Mantoux, Tine and Heaf tests. 10/16/2022 DR-Mazin M AL-Mubasher 42  The extent of local skin erythema, induration and blistering (in vigorous responses) are measured 48 h after injection in order to grade responses. 10/16/2022 DR-Mazin M AL-Mubasher 43 10/16/2022 DR-Mazin M AL-Mubasher 44 10/16/2022 DR-Mazin M AL-Mubasher 45 10/16/2022 DR-Mazin M AL-Mubasher 46 10/16/2022 DR-Mazin M AL-Mubasher 47  The release of Interferon Gamma (IFNγ) by T lymphocytes in response to mycobacterial antigens has recently been exploited in the development of Interferon Gamma Release Assays (IGRA) for the detection of MTB infection. 10/16/2022 DR-Mazin M AL-Mubasher 48  Although individuals clearly vary in their immune capacity to contain or eliminate MTB, it must be emphasized that immune responses to MTB – however generated – are generally not protective against further infection. 10/16/2022 DR-Mazin M AL-Mubasher 49  A common misconception is that PPD skin responsiveness is correlated with the effectiveness of immunity to MTB. 10/16/2022 DR-Mazin M AL-Mubasher 50 10/16/2022 DR-Mazin M AL-Mubasher 51  In the usual course of events, somewhere between 5% and 10% of people will develop active TB after MTB infection.  About 3% develop disease within the first year with the remainder developing disease with ever- diminishing frequency thereafter. 10/16/2022 DR-Mazin M AL-Mubasher 52  More than 90% of MTB infections, therefore, do not result in disease within a normal human lifespan. 10/16/2022 DR-Mazin M AL-Mubasher 53  The clinical manifestation of TB among those who develop active disease depends on two things: the state of the immune system and the location of the bulk of the MTB multiplication. 10/16/2022 DR-Mazin M AL-Mubasher 54  In those cases where disease occurs soon after primary infection, the bacilli multiply and spread in the context of a naïve immune system. 10/16/2022 DR-Mazin M AL-Mubasher 55  Primary forms of disease therefore occur at common thoracic sites of initial multiplication; hence pleurisy extending from an alveolar focus and cavitation in hilar lymph nodes. 10/16/2022 DR-Mazin M AL-Mubasher 56 10/16/2022 DR-Mazin M AL-Mubasher 57  They also tend to disseminate to multiple sites including the central nervous system; hence tuberculous meningitis and ‘miliary’ tuberculosis.  In disseminated disease, mini-granulomata (tubercles) develop around small numbers of bacilli which are widely distributed within tissues. 10/16/2022 DR-Mazin M AL-Mubasher 58 10/16/2022 DR-Mazin M AL-Mubasher 59 10/16/2022 DR-Mazin M AL-Mubasher 60 10/16/2022 DR-Mazin M AL-Mubasher 61 10/16/2022 DR-Mazin M AL-Mubasher 62  In those cases where disease occurs a long time after primary infection, either as reactivation of latent infection or as a result of reinfection with a new strain of MTB, the bacilli multiply in the context of a sensitized immune system. 10/16/2022 DR-Mazin M AL-Mubasher 63  The associated DTH responses tend to lead to tissue destruction at the site of multiplication; hence cavitating caseous lesions, in which large numbers of multiplying bacilli are contained by an encircling rim of giant cells and granulomata – the hallmark of tuberculous pathology. 10/16/2022 DR-Mazin M AL-Mubasher 64 10/16/2022 DR-Mazin M AL-Mubasher 65  These ‘postprimary’ lesions are most commonly in the apices of the lungs, the theory being that this location provides the most conducive combination of ventilation and perfusion for longterm latency. 10/16/2022 DR-Mazin M AL-Mubasher 66 10/16/2022 DR-Mazin M AL-Mubasher 67 10/16/2022 DR-Mazin M AL-Mubasher 68  They may also occur at any site to which bacilli were seeded during initial multiplication around the time of primary infection. 10/16/2022 DR-Mazin M AL-Mubasher 69  Given sufficient time, postprimary-type disease in the lungs is likely to result in communication between the cavitating pathology and an airway.  MTB bacilli can then be aerosolized in droplet nuclei and expelled into the atmosphere when the affected individual coughs, sneezes or talks. 10/16/2022 DR-Mazin M AL-Mubasher 70 10/16/2022 DR-Mazin M AL-Mubasher 71  Patients with cavitating lung disease are therefore the main sources of new MTB infections. 10/16/2022 DR-Mazin M AL-Mubasher 72  Risk factors for MTB infection fall into two broad categories:  1- those which put people in a setting in which MTB containing droplet nuclei accumulate in the atmosphere;  2- those decreasing the ability of alveolar macrophages to incapacitate MTB once taken up. 10/16/2022 DR-Mazin M AL-Mubasher 73  The first category includes prolonged contact with a person or people with pulmonary TB (especially cavitating disease) and the environmental features associated with poverty. 10/16/2022 DR-Mazin M AL-Mubasher 74  Overcrowded and poorly ventilated living and working conditions are clearly ideal for MTB transmission. 10/16/2022 DR-Mazin M AL-Mubasher 75  As MTB is susceptible to killing on exposure to ultraviolet light,  dark and humid conditions such as may be found in mines and prisons also favour transmission. 10/16/2022 DR-Mazin M AL-Mubasher 76  The second category includes anything capable of compromising alveolar macrophage killing of MTB, such as corticosteroid therapy and HIV infection. 10/16/2022 DR-Mazin M AL-Mubasher 77  Risk factors for disease have in common their ability to impair cell-mediated immunity, particularly those functions dependent on T cells.  Examples include HIV infection, malnutrition (particularly vitamin D deficiency) and corticosteroid therapy. 