Tuberculosis (TB) is the most common cause of infection related death world w ide.

In 1993, the World Health Organization (WHO) declared TB to be a global pub lic health emergency. Mycobacterium tuberculosis is the most common cause of TB. Very rare causes are Mycobacterium bovis and Mycobacterium africanum. Tubercle bacilli belong to the family Mycobacteriaceae and the order Actinomycetales. The acid-fast characteristic of the mycobacteria is their unique feature. Mycobacte rium tuberculosis is an aerobic, non-spore-forming, non motile, and slow-growing bacillus with a curved and beaded rod-shaped morphology. It is a very hardy bac illus that can survive under adverse environmental conditions. Humuns are the on ly known reservoirs for M. tuberculosis10

Tuberculosis (TB) is a disease caused by bacteria called Mycobacterium tuberculo sis. The bacteria usually attack the lungs. But, TB bacteria can attack any part of the body such as the kidney, spine, and brain. If not treated properly, TB d isease can be fatal.

TB is spread through the air from one person to another. The bacteria are pu t into the air when a person with active TB disease of the lungs or throat cough s or sneezes. People nearby may breathe in these bacteria and become infected.

However, not everyone infected with TB bacteria becomes sick. People who are not sick have what is called latent TB infection. People who have latent TB inf ection do not feel sick, do not have any symptoms, and cannot spread TB to other s. But, some people with latent TB infection go on to get TB disease16.

People with active TB disease can be treated and cured they seek medical hel p. Even better, people with latent TB infection can take medicine so that they w ill not develop active TB disease12.

CLASSIFICATION Pulmonary TB Endobranchial TB with enlargement of lymph nodes. Tubercular pleural effusion Progressive primary TB Reactivation TB

Extrapulmonary TB Lymphadenopathy Tubercular meningitis Military TB Bone or joint TB Additional sites10

Pulmonary TB Symptoms of primary pulmonary disease in the pediatric population often are meager. Symptoms are more likely to occur in infants. Fever, night sweats, anore xia, non productive cough, failure to thrive, and difficult gaining may occur. I t include

Endobranchial TB with enlargement of lymph nodes: This is the most common variety of pulmonary TB. Symptoms are the result of impingement on various structures by the enlarged lymph nodes. Persistent cough may be indicative of bronchial obstruction, while difficulty in swallowing may r esult from esophageal compression. Vocal cord paralysis may be suggested by hoar seness or difficulty breathing.

Tubercular pleural effusion: Pleural effusions due to TB usually occur in older children rather than in i nfants and rarely are associated with military disease. Typically history reveal s an acute onset of fever, chest pain that increases in intensity on deep inspir ation, and shortness of breath. Fever usually persists for 14-21 days.

Progressive primay TB Progression of the pulmonary parenchymal component leads to enlargement of t he caseous area and may lead to pneumonia, atelectasis, and air trapping. This i s more likely to occur in young children than adolescents. The child usually app ears ill with symptoms of fever, cough, malaise and weight loss.

Reactivation TB This condition usually has a sub acute presentation with weight loss, fever, cough and rarely, hemoptysis. TB typically occurs in older children and adolesc ents. The condition is more common in patients who acquire TB when older than 1 years10.

Extrapulmonary TB Lymphadenopathy Patients with lymphadenopathy (ie., scrofula) may have a history of enlarged nodes. Fever, weight loss, fatigue, and malaise are either absent or minimal. L ymp node involvement typically occurs 6-9 months following infection by the tube rcle bacilli. More superficial nodes commonly are involved. Frequent sites of in volvement are the anterior cervical, submandibular, and supraclavicular nodes. T B of the skeletal system may lead to involvement of the inguinal, epitrochlear o r auxiliary lymph nodes.

Tubercular meningitis One of the most severe complications of TB is tubercular meningitis. Tubercu lar meningitis develops in 5-10% of children who become infected when younger th an 2 years thereafter, the frequency drops to less than 1%. A very high index of suspicion is required to make a timely diagnosis because of the insidious onset of the disease. A sub acute presentation usually occurs within 3-6 months after the initial infection. Nonspecific symptoms such as anorexia, weight loss and f ever may be present. After 1-2 weeks patients may experience vomiting and

seizures or alteration in the sensorium. Deterioration of mental status, coma an d death may occur despite prompt diagnosis and early intervention.

Miliary TB This is a complication of primary TB in young children. It may manifest sub acutely with low-grade fever, malaise, weight loss, and fatigue. A rapid onset o f fever and associated symptoms also may be observed. History of cough and respi ratory distress may be obtained.

Bone or joint TB This may present acutely or sub acutely. Vertebral TB may go unrecognized fo r months to years because of its indolent nature.

Additional sites Other unusual sites for TB include the middle ear, gastrointestinal tract. S kin, kidneys, and ocular structures10.

EPIDEMIOLOGY Internationally: according to the WHO, more than 8 million new cases of TB occur each year. Currently, 19-43.5% of the world's population is infected with M tub erculosis. TB occurs disproportionately among disadvantaged populations, such as homeless individuals, malnourished individuals, and those living in crowded are as. According to the WHO, developing countries including India, China, Pakistan, Philippines, Thailand, Indonesia, Bangladesh, and the Democratic Republic of Co ngo account for nearly 75% of all cases of TB9.

In the US: Approximatley 15 million people are infected with M tuberculosis in t he United States. The number of TB cases reported annually in the United States dropped 74% between 1953 and 1985. subsequently, a resurgence in the number of T B cases was reported, with a peak of 26,673 cases in 1992. while the incidence i ncreased by approximately 13% in all ages from 1985-1994, the rate among childre n younger than 15 years increased by 33%. This resurgence was attributed to the HIV epidemic, which increased the risk of developing active TB among persons wit h latent TB infection. Other contributory factors were emigration from developin g countries and transmission in settings such as endemic hospitals and prisons.

