Tuberculosis caused by the bacillus- Mycobacterium tuberculosis and

                      

                    Tuberculosis continues to
be a major public health problem throughout the world, particularly in the
developing countries. Nearly one-third of the global population (i.e. two
billion people) is infected with Mycobacterium tuberculosis and is at risk of
developing the disease. More than eight million people develop active
tuberculosis every year and about two million die of the disease. It is the
leading cause of death due to a single infectious agent among adults. Tuberculosis
is an infectious disease caused by the bacillus- Mycobacterium tuberculosis and
occasionally by Mycobacterium bovis and Mycobacterium africanum. Tuberculosis
commonly affects the lungs, but it can affect any other organ in the body. The
bacteria that cause tuberculosis usually spread through air. When patient with
infectious pulmonary tuberculosis coughs, sneezes or laughs, bacilli are
expelled into the air in the form of tiny droplets. These droplets dry up
rapidly to form droplet nuclei and may remain suspended in the air for several
hours. Adequate through and through ventilation removes and dilutes these
droplet nuclei, and direct sunlight quickly kills the bacilli, but they can
survive in the dark for several days. When a healthy person inhales these
droplet nuclei containing the tubercle bacilli, he/she may become infected.
Risk of infection an individual’s risk of infection depends on the extent of
exposure to an infectious source and susceptibility of the individual to
infection. The risk of infection is therefore high in a person who has close,
prolonged exposure to a person with sputum smear positive pulmonary TB. The
risk of transmission of infection from sputum smear-negative pulmonary TB is
low and with extra pulmonary TB, still lower.     

                      Tuberculosis develops in
two stages. The first stage occurs when the tubercle bacilli form an infectious
source enter the body of an individual but remain dormant without causing
disease and is called tuberculous infection. The second stage is when the
infected individual actually develops the disease and is called tuberculosis or
tuberculous disease.

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                   Risk of progression of
infection to disease once infected with M.tuberculosis, a person probably
remains infected for life. Approximately 10% of people infected will develop
active disease during their lifetime. The majority (90%) of people will not
develop the disease and the only evidence of infection in these individuals,
may be a positive tuberculin skin test. However the organisms may remain
dormant within the body and the disease can develop at any time. The chance of
developing the disease is greatest shortly after infection (within the first
two years) and lessens as time goes by, but the risk probably remains for life.
Any weakening of the immune system will lead to progression of infection to
disease e.g. HIVinfection, diabetes, malnutrition, prolonged steroid therapy,
chronic alcoholism, and malignancies etc.PathogenesisPrimary infection Primary
infection occurs on first exposure of a person to tubercle bacilli. Once the
tubercle bacilli enter the respiratory tract through inhalation, the organisms
reach the alveoli of the lungs and start multiplying to form the Ghon’s focus.
The bacilli spread through the lymphatic’s to the hilar lymph nodes causing
enlargement of the nodes. The Ghon’s focus and the hilar lymphadenopathy form
the Primary Complex. Bacilli from the primary complex may spread via the blood
stream and lymphatic’s to other parts of the body .The immune response (delayed
hypersensitivity and cellular immunity) develops about 4-6 weeks after the
primary infection. In most cases the immune response is sufficient to stop the
multiplication of bacilli and prevent development of disease. The primary
lesion may heal by fibrosis or by calcification. A positive tuberculin skin
test may be the only evidence of infection. In few cases (e.g. the new born,
malnutrition, HIV) the immune response may not be sufficient to prevent the
multiplication of bacilli and the tuberculous infection may progress to
tuberculous disease within a few months.

                     The five essential anti-TB
drugs are: Isoniazid (H) Rifampicin (R) Pyrazinamide (Z) Ethambutol (E)
Streptomycin (S) Mode of action of anti-TB drugs. A population of TB bacilli in
a TB patient consists of the following groups. 1. Metabolically active,
continuously growing bacilli inside cavities 2. Intra cellular dormant forms –
bacilli inside macrophages 3. Extra cellular dormant forms a) Bacilli which
undergo occasional spurts of metabolism (semi dormant) b) Dormant bacilli,
which gradually die on their own. Different anti-TB drugs act against different
groups of bacilli. Isoniazid, rifampicin, Ethambutol, PAS are active against
metabolically active bacilli. Rifampicin has a special action against the semi
dormant forms. Pyrazinamide acts in an acid environment inside cells e.g.
macrophages .So far there is no drug, which can act on dormant bacilli TB
treatment regimens. Treatment regimens consist of two phases: 1. Initial
intensive phase 2. Continuation phase Intensive phase during the initial
intensive phase, there is rapid killing of TB bacilli. Infectious patients
quickly become non-infectious (within about two weeks) and symptoms improve.
Most patients with sputum smear-positive pulmonary TB becomes smear negative
within two months. Directly Observed Therapy (DOT) is essential in the initial
phase to ensure that the patient takes every single dose. This prevents
development of drug resistance. The risk of development of drug resistance is
higher during the early stages of anti-TB treatment, when there are more
bacilli. Continuation Phase During the continuation phase, fewer drugs are
necessary, but for a longer period. The sterilizing effect of the drugs
eliminates the remaining bacilli, thus preventing subsequent relapses .Patients
who has taken anti-tuberculosis drugs previously are much more likely to
develop drug resistance, which may have been acquired through inadequate prior
chemotherapy. Such patients require a stronger regimen consisting of more drugs
and for a longer period. Therefore before starting treatment, it is essential
to question all patients closely and carefully to determine whether or not they
have previously taken treatment for tuberculosis, so that they can be given the
proper treatment regimen. Standard code for TB treatment regimens there is a
standard code for TB treatment regimens and each anti-tuberculosis drug has an
abbreviation. H – Isoniazid R – Rifampicin Z – Pyrazinamide E – Ethambutol S –
Streptomycin A TB treatment regimen consists of two phases, the intensive phase
and the continuation phase. The number before a phase is the duration of that
phase in months. A subscript number (e.g. 3) after a letter indicates the number
of doses of that drug per week. No subscript number after a letter indicates
that the treatment is daily. E.g.: 4 HR means 4 months of Isoniazid and
Rifampicin daily.5 H3 R3 E3 means 5 months of Isoniazid, Rifampicin and
Ethambutol three times a week.