10/16/2022 DR-Mazin M AL-Mubasher 78 10/16/2022 DR-Mazin M AL-Mubasher 79  The superimposition of HIV infection in people with pre-existing MTB infection increases the risk of developing tuberculosis from 5–10% over a lifetime to around 15% per year. 10/16/2022 DR-Mazin M AL-Mubasher 80  In addition to this increased risk of reactivation disease, HIV-infected people are at increased risk of acquiring new MTB infections which may also progress to disease. 10/16/2022 DR-Mazin M AL-Mubasher 81  In those parts of the world where the prevalence of MTB infection and HIV infection overlap geographically, there has been an explosive increase in the number of TB cases, which has increased the annual risk of MTB infection for both HIV-infected and HIV-uninfected people. 10/16/2022 DR-Mazin M AL-Mubasher 82  Both HIV infection and MTB infection tend to affect adolescents and adults in the middle decades of life; their most economically productive years. 10/16/2022 DR-Mazin M AL-Mubasher 83 10/16/2022 DR-Mazin M AL-Mubasher 84  Pulmonary features predominate in around 85% of all TB disease presentations.  Although in most instances pulmonary disease will be the only obvious pathology, it may be associated with tuberculous pathology in other organ systems. 10/16/2022 DR-Mazin M AL-Mubasher 85 10/16/2022 DR-Mazin M AL-Mubasher 86  Parenchymal lung disease may extend and include pericardial disease or regional lymph node cavitation. 10/16/2022 DR-Mazin M AL-Mubasher 87 10/16/2022 DR-Mazin M AL-Mubasher 88 10/16/2022 DR-Mazin M AL-Mubasher 89 10/16/2022 DR-Mazin M AL-Mubasher 90  Conversely, both pericardial tuberculosis and tuberculous lymphadenitis may occur in the absence of any concurrent pulmonary pathology and would then be classified as extrapulmonary disease. 10/16/2022 DR-Mazin M AL-Mubasher 91  Two forms of intrathoracic TB pathology are classified as extrapulmonary tuberculosis when they occur in the absence of concurrent parenchymal lung disease: mediastinal lymphadenopathy and pleurisy. 10/16/2022 DR-Mazin M AL-Mubasher 92 10/16/2022 DR-Mazin M AL-Mubasher 93  This serves to emphasize that any clinical presentation in which pulmonary parenchymal disease is present is classified as pulmonary, and only patients with pulmonary disease, not extrapulmonary disease, are capable of transmitting MTB to others. 10/16/2022 DR-Mazin M AL-Mubasher 94  Among extrapulmonary presentations, lymphadenitis and pleurisy are the most common, each accounting for approximately 25% of the total. 10/16/2022 DR-Mazin M AL-Mubasher 95 10/16/2022 DR-Mazin M AL-Mubasher 96  Genitourinary TB is next at around 15%, followed by miliary and bone TB at around 10%.  Meningeal and peritoneal TB each account for less than 5% of extrapulmonary TB disease. 10/16/2022 DR-Mazin M AL-Mubasher 97 10/16/2022 DR-Mazin M AL-Mubasher 98 10/16/2022 DR-Mazin M AL-Mubasher 99 10/16/2022 DR-Mazin M AL-Mubasher 100 10/16/2022 DR-Mazin M AL-Mubasher 101 10/16/2022 DR-Mazin M AL-Mubasher 102  The majority of TB presentations, whether pulmonary or extrapulmonary, are insidious in onset. 10/16/2022 DR-Mazin M AL-Mubasher 103  Varying combinations of the chronic constitutional symptoms of fevers, night sweats, weight loss and malaise (perhaps secondary to an associated anaemia of chronic disease) are common but are neither universal nor specific indicators of TB. 10/16/2022 DR-Mazin M AL-Mubasher 104 10/16/2022 DR-Mazin M AL-Mubasher 105 10/16/2022 DR-Mazin M AL-Mubasher 106  Beyond the systemic manifestations, the symptoms and signs of TB depend on the site of the major pathology. 10/16/2022 DR-Mazin M AL-Mubasher 107  As pulmonary disease is the most common form of the disease in adults and adolescents and the priority target for public health intervention. 10/16/2022 DR-Mazin M AL-Mubasher 108  Persistent coughing of insidious onset is easily the most common symptom indicating pulmonary TB.  As pulmonary pathology advances, the cough becomes more productive of mucopurulent sputum and chest pains may occur with severe coughing. 10/16/2022 DR-Mazin M AL-Mubasher 109  However, it is important to remember that some patients with early pulmonary disease may not produce much sputum. 10/16/2022 DR-Mazin M AL-Mubasher 110  The sputum may be streaked with blood in about 10% of cases, and this usually indicates that the cavitating pathology has led to local damage of small blood vessels. 10/16/2022 DR-Mazin M AL-Mubasher 111  Frank or catastrophic haemoptysis can occur if the larger blood vessels become involved, but this is rare, occurring in fewer than 1% of cases. 10/16/2022 DR-Mazin M AL-Mubasher 112  Patients with TB may be wasted.  Other than this, the signs are dependent on the site and extent of the underlying pathology.  Much is often made of chest signs such as ‘amphoric breathing’ and consolidation. 10/16/2022 DR-Mazin M AL-Mubasher 113  Certainly, the lung damage can be extensive and often includes signs of volume loss, including tracheal shift. 10/16/2022 DR-Mazin M AL-Mubasher 114  The truth is that most patients with pulmonary disease have very few chest signs and, apart from detecting massive pleural effusions that need draining. 10/16/2022 DR-Mazin M AL-Mubasher 115  Patients with advanced pulmonary disease in the tropics may have finger clubbing, a sign that is otherwise not often associated with TB in Europe and North America. 10/16/2022 DR-Mazin M AL-Mubasher 116 10/16/2022 DR-Mazin M AL-Mubasher 117  Apart from tuberculous lymphadenitis , which usually presents as a unilateral chain of matted lymph nodes that may occasionally ulcerate and discharge, extrapulmonary TB is notoriously difficult to diagnose. 10/16/2022 DR-Mazin M AL-Mubasher 118 10/16/2022 DR-Mazin M AL-Mubasher 119  This is because non-specific systemic manifestations predominate in the early stages and these forms of disease have not been amenable to any investigations that come close to the immediacy and specificity of sputum smear microscopy for AFB. 10/16/2022 DR-Mazin M AL-Mubasher 120  As pathology advances, more useful signs such as meningism, bone damage, serous effusions and fistulae may become apparent. 