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ANTIMYCOBACTERIALS I
PHARMACOLOGY IV
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Antimycobacterials
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Antimicrobials
Used in the Treatment of Tuberculosis
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Tuberclosis (TB)
• Tuberclosis (TB) is a bacterial infection, treatable by anti-TB
drugs.
• In 2008, there were an estimated 9 million cases of tuberclosis
and 2 million death from the disease worldwilde.
• One-third of the word’s population is infected with tubercle
bacillus.
• TB infection usually occurs by the respiratory routes.
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Mycobacteria
Mycobacterum species include:
M.tuberclosis complex: M. tuberclosis, M. bovis, M africanum
Mycobacterium tuberculosis, can lead to serious infections
of the lungs, genitourinary tract, skeleton, and meninges.
Mycobacteria other than tuberclosis: Around 15 are recognized
as pathogenic to human and some cause pulmonary disease
resembling TB.
Mycobacterium leprae: the cause of leprosy
• Mycobacterial infections are intracellular and, generally, result
in the formation of slow-growing granulomatous lesions that are
responsible for major tissue destruction.
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Mycobacteria
• Mycobacteria are intrinsically resistant to most antibiotics.
Because they grow slowly compared with other bacteria,
antibiotics that are most active against growing cells are
relatively ineffective.

• Mycobacterial cells can also be dormant and thus completely

resistant to many drugs or killed only very slowly. The lipid-rich
mycobacterial cell wall is impermeable to many agents.

• Mycobacterial species are intracellular pathogens, and

organisms residing within macrophages are inaccessible to
drugs that penetrate these cells poorly.
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Clinical aspects
• TB infection usually occurs by the respiratory routes.
• The lung lesions caused by infection commonly heal , leaving
no residual changes except occasional pulmonary or
tracheobronchial lymph node calcification.
• About 5% of those initially infected will develop active primary
disease. This can include pulmonary disease, through local
progression in the lungs, or by lymphatic or hematogenous
spread of bacilli, to pulmonary, meningeal or other extra
pulmonary involvement or lead to disseminated (miliary TB).
• In the other 95%, the primary lesion heals without intervention
but in at least one-half of patients, the bacilli survive in a
latent form, which may then reactivate later in life.
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Risk groups
Certain groups are at increased risk of latent TB infection (LTBI)
and possibly TB disease if exposed. These include:
I. Close contacts of patients with TB, especially those with
sputum smear- positive pulmonary disease
II. Casual contacts (e.g. colleagues) if they are
immunosuppressed
III. People from countries with high incidence of TB
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Risk groups
Factors that increase risk of developing active tuberclosis in
infected:
1. HIV positive
2. Injecting drug users
3. Organ transplantation, gastrectomy
4. Haemotological malignancy, for example lukemia and
lymphomas
5. Chronic renal failure or receiving haemodialysis
6. Silicosis (chronic lung disease caused by inhaling particles of
silica or similar substances that lead to loss of lung function)
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Impact of HIV infection

• People with HIV infection have an increased risk of developing
TB if exposed to infection.
• The estimated annual risk of TB in those with HIV infection and
TB co-infection is around 10% as opposed to 10% lifetime
chance in some one infected with TB, but not HIV.
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Symptoms
The symptoms and sign of TB include:
Cough for 3 weeks or more
Sputum usually mucopurulent or purulent
Haemoptysis not always a feature
Fever may be associated with night sweats
Tiredness
Weight loss
Anorexia
Malaise

• Haemoptysis : The spitting of blood derived from the lungs or

bronchial tubes as a result of pulmonary or bronchial hemorrhage
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Clinical diagnosis
• The clinical diagnosis of TB disease is based on the symptoms
and signs in the patient together with chest radiography,
microscopy of sputum followed by culture and tuberculin skin
testing.