Mortality/Morbidity: The mortality rate from TB in the United States is currentl y 0.6 deaths per 100,000 individuals, which represents approximately 1,700 death s per year and an annual mortality rate of approximately 7% per newly identified case. In 1953, the mortality rate was 12.5 per 100,000 individuals. This decrea se in mortality is attributed to improved health care and prompt initiation of t herapy. MDR-TB cases have a reported fatality rate of greater than 70%. Worldwid e, deaths due to TB are estimated at 3 million per year15.

Race: According to the Centers for Disease Control and Prevention (CDC), rates o f TB are 10 times higher among Asians and Pacific Islanders, 8 times higher amon g non-Hispanic blacks, and 5 times higher among Hispanics, Native Americans, and Native Alaskans compared to non-Hispanic whites. However, race may not be an in dependent risk factor, and risk is best defined on the basis of social, economic and material factors as well. Sex: TB equally affects females and males Age: An increased risk of mortality from TB exists at the extremes of age10.

AETIOLOGY Tuberculosis infection is caused by tubercle bacilli. Pulmonary tuberculosis is more common than extra pulmonary tuberculosis. Sites of extra pulmonary tube rculosis can include the pleura, lymph nodes, pericardium, kidney, meninges, bon es, joints, larynx, skin, intestine, peritoneum and eye. Lymph nodes are the com monest site for extra pulmonary disease2

TB is spread through the air from one person to another. The bacteria are put in to the air when a person with active TB disease of the lungs or throat coughs or sneezes. The people nearby may breath in these bacteria are become infected. Wh en a person breathes in TB bacteria, it can settle in the lungs and begin to gro w. From there, they can move through the blood to other parts of the body, such as the kidney, spine and brain.

People with active TB disease are most likely to spread it to others. TB bac teria become active if the immune system cannot stop them from growing. The acti ve bacteria begin to multiply in the body and cause active TB disease. The bacte ria attack the body and destroy tissue. If this occurs in the lungs, the bacteri a can actually create a hole in the lungs20.

Some people develop active TB disease soon after becoming infected, before t heir immune system can fight the TB bacteria. Other people may get sick later, w hen their immune system become weak for another reason. People have weak immune system especially with Diabetes mellitus Cancer of head Leukemia Severe kidney disease Low body weight Substance abuse Silicosis Certain medical treatment

A person with active TB disease has symptoms. may spread TB to others usually has a positive skin test may have an abnormal chest X-ray

In some people who breathe in TB bacteria and become infected, the body is able to fight the bacteria to stop them from growing. The bacteria become inactive, b ut they remain alive in the body and can become active later. This is called lat ent TB infection. People with latent TB infection. have no symptom do not feel sick cannot spread TB to others usually have a positive skin test can develop active TB disease if they do not receive treatment. has a normal chest X-ray.

The tuberculosis infection depends upon the following factors Agent factors Agent: Tuberculosis is caused by M. tuberculosis Source of infection: There are two source of infection Human source: The most common source of infection is human whose sputum is posit ive with tubercle bacilli Bovine source: The bovine source of infection is usually infected milk. Communicability: Patients are infective as long as they remain untreated.

Host factors: Age: Tuberculosis affects all ages Sex: More prevalent in males than in females Heredity: Tuberculosis is not a hereditary disease Nutrition: Malnutrition is widely predispose to TB Immunity: Man have no inherited immunity against TB

It is acquired as a result of natural infection or BCG vaccination.

Social factors It include poor quality of life, poor housing, and over crowding, population exp losion, under nutrition, lack of education, large families, lack of awareness of causes of illness4.

PATHOPHYSIOLOGY TB occurs when individuals inhale bacteria aerosolized by infected persons. The organism is slow growing and tolerates the intracellular environment, where it may remain metabolically inert for years before reactivation and disease. The main determinant of the pathogenicity of TB is its ability to escape host defen se mechanisms, including macrophages and delayed hypersensitivity responses. Amo ng the several virulence factors in the mycobactyerial cell wall are the cord fa ctor lipoarabinomannan (LAM) and a highly immunogenetic 65-kd M. tuberculosis he at shock protein. Cord factor is a surface glycolipid present only in virulent s trains that causes M. tuberculosis to grow in serpent cords in vitro. LAM is a h etero polysaccharide that inhibits macrophage activation by interferon - g and i nduces macrophages to secrete tumor necrosis factor - a (TNF - a), which causes fever, weight loss, and tissue damage. Heat shock protein have a role in autoimm une reaction induced by M. tuberculosis.

The infective droplet nucleus is very small, measuring 5 micrometers or less

, and may contain approximately 1 - 10 bacilli. Although a single organism may c ause disease, 5-200 inhales bacilli are usually necessary for infection. The sma ll size of the droplets allows them to remain suspended in the air for a prolong period of time. Primary infection of the respiratory tract occurs as a result o f inhalation of these aerosols upon inhalation, the bacilli are deposited into t he distal respiratory bronchiole or alveoli, which are sub pleural in location. Subsequently, the alveoli macrophages phagocytose the inhaled bacilli. However, these macrophages are unable to kill the mycobacteria and bacilli continue to mu ltiply10.

The pattern of host response depends on primary infection exposure to the or ganism or secondary reaction in an already sensitized host.

Primary infection

Primary phase of M. tuberculosis infection begins with inhalation of the myc obacteria and ends with a T cell - mediated immune response that induces hyperse nsitivity to the organisms and controls 95% of infections. Inhaled M. tuberculos is is first phagocytosed by alveolar macrophages and transported by these cells to hilar lymph nodes. Naive macrophages are unable to kill the mycobacteria, whi ch multiply, lyses the host cell, infect other macrophages and sometimes dissemi nate through blood to other parts of the lung and elsewhere in the body. After a few weeks T-cell mediated immunity demonstrable by a positive purified protein derivative (PPD) test reaction develops.