                   Isoniazid is highly
bactericidal against replicating tubercle bacilli. It is rapidly absorbed and
diffuses readily into all fluids and tissues. The plasma half-life, which is
genetically determined, varies from less than one hour in fast acetylators to
more than three hours in slow acetylators. It is largely excreted in the urine
within 24 hours, mostly as inactive metabolites. Uses • Isoniazid is a
component of all TB chemotherapeutic regimens currently recommended by WHO. •
Isoniazid alone is occasionally used in chemoprophylaxis Administration
Isoniazid is normally given orally. Dosages For treatment-Adults and children:
5mg/kg (4-6mg/kg) daily, maximum 300mg. 10 mg/kg 3 times weekly Preventive
therapy: Adults: 300mg daily for at least 6 months Children: 5mg/kg daily
(maximum 300mg) for at least 6 months Side-effects Isoniazid is generally well
tolerated at recommended doses.• Systemic or cutaneous hypersensitivity
reactions occasionally occur during the first weeks of treatment.• Peripheral
neuropathy may occur in persons with malnutrition, chronic alcoholics, and
pregnant women or in diabetics. This can be prevented or minimized by giving,
supplementary pyridoxine 10 mg daily to those at risk.• Other less common forms
of neurological disturbances including optic neuritis, toxic psychosis, and
generalized convulsions can develop in susceptible individuals, particularly in
the later stages of treatment, which occasionally may necessitate withdrawal of
Isoniazid.• Hepatitis is an uncommon but potentially serious reaction that can
usually be averted by prompt withdrawal of the treatment. Monitoring of hepatic
transaminases should be done in patients with pre-existing chronic liver
disease. • Isoniazid tends to raise plasma concentrations of phenytoin and
carbamazepine by inhibiting their metabolism in the liver. Therefore it may be
necessary to reduce the dosages of these drugs during treatment with Isoniazid.
• Patients on treatment with Isoniazid should be cautioned against eating ‘Red
fish’ such as skipjack and tuna, which contain high concentrations of
histamine. Isoniazid is an inhibitor of histaminase, which is normally present
in the tissues and is responsible for the inactivation of ingested histamine.
As a result, the histamine level in the tissues of the patient tends to rise
shortly after a meal containing these varieties of fish, and the patient may
experience symptoms of histamine intoxication like erythema, severe headache,
red eyes, palpitation, diarrhoea, vomiting and wheezing. Isoniazid is not
teratogenicity and can be used during pregnancy. Rifampicin has a potent
bactericidal and sterilizing effect against tubercle bacilli in both cellular
and extra-cellular locations. Following oral administration, it is rapidly
absorbed and distributed throughout the cellular tissues and body fluids. Since
resistance develops rapidly, Rifampicin must always be administered in
combination with other effective anti-mycobacterial agents. Uses it is a
component of all 6 months and 8 months TB chemotherapeutic regimens currently
recommended by WHO. Administration and dosage: Rifampicin is administered
orally and should preferably be given at least 30 minutes before meals, since
absorption is reduced when it is taken with food. This however may not be
clinically significant and food can reduce intolerance to the drugs. Adults and
children: 10 mg/kg (8-12 mg/kg) daily, maximum 600mg daily. 10mg/kg 3 times
weekly Side-effects Rifampicin is well tolerated by most patients at currently
recommended doses Side-effects include:• Gastro-intestinal – nausea, anorexia,
vomiting and abdominal pain• Hepatitis is a major side effect although it is
rare. Alcoholics and pre-existing liver disease may increase the risk and it
may be advisable to monitor the liver function tests in these high-risk groups.
The following reactions are more likely to occur with intermittent therapy: •
‘Flu’ syndrome – consisting of attacks of fever, chills, malaise headache, bone
pain • Cutaneous reaction – consisting of flushing, and pruritus with or
without a rash • *Thrombocytopenia and purpura • *Haemolytic anaemia and acute
renal failure may occur • *Respiratory shock syndrome consisting of shortness
of breath and rarely associated with collapse and shock. May occur* If these
reactions occur Rifampicin must be stopped immediately and admitted to hospital
for management. It should not be given again. Drug interactions Rifampicin
induces hepatic enzymes and may accelerate clearance of drugs metabolized by
the liver, and patients may need higher dosages of these drugs. These include
corticosteroids, oral contraceptives, oral hypoglycaemic agents, oral
anticoagulants, anticonvulsants, and cimetidine, cyclosporine and digitalis
glycosides. Since Rifampicin reduces the effectiveness of oral contraceptives,
women should be advised to use an alternative method of contraception.
Rifampicin is excreted in urine, tears, sweat and other body fluids and may
colour them red or orange. Patients should be warned of discoloration of urine
and other body fluids. Rifampicin may be used safely in pregnancy. Vitamin K
should be administered at birth to an infant of a mother taking Rifampicin
because of the risk of postnatal haemorrhage.

