Pulmonary Tuberculosis PDF

# PULMONARY TUBERCULOSIS - Tuberculosis is a major global cause of disability and death especially in developing countries. - Tuberculosis is a social disease with medical aspects and is an indicator of social welfare. - In Egypt the disease is an important public health problem with an annual inci...

# PULMONARY TUBERCULOSIS - Tuberculosis is a major global cause of disability and death especially in developing countries. - Tuberculosis is a social disease with medical aspects and is an indicator of social welfare. - In Egypt the disease is an important public health problem with an annual incidence of nearly 12 new cases per 100,000 populations as of the year 2019; half of them were smear positive. - However, annual incidence was 20 per 100,000 in 2000. ## STANDARD CASE DEFINITION ### Suspected case of pulmonary tuberculosis - Any patient with any type of cough for more than two weeks associated with fever, loss of weight and night sweating. ### Confirmed case of pulmonary tuberculosis - **Pulmonary tuberculosis, smear positive cases** are those with positive sputum for acid-fast bacilli by direct microscopic examination of two initial specimens. - **OR** - Positive sputum for acid fast bacilli by direct microscopic examination of a single specimen and radiologic abnormalities consistent with active pulmonary tuberculosis as determined by the treating medical officer. - **OR** - Positive sputum for acid-fast bacilli by direct microscopic examination of a single smear specimen and, culture positive for acid fast bacilli. - **Pulmonary tuberculosis, smear negative cases** are those with suggestive symptoms of pulmonary tuberculosis; with at least three negative sputum smear specimens for acid fast bacilli by direct microscopic examination; and with radiographic abnormalities consistent with active pulmonary tuberculosis determined by a medical officer followed by decision to treat the patient with full course of anti-tuberculosis therapy. - **OR** - Culture positive for acid-fast bacilli but negative sputum smear by direct microscopic examination. ### Confirmed case of extra-pulmonary tuberculosis - A patient with culture positive specimens from an extra pulmonary site, or histological evidence consistent with active extra-pulmonary tuberculosis followed by a decision by medical officer to treat with a full course of antituberculosis therapy. ## DESCRIPTIVE EPIDEMIOLOGY: (PERSON – PLACE – TIME) ### Person - Some personal characteristics increase the risk of tuberculosis. - The risk of the disease increases with the increase of age. - In early childhood, both male and female are equally susceptible. - However, with the advance in age, it becomes a disease of elderly men. - Poor health status and morbid conditions increase the risk of the disease. - A latent infection may be converted into a tuberculous case after an attack of measles, uncontrolled diabetes mellitus, malignancies, renal failure, major surgeries, mental strain, HIV/AIDS and the prolonged intake of immunosuppressive drugs. - Malnourished individuals are more prone to tuberculosis because of poor immune system. - Also, tuberculosis may precipitate malnutrition in patients with border line nutrition. - Increased physical activity with heavy work leads to increase in respiration and circulation enhances the extension of the infection. - Certain occupations increase the risk of contracting the infection and the development of the disease as healthcare workers and workers exposed to silica dust. - Persons living under low socioeconomic conditions are more prone to the disease. - Illiteracy, unemployment, poor housing condition, overcrowding, and low quality of life are interrelated factors. - These factors contribute to the occurrence and spread of the disease among the population. ### Place - Tuberculosis is more prevalent in developing countries. - Nowadays it is an emerging problem in many developed countries. - Within countries, it is uniformly distributed in urban and rural areas. - In urban areas, it is found more frequently among slum dwellers and lower socioeconomic groups. ### Time - Since the middle of the 20th century, morbidity and mortality from tuberculosis showed a declining secular trend due to the improvement of living conditions and the advancement in antimicrobial chemotherapy (figure1 shows an example). - The clustering of cases of tuberculosis in families is attributed to the risk of exposure and not to genetic predisposition or hereditary tendency. - The Mycobacteria are not transferred across the healthy placenta. ## CYCLE OF INFECTION ### Causative agent - Tuberculosis is a bacterial infection caused by *Mycobacterium tuberculosis* that