Mycobacteria activated T-cells interact with macrophages in three ways. Firs t, CD4+ helper T-cells secrete interferon-g, which activates macrophages to kill intracellular mycobacteria through reactive nitrogen intermediates, including N O, NO2, and HNO3. This is associated with the formation of epithelioid cell gran ulomas and clearance of mycobacteria. Second CD8+ suppressor T-cells lyse macrop hages infected with mycobacteria through a Fas-independent, granule dependent re CD8 T-cell lyse macrophages in a Fas-de action and kill mycobacteria. Third, CD4 pendent manner, without killing mycobacteria. Lyses of macrophages results in th e formation of caseating granulomas (delayed type hypersensitivity reaction). Di rect toxicity of the mycobacteria to the macrophages may contribute to the necro tic caseous centers. Mycobacteria cannot grow in this acidic, extra cellular env ironment lacking in oxygen, and so the mycobacterial infection is controlled. Th e ultimate residuum of the primary infection is a calcified scar in the lung par enchyma and in the hilar lymph node, together referred to as Ghon complex.

Secondary and Disseminated Tuberculosis Some individuals become reinfected with mycobacteria, reactivate dormant dis ease or progress directly from the primary mycobacterial lesions in to dissemina ted disease. This may be because the strain of mycobacterium is particularly vir ulent or the host is particulary susceptible. Granulomas of secondary tuberculos is most often occur in the apex of the lungs but may be widely disseminated in t he lungs, kidney, meninges, marrow and other organs. These granulomas, which fai l to contain the spread or the mycobacterial infection, are the major cause of t issue damage in tuberculosis and are a reflection of delayed type hypersensitivi ty. Two special features of secondary tuberculosis are caseous necrosis and cavi ties; necrosis may cause rupture into blood vessels, spreading mycobacteria thro ugh out the body, and break into air ways, releasing infections mycobacteria in aerosols1

SIGNS AND SYMPTOMS Symptoms of TB depend on where in the body the TB bacteria are growing. TB b acteria usually grow in the lungs. TB in the lungs may cause symptoms such as A bad cough that lasts 3 weeks or longer Pain in the chest Coughing up blood or sputum

Other symptoms of active TB disease are weakness or fatigue weight loss no appetite chills fever night sweats constant tiredness16

INVESTIGATION Tuberculin Test Tuberculin test is used to confirm infection. Two tests are commonly used. T hey are (a) Heaf (multiple puncture) test and (b) Mantoux tests. Both use soluti on of tuberculin purified protein derivative (PPD). Several strengths of PPD are available, and it is important that correct solution is used. Heaf Test Heaf test is quick and simple. It is particularly useful where large numbers of tests are performed, such as in BCG vaccination programmes in schools. A sol ution of 100000 units per ml of PPD is applied in sufficient amount to spread ov er the gun head and the Heaf gun, with six needles arranged in a circle, is used to puncture the skin. The result is ideally read in 7 days but can be react fro m 3-10 days. There are 5 grades response19. Grade 0 : No induration at puncture sites. Erythema only present Grade 1 : Discrete induration at 4 or more needle sites Grade 2 : Confluent areas of induration forming a ring with a clear centre Grade 3 : A disc of induration 5-10 mm wide Grade 4 : Solid induration greater than 10 mm. vesiculation or ulceration may al so occur. Grade 3 and 4 reactions are considered to indicate infection along with grad e 2 response in a tuberculosis contact who has not previously had the BCG (bacil le Calmette Guerin) vaccine. Grade 3 and Grade 4 are said to be strongly positiv e. Anyone Heaf tested as a TB contact, or in a vaccination programme, and found to have these reactions needs to be referred to a chest clinic for further inves tigation, including chest radiography.

The Mantoux Test It is more time consuming and requires greater skill to administer. The PPD for routine use in this test contains 100 units per ml. (for individuals in whom tuberculosis is suspected, or who are known to be hyper sensitive to tuberculin , the preparation containing 10 units/ml should be used). In this test 0.1 ml of the appropriate solution is injected intradermally so that a bleb is produced. The results should be read 48-72 hours later, but a valid reading can be obtaine d upto 96 hours. A positive result consists of induration with a transverse diam eter of at least 5mm following injection of 0.1 ml of PPD 100 units/ml.

Sputum Examination Sputum smear examination by direct microscopy is considered the method of ch oice. The reliability, cheapness and ease of direct microscopic examination has made it number one case-finding method all over the world. It enables us to disc over the epidermologically most important case of pulmonary tuberculosis. Direct

microscopy sputum using Zichl-Neelsen or fluorescent rhodamine-auramine stains is the simplest and quickest method of detecting the infectious patient, althoug h this test is used to be positive in only 60% of culture confirmed cases2.

Sputum culture These are much less useful in non-pulmonary and childhood disease, the diagn osis of which depends more on culture. With conventional culture methods, such a s the Lowenstein-Jensen medium, growth may take up to 6 weeks4. Culture examinat ions of sputum is only second in importance in a case finding programme. It is n ot only difficult, lengthy (take at least 6 weeks) and expensive but also need s pecial training and expertise. This method of examination is offered only to pat ients presenting themselves with chest symptoms, whose sputum smear is negative by direct microscopic examination. Culture of sputum is necessary for carrying o ut sensitivity tests and monitoring drug treatment.

Chest Radiography Chest X-Ray shows if nay damage has been done to the lungs4

GOALS OF ANTI TUBERCULAR CHEMOTHERAPY Kill dividing bacilli Drugs with early bactericidal action rapidly reduce bacillary load in the pa tient and achieve quick sputum negatively so that the patient is non-contagious to the community: transmission of TB is interrupted. This also affords quick sym ptom relief Kill persisting bacilli To effect cure and prevent relapse. This depends on sterilizing capacity of the drug. Prevent emergence of resistance So that the bacilli remain susceptible to the drugs.

ANTI TUBERCULAR DRUGS They are classified in to First line drugs Have high antitubercular efficacy and less toxicity. They are bactericid al drugs9.

