TUBERCULOSIS - CHEMOTHERAPY
K. SabithaHH, Anil Babu
National College of Pharmacy, Manassery, Calicut
Tuberculosis (TB) is the most common cause of infection related death world wide. In 1993, the World Health Organization (WHO) declared TB to be a global public 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. Mycobacterium 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 bacillus that can survive under adverse environmental conditions. Humuns are the only known reservoirs for M. tuberculosis10
Tuberculosis (TB) is a disease caused by bacteria called Mycobacterium tuberculosis. 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 disease can be fatal.
TB is spread through the air from one person to another. The bacteria are put into the air when a person with active TB disease of the lungs or throat coughs 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 infection do not feel sick, do not have any symptoms, and cannot spread TB to others. 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 help. Even better, people with latent TB infection can take medicine so that they will not develop active TB disease12.
- Pulmonary TB
- Endobranchial TB with enlargement of lymph nodes.
- Tubercular pleural effusion
- Progressive primary TB
- Reactivation TB
- Extrapulmonary TB
- Tubercular meningitis
- Military TB
- Bone or joint TB
- Additional sites10
Symptoms of primary pulmonary disease in the pediatric population often are meager. Symptoms are more likely to occur in infants. Fever, night sweats, anorexia, non productive cough, failure to thrive, and difficult gaining may occur. It 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 result from esophageal compression. Vocal cord paralysis may be suggested by hoarseness or difficulty breathing.
- Tubercular pleural effusion:
Pleural effusions due to TB usually occur in older children rather than in infants and rarely are associated with military disease. Typically history reveals an acute onset of fever, chest pain that increases in intensity on deep inspiration, and shortness of breath. Fever usually persists for 14-21 days.
- Progressive primay TB
Progression of the pulmonary parenchymal component leads to enlargement of the caseous area and may lead to pneumonia, atelectasis, and air trapping. This is more likely to occur in young children than adolescents. The child usually appears 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 adolescents. The condition is more common in patients who acquire TB when older than 1 years10.
Patients with lymphadenopathy (ie., scrofula) may have a history of enlarged nodes. Fever, weight loss, fatigue, and malaise are either absent or minimal. Lymp node involvement typically occurs 6-9 months following infection by the tubercle bacilli. More superficial nodes commonly are involved. Frequent sites of involvement are the anterior cervical, submandibular, and supraclavicular nodes. TB of the skeletal system may lead to involvement of the inguinal, epitrochlear or auxiliary lymph nodes.
- Tubercular meningitis
One of the most severe complications of TB is tubercular meningitis. Tubercular meningitis develops in 5-10% of children who become infected when younger than 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 fever may be present. After 1-2 weeks patients may experience vomiting and
seizures or alteration in the sensorium. Deterioration of mental status, coma and 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 of fever and associated symptoms also may be observed. History of cough and respiratory distress may be obtained.
- Bone or joint TB
This may present acutely or sub acutely. Vertebral TB may go unrecognized for months to years because of its indolent nature.
- Additional sites
Other unusual sites for TB include the middle ear, gastrointestinal tract. Skin, kidneys, and ocular structures10.
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 tuberculosis. TB occurs disproportionately among disadvantaged populations, such as homeless individuals, malnourished individuals, and those living in crowded areas. According to the WHO, developing countries including India, China, Pakistan, Philippines, Thailand, Indonesia, Bangladesh, and the Democratic Republic of Congo account for nearly 75% of all cases of TB9.
In the US: Approximatley 15 million people are infected with M tuberculosis in the 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 TB cases was reported, with a peak of 26,673 cases in 1992. while the incidence increased by approximately 13% in all ages from 1985-1994, the rate among children 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 with latent TB infection. Other contributory factors were emigration from developing countries and transmission in settings such as endemic hospitals and prisons.
Mortality/Morbidity: The mortality rate from TB in the United States is currently 0.6 deaths per 100,000 individuals, which represents approximately 1,700 deaths 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 decrease in mortality is attributed to improved health care and prompt initiation of therapy. MDR-TB cases have a reported fatality rate of greater than 70%. Worldwide, deaths due to TB are estimated at 3 million per year15.
Race: According to the Centers for Disease Control and Prevention (CDC), rates of TB are 10 times higher among Asians and Pacific Islanders, 8 times higher among 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 independent 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.