10/16/2022 DR-Mazin M AL-Mubasher 121 10/16/2022 DR-Mazin M AL-Mubasher 122 10/16/2022 DR-Mazin M AL-Mubasher 123  Pulmonary tuberculosis in the tropics has a wide differential diagnosis. Some of these, such as pulmonary paragonimiasis, nocardiosis, actinomycosis, coccidioidomycosis and melioidosis, are defined by their geographical distribution. 10/16/2022 DR-Mazin M AL-Mubasher 124  Others, such as Pneumocystis jirovecii pneumonia (PCP) and pulmonary Kaposi’s sarcoma (KS), occur in the context of HIV infection. 10/16/2022 DR-Mazin M AL-Mubasher 125  The remainder, including bacterial pneumonias, lung abscess, bronchial carcinoma, bronchiectasis, sarcoidosis, Wegener’s granulomatosis and cryptogenic fibrosing alveolitis, are more universal. 10/16/2022 DR-Mazin M AL-Mubasher 126  The differential diagnosis of the most common extrapulmonary forms of TB, lymphadenitis and pleurisy, is mainly from neoplastic processes such as KS, lymphoma and metastatic bronchial carcinoma. 10/16/2022 DR-Mazin M AL-Mubasher 127 10/16/2022 DR-Mazin M AL-Mubasher 128  Isolation of MTB by culture from clinical specimens is the gold standard for the definitive diagnosis of tuberculosis. 10/16/2022 DR-Mazin M AL-Mubasher 129  However, because of the slow generation time, mycobacterial culture takes between 2 weeks (modern liquid-based culture techniques) and 12 weeks (more universal, solid-based culture techniques). 10/16/2022 DR-Mazin M AL-Mubasher 130  This is clearly too long to be useful in guiding clinical decision-making.  In addition, the laboratory infrastructure required to sustain quality-assured culture of mycobacteria is frequently unavailable in the poorer parts of the tropics. 10/16/2022 DR-Mazin M AL-Mubasher 131  Sputum smear microscopy for tubercle bacilli has therefore been absolutely central to the diagnosis of tuberculosis. 10/16/2022 DR-Mazin M AL-Mubasher 132 10/16/2022 DR-Mazin M AL-Mubasher 133  Approximately half of all culture-proven cases of pulmonary tuberculosis produce more than the threshold 10 000 organisms per ml of sputum required for detection by microscopy. 10/16/2022 DR-Mazin M AL-Mubasher 134  These smear positive cases tend to have more cavitating lung disease and are more infectious than smear-negative cases. 10/16/2022 DR-Mazin M AL-Mubasher 135  While smear microscopy is a specific test for pulmonary tuberculosis, it lacks sensitivity, particularly for early disease that has not yet cavitated. 10/16/2022 DR-Mazin M AL-Mubasher 136  Light microscopic examination of ZN stained smears prepared direct from three sputum specimens remains the most universally available diagnostic technique in the tropics.  This situation, however, is changing rapidly due to a number of advances. 10/16/2022 DR-Mazin M AL-Mubasher 137  First, the number of specimens required and the timing of their submission has been simplified. 10/16/2022 DR-Mazin M AL-Mubasher 138  Secondly, a systematic review suggests that using auramine-phenol staining and fluorescence microscopy can increase sensitivity by an average of 10% over that achieved by ZN staining and light microscopy, without loss of specificity. 10/16/2022 DR-Mazin M AL-Mubasher 139 10/16/2022 DR-Mazin M AL-Mubasher 140  Conventional fluorescence microscopes are expensive and costly to run because of the need for frequent halogen bulb changes and a consistent power supply. 10/16/2022 DR-Mazin M AL-Mubasher 141  However, new Light Emitting Diode (LED) fluorescence microscopes can run on batteries and look set to replace light microscopes and can potentially be set up in most microscopy centres. 10/16/2022 DR-Mazin M AL-Mubasher 142  Thirdly, automated nucleic acid amplification tests (NAAT) are now becoming available for use in primary care for the first time.  Xpert MTB/RIF® was recently endorsed by the WHO. 10/16/2022 DR-Mazin M AL-Mubasher 143  When compared against mycobacterial culture, it has a sensitivity of nearly 100% for smear-positive cases and around 70% for smear-negative cases.  For both categories it has a specificity approaching 100%. 10/16/2022 DR-Mazin M AL-Mubasher 144  In addition, Xpert MTB/RIF® can reliably detect rifampicin resistance as a proxy for multidrug resistant (MDR) TB. 10/16/2022 DR-Mazin M AL-Mubasher 145  Xpert MTB/RIF® can be used on a desk top without laboratory isolation facilities, but is limited by the high cost of the consumables (mainly highly sophisticated cartridges) required and the requirement for an uninterrupted power supply. 10/16/2022 DR-Mazin M AL-Mubasher 146  The main problem in the diagnosis of tuberculosis lies with patients who have clinical features suggestive of pulmonary TB but whose sputum is negative for AFB or by Xpert MTB/RIF®. 10/16/2022 DR-Mazin M AL-Mubasher 147  Unless there are strong clinical indicators of an alternative diagnosis, the decision on whether or not to treat for tuberculosis lies with chest radiography. 10/16/2022 DR-Mazin M AL-Mubasher 148  Unfortunately, chest X-rays of smear- negative TB cases are notoriously difficult to interpret as the features that are most specific to TB (such as cavitation) are frequently absent. 10/16/2022 DR-Mazin M AL-Mubasher 149  Films may even be normal.  PPD skin test positivity is used as a marker of MTB infection and high-grade PPD responses are correlated with the presence of active disease.  However, false-positives may occur after exposure to nonpathogenic environmental mycobacteria or BCG vaccination. 10/16/2022 DR-Mazin M AL-Mubasher 150  Similarly, false-negatives are a problem when immune responses are blunted, e.g. by HIV, measles, drugs or severe malnutrition. 