Second line drugs Have low antitubercular efficacy and high toxicity. They are bacteriosta tic drugs.

First line drugs Isoniazide (INH) (H) Most powerful drug in the treatment of TB. It can easily penetrate to cell m embrane, and is active against intracellular and extra cellular bacilli. Its act ion is most marked on rapidly multiplying bacilli. It is less active against slo w multipliers and atypical mycobacteria3. MOA: It inhibit mycolic acid synthesis which is unique for mycobacterial cell wa ll. Pharmacokinetics: Absorbed orally and penetrate all body tissues. Metabolized in liver, excreted through urine. Dose: Single daily dose 4-5 mg/kg of body weight or 300mg oral i.m, i.v qd Adver se effect: Peripheral neuritis and a varity of neurological manifestations. Thes e are due to interference with utilization of pyridoxine and its increased excre tion in urine. INH neurotoxicity is treated by pyridoxine 100mg/day given prophy lactically. Other side effects rashes, fever, etc.

Rifampicin (R) It is a better sterilizing agent than INH. It is equally effective against i ntracellular and extra cellular bacilli. It is the only bactericidal drug active against dormant bacilli. In combination with INH, it can cure extensive tubercu losis in about 9 months. Bactericidal action covers all subpopulation of TB baci lli, but acts best on slowly or intermittently dividing bacilli as well as on ma ny atypical mycobacteria5 MOA: It inhibit DNA dependant RNA synthesis Pharmacokinetics: Well absorbed orally. Widely distributed in the body. Metaboli zed in liver to an active deacetylated metabolite. Excreted mainly in bile, some in urine also. Dose: Daily dose 10-12mg/kg body weight or 450-600mg oral, i.v qd. Adverse effect: Hepatitis, Respiratory syndrome, Cutaneous syndrome, abdominal s yndrome.

Streptomycin (S) It is an amino glycoside antibiotics. It acts entirely on rapidly multiplyin g bacilli. It is less active against slow multipliers. No action of dormant baci lli. It is act only on extracellular bacilli.

MOA: Bind to 30s and 50s sub units of ribosomes as well as their interface, free ze initiation, interfere with polysome formation and cause misreading of mRNA co de, thus inhibit protein biosynthesis. Pharmacokinetics: It is neither absorbed nor destroyed in the g.i.t. It is absor bed from injection site in muscles is rapid. It is distributed only extra cellul arly. It is not metabolized - excreted unchanged in urine. Dose: Daily dose 0.75 - 1g in a single injection i.m, i.v qd. Adverse effects: Ototoxicity, Nephrotoxicity

Pyrazinamide (Z) It is active against the slow multiplying intra cellular bacilli. It has bee n found to increase the sterilizing ability of rifampicin. Therefore, it has bee n incorporated in short-course chemotherapy regimen.Its use has enabled regimens to be shortened and risk of relapse to be reduced. MOA: It inhibit mycolic acid synthesis6. Pharmacokinetics: It is absorbed orally, widely distributed, has good penetratio n in CSF, extensively metabolized in liver and excreted in urine. Dose: Daily dose 20-30 mg/kg of body weight oral qd or bid Adverse effect: Hepatotoxicity. It is contra indicated in liver disease. Hyperur icemia is due to inhibition of uric acid secretion in kidney.

Ethambutol (E) It is bacteriostatic and active than streptomycin. Fast multiplying bacilli are more susceptible than many atypical mycobacteria. Added to the triple drug r egimen of RHZ it has been found to hasten the rate of sputum conversion and to p revent the development of resistance. MOA: Interfere with mycolic acid incorporation in to mycobacterial cell wall. Pharmacokinetics: Absorbed orally. It is distributed widely but penetrate mening es. Less metabolized excreted in urine. Dose: Daily dose 15mg/kg body weight oral, i.v. qd8 Adverse effect: Loss of visual acuity/color vision due to optic neuritis, hyper urecimea

Second line drugs Thiacetazons (Tzn) It is tuberculostatic, low efficacy drug, do not add the therapeutic eff ect of isoniazid, streptomycin or ethambutol, but delay resistance to these drug s.

Pharmacokinetic: Orally active, excreted unchanged in urine with t of 12 hr. Dose: 150mg OD in adults, 2.5 mg/kg in children Sideeffects: Hepatitis, gastrointestinal disturbances, blurred vision, haemolyti c anoumia, utricasia and bone marrow depression.

Para amino salicylic acid (PAS) It is tuberculostatic, one of the least active drug used as sodium and c alcium salts. Resistance to PAS is slow to develop. MOA: Inhibit the PABA in corporation in to bacterial cell wall Pharmacokinetic: Absorbed completely by the oral rout and distributed all over e xcept in CSF. It is metabolized by acetylation and excreted by glomerular filtra tion. Dose: 10-12g per day in divided dose oral bid or tid Side effects: Anorexia, Nausea, Epigasteric pain, rashes, fever, goiter, liver d ysfunction and blood dyscrasias.

Ethionamide (Etm) It acts on both extra and intra cellular organism. It is a tuberculostat ic drug. A typical bacteria are sensitive. But it has low efficacy. MOA: It inhibit peptide synthesis in bacteria by blocking incorporation of sulfu r containing amino acids such as methionine and cystine Pharmacokinetics: Absorbed orally distributed all over including CSF. Completely metabolized and has a short duration of action. Dose: 0.5 - 0.75g/per day oral qd or bid Side effects: Anorexia, nausea, vomiting, abdominal upset, rashes, pain, hepatit is, mental disturbances and impotence

Cycloserine (Cys) It is bacteriostatic and inhibit some other gram positive bacteria E col i, Chlamydia. Resistance to cyclosexine develop slowly. No cross resistance. MOA: Inhibit bacterial cell wall synthesis by inactivating the enzyme which rece mize L-alanine and link two D-alanine residue. Pharmacokinetics: it is absorbed orally. Diffuses all over CSF concentration equ al to plasma. About 1/3 of the dose metabolized, rest excreted unchanged by kidn ey. Dose: 250-500mg oral qd or bid Side effects: CNS toxiary- sleepiness, headache, tremor and psychosis7.