Tuberculosis infection is caused by tubercle bacilli. Pulmonary tuberculosis is more common than extra pulmonary tuberculosis. Sites of extra pulmonary tuberculosis can include the pleura, lymph nodes, pericardium, kidney, meninges, bones, joints, larynx, skin, intestine, peritoneum and eye. Lymph nodes are the commonest site for extra pulmonary disease2
TB is spread through the air from one person to another. The bacteria are put into 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. When a person breathes in TB bacteria, it can settle in the lungs and begin to grow. 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 bacteria become active if the immune system cannot stop them from growing. The active bacteria begin to multiply in the body and cause active TB disease. The bacteria attack the body and destroy tissue. If this occurs in the lungs, the bacteria can actually create a hole in the lungs20.
Some people develop active TB disease soon after becoming infected, before their immune system can fight the TB bacteria. Other people may get sick later, when their immune system become weak for another reason. People have weak immune system especially with
- Diabetes mellitus
- Cancer of head
- Severe kidney disease
- Low body weight
- Substance abuse
- 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, but they remain alive in the body and can become active later. This is called latent 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 positive 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 explosion, under nutrition, lack of education, large families, lack of awareness of causes of illness4.
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 defense mechanisms, including macrophages and delayed hypersensitivity responses. Among the several virulence factors in the mycobactyerial cell wall are the cord factor lipoarabinomannan (LAM) and a highly immunogenetic 65-kd M. tuberculosis heat shock protein. Cord factor is a surface glycolipid present only in virulent strains that causes M. tuberculosis to grow in serpent cords in vitro. LAM is a hetero polysaccharide that inhibits macrophage activation by interferon - g and induces macrophages to secrete tumor necrosis factor - a (TNF - a), which causes fever, weight loss, and tissue damage. Heat shock protein have a role in autoimmune 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 cause disease, 5-200 inhales bacilli are usually necessary for infection. The small 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 of inhalation of these aerosols upon inhalation, the bacilli are deposited into the 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 multiply10.
The pattern of host response depends on primary infection exposure to the organism or secondary reaction in an already sensitized host.
Primary phase of M. tuberculosis infection begins with inhalation of the mycobacteria and ends with a T cell - mediated immune response that induces hypersensitivity to the organisms and controls 95% of infections. Inhaled M. tuberculosis is first phagocytosed by alveolar macrophages and transported by these cells to hilar lymph nodes. Naive macrophages are unable to kill the mycobacteria, which multiply, lyses the host cell, infect other macrophages and sometimes disseminate 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. First, CD4+ helper T-cells secrete interferon-g, which activates macrophages to kill intracellular mycobacteria through reactive nitrogen intermediates, including NO, NO2, and HNO3. This is associated with the formation of epithelioid cell granulomas and clearance of mycobacteria. Second CD8+ suppressor T-cells lyse macrophages infected with mycobacteria through a Fas-independent, granule dependent reaction and kill mycobacteria. Third, CD4 – CD8 T-cell lyse macrophages in a Fas-dependent manner, without killing mycobacteria. Lyses of macrophages results in the formation of caseating granulomas (delayed type hypersensitivity reaction). Direct toxicity of the mycobacteria to the macrophages may contribute to the necrotic caseous centers. Mycobacteria cannot grow in this acidic, extra cellular environment lacking in oxygen, and so the mycobacterial infection is controlled. The ultimate residuum of the primary infection is a calcified scar in the lung parenchyma and in the hilar lymph node, together referred to as Ghon complex.
Secondary and Disseminated Tuberculosis
Some individuals become reinfected with mycobacteria, reactivate dormant disease or progress directly from the primary mycobacterial lesions in to disseminated disease. This may be because the strain of mycobacterium is particularly virulent or the host is particulary susceptible. Granulomas of secondary tuberculosis most often occur in the apex of the lungs but may be widely disseminated in the lungs, kidney, meninges, marrow and other organs. These granulomas, which fail to contain the spread or the mycobacterial infection, are the major cause of tissue damage in tuberculosis and are a reflection of delayed type hypersensitivity. Two special features of secondary tuberculosis are caseous necrosis and cavities; necrosis may cause rupture into blood vessels, spreading mycobacteria through 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 bacteria 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
- night sweats
- constant tiredness16
- Tuberculin Test
Tuberculin test is used to confirm infection. Two tests are commonly used. They are (a) Heaf (multiple puncture) test and (b) Mantoux tests. Both use solution 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 solution of 100000 units per ml of PPD is applied in sufficient amount to spread over 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 from 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 also occur.