10/16/2022 DR-Mazin M AL-Mubasher 151  PPD skin testing is mainly used in the diagnosis of TB in children, in whom most disease is of primary type and only rarely smear-positive. 10/16/2022 DR-Mazin M AL-Mubasher 152  The IGRA techniques mentioned above are more specific and sensitive in detecting latent MTB infections than PPD skin-testing. 10/16/2022 DR-Mazin M AL-Mubasher 153  A variety of laboratory tests indicating chronic inflammation, such as raised erythrocyte sedimentation rate and C- reactive protein, or anaemia of chronic disease may help in difficult cases but only have a limited role in the investigation of suspected TB cases in the tropics. 10/16/2022 DR-Mazin M AL-Mubasher 154 10/16/2022 DR-Mazin M AL-Mubasher 155  Tuberculosis treatment aims to: 1. cure the patient of TB; 2. prevent death from active TB or its late effects; 3. prevent relapse of TB; 4. decrease transmission of TB to others. 10/16/2022 DR-Mazin M AL-Mubasher 156  These aims can be achieved while preventing the selection of resistant bacilli in infectious patients through the careful use of modern chemotherapy. 10/16/2022 DR-Mazin M AL-Mubasher 157  Monotherapy for tuberculosis disease should never be given as it will lead to the development of antibiotic resistance. 10/16/2022 DR-Mazin M AL-Mubasher 158  The drugs used to treat drug resistant TB are grouped into five categories. 1. Group 1 First-line oral TB agents 2. Group 2 Injectable TB agents 3. Group 3 Fluoroquinolones 4. Group 4 Oral bacteriostatic second-line TB drugs 5. Group 5 Anti-TB agents with unclear efficacy (not recommended by WHO for routine use in MDR-TB patients) 10/16/2022 DR-Mazin M AL-Mubasher 159 10/16/2022 DR-Mazin M AL-Mubasher 160 10/16/2022 DR-Mazin M AL-Mubasher 161 10/16/2022 DR-Mazin M AL-Mubasher 162 10/16/2022 DR-Mazin M AL-Mubasher 163  In principle, it is important to follow national or regional guidelines for chemotherapy. 10/16/2022 DR-Mazin M AL-Mubasher 164  The most important first step in deciding on what treatment regimen to use is to categorize the patient according to  (a) whether or not they have previously received one month or more of TB treatment and  (b) the outcome of the previous TB treatment. 10/16/2022 DR-Mazin M AL-Mubasher 165  It is therefore important to take a careful history about previous treatment before starting a patient on TB chemotherapy.  A ‘trial of therapy’ as a way of confirming a TB diagnosis is not recommended, unless the situation is life-threatening. 10/16/2022 DR-Mazin M AL-Mubasher 166  In some instances, non-TB infections may respond to the broad-spectrum antibiotic effect of drugs such as streptomycin and rifampicin. 10/16/2022 DR-Mazin M AL-Mubasher 167  There is also an increased risk of chaotic ingestion of drugs and the consequent development of drug resistance. 10/16/2022 DR-Mazin M AL-Mubasher 168 10/16/2022 DR-Mazin M AL-Mubasher 169  A single standard combination of drugs is now recommended for all new TB patients who are presumed, or known, to have drug- susceptible TB.  Daily dosing is considered optimal, but three times per week dosing is also acceptable under certain conditions. 10/16/2022 DR-Mazin M AL-Mubasher 170 10/16/2022 DR-Mazin M AL-Mubasher 171 10/16/2022 DR-Mazin M AL-Mubasher 172 10/16/2022 DR-Mazin M AL-Mubasher 173  Deciding on which regimen to use for previously treated patient depends on the availability of routine drug sensitivity testing (DST) to guide therapy of individual patients as well as the availability of reliable surveillance data on drug resistance patterns in the population as a whole. 10/16/2022 DR-Mazin M AL-Mubasher 174  Wherever TB chemotherapy is delivered – especially if delivery is chaotic or disrupted – drug resistance develops and some organisms accumulate resistance to successive drugs. 10/16/2022 DR-Mazin M AL-Mubasher 175 10/16/2022 DR-Mazin M AL-Mubasher 176  Patients with smear-positive pulmonary TB should be monitored by sputum smear examination: once at the end of the intensive phase; once during the continuation phase; and once at the end of therapy.  It is unnecessary and wasteful of resources to monitor using chest radiography. 10/16/2022 DR-Mazin M AL-Mubasher 177  For patients with smear-negative pulmonary TB and extrapulmonary TB, clinical monitoring is the usual, if somewhat unsatisfactory, way of assessing response to treatment. 10/16/2022 DR-Mazin M AL-Mubasher 178  Routine monitoring by mycobacterial culture of sputum is rarely feasible in developing countries in the tropics. 10/16/2022 DR-Mazin M AL-Mubasher 179  At the end of the intensive phase, most patients will have negative sputum smears.  Such patients can then start the continuation phase of treatment. 10/16/2022 DR-Mazin M AL-Mubasher 180  If sputum smears remain positive at this stage despite careful adherence to treatment it may indicate that the patient had a particularly heavy initial bacillary load. 10/16/2022 DR-Mazin M AL-Mubasher 181  Rarely, this is an indication of drug-resistant TB.  Whatever the reason, the initial phase should be prolonged for a third month.  The patient then starts the continuation phase. 10/16/2022 DR-Mazin M AL-Mubasher 182  If smears remain positive after a month of the continuation phase, this constitutes treatment failure and the patient should be restarted on a full course of an appropriate re-treatment regimen. 10/16/2022 DR-Mazin M AL-Mubasher 183 10/16/2022 DR-Mazin M AL-Mubasher 184  At the end of the treatment course, treatment outcomes are recorded according to one of six categories.  This allows for systematic cohort analysis and reporting of cure rates – an important part of TB control. 