COMBINATION THERAPY The relative activity of first line drugs in achieving the goals differs, eg : H and R are the most potent bactericidal drugs active against all population T B bacilli, while Z acts best on intra cellular bacilli and those at inflamed sit es has very good sterilizing activity. On the other hand S is active only agains t rapidly multiplying extra cellular bacilli. E is bacteriostatic - mainly serve s to prevent resistance and may hasten sputum converstion7

So drug combinations are selected to maximize the above action together with consideration of cost, convenience and feasibility.

Long course regimen Long course conventional chemotherapeutic regions depended up on the use of INH along with one or two bacteriostatic drugs. The role of bacteriostatic drugs was to prevent the emergence of INH resistant strains. Sterilization thus depen ded entirely on INH and 18 months of treatment was required. Two main drug regio ns are there. These are: 1) Daily regeions 2) Biweekly or intermittent regions

1) Daily regions The most frequently used combination is INH (300mg for adults) plus a compan ion drug, which is usually thiacetazone (150mg) given together is a single daily dose. This combination is inexpensive, easy to administration and convenient to the patient because he has to swallow only one tablet a day. Streptomycin is gi ven initially for the first two or three months. The total duration of treatment is usually 18 months17.

Since thioacetazone may have an adverse effect on liver function, it should be rectified with vit B. complex. In case of toxicity, thiacetazone may be repla ced by PAS or ethambutol. For treatment of young children, PAS is preferred to e tambutol because of ocular toxicity.

The major cause of treatment failure is that patient defaulted before the en d of this long period of treatment. Irregularity of daily drug intake is another

factor leading to the emergence of drug-resistant organisms.

2. Biweekly or intermittent regimen It can be equally effective. They are also cheaper and less toxic to the pat ient. The standard biweekly region is Streptomycin INH 1 g or 0.75g

600 or 700mg 10mg

Pyridoxine

INH is to be taken in a single dose orally; and streptomycin by intramuscula r injection. Streptomycin in a dose of 0.75g is recommended for patient aged 40 yrs and above due to incidence of drug toxicity, is higher when 1g of streptomyc in is administered. Pyriodoxine is given to prevent polyneuritis.

The main advantage of biweekly regimen is that it is fully supervised, i.e., every dose is administered under direct supervision, hence also called "Supervi sed" chemotherapy.

Short-course chemotherapy The addition of rifampicin or pyrazinamide to regimens containing INH, reduc e the duration of treatment.

The advantages of short course therapy is that rapid bacteriological convers ion, lower failure rates and a reduction in the frequency of emergence of drug r esistant bacilli. Patient compliance is improved, they become non-infections ear lier. The disadvantage is that the high cost of short-term therapy.

Two phase chemotherapy There are two phases in the effective treatment of TB 1) the first is a shor t, aggressive or intense phase early in the treatment, lasting 1-3 months. Durin g this phase 3 or more drugs are combined to kill many bacillus as possible. The more rapidly growing bacilli are killed initially 2) in second or continuation phase, sterilizing the smaller number of dorment or persisting bacilli4.

Treatment of TB is categorized by Site of disease (pulmonary or extra pulmonary) and its severity the bacillacy lo ad and acute threat to life or permanent handicap are taken into consideration. Sputums mearpositivity/negativity: positive cases are infectious and have higher mortality. History of previous treatment: risk of drug resistance is more in irregularly tr eated patients18

Rationale Patients of smear positive pulmonary TB harbour and disseminate la rge number of bacilli Initial treatment with 4 drugs reduces risk of selecting r esistant bacilli as well as covers patients with primary resistance. When few ba cilli are left only 2 drugs in the continuation phase are enough to effect cure. Smear negative pulmonary TB and extrapulmonary TB patients harbour fewer bacill i in their lesions risk of selecting resistant bacilli is less; regimens containin g only 3 drugs in the initial phase and 2 in the continuation phase are of prove n efficacy. Accordingly, previously treated/failure/default/ relapse cases are t reated with a longer intensive phase 5 drugs for 2 months and 4 drugs for 1 month followed by 3 drugs in the continuation phase of 5 months duration (instead of u sual 4 months). Category I This category includes: New (untreated) smear positive pulmonary TB. New smear negative pulmonary TB with extensive parenchymal involvement. New cases of severe forms of extra pulmonary TB vs. meningitis, miliary, pericar ditis, peritonitis, bilateral or extensive pleural effusion, spinal, intestinal, genitourinary TB.

Initial phase Four drugs HRZ + E or S are given daily or thrice weekly for 2 mon ths. Out of the WHO recommended regiment RNTCP has decided to follow 3 weekly re giment, since it is equally effective, save drug and effort, and is more practic al. The RNTCP recommended that if the patient is sputum positive at 2 months, th e intensive phase should be extended by another month; then continuation phase i s started regardless of sputum status at 3 months. Treatment regiment for tuberculosis TB category

Initial phase

Continuation phase

Total duration

2HRZE(S)

4HR/4H3R3 or 6HR

6 8 II 2HRZES + 1HRZE 5HRE or 5H3R3E3 8 8 HI 2HRZ 4HR/4H3R3 Or 6HE 6 8 IV Chronic case:

Continuation phase: Two drugs HR for 4 months or HE for 6 months are given. When both H and R are used, thrice weekly regimen is permissible. Under RNTCP thrice weekly treatment with H and R is given for 4 months. This phase is extended to

6-7 months (total duration 8-9 months) for TB meningitis, miliary and spinal dis ease. In areas where DOTS has not been implemented, use of Tzn in place of E-in the continuation phase is permitted except in HIV positive cases.

Category II: If There are smear positive failure, relapse and interrupted treatm ent cases: Treatment failure: Patient who remains or again becomes smear positive 5 months or later after commencing treatment. Also one who was smear negative at start of therapy and becomes smear positive after the 2nd month.