           Pyrazinamide is bactericidal and
particularly effective against bacilli in an acid environment inside
macrophages. It is highly effective during the first two months of treatment by
destroying the intracellular bacilli and reduces the risk of relapse. Uses: It
is a component of all 6 month and 8 month TB chemotherapeutic regimens
currently recommended by WHO. Administration and dosage: It is administered
orally and is rapidly absorbed from the gastro-intestinal tract and rapidly
distributed throughout all tissues and fluids. Adults and children: (for the
first 2 or 3 months) 25mg/kg daily (20-30 mg/kg) 35 mg/kg (30-40mg/kg) 3 times
weekly Side-effects • Gastro intestinal symptoms- nausea, anorexia •
Hypersensitivity reactions are rare, but some patients may complain of flushing
of the skin • Hepatitis is the most important adverse effect, though it is
rare. • Hyperuriceamia may occur due to diminished excretion of uric acid in
urine, but this is often asymptomatic. Arthralgia may occur and treatment with
simple analgesics is often sufficient. Attacks of acute gout are uncommon.
Ethambutol has a bacteriostatic effect. It is used in combination with other
ant-TB drugs to prevent the emergence of drug resistant strains. It is given
orally and absorbed readily from the gastro intestinal tract. Administration
and dosage: Ethambutol is given orally Adults: 15mg/kg (15-20 mg/kg) daily
30mg/kg (25-35mg/kg) 3 times weekly. Children: Maximum 15mg/kg daily 35

           Ethambutol is not recommended in
children who are too young for assessment of visual acuity and red- green
colour discrimination (generally under 6 years of age).Side-effects Dose
dependant optic neuritis is the most important side effect and can result in
impairment of visual acuity and colour vision. Early changes are usually
reversible, but blindness can occur if treatment is not discontinued promptly.
Therefore patients should be advised to report immediately to a clinician if
their vision deteriorates. Streptomycin is bactericidal in action. It is not
absorbed from the gastrointestinal tract and must be given by intra-muscular
injection Streptomycin is excreted entirely through the kidneys and therefore
drug should be used in reduced dosage and with extreme caution in patients with
renal insufficiency and in the elderly .Administration and dosage: Streptomycin
must be administered by deep intra-muscular injection. Syringes and needles
should be sterilized properly. Whenever possible use disposable syringes and
needles. Adults and children: 15mg/kg (12-18mg/kg) daily or 3 times weekly.
Patients over the age of 60 years may not be able to tolerate more than 500mg
daily. Side-effects • Hypersensitivity reactions are rare. If they do occur
(usually during the first few weeks of treatment), streptomycin should be
withdrawn immediately. Once fever and skin rash have resolved, desensitization
may be attempted. • Auditory nerve damage can occur resulting in deafness and
is more common in elderly and in patients with renal impairment. • Vestibular
damage is uncommon, with the recommended doses, but if headache, vomiting, vertigo,
dizziness and nystagmus occur, doses should be reduced. • Nephrotoxicity can
occur Streptomycin should not be used in pregnancy. It crosses the placenta and
can cause auditory nerve impairment and nephrotoxicity in the foetus.

            Most anti-TB drugs can damage the
liver. Isoniazid, pyrazinamide and rifampicin are the drugs most commonly
responsible and Ethambutol rarely.  Novel
chemotherapeutic drugs are needed to improve tuberculosis control. Given the
magnitude of the problem and the resources available in countries that have the
highest burden of disease the present standards of care for the treatment of
drug- susceptible TB, drug resistant TB and latent TB infection are all
unsatisfactory. Because no truly novel compounds for the treatment of TB have
been discovered in the past 40 years, the recent enhanced activity in the
research and development of new drugs is extremely encouraging. (2)

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