belongs to the genus *Mycobacteria*. - The organism commonly affects the lungs causing pulmonary tuberculosis and less commonly affects other body sites causing extrapulmonary tuberculosis. - The *Mycobacteria* are aerobic rod-shaped non-spore forming organisms. - Although they do not stain readily, once stained they resist decolorization by acid and are therefore called “acid fast” bacilli. - The high lipid content (mycolic acid) of their cell wall makes *Mycobacteria* acid and alcohol fast. - The commoner species are classified into two groups: - **Typical Mycobacteria** includes human type (*M. tuberculosis*) and bovine type (*M. bovis*) and closely related species in the *M. tuberculosis* complex. - They cause chronic diseases producing lesions of the infectious granuloma type that affect man. - They are acid fast and alcohol fast. - Another form of *Mycobacteria* that is pathogenic to man is *Mycobacterium leprae*. - **Atypical Mycobacteria (Nontuberculous Mycobacteria (NTM))**: *Mycobacteria* other than typical tubercle bacilli (MOTT bacilli) include: - Commensals as smegma bacilli (*M. smegmatis*) which are normally present around the urethra in males and females. - They are acid fast but not alcohol fast. - Saprophytic which are normally found in soil and water, but occasionally cause opportunistic infections in man. ### Morphology - *Mycobacterium tuberculosis* are thin straight or slightly curved rods which may show beading. - They are non-motile, non-spore forming and non-capsulated. - They are acid fast (25% H2SO2) and alcohol fast bacilli. - Stained by either Ziehl Neelsen stain (ZN) or fluorochrome stain (figure 2a). ### Cultural characters - *Mycobacteria* are obligate aerobes. - Optimum temperature for growth is 37°C incubated for 2 to 8 weeks (they grow slowly) with weekly inspection for growth (figure 2b). - They can grow on media containing complex organic substances including: - Dorset egg and egg saline media; are enriched egg media. - Selective media as Lowenstein Jensen media (L.J.) containing malachite green to inhibit bacteria other than *Mycobacteria*. ### Sensitivity to physical and chemical agents - *Mycobacteria* are killed by moist heat at 60°C for 15-20 min. - So, pasteurization renders milk safe. - They are susceptible to sunlight and ultraviolet rays. - *Mycobacteria* tend to be more resistant to chemical agents than other bacteria as malachite green and antibiotics as penicillin so they can be incorporated into the media to inhibit bacteria other than tubercle bacilli. - Also, they can resist acid and alkali (used for decontamination of the specimen). - Tubercle bacilli are resistant to drying for long periods and 5% phenol for several hours. ### Reservoir of infection - In human type, the reservoir of infection are cases of pulmonary tuberculosis with positive sputum for acid fast bacilli. - In bovine type, the reservoir is infected cattle. ### Source of Infection - The source of infection is respiratory secretions of a case of pulmonary tuberculosis who excrete large numbers of tubercle bacilli. - Unpasteurized milk of cattle affected by tuberculosis is the source of infection in bovine tuberculosis. ### Portal of exit - The portal of exit for the human type is the respiratory tract where organisms leave the body via the nose and mouth. - For the bovine type, the exit is the udder of infected cattle where organisms are liberated with the milk. ### Portal of inlet - The portal of entry is the nose and mouth in case of human tuberculosis. - In the bovine type the organisms enter through the mouth. ### Mode of transmission - **Contact transmission**: droplet transmission and less commonly indirect contact with contaminated articles (fomites or dishes) - **Airborne transmission**: droplet nuclei and dust nuclei - **Common vehicle**: the vehicle of transmission is unpasteurized milk and dairy products ### Period of communicability - Tuberculosis is a disease of moderate communicability as measured by the secondary attack rate (48%). - Patients are infective as long as they remain untreated; effective treatment reduces infectivity by 90% within 48 hours. - Communicability is affected by the characteristics of the case and contacts as well as environmental factors. - Characteristics of the case: clinical type, frequency of cough, amount of sputum and level of personal hygiene. - Characteristics of contacts: resistance, age, and closeness with the case. - Environmental factors: level of crowdedness, ventilation and measures of disinfections. ### Susceptibility - Susceptibility is general but higher among individuals with personal characteristics favoring acquiring the infection and developing the disease. - The