Relapse: A patient declared from any form of TB in the past after receiving one full course of chemotherapy and now has become sputum positive17.

Treatment after interruption (Default): A patient who interrupts treatment for 2 months or more and returns with sputum positive or clinically active TB. These patients may have resistant bacilli and are at increased risk of devel oping MDR-TB.

Initial phase All 5 first line drugs are given for 2 months followed by 4 drugs (HRZE) for another month. Continuation phase is started if sputum is negative, b ut 4 drug treatment is continued for another month if sputum is positive at 3 mo nths.

Continuation phase Three drugs (HRE) are given for 5 months either daily or thri ce weekly (only thrice weekly under RNTCP).

Category III These are new cases of smear negative pulmonary TB with limited par enchyma! involvement or less severe forms of extrapulmo-nary TB, viz, lymphnode, unilateral pleural effusion, bone (excluding spine), peripheral joint or skin T B. Initial phase Three drugs HRE given for 2 months are enough because the bacillar y load is smaller.

Continuous phase: This is similar to category I, i.e., 4 month daily/thrice week ly HR or 6 month daily HE (Tzn) therapy. Under RNTCP only thrice weekly HR regim en is followed.

Category IV These are chronic cases who have remained or have become smear posit ive after completing fully supervised retreatment (Category D) regimen. These ar e most likely MDR cases. Multidrug resistant (MDR) TB is defined as resistance t o both H and R and may be any number of other anti-TB drugs. MDR-TB has a more r apid course (some die in 4-16 weeks). Treatment of these cases is difficult beca use the second line drugs are less efficacious, less convenient, more toxic and more expensive. Treatment is prescribed only if its compliance can be assured. O therwise there is risk of developing further resistance.

Therapy depends on drugs used in the earlier regimen, dosage and regularity with which they were taken, presence of associated disease like AIDS/ diabetes/l eukemia/silicosis, and whether sensitivity of the pathogen to various drugs is k nown (by in vitro testing) or unknown. If sensitivity of the TB bacilli is known , the drug/ drugs to which they are resistant is/are excluded and other first li ne drugs are prescribed with or without 1-3 second line drugs (only if practicab le), Eg: For H resistance RZE given for 12 months recommended. For H + R resistance ZE + S/Etm + Cipro/ ofl could be used. The actual regimen is devised according to the features of the individual patien t. In India > 200,000 patients have been treated under DOTS by the early 2001 with a cure rate of 75-80%. In other countries 80-93% cure rates have been obtained7. DIRECTLY OBSERVED THERAPY For successful chemotherapy adequate and regular drug intake should be maint ained. The best way to remember to take medicine is to get directly observed the rapy (DOT). If a patient get DOT, he will meet with a healthcare worker every da y or any other convenient location. The patient will take his medicine at this p lace while the healthcare worker watches.

DOTs helps in several ways. The healthcare worker can help patient remember to take his medicine and complete his treatment. With DOT patient may need to ta ke medicine only 2 or 3 times every week instead of every day9.

The healthcare worker will make sure that the medicine is working as it shou ld. This person will also watch for side effects and answer questions patients h ave about TB14.

In DOTs during the intensive phase of treatment a health worker watches as t he patient swallow the drug in his presence. During continuous phase the patient is issued medicine for one week in a multiblister combipack of which the first dose is swallowed by the patient in the presence of healthcare worker or trained person. The consumption of medicine in the continuous phase is also checked by return of empty multiblister combipack when the patient comes to collect medicin e for the next week. The drugs are provided in patient wise boxes with sufficien t shelf life4.

TREATMENT OF TUBERCULOSIS IN SPECIAL CIRCUMSTANCES

Tuberculosis in children Doses are generally estimated to facilitate prescription of easily given vol umes of syrup, or tablets of appropriate strength. Ethambutol should not routine ly be used in young children who would be unable to report visual toxicity if it occurred. However, it may have to be used if toxicity or resistance to other ag ents occurs.

Pregnancy Pregnant women should be given standard therapy, although streptomycin shoul d not be used as it may be ototoxic to the fetus. Although the other first-line drugs -have not been shown to be teratogenic, they are timer contraindicated or must only be used with caution. It is considered safe for mothers to breastfeed while taking antituberculous agents15.

Patients should be warned of the reduced effectiveness of oral or injectable contraceptives in regimens containing rifampicin.

Renal disease Patients with renal disease may be given isoniazid, rifampicin and pyrazinamide in standard doses as these drugs are eliminated by predominantly non-renal route s. Ethambutol undergoes extensive renal elimination and therefore dose reduction is needed. Streptomycin must be used with considerable caution if toxicity is t o be prevented, and is best avoided in renal failure. Rifampicin may be given in standard doses to patients on dialysis. The doses of the other agents need to b e modified. A number of different regiments have been suggested.

Liver disease

In patients who present with liver failure or in alcoholics, monitoring of l iver enzymes is recommended as rifampicin, isoniazid and pyrazinamide are all kn own to be potentially hepatotoxic. However, increases in transaminasces at the s tart of antitubercular treatment occur frequently. These are usually transient a nd not a reason for stopping treatment unless frank jaundice or hepatitis develo p, in which case all drugs should be stopped. It is usually possible to restart treatment when values have returned to pretreatment levels.

Immunocompromised patients Patients who are immunocompromised, including those with HTV Infection, shou ld be treated with normal first- line agents unless multidrug-resistant tubercul osis is suspected. Theoretically these patients have a greate, risk of relapse a nd may need to be treated for longer than the normal 6 months. On current eviden ce, at the completion of treatment life-long chemoprophylaxis with isoniazid sho uld be instituted.