• Blood based immunological tests, introduced in the last few

years, will play increasingly important role in TB diagnosis.
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Important factors in treating TB

In treating TB, number of factors are important:
I. Choice of drugs
II. Length of treatment
III. Co-morbidity especially HIV infection, liver and renal disease
IV. Adherence to treatment by patients

• It is important to tailor the management of patient according to

his or her situation, rather than just focus on the drug treatment
of TB , as other factors in the patient’s life may affect
adherence.
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Chemotherapy for tuberculosis

Treating tuberculosis as well as other mycobacterial infections
presents therapeutic problems:
I. Patients compliance
II. The intra-cellular location of mycobacteria
III. The organism grows slowly; thus, are difficult to culture and
the response of mycobacterial infections to chemotherapy is
slow, may have to be treated for 6 months to 2 years.
IV. Resistant organisms readily emerge, particularly in patients
who have had prior therapy or who fail to adhere to the
treatment protocol.
V. The chronic nature of mycobacterial disease which requires
protracted drug treatment and is associated with drug
toxicities.
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Multidrug regimen
• The multidrug regimen is
continued well beyond the
disappearance of clinical
disease to eradicate any
persistent organisms.
• For example, the initial short-
course chemotherapy for
tuberculosis includes isoniazid,
rifampin, ethambutol and
pyrazinamide for 2 months
(initial phase) and then
isoniazid and rifampin for the
next 4 months (the
“continuation phase”).
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Multidrug regimen
• A longer period of treatment rather than standard 6 months is
needed for meningeal TB and where there is direct spinal cord
involvement.
• Patients should be started on standard treatment regimen on
clinical diagnosis .The drugs used can be changed if drug
susceptibility testing shows evidence of resistance.
• The purpose of concurrent use of 4 drugs in the initial phase is
to reduce the bacterial population as rapidly as possible and
prevent the emergence of drug-resistance bacteria.
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Drug resistance TB
• Multi drug-resistance tuberculosis (MDR-TB) is caused by
bacteria that are resistance to at least isoniazid and rifampin ,
the most effective anti-TB drugs.
• MDR-TB result from either primary infection with resistance
bacteria or may develop in course of patient’s treatment.
• Extensively drug-resistance tuberculosis (XDR-TB) is a
form of TB caused by bacteria that are resistant to isoniazid
and rifampicin, that is, MDR-TB, as well as any fluoroquinolone
and any of the second line anti-TB injectable drugs including
amikacin, kanamycin, capreomycin.
• The treatment of drug-resistance TB is complex, costlier,
and longer of duration than drug susceptible cases.
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Strategies for addressing drug resistance

Strains of M. tuberculosis that
are resistant to a particular
agent emerge during treatment
with a single drug.

For example, Figure shows

that resistance rapidly
develops in patients given only
streptomycin.
Multidrug therapy is employed
when treating tuberculosis in
an effort to delay or prevent
the emergence of resistant
strains.
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Strategies for addressing drug resistance

Isoniazid, rifampin (or rifabutin or rifapentine), ethambutol,
and pyrazinamide are the principal or so-called “first-line”
drugs because of their efficacy and acceptable degree of
toxicity.
Because of poor patient compliance and other factors, the
number of multidrug-resistant organisms has risen.
Some bacteria have been identified that are resistant to as
many as seven antitubercular agents. Therefore, although
treatment regimens vary in duration and in the agents employed
, they always include a minimum of two drugs, preferably with
both being bactericidal. The combination of drugs should
prevent the emergence of resistant strains.
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Isoniazid
Isoniazid, the hydrazide of isonicotinic acid, is a synthetic
analog of pyridoxine.
It is the most potent of the antitubercular drugs, but is never
given as a single agent in the treatment of active tuberculosis.
Its introduction revolutionized the treatment of tuberculosis.
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Mechanism of action
Isoniazid, often referred to as INH, is a pro-drug that is activated
by a mycobacterial catalase-peroxidase (KatG).
Genetic and biochemical evidence has implicated at least two
different target enzymes for isoniazid within the unique Type II
fatty acid synthase system involved in the production of mycolic
acids.
Note:Mycolic acid is a unique class of very-long-chain, β-hydroxylated
fatty acids found in mycobacterial cell walls. Decreased mycolic acid
synthesis corresponds with the loss of acid-fastness after exposure to
isoniazid.
The targeted enzymes are enoylacyl carrier protein reductase
(InhA) and a β-ketoacyl-ACP synthase (KasA). The activated
drug covalently binds to and inhibits these enzymes, which are
essential for the synthesis of mycolic acid.
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Antibacterial spectrum
For bacilli in the stationary phase, isoniazid is bacteriostatic, but
for rapidly dividing organisms, it is bactericidal.