10/16/2022 DR-Mazin M AL-Mubasher 185 10/16/2022 DR-Mazin M AL-Mubasher 186 10/16/2022 DR-Mazin M AL-Mubasher 187 10/16/2022 DR-Mazin M AL-Mubasher 188  For patients with active TB in whom HIV infection is diagnosed and ART is indicated, the first priority is to initiate TB treatment in accordance with NTP guidelines as there is continuing debate and discussion regarding the optimal time for imitation of ART. 10/16/2022 DR-Mazin M AL-Mubasher 189  Case-fatality rates in patients with TB during the first two months of TB treatment are high HIV prevalence settings.  This suggests that ART should begin early. 10/16/2022 DR-Mazin M AL-Mubasher 190  Alternatively, the potential issues of high pill burden, drug-drug interactions, toxicity and immune reconstitution inflammatory syndrome (IRIS) suggest that later initiation of ART may be helpful. 10/16/2022 DR-Mazin M AL-Mubasher 191 10/16/2022 DR-Mazin M AL-Mubasher 192  The most important drug-drug interactions in the treatment of HIV related TB are those between rifampin and the non-nucleoside reverse transcriptase inhibitors (NNRTIs), efavirenz (EFV) and nevirapine (NVP). 10/16/2022 DR-Mazin M AL-Mubasher 193  Rifampin is the only rifamycin available in most of the world, and initial antiretroviral regimens in areas with high rates of TB consist of EFV or NVP (in combination with nucleoside analogues). 10/16/2022 DR-Mazin M AL-Mubasher 194  Furthermore, because of its potency and durability on randomized clinical trials, EFV- based therapy is a preferred option for initial ART in developed countries.  There are a certain considerations based on drug-drug interactions between rifampin and NNRTIs, EFV and NVP. 10/16/2022 DR-Mazin M AL-Mubasher 195  Rifampin causes a measurable, though modest, decrease in EFV concentrations.  Increasing the dose of EFV from 600 mg daily to 800 mg daily compensates for the effect of rifampin, but it does not appear that this dose increase is necessary to achieve excellent virological outcomes of therapy. 10/16/2022 DR-Mazin M AL-Mubasher 196  Trough concentrations of EFV, the best predictor of its virological activity, remain well above the concentration necessary to suppress HIV in-vitro among patients on concomitant rifampin. 10/16/2022 DR-Mazin M AL-Mubasher 197  Therefore, this combination—EFV-based ART and rifampin-based TB treatment, at their standard doses—is the preferred treatment for HIV-related TB Some experts recommend an 800 mg dose of EFV for patients weighing >60 kg. 10/16/2022 DR-Mazin M AL-Mubasher 198  Alternatives to EFV-based antiretroviral therapy are needed for certain patients with HIV-related TB: EFV cannot be used during pregnancy (at least during the first trimester), some patients are intolerant to EFV, and some are infected with NNRTI- resistant strains of HIV. 10/16/2022 DR-Mazin M AL-Mubasher 199  Alternative first-line treatment regimens include Nevirapine (NVP) and triple Nucleoside Retro-Transcriptase Inhibitors (NRTIs) - based on Tenofovir DF (TDF) or Abacavir (ABC) regimens. 10/16/2022 DR-Mazin M AL-Mubasher 200  For NVP-containing regimens, ALT should be checked at 4, 8 and 12 weeks; treatment should be decided on the basis of symptoms thereafter. 10/16/2022 DR-Mazin M AL-Mubasher 201  Standard protease inhibitor regimens, whether Ritanovir boosted or not, cannot be given with Rifampin. 10/16/2022 DR-Mazin M AL-Mubasher 202  Occasionally, patients with HIV-related TB may experience a temporary exacerbation of symptoms, signs or radiographic manifestations of TB after beginning anti-TB treatment. 10/16/2022 DR-Mazin M AL-Mubasher 203  This paradoxical reaction in HIV infected patients with TB is thought to be a result of immune reconstitution. 10/16/2022 DR-Mazin M AL-Mubasher 204  This can occur as a result of TB treatment alone or the initiation of ART with concomitant TB treatment.  Symptoms and signs may include high fever, lymphadenopathy, expanding central nervous system lesions and worsening of chest x-ray findings. 10/16/2022 DR-Mazin M AL-Mubasher 205  A thorough evaluation is necessary to exclude other causes, particularly TB treatment failure, before diagnosing a paradoxical reaction. 10/16/2022 DR-Mazin M AL-Mubasher 206  Administering prophylactic co-trimoxazole may prevent Pneumocystis Carnii and bacterial infections in HIV-positive TB patients.  CPT substantially reduces mortality in HIV- positive TB patients (by up to 48% in the WHO African Region). 10/16/2022 DR-Mazin M AL-Mubasher 207  For TB patients, CPT should be initiated as soon as possible, irrespective of the CD4 cell count, and given throughout anti-TB treatment; continuation of CPT after TB treatment is completed should be considered in accordance with national guidelines. 10/16/2022 DR-Mazin M AL-Mubasher 208  DOT should be employed for all TB patients infected with HIV as the adverse reactions and mortality associated with treatment interruption are much greater than with TB patients without HIV infection.  DOT strategies can be adopted for ART as well, a least during TB treatment. 10/16/2022 DR-Mazin M AL-Mubasher 209  This approach is resource-intensive and difficult to introduce on a large scale and for the lifelong duration of ART.  However, it may be helpful for early patient training.  Coordination between TB and HIV services to provide joint DOT for both medications would be ideal. 10/16/2022 DR-Mazin M AL-Mubasher 210  More information on the clinical management of HIV infection in TB patients is available in the WHO publication, TB/HIV: A Clinical Manual.  More information on collaborative TB/ HIV Activities, including the Three I’s can be found in the WHO publication, Interim Policy on Collaborative TB/HIV Activities. 