Steroids Corticosteroids have long been used in the treatment of tuberculosis, chiefl y for their anti-inflammatory properties. They may be of benefit, and a dose of around 60-80 mg of prednisolone has been used. Because of enzyme induction, the dose of corticosteroids taken for other conditions should be adjusted if rifampi cin is used. Steroids probably find their greatest use for pericarditis or pleur al disease and endobronchial disease in children. They are also used in genitour inary tuberculosis where they help reduce the symptoms of cystitis and obstructi on. In tuberculous meningitis, corticosteroids are said to improve survival and reduce sequelae.

Monitoring Treatment In pulmonary tuberculosis, sputum examination and culture are the most sensi tive markers of the success of treatment. Patients taking regimens containing ri fampicin and isoniazid should be non-infective with in 2 weeks. If a patient doe s not become culture-negative, it may be due to either drug resistance or non-ad herence, the latter being most likely. Chest radiographs provide only limited in formation as to the progress of treatment. Good adherence is essential if treatm ent is to be successful, and checking adherence is not easy, especially when a p atient is uncooperative. Rifampicin will colour the urine red within about 4 hou rs of a dose and this has been used to monitor adherence.

DISEASE CONTROL AND PREVENTION Four priorities for tuberculosis control and prevention have been identified. Cases of tuberculosis must be identified and treated promptly. This includes awa reness of tuberculosis as a possible diagnosis in those with medical or other ri sk factors, who have a chronic cough, or lower respiratory tract infection not r esponding to antibiotic treatment. Prompt treatment ensures that patients with i nfectious tuberculosis become non-infectious, as soon as possible, usually withi n 2 weeks of starting treatment. Those at increased risk of infection with M. tuberculosis should be investigated without delay. This includes: close contacts of known cases recent immigrants from high prevalence countries.

The possibility of HIV infection should be considered in all cases of tuberculos is. All cases of tuberculosis should be notified. This ensures that examination of c ontacts is carried out, and local and national surveillance of tuberculosis is m aintained.

Chemoprophyfaxis Chemoprophylaxis is recommended routinely for the following risk of infection Contacts under 16 years of age with Heaf grade 2-or equivalent and do history of BCG, and those with grade 3 or 4 with prior BCG vaccination Contacts in whom recent conversion to tuberculin positivity has been noted Children under 2 years of age who arc close contacts of smear-positive cases and

who have not had BCG vaccination; they should receive chcmoprophylaxis irrespec tive of their tuberculin status, followed by BCG vaccine, where appropriate, at the completion of chemoprophylaxis. HIV infected close contacts of a patient with smear- I positive pulmonary diseas e.

Prophylaxis is usually with isoniazid alone for 6 months or rifampicin and isoni azid for 3 months. Both regimens are equally effective.

BCG vaccinations BCG vaccine does not protect against infection. Instead it prevents the more serious forms of disease such as miliary tuberculosis and tuberculous meningiti s2

1. Aim The aim of BCG vaccination is to induce a benign artificial primary infectio n which will stimulate an acquired resistance to possible subsequent infection w ith virulent tubercle bacilli, and thus reduces the morbidity and mortality from primary tuberculosis risk.

2. Vaccine It consist of living bacteria derived from an attenuated bovine strain of tu bercle bacilli.

3. Types of vaccine There are two types of BCG ze dried vaccine. Freeze dried vaccine. BCG vaccine is stable pical climate, and for up to 1 a cool environment. vaccine - the liquid (fresh) vaccine and the free vaccine is a more stable preparation than liquid for several weeks at ambient temperature in a tro year if kept away from direct light and stored in

The vaccine must be protected from exposure to light during storage. Normal saline is recommended as a diluent for reconstituting the vaccine, as distilled water may cause irritation. The reconstituted vaccine may be used up within 3 ho urs and the left over vaccine should be discarded.

4. Dosage For vaccination, the usual strength is 0.1mg in 0.2ml volume. The dose to ne w born aged below 4 weeks is 0.05 ml.

5. Administration The standard procedure recommended by WHO is to inject the vaccine interderm ally using "Tuberculin" syringe. The vaccine must not be contaminated with an an tiseptic or detergent. If alcohol is used to swab the skin, it must be allowed t o evaporate before the vaccine is given.

6. Age The national vaccination policies differ from country to country. In countri es where tuberculosis is prevalent and the risk of childhood infection is high t he national policy is to administer BCG very early in infancy either at birth or at 6 weeks of age simultaneously with other immunizing agents such as DPT and P olio BCG administered easily in life provides a high level of protection, partic ularly against the severe forms of childhood tuberculosis and tuberculous mening itis.

7. Phenomena after vaccination Two or three weeks after a correct inteadermal injection of a potent vaccine , a papule develops at the site of vaccination. It increases slowly in size and reaches a diameter about 4 to 8mm in about 5 weeks. It then subsides or breaks i nto a shallow ulcer, rarely open, but usually seen covered with a crust. Healing occurs spontaneously within 6 to 12 weeks leaving a permanent, tiny, round scar , typically 4-8mm in diameter. This is a normal reaction15.

8. Complications BCG has been associated with adverse reactions which include prolonged sever e ulceration at the site of vaccination, suppurative lymphadenitis, osteomyeliti es, disseminated BCG infection and death.

9. Protective value The duration of protection is from 15 to 20 years. The local BCG infection g enerates an immunity response, which is associated with the development of tuber culin hypersensitivity and with it, possibly, some immunity.

Studies shown that the range of protection offered by BCG varied from 0 to 8 0% in different parts of the world. the varying degree of protection, is due to increasing epidemlogical support, is that prior exposure to some non-tuberculous environmental mycobacteria may have conferred partial immunity and potential be nefit of BCG vaccination. Exposure to other species have an antagonistic action against BCG.

10. Revaccination BCG vaccination has not been included in the official immunization schedule in India under the expanded programme on immunization. However, there are other who recommended revaccination at school age irrespective of vaccination at birth , to prevent adult type of tuberculosis. Prevent adult type of tuberculosis.

11. Contraindications BCG should not be given to patients suffering from generalized eczemia, infe ctive dermatosis, hypogamma globulinaemia and those with a history of deficient immunity.