immunity is cell mediated depending on cellular proliferation. - Immunity is either a natural active immunity following infection or artificial active immunity following BCG vaccination. - Newborns do not acquire passive natural immunity from their mothers. ## PATHOLOGY & PATHOGENESIS ### Pathogenesis and immunity - At the time of exposure, organisms in droplets of 1-5 u are inhaled and reach the alveoli. - Tubercle bacilli spread in the host by direct extension, and through the lymphatic channels and blood stream (in case of infection by *M. bovis*, it is transmitted by ingestion of milk from infected cows and causes intestinal tuberculosis). - The organism acquires intracellular location inside macrophages and cells of reticuloendothelial system. - Once *M. tuberculosis* enters the respiratory airways, they are phagocytized by alveolar macrophages. - In a large percent of macrophages *M. tuberculosis* prevents fusion of the phagosome with lysosomes protecting itself from intracellular killing. - In response, macrophages secrete interleukin (IL)-12 and tumor necrosis factor (TNF)-α, that induce cell mediated immune response, with recruitment of T cells and natural killer (NK) cells into the area of the infected macrophages, inducing T-cell differentiation into TH1 cells (T-helper cells), with subsequent secretion of interferon (IFN)-γ. - Primary infection (the first contact with tubercle bacilli) results in an acute exudative lesion in the lung which spreads to the lymphatics and regional lymph nodes (Gohn's complex). - Granuloma formation: Alveolar macrophages, epithelioid cells, and Langhans giant cells (fused epithelioid cells) with intracellular *Mycobacteria* become organized to form the central core of a necrotic mass that is surrounded by a dense wall of macrophages and T cells. - This structure is called granuloma. It prevents further spread of the bacteria. - If a small antigenic burden is present at the time the macrophages are stimulated, the granuloma is small and the bacteria are destroyed with minimal tissue damage. - However, if many bacteria are present, the large necrotic or caseous granulomas become encapsulated with fibrin. - The bacteria can remain dormant (latent tuberculosis) in this stage or can be reactivated years later when the patient's immunologic responsiveness wanes as the result of old age or immunosuppressive disease or therapy (reactivation). - Extra pulmonary tuberculosis can occur as the result of the hematogenous spread of the bacilli during the initial phase of multiplication. ## CLINICAL PICTURE ### Incubation period - The incubation period is 4 to 12 weeks from infection until the appearance of the primary lesion. - The period between the infection to the development of progressive pulmonary or extra-pulmonary tuberculosis is about 6-12 months or may be longer. ### Signs and symptoms - Tuberculosis is called general simulator, so it can present with any symptom or sign, and these symptoms and signs are different according to the site of infection and according to the immune status of the patient. #### Symptoms - **General symptoms** - Asymptomatic discovered accidentally. - Tiredness and malaise. - Loss of weight, appetite, night fever and sweating. - Recurrent colds. - Amenorrhea. - **Chest symptoms** - Persistent cough - Sputum production of different quantity or color - Hemoptysis; yet never diagnostic or specific for tuberculosis - Chest pain varies from a dull ache, chest tightness to pleuritic pain - Wheezes and dyspnea may occur in patients with endobronchial tuberculosis #### Signs - **Chest examination** - No signs. - Signs localized to the upper zones of chest: crepitation - Signs of cavitation, or fibrosis. - Localized or generalized wheezes. - Signs of consolidation, collapse or fibrosis. - **General examination** - Pallor and cachexia. - Fever, increase in heart rate and respiratory rate. - Clubbing is unusual. ## DIAGNOSIS ### Radiologic diagnosis - Chest x-ray is a very important tool for increasing the sensitivity of the diagnosis of tuberculosis and is considered part of the local examination of chest in suspected cases of tuberculosis. - In chest x-ray, tuberculosis can be presented as consolidation, fibrosis, cavitary changes, pleural effusion or even as miliary pattern (figure 3). - Other modalities of radiology like CT, MRI and ultrasound give more information and help more in the diagnosis of extra pulmonary tuberculosis. ### Laboratory diagnosis #### 1. Laboratory diagnosis of active tuberculosis - Diagnosis is generally done by demonstrating the presence of tubercle bacilli in a clinical specimen. - **Specimens** - The specimen depends on the site of infection. - The specimen