10/16/2022 DR-Mazin M AL-Mubasher 211 10/16/2022 DR-Mazin M AL-Mubasher 212  All female patients of childbearing age should be tested for pregnancy upon initial evaluation for TB.  In principle, most first-line anti-TB drugs (rifampicin, isoniazid, pyrazinamide and ethambutol) can be used safely during pregnancy and while breastfeeding. 10/16/2022 DR-Mazin M AL-Mubasher 213  Whenever possible the six month regimen based on isoniazid, rifampicin and pyrazinamide should be used during pregnancy. 10/16/2022 DR-Mazin M AL-Mubasher 214  When using pyrazinamide, vitamin K should be administered to the infant at birth due to the risk of postnatal hemorrhage; treatment should be monitored in conjunction with a pediatrician. 10/16/2022 DR-Mazin M AL-Mubasher 215  During the intensive phase for a pregnant woman, ethambutol should be used rather than streptomycin which crosses the placenta and can cause auditory nerve impairment and nephrotoxicity to the fetus. 10/16/2022 DR-Mazin M AL-Mubasher 216  Streptomycin should not be used during pregnancy as it can cause permanent deafness in the baby; however it may be used safely during breastfeeding. 10/16/2022 DR-Mazin M AL-Mubasher 217  Active TB in pregnancy must be treated because untreated disease has a greater risk for the health of the mother and unborn child than the use of first-line drugs. 10/16/2022 DR-Mazin M AL-Mubasher 218  Rifampicin decreases the effectiveness of birth control pills in preventing ovulation. 10/16/2022 DR-Mazin M AL-Mubasher 219  All non-pregnant women should be advised to use an alternative form of birth control while on TB treatment such as a condom or intrauterine device if they do not wish to become pregnant. 10/16/2022 DR-Mazin M AL-Mubasher 220  Pregnancy is not a contraindication for treatment of active drug-resistant TB, which poses great risks to the lives of both mother and fetus. 10/16/2022 DR-Mazin M AL-Mubasher 221  However, birth control is strongly recommended for all non-pregnant women receiving therapy for drug-resistant TB because of the potential consequences for both mother and fetus resulting from frequent and severe adverse drug reactions. 10/16/2022 DR-Mazin M AL-Mubasher 222  Pregnant patients should be carefully assessment , taking into consideration gestational age and severity of the drug- resistant TB. 10/16/2022 DR-Mazin M AL-Mubasher 223  The risks and benefits of treatment should be carefully considered, with the primary goal of smear conversion to protect the health of the mother and child, both before and after birth. 10/16/2022 DR-Mazin M AL-Mubasher 224  The following are some general guidelines: 1. Start treatment of drug-resistant TB in second trimester or sooner if patient’s condition is severe 2. Avoid injectable agents 3. Avoid ethionamide 10/16/2022 DR-Mazin M AL-Mubasher 225 10/16/2022 DR-Mazin M AL-Mubasher 226  Anti-TB chemotherapy is well tolerated by children and teenagers.  Categories of TB treatment regimens are the same as for adults.  Once TB has been diagnosed, the TB specialist will determine the appropriate regimen and dose based on weight. 10/16/2022 DR-Mazin M AL-Mubasher 227  Since children usually develop TB disease as an immediate consequence of primary infection, they typically have fewer mycobacteria than adults. 10/16/2022 DR-Mazin M AL-Mubasher 228  Therefore, anti-TB drug resistance that develops during treatment is usually uncommon in children.  Most drug resistance found in children is usually a result of primary infection with a drug-resistant strain. 10/16/2022 DR-Mazin M AL-Mubasher 229  While every effort should be made to establish a bacteriological diagnosis (and obtain DST) in a child with suspected MDR- TB, in practice paediatric cases are often not confirmed bacteriologically. 10/16/2022 DR-Mazin M AL-Mubasher 230  Because children with TB may never become sputum smear positive, it is reasonable to initiate MDR-TB therapy based on the DST pattern of the index case. 10/16/2022 DR-Mazin M AL-Mubasher 231  Children are more likely than adults to develop extrapulmonary forms of TB, particularly disseminated disease and TB meningitis 10/16/2022 DR-Mazin M AL-Mubasher 232  The pharmacokinetics of anti-TB drugs differs between children and adults.  Children tend to tolerate larger doses per kilogram of body weight and have fewer adverse reactions than adults 10/16/2022 DR-Mazin M AL-Mubasher 233  Children may have problems absorbing the available dosage forms of anti-TB drugs since most are formulated for adults.  When possible, pediatric formulations should be used. 10/16/2022 DR-Mazin M AL-Mubasher 234 10/16/2022 DR-Mazin M AL-Mubasher 235  Although MDR-TB may be the most well known type of drug-resistant TB, four different categories of drug resistance have been established: Mono-resistance: resistance to one anti-TB drug Poly-resistance: resistance to more than one anti-TB drug, but not both isoniazid and rifampicin 10/16/2022 DR-Mazin M AL-Mubasher 236  Multidrug-resistance: resistance to at least isoniazid and rifampicin Extensive drug-resistance: in addition to multidrug-resistance, resistance also to any fluoroquinolone, and at least one of three injectable second-line drugs (capreomycin, kanamycin and amikacin 10/16/2022 DR-Mazin M AL-Mubasher 237  Treatment of drug-resistant TB can be very challenging due to the limited number of drugs available, the toxicity of these drugs, and the severity of adverse reactions. 10/16/2022 DR-Mazin M AL-Mubasher 238  Consult with an MDR-TB specialist from the NTP when treating these patients.  There are two alternatives for drug-resistant TB treatment regimens: standardized and individualized. 10/16/2022 DR-Mazin M AL-Mubasher 239  Standardized regimens are based on the prevalent pattern of drug resistance in the community, identified in special DST studies by reference laboratories with controlled quality control. 