12. Impact BCG vaccination is less effective in controlling tuberculosis compared to ac tive case finding and chemotherapy, as BCG offers only partial protection. BCG v accination of uninfected individuals can prevent tuberculosis in them, it can ha ve only a relatively small epidemiological effect in that it will not contribute significantly to the reduction in the overall risk of infection in the communit y4.

PATIENT CARE It is possible to cure virtually all patients with tuberculosis infection or disease provided that an adequate regimen is prescribed and the patient complie s with treatment By far the largest cause of treatment failure is non-adherence by the patient Non-adherence has serious consequences: treatment may fail and di sease may relapse, in some cases with resistant organisms. If a non-adherent pat ient remains infectious they will also be a public health hazard.

Factors affecting adherence An adherence falls as the number of tablets to be taken per day increases, a

nd falls still further if doses have to be taken frequently through the day. Ide ally, the least number of tablets should be given.

Patients may fail to adhere because they feel better and do not appreciate t he need to continue with their medication. Lack of clarity of instructions, writ ten, verbal or other, may compromise adherence, particularly if the patient is c onfused by conflicting advice by different health care professionals. Finally, a dverse effects, or symptoms perceived to be adverse effects, may reduce adherenc e.

Improving patient adherence Antituberculous therapy should be prescribed once a day-using a few tablets as possible. Single daily dosing enables patients to fit their medication into t heir daily routine. Rifampicin and isoniazid are both well absorbed when taken o n an empty stomach. However, absorption is reduced and delayed when taken with o r after food20. It is therefore recommended that both are taken 1 hour before fo od to achieve rapid high blood levels. It is usually recommended that patients' take their antiruberculous medication before breakfast Cueing tablet taking to a regular activity such as brushing the teeth may improve adherence in-some patie nts.

The number of tablets to be taken each day may be reduced by using combinati on preparations. These also have the advantage of reducing the possibility of mo notherapy and consequent resistance. There are a number of combination preparati ons available. Some of the preparations, for example Rifater, contain ratios of drugs that differ slightly from the dosages recommended by the British Thoracic Society. This difference in dosage is probably, not clinically significant and i s far preferable to potential under treatment due to non-adherence. Mynah is a p reparation available in a number of different ratios to facilitate administratio n of the correct dose. Combination preparations may not be suitable for use in children as the requ ired dose regimens differ from those of adults.

Patient education Written instruction and/or patient information leaflets may be offered to su pport verbal counseling if there is any doubt as to the patient's understanding. It should be emphasized that the disease will be cured but this will take some months and the tablets will need to be taken as prescribed even if the patient f eels better. Some patients will adhere initially while they are unwell, but will fail to adhere later as they begin to feel better. The occurrence of some adverse effects may require discontinuation of a drug , but others are harmless. The patient should be told which side-effects to expe ct and which require referral to a member of the health care team. Again written instructions may be helpful9.

A number of patients from abroad with tuberculosis have a poor command of En glish It may still be possible to give written instructions on dosage as some ph armaceutical companies are able to provide pictorial and dosage sheets in a numb er of languages.

Counseling points Patients taking rifampicin should be told that the drug will cause a harmles s discoloration of their urine and other body fluids, for example sweat and tear s. The staining of tears is important if the patient uses soft contact lenses as these may be permanently stained. Gas-permeable and hard lenses are unaffected. Women using the oral contraceptive pill should be advised to use cither non-hor monal methods of contraception for the duration of treatment with rifampicin and for 8 weeks afterwards. Although ocular side-effects are rare when ethambutol i s taken in normal dosages, patients should be warned of this potentially serious side-effect They should be advised to stop the drug and report to their doctor if they notice any changes in vision, such as a reduction in visual acuity or ch anges in colour vision. This is especially important because visual changes are usually reversible on discontinuation of the drug but may be permanent if the dr ug is not stopped4.

CONCLUSION

Even though TB is an infections disease it is curable if proper treatment and ca re are given so as to safeguard our newer generation from the shadow of this dis ease they should be given BCG vaccines. Prophylactics measurement should be take n in order to prevent spread of the epidemic infection.

REFERENCE

Robins pathological basis of disease edited by Cotran, Kumar, Collins, 6th editi on, pg no. 83, 84, 349-356.

Clinical pharmacy and therapeutics edited by Roger Walker, Clive Edward, 3rd edi tion, pg no. 583-596. Goodman and Ginmans pharmaceutical basis of therapeutics by Joel. G. Hardman, Le e E. Limbard 10th edition pg no. 1273-1286. Park text book of preventive and social medicine by K. Park, 17th edition, pg no . 138. Pharmacotherapy, a pathophysiological approach by Joseph T. Tipiro, Robert L. Ta lbert, 5th edition, pg no. 1917. Pharmacology and Pharmaco therapeutics by R.S. Sathoskar and S.D. Bhandarkar, 13 th edtion, pg no. 648. Essentials of medicinal pharmacology by K.D. Tripath, 5th edition, pg no. 698. balasubramanian R: Directly observed treatment short course : Tuberculosis cure for all ICMR bulletins 37-43, 2001. http://tuberculosis/TB resourcesabouttuberculosis.html http://emedicine-tuberculosisarticilesbyvandana Batra,MD.html. http://tuberculosis/DTBE-mantouxTBskintestfacilitatorguide introduction.html. http://tuberculosis/DTBE-questionsandanswer-glossary.html. http://tuberculosis/whatisTB. html. http://tuberculosis/firstustuberculosisvaccinetrialin60yearsbeings, januray http://tuberculosis/3files/pitchenik.html http://tuberculosis/DTBE-questionsand answers-activeTBdisease.html http://tuberculosis/currentmedicaltreatmentfortuberculosis-chanand iseman325 http://tuberculosis/TBresourcesgettingcured.html http://tuberculosis/TBresourcestuberculosisskintest.html http://tuberculosis/TB.html