in pulmonary tuberculosis is early morning sputum for three successive days. - When sputum is not expectorated, gastric lavage or bronchial lavage could be done. - The specimen in extra-pulmonary tuberculosis is urine, pleural fluid, cerebrospinal fluid, joint fluid, biopsy material, or any other suspected material depending on the site of infection. - **Direct smear for microscopy of collected specimens** - Specimens are stained by Z.N. stain or fluorochrome stain. - Microscopy is cheap and has high specificity but low sensitivity. - A positive acid-fast stain reaction corresponds to higher infectivity. - **Culture** - Sputum culture is required to confirm the diagnosis in suspected cases whose sputum smear is negative and to detect the sensitivity of bacilli to drugs especially in drug resistant cases. - Specimens such as sputum are initially treated with a decontaminating reagent (e.g. 2-4% sodium hydroxide) to eliminate colonizing organisms. - *Mycobacteria* can tolerate brief alkali treatment that kills the rapidly growing bacteria and permits selective isolation of *Mycobacteria*. - **Conventional culture**: specimens inoculated onto egg-based (e.g. Löwenstein-Jensen) and agar-based (e.g. Middlebrook) media generally take from 2- 8 weeks for *M. tuberculosis* to be detected. - **Automated culture systems**: different automated culture systems are available that offer continuous monitoring of *Mycobacterial* growth in broth media; through the detection of bacterial metabolism as oxygen consumption and pH changes in the media (e.g. BacT/ALERT shown in figure 4). - **Identification from culture** - Identification of the organism from culture is by Z.N. stained film, colonial morphology from solid media and biochemical reactions including ability to grow on media containing PNBA. - Both human and bovine types do not grow on paranitrobenzoic acid medium (PNBA). - **Molecular diagnosis** - A variety of molecular techniques were developed to rapidly detect specific mycobacterial nucleic acid sequences present in clinical specimens (e.g. PCR and probes). - Gene expert is an example of commercial molecular assays currently used for screening for tuberculosis. - It can detect *M. tuberculosis* in clinical specimens as well as it can determine the susceptibility to rifampin; a marker for multidrug resistant (MDR) strain. - N.B; MDR-TB:- Tuberculosis strains that are resistant to both rifampicin and isoniazid. - **Susceptibility testing of Mycobacteria** - Susceptibility of *Mycobacteria* to different antituberculosis drugs is important for selection of effective therapy. #### 2. Laboratory diagnosis of latent tuberculosis - These tests assess the patient's immunological response to exposure to *M. tuberculosis*. - Following the primary infection, a state of hypersensitivity (allergy) develops to tubercle bacilli and the patient has sensitized T-cells to the tubercle bacilli. - **Tuberculin test** - Type of test: Tuberculin test is an intradermal test that is used to detect the state of cell mediated hypersensitivity to tubercle bacilli. - Materials used: Purified protein derivative (PPD which is mycobacterial antigens. - Methods of tuberculin test: Mantoux test - This is the standard method with which all other methods are compared. - A test dose of PPD 5 tuberculin units is injected intradermally into the skin of the anterior aspect of the forearm. - The site is examined and palpated 48-72 hours later. - The development of an area of palpable, firm induration equal or greater than 10 mm in diameter is recorded as positive. - A positive reaction usually develops 4 to 6 weeks of the exposure to *M. tuberculosis*. - Interpretation of tuberculin test: - A positive tuberculin test indicates that the individual has been infected. - It does not imply that active disease or immunity to the disease is present; but there is a risk of developing reactivation from the primary latent infection. - Latent tuberculosis is a condition in which a person is infected with *Mycobacterium tuberculosis* bacilli but does not currently have active disease. - Value of tuberculin test is - The study of the epidemiology of tuberculosis in surveys. - It is the only mean of estimating the prevalence of infection in a population especially among children (in countries where BCG vaccination is not obligatory). - Before BCG vaccination to identify tuberculin negative who are eligible for vaccination - Evaluate the effectiveness of BCG vaccine as BCG vaccine converts tuberculin negative persons to tuberculin positive. - The test eliminates tuberculosis from the differential diagnosis of any disease. - The test is capable of detecting latent tuberculosis - Limitations of tuberculin