10/16/2022 DR-Mazin M AL-Mubasher 240  These regimens are decided upon at national level by the TB control program.  Individualized regimens are normally based on the susceptibility pattern of the M. tuberculosis isolate of the case patient; except in severely ill patients when treatment may be based on the history of previous treatment. 10/16/2022 DR-Mazin M AL-Mubasher 241  Care should be taken to avoid amplification of drug resistance by never adding a single drug to a failing regimen.  Drugs used to treat patients with drug- resistant strains are grouped according to hierarchy, starting with the group that is most important to include in a drug regimen for MDR-TB. 10/16/2022 DR-Mazin M AL-Mubasher 242  The drugs used to treat drug resistant.  Because XDR-TB is resistant to first- and second-line drugs, treatment options are limited. 10/16/2022 DR-Mazin M AL-Mubasher 243  However, XDR-TB can be treated through the use of a well-organized management scheme including systematic drug-susceptibility testing, strict treatment supervision, adverse- event management, psychological support, nutritional support, and bacteriologic and clinical monitoring, in addition to individualized drug regimens and, if needed, surgery. 10/16/2022 DR-Mazin M AL-Mubasher 244  XDR- TB should only be treated by experienced TB clinicians. 10/16/2022 DR-Mazin M AL-Mubasher 245  There is only limited reported experience with the use of SLDs for extended periods in children.  The risks and benefits of each drug should be carefully considered in designing a regimen. 10/16/2022 DR-Mazin M AL-Mubasher 246  Frank discussion with family members is critical, especially at the outset of therapy.  In general, anti-TB drugs should be dosed according to body weight. 10/16/2022 DR-Mazin M AL-Mubasher 247  Monthly monitoring of body weight is therefore especially important in pediatric cases, with adjustment of doses as children gain weight.  Treatment of MDR-TB in children should be managed in consultation with an MDR-TB specialist. 10/16/2022 DR-Mazin M AL-Mubasher 248  The recommended duration of treatment for MDR-TB regimens is guided by culture conversion.  Currently, WHO recommends continuing therapy for a minimum of 18 months after culture conversion. 10/16/2022 DR-Mazin M AL-Mubasher 249  Extension of therapy to 24 months may be indicated in chronic cases with extensive pulmonary damage.  However it is important to keep in mind that management of MDR-TB can be difficult, as these cases can be very complex, and should only be undertaken in consultation with an expert. 10/16/2022 DR-Mazin M AL-Mubasher 250  Given that many patients develop resistance while receiving anti-TB drugs dues to poor supervision or inadequate regimen design it is imperative that all MDR-TB treatment be given by full DOT with incentives and enablers. 10/16/2022 DR-Mazin M AL-Mubasher 251  DOT should be given by health care workers trained specifically for MDR-TB case management.  Many patients are hospitalized until they smear convert or in some cases until the end of the intensive phase. 10/16/2022 DR-Mazin M AL-Mubasher 252  You should consult with a MDR-TB specialist from NTP when involved in provision of DOT for these patients. 10/16/2022 DR-Mazin M AL-Mubasher 253  Consult the WHO Guidelines for the programmatic management of drug-resistant tuberculosis for more information on MDR- TB management. 10/16/2022 DR-Mazin M AL-Mubasher 254 10/16/2022 DR-Mazin M AL-Mubasher 255 10/16/2022 DR-Mazin M AL-Mubasher 256 10/16/2022 DR-Mazin M AL-Mubasher 257 10/16/2022 DR-Mazin M AL-Mubasher 258 10/16/2022 DR-Mazin M AL-Mubasher 259 10/16/2022 DR-Mazin M AL-Mubasher 260 10/16/2022 DR-Mazin M AL-Mubasher 261  Routinely admitting smear-positive TB patients in order to ‘isolate’ them from the community is not an absolute requirement. 10/16/2022 DR-Mazin M AL-Mubasher 262  In most cases, any onward community transmission of MTB from a smear positive case will have occurred by the time the diagnosis is established and modern chemotherapy will render such patients non- infectious by the end of the second week of treatment in more than 95% of cases, provided the initial isolate is fully drug sensitive. 10/16/2022 DR-Mazin M AL-Mubasher 263  Protecting others from infection is, on the whole, best achieved by careful chemotherapy rather than physical isolation. 10/16/2022 DR-Mazin M AL-Mubasher 264  Admitting patients to hospital should only be necessary where the patient is severely ill and needs full hospital care and it must be remembered that a TB case is more likely to come into contact with individuals who are vulnerable to MTB infection (such as those infected with HIV) in hospital than in the general community 10/16/2022 DR-Mazin M AL-Mubasher 265  If hospital admission is necessary then this should be to a dedicated well-ventilated TB ward located away from other inpatients.  Individual isolation rooms for TB patients are mostly unavailable in countries with high TB incidence.  This will need to change with the increasing prevalence of drug resistant TB. 10/16/2022 DR-Mazin M AL-Mubasher 266 10/16/2022 DR-Mazin M AL-Mubasher 267 10/16/2022 DR-Mazin M AL-Mubasher 268 10/16/2022 DR-Mazin M AL-Mubasher 269 10/16/2022 DR-Mazin M AL-Mubasher 270 10/16/2022 DR-Mazin M AL-Mubasher 271 10/16/2022 DR-Mazin M AL-Mubasher 272  Many advocate the concurrent use of high- dose corticosteroids with TB treatment for large pleural and pericardial tuberculous effusions. 