It is effective against intracellular bacteria. Isoniazid is specific

for treatment of M. tuberculosis, although Mycobacterium
Kansasii (an organism that causes three percent of the clinical
illness known as tuberculosis) may be susceptible at higher drug
levels. When it is used alone, resistant organisms rapidly
emerge.
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Resistance
This is associated with several different chromosomal mutations,
each of which results in one of the following:
I. mutation or deletion of KatG (producing mutants incapable
of pro-drug activation)
II. varying mutations of the acyl carrier proteins
III. over expression of InhA

Cross-resistance does not occur between isoniazid and other

anti tubercular drugs.
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Pharmacokinetics
Orally administered isoniazid is readily absorbed.
Absorption is impaired if isoniazid is taken with food,
particularly carbohydrates, or with aluminum-containing
antacids.
The drug diffuses into all body fluids, cells, and caseous
material (A type of tissue death in which all cellular outline is lost and tissue
appears crumbly and cheese like, usually seen in tuberculosis).
Drug levels in the cerebrospinal fluid (CSF) are about the same
as those in the serum.
The drug readily penetrates host cells and is effective against
bacilli growing intracellularly. Infected tissue tends to retain the
drug longer.
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Pharmacokinetics
Isoniazid undergoes N-acetylation and hydrolysis, resulting in
inactive products.
Chronic liver disease decreases metabolism, and doses must
be reduced.
Excretion is through glomerular filtration, predominantly as
metabolites.
Slow acetylators excrete more of the parent compound.
Severely depressed renal function results in accumulation of
the drug, primarily in slow acetylators.
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Slow acetylator
A slow acetylator is a person who has an recessive single gene
which effects the N acetylate transferase enzyme in the liver.
This gene causes the enzyme to work slowly in the metabolism
of certain drugs. Because of this slow pace situation, the slow
acetylator person will receive more of the given drug in his
general circulation than a fast acetylator who is metabolizing the
drug and sending it out of his body via the kidneys and urine at a
quicker rate and thus leaving a smaller amount in the general
circulation i.e., bloodstream.
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Clinical uses
• INH is the single most important drug used in tuberculosis and
is a component of most drug combination regimen.
• In the treatment of latent infection (known as prophylaxis)
including skin test converters, and for close contact of patients
with active disease, INH is given as the sole drug.
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Adverse effects
Except for hypersensitivity, adverse effects are related to the
dosage and duration of administration.
a.Peripheral neuritis:
Peripheral neuritis (manifesting as paresthesias of the hands
and feet), which is the most common adverse effect, appears to
be due to a relative pyridoxine deficiency.
Most of the toxic reactions are corrected by supplementation of
25 to 50 mg per day of pyridoxine (vitamin B6).
Functional pyridoxine deficiency is the likely mechanism of INH-
induced peripheral neuropathy.
• INH induces a state of functional pyridoxine deficiency by at least two mechanisms. First, INH
metabolites directly attach to and inactivate pyridoxine species. Second, INH inhibits the enzyme
pyridoxine phosphokinase; this enzyme is necessary to activate pyridoxine to pyridoxal 5'
phosphate, the active cofactor in many "pyridoxine-dependent" reactions.
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Adverse effects
b. Hepatitis and hepatotoxicity:
Potentially fatal hepatitis is the most severe side effect
associated with isoniazid.
It has been suggested that this is caused by a toxic metabolite
of monoacetyl hydrazine, formed during the metabolism of
isoniazid.
The incidence increases among patients with increasing
age, among patients who also take rifampin, or among those
who drink alcohol daily.
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Adverse effects
Other adverse effects:
 Mental abnormalities
 Convulsions in patients prone to seizures
 Optic neuritis
 Hypersensitivity reactions include rashes and fever
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Drug interactions
Because isoniazid inhibits metabolism of phenytoin, isoniazid
can potentiate the adverse effects of that drug (for example,
nystagmus and ataxia). Slow acetylators are particularly at risk.

Note: Isoniazid can achieve levels in breast milk that are high
enough to cause a pyridoxine deficiency in the infant unless the
mother is supplemented with the vitamin.
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