testing are - Tuberculin test is of little value as a diagnostic tool for case finding of tuberculosis because it cannot differentiate between active and latent infection as well as the presence of false negative and false positive results. - Causes of false negative results include; early in the infection (incubation period) and immunosuppression as in HIV/AIDS patients. - Causes of false positive results include; BCG vaccination and infection with atypical *Mycobacteria*. - **Interferon-gamma release assays for detection of latent tuberculosis (IGRAs)** - If an individual was previously infected with *M. tuberculosis*, exposure of sensitized T cells present in whole blood to *M. tuberculosis* specific antigen results in IFN-γ production. - Thus, on stimulation of these sensitized cells by specific *M. tuberculosis* antigens (absent from atypical *Mycobacteria* and BCG strain), they produce interferon-gamma in high amounts. -This interferon-gamma can be measured using the interferon-gamma release assays (IGRAs) which are used to detect latent tuberculosis. - **Advantages over tuberculin skin test are**: - results are not affected by prior BCG vaccination or atypical mycobacterial infection (i.e. more specific) and it requires only one patient visit. ## DRUGS USED FOR THE TREATMENT OF TUBERCULOSIS - Drugs used for the treatment of tuberculosis are categorized into first line drugs and second line drugs. - **First line drugs** are for drug susceptible tuberculosis. - These drugs combine the greatest level of efficacy with an acceptable degree of toxicity. - First line drugs include isoniazid, rifampin, pyrazinamide, and ethambutol. - The large majority of patients with tuberculosis can be treated successfully with those drugs. - **Second line drugs** are for drug resistant tuberculosis. - Antituberculosis drugs are used in combination to produce the following effects: - Rapid reduction in the number of actively growing bacilli in the patient, thereby decreasing severity of the disease, preventing death and halting transmission of *M. tuberculosis*. - Eradicate persistent bacilli in order to achieve durable cure (prevent relapse) after completion of therapy - Prevent of emergence of drug resistance strains of *M. tuberculosis* ### **1. FIRST-LINE DRUGS** #### **1.1. ISONIAZID (INH)** - **Anti-mycobacterial activity** - Isoniazid is a first-line agent for treatment of all forms of tuberculosis. - It has profound early bactericidal activity against rapidly growing bacilli. - It also penetrates cells with ease and thus is able to act on intracellular bacteria. - It is very effective against rapid multipliers. - **Pharmacokinetics** - Isoniazid is readily absorbed from the gastrointestinal tract. - It diffuses into all body fluids and tissues including cerebrospinal fluid. - It is rapidly diffuse inside the cell, thus intracellular and the extracellular levels are similar. - Isoniazid undergoes N-acetylation and hydrolysis, resulting in inactive products. - **Mechanism of action** - Isoniazid is a prodrug that is activated by the mycobacterial catalase-peroxidase. - It inhibits synthesis of mycolic acids, which are essential components of mycobacterial cell walls. - **Therapeutic uses** - Isoniazid is used for treatment of tuberculosis in combination with other antituberculosis drugs. - It is also used as chemoprophylaxis, to prevent the disease among exposed individuals and contacts of newly diagnosed case of tuberculosis. - Duration of chemoprophylaxis is 6-9 months. - **Adverse drug reactions** - Isoniazid is well tolerated; incidence of side effects is 5.4% -Adverse effects include: - It interferes with pyridoxine metabolism by inhibiting the formation of the active form of the vitamin. - Pyridoxine output in urine is increased. - The principal effect is peripheral neuropathy with numbness and tingling of the feet. - Liver injury ranges from moderate elevation of hepatic enzymes to severe hepatitis with fatal outcome. - The risk of hepatitis is greater in older age groups and in alcoholics. - Routine monitoring is not necessary. - However, for patients who have preexisting liver disease, liver function tests should be done monthly. - Mental disturbances, and ataxia may also occur. - Hemolysis in glucose-6-phosphate dehydrogenase deficiency. - Systemic lupus erythematosus-like syndrome. - Hypersensitivity reactions. - **Drug interactions** - Isoniazid may precipitate convulsions in epileptic patients - Isoniazid inhibits the metabolism of some antiepileptic drugs e.g., carbamazepine and ethosuximide, which causes symptoms of overdosage; (excessive sedation). #### **1.2. RIFAMPIN (RIF)** - **Anti-mycobacterial activity** - Rifampin (RIF) has