Grade 3 and 4 reactions are considered to indicate infection along with grade 2 response in a tuberculosis contact who has not previously had the BCG (bacille Calmette Guerin) vaccine. Grade 3 and Grade 4 are said to be strongly positive. 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 investigation, 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 obtained upto 96 hours. A positive result consists of induration with a transverse diameter 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 choice. 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 discover 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, although this test is used to be positive in only 60% of culture confirmed cases2.
These are much less useful in non-pulmonary and childhood disease, the diagnosis of which depends more on culture. With conventional culture methods, such as the Lowenstein-Jensen medium, growth may take up to 6 weeks4. Culture examinations of sputum is only second in importance in a case finding programme. It is not only difficult, lengthy (take at least 6 weeks) and expensive but also need special training and expertise. This method of examination is offered only to patients presenting themselves with chest symptoms, whose sputum smear is negative by direct microscopic examination. Culture of sputum is necessary for carrying out 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 patient and achieve quick sputum negatively so that the patient is non-contagious to the community: transmission of TB is interrupted. This also affords quick symptom 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 bactericidal drugs9.
- Second line drugs
Have low antitubercular efficacy and high toxicity. They are bacteriostatic drugs.
First line drugs
- Isoniazide (INH) (H)
Most powerful drug in the treatment of TB. It can easily penetrate to cell membrane, and is active against intracellular and extra cellular bacilli. Its action is most marked on rapidly multiplying bacilli. It is less active against slow multipliers and atypical mycobacteria3.
MOA: It inhibit mycolic acid synthesis which is unique for mycobacterial cell wall.
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 Adverse effect: Peripheral neuritis and a varity of neurological manifestations. These are due to interference with utilization of pyridoxine and its increased excretion in urine. INH neurotoxicity is treated by pyridoxine 100mg/day given prophylactically. Other side effects rashes, fever, etc.
- Rifampicin (R)
It is a better sterilizing agent than INH. It is equally effective against intracellular and extra cellular bacilli. It is the only bactericidal drug active against dormant bacilli. In combination with INH, it can cure extensive tuberculosis in about 9 months. Bactericidal action covers all subpopulation of TB bacilli, but acts best on slowly or intermittently dividing bacilli as well as on many atypical mycobacteria5
MOA: It inhibit DNA dependant RNA synthesis
Pharmacokinetics: Well absorbed orally. Widely distributed in the body. Metabolized 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 syndrome.
- Streptomycin (S)
It is an amino glycoside antibiotics. It acts entirely on rapidly multiplying bacilli. It is less active against slow multipliers. No action of dormant bacilli. It is act only on extracellular bacilli.
MOA: Bind to 30s and 50s sub units of ribosomes as well as their interface, freeze initiation, interfere with polysome formation and cause misreading of mRNA code, thus inhibit protein biosynthesis.
Pharmacokinetics: It is neither absorbed nor destroyed in the g.i.t. It is absorbed from injection site in muscles is rapid. It is distributed only extra cellularly. 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 been found to increase the sterilizing ability of rifampicin. Therefore, it has been 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 penetration 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. Hyperuricemia 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 regimen of RHZ it has been found to hasten the rate of sputum conversion and to prevent the development of resistance.
MOA: Interfere with mycolic acid incorporation in to mycobacterial cell wall.
Pharmacokinetics: Absorbed orally. It is distributed widely but penetrate meninges. 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 effect of isoniazid, streptomycin or ethambutol, but delay resistance to these drugs.
Pharmacokinetic: Orally active, excreted unchanged in urine with t½ of 12 hr.
Dose: 150mg OD in adults, 2.5 mg/kg in children
Sideeffects: Hepatitis, gastrointestinal disturbances, blurred vision, haemolytic anoumia, utricasia and bone marrow depression.
- Para amino salicylic acid (PAS)
It is tuberculostatic, one of the least active drug used as sodium and calcium 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 except in CSF. It is metabolized by acetylation and excreted by glomerular filtration.
Dose: 10-12g per day in divided dose oral bid or tid
Side effects: Anorexia, Nausea, Epigasteric pain, rashes, fever, goiter, liver dysfunction and blood dyscrasias.