10/16/2022 DR-Mazin M AL-Mubasher 273  There are some trials indicating that this is helpful for rapid relief of symptoms and for reduction in complication rates but systematic reviews suggest that the evidence is not strong and is certainly not available for HIV-infected patients with TB. 10/16/2022 DR-Mazin M AL-Mubasher 274  The potential disadvantages of corticosteroid therapy, including pharmacokinetic interactions with TB drugs and reactivation of other latent infections (such as strongyloidiasis), should be weighed carefully against potential benefits. 10/16/2022 DR-Mazin M AL-Mubasher 275 10/16/2022 DR-Mazin M AL-Mubasher 276  The WHO-recommended DOTS strategy is the internationally recognized central approach to TB control.  Bacillus Calmette–Guérin (BCG) vaccination and isoniazid preventive therapy are mentioned briefly for completeness. 10/16/2022 DR-Mazin M AL-Mubasher 277  The BCG vaccine has been available since the 1920s and remains a part of the vaccination schedule in most resource-poor countries.  It is a live attenuated vaccine which is given intradermally. 10/16/2022 DR-Mazin M AL-Mubasher 278  Unfortunately, there is little evidence that it provides long-lasting protection against the development of pulmonary TB. 10/16/2022 DR-Mazin M AL-Mubasher 279  This appears to be particularly true from the trials conducted in the tropics.  Nonetheless, BCG is still included in the Expanded Programme of Immunization, mainly because there is evidence that it protects against disseminated forms of TB in children. 10/16/2022 DR-Mazin M AL-Mubasher 280  It has also been shown to be protective against leprosy and Buruli ulcer. 10/16/2022 DR-Mazin M AL-Mubasher 281  The rationale behind preventive therapy is to eradicate latent infection before it develops into active disease.  Several placebo-controlled trials in HIV negative people infected with MTB have shown that daily isoniazid given for 6–12 months substantially reduces the subsequent risk of tuberculosis disease. 10/16/2022 DR-Mazin M AL-Mubasher 282  However, preventive therapy has not been recognized as a cost-effective universal approach to TB control, but instead has been focused on individuals at increased risk of developing active disease. 10/16/2022 DR-Mazin M AL-Mubasher 283  Such individuals are usually identified by skin testing and are either contacts of known smear-positive index cases or people who are occupationally exposed to infection (such as nurses and doctors). 10/16/2022 DR-Mazin M AL-Mubasher 284  A series of randomized controlled trials have indicated that isoniazid preventive therapy also reduces the risk of subsequent tuberculosis in HIV-infected individuals with latent MTB infection – at least while they continue to take the isoniazid. 10/16/2022 DR-Mazin M AL-Mubasher 285 10/16/2022 DR-Mazin M AL-Mubasher 286  The objectives of TB control are to reduce mortality, morbidity and disease transmission and to prevent the development of drug resistance. 10/16/2022 DR-Mazin M AL-Mubasher 287  The strategy recommended to meet these objectives is to provide standardized short- course chemotherapy under direct observation during the initial phase of treatment to, at least, all identified smear- positive TB cases (the sources of infection). 10/16/2022 DR-Mazin M AL-Mubasher 288  The success of this strategy depends on the implementation of a five point package. 10/16/2022 DR-Mazin M AL-Mubasher 289 10/16/2022 DR-Mazin M AL-Mubasher 290  1 Direct smear microscopy for case detection among symptomatic patients self-reporting to health services. 10/16/2022 DR-Mazin M AL-Mubasher 291  2 Observation of therapy for administration of standardized short-course chemotherapy, to ensure adherence. 10/16/2022 DR-Mazin M AL-Mubasher 292  3 Treatment monitoring through a standardized recording and reporting system, allowing continuous assessment of treatment results. 10/16/2022 DR-Mazin M AL-Mubasher 293  4 Short course chemotherapy through a system of regular drug supply of all essential antituberculosis drugs, which should be free to patients at the point of delivery. 10/16/2022 DR-Mazin M AL-Mubasher 294  5 Government or non-governmental organization (NGO) commitment to ensure a sustained approach to policy and funding. 10/16/2022 DR-Mazin M AL-Mubasher 295 10/16/2022 DR-Mazin M AL-Mubasher 296  Tuberculosis control activities should aim to meet two minimum targets: a cure rate of 85% and a case detection rate of 70%. 10/16/2022 DR-Mazin M AL-Mubasher 297  In its purest form DOT (distinct from the five- point DOTS policy package) dictates that the health system should hold a given patient’s TB treatment so that the patient can swallow every dose under the watchful eye of the health care worker – at least for the intensive phase. 10/16/2022 DR-Mazin M AL-Mubasher 298 10/16/2022 DR-Mazin M AL-Mubasher 299 10/16/2022 DR-Mazin M AL-Mubasher 300  Many now accept that this system does not always make it easy for patients to adhere to every prescribed dose of treatment.  If, for example, patients live far from the health care worker, they will inevitably incur considerable direct and opportunity costs in the daily travel required. 10/16/2022 DR-Mazin M AL-Mubasher 301  Many innovative approaches to DOT have been piloted, including DOT by grocery store keepers in rural areas, workplace DOT and DOT by respected family members. 10/16/2022 DR-Mazin M AL-Mubasher 302  The guiding principle should be to make it as easy as possible for patients to stick with therapy for the full course. 10/16/2022 DR-Mazin M AL-Mubasher 303  The increasing use of three- and four-drug fixed-dose combinations to supplement the existing two-dose combinations of rifampicin and isoniazid should make it easier for patients to adhere (because of reduced pill burden) and harder for drug resistance to emerge. 10/16/2022 DR-Mazin M AL-Mubasher 304  Thank You! 10/16/2022 DR-Mazin M AL-Mubasher 305