activity against organisms that are rapidly multiplying (early bactericidal activity), slowly multiplying (dormant) and intermittently multiplying (semi-dormant) bacterial populations, thus accounting for its sterilizing activity. - N.B. RIF inhibits the growth of most gram-positive (Staphylococcus aureus) and many gram-negative micro-organisms, such as E. coli, Neisseria meningitidis, and Haemophilus influenzae. - **Pharmacokinetics** - The drug is well absorbed after oral administration. - It is partly metabolized in the liver. Rifampin and its metabolites are eliminated in mainly bile and feces - It is a cytochrome P450-inducer and increases its own metabolism (as well as that of several other drugs). - Rifampin crosses cell membranes and so can attack intracellular bacilli. - The drug penetrates well into most tissues including the meninges and reaches CSF in effective concentration, particularly if they are inflamed. - Rifampin metabolites may impart an orange-red color to the urine, feces, saliva, sputum, sweat, tears, and contact lenses; thus the patients should be warned. - **Mechanism of action** - Rifampin acts by inhibiting RNA synthesis. It binds strongly to bacterial DNA-dependent RNA polymerase, thus inhibits RNA synthesis in bacteria. Human RNA polymerase is not affected. - **Adverse drug reactions** - An influenza-like syndrome (The flu-syndrome) with fever, chills, and myalgias may develop in 20% of patients on an intermittent schedule (less than twice weekly) due to sensitization, this may extend to acute renal failure. - Hepatotoxicity may occur. It is more common when the drug is given in combination with INH. Liver functions monitoring should be performed when the drug is used in old patients and those with underlying liver disease. - Cutaneous reactions, such as pruritis, may occur in some persons taking rifampin. They are generally self-limited and may not be a true hypersensitivity; continued treatment may be possible. - Rarely, rifampin can be associated with hypersensitivity reactions and thrombocytopenia; associated with the presence of circulating IgG and IgM antibodies. - **Drug interaction** - Rifampin is a powerful inducer of hepatic drug metabolizing enzymes (cytochrome P450). It interacts with a number of drugs (including warfarin and hormonal contraceptives). Women using hormonal contraceptives should be advised to consider an alternative method of contraception. #### **1.3. ETHAMBUTOL** - **Anti-mycobacterial activity** - Ethambutol is included in the initial treatment regimens primarily to prevent emergence of resistance to rifampin when primary resistance to isoniazid may be present. - **Pharmacokinetics** - Over 75% of the drug is absorbed from GIT after oral administration. It enters most body tissues. - Insignificant amounts of ethambutol crosses into the CSF if the meninges are not inflamed, but in tuberculous meningitis sufficient amounts may reach the CSF to inhibit mycobacterial growth. It is eliminated mainly unchanged in urine. It needs dose adjustment in renal impairment. - **Mechanism of action** - Ethambutol inhibits mycobacterial synthesis of arabinoglycan, an essential component of mycobacterial cell wall. - **Adverse drug reactions** - Opctic neuritis: The main problem is ocular damage with diminished visual acuity and red-green color blindness. - These effects are dose related and occur in less than 1 % of patients. - Recovery usually occurs when ethambutol is withdrawn. - If the drug is not stopped the patient may go into blindness. - Patients should have baseline visual acuity testing and testing of color discrimination. - At each monthly visit, patients should be questioned regarding possible visual disturbances including blurred vision or visual field defect. - Elevation of plasma uric acid (due to inhibition of renal tubular secretion of uric acid). - Peripheral neuritis is frequent. - Ethambutol is not recommended for children under 13 years of age because of concern about the ability to test their visual acuity reliably. #### **1.4. PYRAZINAMIDE (PZA)** - **Anti-mycobacterial activity** - Pyrazinamide is believed to exert greatest activity against the population of dormant or semidormant (slow multiplier) organisms which might cause relapse. - **Pharmacokinetics** - Pyrazinamide is well absorbed from GIT after oral administration. It is widely distributed throughout the body and CSF. It is partly metabolized in the liver. Parent drug and metabolite are excreted in urine - **Mechanism of action** - Pyrazinamide is a prodrug, which is converted to the active form “pyrazinoic acid” by the enzyme pyrazinamidase that is found in *Mycobacterium tuberculosis*. - The product pyrazinoic acid