- Ethionamide (Etm)
It acts on both extra and intra cellular organism. It is a tuberculostatic drug. A typical bacteria are sensitive. But it has low efficacy.
MOA: It inhibit peptide synthesis in bacteria by blocking incorporation of sulfur 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, hepatitis, mental disturbances and impotence
- Cycloserine (Cys)
It is bacteriostatic and inhibit some other gram positive bacteria E coli, Chlamydia. Resistance to cyclosexine develop slowly. No cross resistance.
MOA: Inhibit bacterial cell wall synthesis by inactivating the enzyme which recemize L-alanine and link two D-alanine residue.
Pharmacokinetics: it is absorbed orally. Diffuses all over CSF concentration equal to plasma. About 1/3 of the dose metabolized, rest excreted unchanged by kidney.
Dose: 250-500mg oral qd or bid
Side effects: CNS toxiary- sleepiness, headache, tremor and psychosis7.
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 TB bacilli, while Z acts best on intra cellular bacilli and those at inflamed sites has very good sterilizing activity. On the other hand S is active only against rapidly multiplying extra cellular bacilli. E is bacteriostatic - mainly serves 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 depended entirely on INH and 18 months of treatment was required. Two main drug regions 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 companion 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 given 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 replaced by PAS or ethambutol. For treatment of young children, PAS is preferred to etambutol because of ocular toxicity.
The major cause of treatment failure is that patient defaulted before the end 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 patient. The standard biweekly region is
Streptomycin 1 g or 0.75g
INH 600 or 700mg
INH is to be taken in a single dose orally; and streptomycin by intramuscular 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 streptomycin 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 "Supervised" chemotherapy.
The addition of rifampicin or pyrazinamide to regimens containing INH, reduce the duration of treatment.
The advantages of short course therapy is that rapid bacteriological conversion, lower failure rates and a reduction in the frequency of emergence of drug resistant bacilli. Patient compliance is improved, they become non-infections earlier. 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 short, aggressive or intense phase early in the treatment, lasting 1-3 months. During 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 load 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 treated patients18
Rationale Patients of smear positive pulmonary TB harbour and disseminate large number of bacilli Initial treatment with 4 drugs reduces risk of selecting resistant bacilli as well as covers patients with primary resistance. When few bacilli are left only 2 drugs in the continuation phase are enough to effect cure. Smear negative pulmonary TB and extrapulmonary TB patients harbour fewer bacilli in their lesions—risk of selecting resistant bacilli is less; regimens containing only 3 drugs in the initial phase and 2 in the continuation phase are of proven efficacy. Accordingly, previously treated/failure/default/ relapse cases are treated 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 usual 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, pericarditis, 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 months. Out of the WHO recommended regiment RNTCP has decided to follow 3 weekly regiment, since it is equally effective, save drug and effort, and is more practical. The RNTCP recommended that if the patient is sputum positive at 2 months, the intensive phase should be extended by another month; then continuation phase is started regardless of sputum status at 3 months.
Treatment regiment for tuberculosis
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 disease. 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 treatment 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 developing 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, but 4 drug treatment is continued for another month if sputum is positive at 3 months.
Continuation phase Three drugs (HRE) are given for 5 months either daily or thrice weekly (only thrice weekly under RNTCP).
Category III These are new cases of smear negative pulmonary TB with limited parenchyma! involvement or less severe forms of extrapulmo-nary TB, viz, lymphnode, unilateral pleural effusion, bone (excluding spine), peripheral joint or skin TB.
Initial phase Three drugs HRE given for 2 months are enough because the bacillary load is smaller.
Continuous phase: This is similar to category I, i.e., 4 month daily/thrice weekly HR or 6 month daily HE (Tzn) therapy. Under RNTCP only thrice weekly HR regimen is followed.
Category IV These are chronic cases who have remained or have become smear positive after completing fully supervised retreatment (Category D) regimen. These are most likely MDR cases. Multidrug resistant (MDR) TB is defined as resistance to both H and R and may be any number of other anti-TB drugs. MDR-TB has a more rapid course (some die in 4-16 weeks). Treatment of these cases is difficult because the second line drugs are less efficacious, less convenient, more toxic and more expensive. Treatment is prescribed only if its compliance can be assured. Otherwise 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/leukemia/silicosis, and whether sensitivity of the pathogen to various drugs is known (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 line drugs are prescribed with or without 1-3 second line drugs (only if practicable),
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 patient.