lowers intracellular pH, inactivates a vital enzyme in fatty acid synthesis and destroys the *Mycobacteria*. - **Adverse drug reactions** - Liver injury: Liver functions monitoring should be performed when the drug is used in patients with underlying liver disease - Non-gouty polyarthralgia: This rarely requires dosage adjustment or discontinuation of the drug. The pain usually responds nonsteroidal anti-inflammatory agents. - Asymptomatic hyperuricemia: This is an expected effect of the drug and is generally without adverse consequence. - Acute gouty arthritis: Acute gout is rare except in patients with pre-existing gout, generally a contraindication to the use of the drug. ### Regimens for treatment of drug-susceptible tuberculosis - Empiric treatment with a 4-drug regimen should be initiated promptly even before the results of acid-fast bacilli (AFB) smear microscopy, molecular tests, and mycobacterial culture are known. - The preferred regimen is a regimen consisting of an intensive phase of 2 months of isoniazid, rifampin, pyrazinamide, and ethambutol followed by a continuation phase of 4 months of INH and RIF. - During the initial phase, the majority of tubercle bacilli are killed, symptoms resolve and the patient usually becomes non-infectious. - The continuation phase is required to eliminate the dormant bacilli. - Pyridoxine (vitamin B6) is given with INH to all persons at risk of neuropathy (e.g. pregnant women, breastfeeding infants, persons infected with human immunodeficiency virus; patients with diabetes, alcoholism, malnutrition, or chronic renal failure, or those who are of advanced age). - With respect to administration schedule, the preferred frequency is once daily for both the intensive and continuation phases. ### 2. SECOND-LINE DRUGS - Second-Line anti-Tuberculosis drugs are less effective but more toxic than isoniazid and rifampicin. - They are used in different combinations for drug resistant tuberculosis. - These drugs are also used in the case of patient's intolerance to first line agents (hypersensitivity or toxicity). - **Oral agents** - Fluoroquinolones - Moxifloxacin - Levofloxacin - Thioamides - Ethionamide - Prothionamide - Linezolid - Cycloserine - Para-aminosalicylic acid - Clofazimine - Delamanid - Bedaquiline - **Parenteral agents** - The second-line injectable agents: they are collectively referring to the aminoglycosides: amikacin, kanamycin, and the cyclic polypeptide capreomycin. These are administered intravenously or by intramuscular injection. - Carbapenems: Imipenem/cilastatin and meropenem. These beta-lactam/carbapenems are only given intravenously ## TREATMENT STRATEGY - DOTS - The direct observation therapy with short course chemotherapy (DOTS) is the recommended strategy for the control of tuberculosis. - **Criteria of potent DOTS** - Short course therapy for a duration of six months under the observation of a healthcare worker at home or in a specialized healthcare facility. - The use of four drugs (INH, rifampin, pyrazinamide, ethambutol) for an initial period of two months followed by two drugs (INH, rifampin) for four months as a continuation phase. - The priority for treatment with DOTS are smear positive pulmonary case. - The treatment should be monitored with sputum smear examination at the end of the initial phase and at the end of the course. - **The basis of the use of the four drugs** - In cases of pulmonary tuberculosis, the causative agent is present in three forms and their sensitivity to antituberculosis drugs are variable. - Rapid multipliers, found near the walls of pulmonary cavities, are sensitive to isoniazid. - Slow multipliers, the intracellular form, are sensitive to pyrazinamide - Intermittent multipliers or persisters, responsible for the relapse, are sensitive to rifampin. - **Advantages of DOTS** - Rapid cure i.e. elimination of both rapid and slow multipliers from the patient's body. - Low failure rate. - Reduce the emergence of drug resistant strains. - Improve patient's compliance - The only disadvantage of DOTS is the high cost. ## MULTIDRUG RESISTANT TUBERCULOSIS (MDR-TB) - Multidrug resistant strain of tuberculosis is an organism that is resistant to at least isoniazid and rifampin, the two most potent drugs. ### Magnitude of the problem - In 2015, an estimated 480,000 people worldwide developed MDR-TB, and an additional 100,000 people with rifampin-resistant tuberculosis were also newly eligible for MDR-TB treatment. - India, China, and the Russian Federation accounted for 45% of these 580,000 cases. - It is estimated that about 9.5% of these cases were extensively drug resistant tuberculosis (XDR-TB); a rare type of MDR-TB that is resistant to isoniazid and