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 maintained. The best way to remember to take medicine is to get directly observed therapy (DOT). If a patient get DOT, he will meet with a healthcare worker every day or any other convenient location. The patient will take his medicine at this place 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 take 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 should. This person will also watch for side effects and answer questions patients have about TB14.
In DOTs during the intensive phase of treatment a health worker watches as the 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 medicine for the next week. The drugs are provided in patient wise boxes with sufficient shelf life4.
TREATMENT OF TUBERCULOSIS IN SPECIAL CIRCUMSTANCES
Tuberculosis in children
Doses are generally estimated to facilitate prescription of easily given volumes of syrup, or tablets of appropriate strength. Ethambutol should not routinely 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 agents occurs.
Pregnant women should be given standard therapy, although streptomycin should 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.
Patients with renal disease may be given isoniazid, rifampicin and pyrazinamide in standard doses as these drugs are eliminated by predominantly non-renal routes. Ethambutol undergoes extensive renal elimination and therefore dose reduction is needed. Streptomycin must be used with considerable caution if toxicity is to 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 be modified. A number of different regiments have been suggested.
In patients who present with liver failure or in alcoholics, monitoring of liver enzymes is recommended as rifampicin, isoniazid and pyrazinamide are all known to be potentially hepatotoxic. However, increases in transaminasces at the start of antitubercular treatment occur frequently. These are usually transient and not a reason for stopping treatment unless frank jaundice or hepatitis develop, in which case all drugs should be stopped. It is usually possible to restart treatment when values have returned to pretreatment levels.
Patients who are immunocompromised, including those with HTV Infection, should be treated with normal first- line agents unless multidrug-resistant tuberculosis is suspected. Theoretically these patients have a greate, risk of relapse and may need to be treated for longer than the normal 6 months. On current evidence, at the completion of treatment life-long chemoprophylaxis with isoniazid should be instituted.
Corticosteroids have long been used in the treatment of tuberculosis, chiefly 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 rifampicin is used. Steroids probably find their greatest use for pericarditis or pleural disease and endobronchial disease in children. They are also used in genitourinary tuberculosis where they help reduce the symptoms of cystitis and obstruction. In tuberculous meningitis, corticosteroids are said to improve survival and reduce sequelae.
In pulmonary tuberculosis, sputum examination and culture are the most sensitive markers of the success of treatment. Patients taking regimens containing rifampicin and isoniazid should be non-infective with in 2 weeks. If a patient does not become culture-negative, it may be due to either drug resistance or non-adherence, the latter being most likely. Chest radiographs provide only limited information as to the progress of treatment. Good adherence is essential if treatment is to be successful, and checking adherence is not easy, especially when a patient is uncooperative. Rifampicin will colour the urine red within about 4 hours 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 awareness of tuberculosis as a possible diagnosis in those with medical or other risk factors, who have a chronic cough, or lower respiratory tract infection not responding to antibiotic treatment. Prompt treatment ensures that patients with infectious tuberculosis become non-infectious, as soon as possible, usually within 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 tuberculosis.
- All cases of tuberculosis should be notified. This ensures that examination of contacts is carried out, and local and national surveillance of tuberculosis is maintained.
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 irrespective 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 disease.
Prophylaxis is usually with isoniazid alone for 6 months or rifampicin and isoniazid for 3 months. Both regimens are equally effective.
BCG vaccine does not protect against infection. Instead it prevents the more serious forms of disease such as miliary tuberculosis and tuberculous meningitis2
The aim of BCG vaccination is to induce a benign artificial primary infection which will stimulate an acquired resistance to possible subsequent infection with virulent tubercle bacilli, and thus reduces the morbidity and mortality from primary tuberculosis risk.
It consist of living bacteria derived from an attenuated bovine strain of tubercle bacilli.
3. Types of vaccine
There are two types of BCG vaccine - the liquid (fresh) vaccine and the freeze dried vaccine. Freeze dried vaccine is a more stable preparation than liquid vaccine. BCG vaccine is stable for several weeks at ambient temperature in a tropical climate, and for up to 1 year if kept away from direct light and stored in a cool environment.
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 hours and the left over vaccine should be discarded.
For vaccination, the usual strength is 0.1mg in 0.2ml volume. The dose to new born aged below 4 weeks is 0.05 ml.
The standard procedure recommended by WHO is to inject the vaccine interdermally using "Tuberculin" syringe. The vaccine must not be contaminated with an antiseptic or detergent. If alcohol is used to swab the skin, it must be allowed to evaporate before the vaccine is given.
The national vaccination policies differ from country to country. In countries where tuberculosis is prevalent and the risk of childhood infection is high the 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 Polio BCG administered easily in life provides a high level of protection, particularly against the severe forms of childhood tuberculosis and tuberculous meningitis.
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 into 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.
BCG has been associated with adverse reactions which include prolonged severe ulceration at the site of vaccination, suppurative lymphadenitis, osteomyelities, disseminated BCG infection and death.
9. Protective value
The duration of protection is from 15 to 20 years. The local BCG infection generates an immunity response, which is associated with the development of tuberculin hypersensitivity and with it, possibly, some immunity.
Studies shown that the range of protection offered by BCG varied from 0 to 80% 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 benefit of BCG vaccination. Exposure to other species have an antagonistic action against BCG.
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.
BCG should not be given to patients suffering from generalized eczemia, infective dermatosis, hypogamma globulinaemia and those with a history of deficient immunity.
BCG vaccination is less effective in controlling tuberculosis compared to active case finding and chemotherapy, as BCG offers only partial protection. BCG vaccination of uninfected individuals can prevent tuberculosis in them, it can have only a relatively small epidemiological effect in that it will not contribute significantly to the reduction in the overall risk of infection in the community4.
It is possible to cure virtually all patients with tuberculosis infection or disease provided that an adequate regimen is prescribed and the patient complies 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 disease may relapse, in some cases with resistant organisms. If a non-adherent patient 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, and falls still further if doses have to be taken frequently through the day. Ideally, the least number of tablets should be given.
Patients may fail to adhere because they feel better and do not appreciate the need to continue with their medication. Lack of clarity of instructions, written, verbal or other, may compromise adherence, particularly if the patient is confused by conflicting advice by different health care professionals. Finally, adverse effects, or symptoms perceived to be adverse effects, may reduce adherence.
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 their daily routine. Rifampicin and isoniazid are both well absorbed when taken on an empty stomach. However, absorption is reduced and delayed when taken with or after food20. It is therefore recommended that both are taken 1 hour before food 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 patients.
The number of tablets to be taken each day may be reduced by using combination preparations. These also have the advantage of reducing the possibility of monotherapy and consequent resistance. There are a number of combination preparations 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 is far preferable to potential under treatment due to non-adherence. Mynah is a preparation available in a number of different ratios to facilitate administration of the correct dose.
Combination preparations may not be suitable for use in children as the required dose regimens differ from those of adults.
Written instruction and/or patient information leaflets may be offered to support 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 feels 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 expect 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 English It may still be possible to give written instructions on dosage as some pharmaceutical companies are able to provide pictorial and dosage sheets in a number of languages.
Patients taking rifampicin should be told that the drug will cause a harmless discoloration of their urine and other body fluids, for example sweat and tears. 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-hormonal methods of contraception for the duration of treatment with rifampicin and for 8 weeks afterwards. Although ocular side-effects are rare when ethambutol is 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 changes in colour vision. This is especially important because visual changes are usually reversible on discontinuation of the drug but may be permanent if the drug is not stopped4.
Even though TB is an infections disease it is curable if proper treatment and care are given so as to safeguard our newer generation from the shadow of this disease they should be given BCG vaccines. Prophylactics measurement should be taken in order to prevent spread of the epidemic infection.
- Robins pathological basis of disease edited by Cotran, Kumar, Collins, 6th edition, pg no. 83, 84, 349-356.
- Clinical pharmacy and therapeutics edited by Roger Walker, Clive Edward, 3rd edition, pg no. 583-596.
- Goodman and Ginmans pharmaceutical basis of therapeutics by Joel. G. Hardman, Lee 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. Talbert, 5th edition, pg no. 1917.
- Pharmacology and Pharmaco therapeutics by R.S. Sathoskar and S.D. Bhandarkar, 13th 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://emedicine-tuberculosisarticilesbyvandana Batra,MD.html.
- http://tuberculosis/firstustuberculosisvaccinetrialin60yearsbeings, januray