rifampin, plus any fluoroquinolone and at least one of three injectable second-line drugs (i.e. amikacin, kanamycin, or capreomycin). ### Patients at risk of MDR-TB are those who - Do not take their antituberculosis medications regularly - Do not take all of their antituberculosis medications as instructed by the treating physician - Develop tuberculosis again, after having taken antituberculosis medications in the past - Come from areas of the world where drug-resistant tuberculosis is common - Have spent time with someone known to have drug-resistant tuberculosis ### Prevention of MDR-TB - The most important measure to prevent the spread of MDR-TB is full compliance with the prescribed regimen; patients should not miss a dose or stop the treatment prematurely. - Patients should discuss with the treating physician the reason of their poor compliance such as drug side effects, cost of medications or unavailability of medications. - Healthcare providers can help prevent MDR-TB by quickly diagnosing cases, following recommended treatment guidelines, monitoring patients' compliance and response to treatment. - Infection with MDR-TB can be prevented by avoiding the exposure to a known MDR-TB patient in closed or crowded places such as hospitals, prisons, or homeless shelters. - Personnel working in hospitals or healthcare settings where cases of tuberculosis are likely to be seen, should consult infection control team or occupational health experts for the suitable respiratory protective devices. ### Control measures for drug-resistant tuberculosis - Cure cases of tuberculosis the first time they are around - Provide access to diagnosis - Ensure adequate infection control in facilities where patients are treated - Ensure the appropriate use of recommended second-line drugs. ## PREVENTION OF TUBERCULOSIS 1. Community development is highly needed to overcome the socioeconomic factors that contribute to the occurrence and spread of the disease. 2. Health education of the public regarding the modes of transmission, methods of control and the importance of early diagnosis and compliance with treatment. 3. Pasteurization of milk is a preventive measure of public health importance to prevent bovine tuberculosis. 4. Immunization of eligible population using BCG vaccine; a live attenuated variant vaccine prepared from bovine tubercle bacilli. - In developing countries, including Egypt, the vaccine is compulsory for infants and children. - It could be administered immediately after birth since cell mediated maternal immunity cannot be transferred to the fetus. -In countries with low prevalence rate of tuberculosis, BCG vaccine is restricted to the high risk groups as tuberculin negative contacts of a sputum positive case of pulmonary tuberculosis, industrial workers exposed to silica and healthcare personnel. - BCG efficacy is more than 80% in preventing tuberculous meningitis and miliary tuberculosis in children. - Among adults, BCG does not prevent infection but it possibly decreases the probability of progression of the infection to active disease. - BCG could be kept frozen in dark bottles to prevent its damage by direct sunlight. - In health center, it is stored between +2°C and +8°C. - The vaccine is in a freeze dried form and is reconstituted in saline and used within six hours after reconstitution. - Cleaning the site of injection with local antiseptic is not recommended as it may damage BCG vaccine. ### Adverse event associated with BCG vaccine include local reaction characterized by severe, unhealed and prolonged ulceration and lymphadenitis. -The risk of local reactions is related to the BCG strains produced by the manufacturer, the high dose of the inoculum and the accidental subcutaneous administration of the vaccine. -Disseminated infection and death is rare and are associated with defects in cellular immunity. -BCG vaccine should not be given to immuno-compromised individuals as HIV/AIDS patients, patients suffering eczema, and malignancies as well as those on immunosuppressive therapy. ## CONTROL OF TUBERCULOSIS 1. Report of cases to local public health authorities of cases meeting the standard case definition of tuberculosis. 2. Isolation of cases at home, if the home condition is suitable, is cost effective. Hospitalization is necessary only for patients with severe illness and for those whose medical and social circumstances make treatment at home impossible. 3. Treatment of cases promptly using first-line drugs and preferably following the DOTS strategy. Case finding and treatment is considered the best measure for the control of tuberculosis. 4. Concurrent and terminal disinfections of patient's sputum are recommended. Decontamination of