Chemotherapy of Tuberculosis & Leprosy (Antimycobacterials)

Introduction:
 Antitubercular drugs- used to treat tuberculosis (TB), caused by
Mycobacterium tuberculosis.
 Antileprotic drugs- used to treat leprosy, caused by Mycobacterium leprae.

Mycobacteria are intrinsically resistant to most antibiotics due to following

characteristics-
1. They grow slowly compared with other bacteria; antibiotics that are most
active against growing cells are relatively ineffective.
2. Mycobacterial cells can also be dormant and thus completely resistant to
many drugs or killed only very slowly by the few drugs that are active.
3. Lipid-rich mycobacterial cell wall is impermeable to many agents.
4. Mycobacterial species are intracellular pathogens, and organisms residing
within macrophages are inaccessible to drugs that penetrate these cells
poorly.
5. Finally, mycobacteria are notorious for their ability to develop resistance.

Combinations of two or more drugs are required to overcome these obstacles and to
prevent emergence of resistance during the course of therapy.
The response of mycobacterial infections to chemotherapy is slow, and treatment
must be administered for months to years, depending on which drugs are used.

Drugs Used In Tuberculosis:

Drugs used in the treatment of TB can be divided into two major catagories-
1. First line agents:
i) Isoniazid (INH) ii) rifampin iii)pyrazinamide iv)ethambutol
v) streptomycin.
2. Second line agents:
• Either less effective, more toxic, or have not been studied as extensively.
• Useful in patients who cannot tolerate the first-line drugs or who are
infected with myobacteria that are resistant to the first-line agents.
• These includes- aminosalicylic acid, amikacin, ethionamide, capreomycin,
cycloserine, ethionamide, fluoroquinolones, macrolids etc.

Isonizid (INH)
 Isoniazid, the hydrazide of isonicotinic acid, is a synthetic analog of
pyridoxine (Vit-B6).
 Most potent of the antitubercular drugs

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  But it is never given as a single agent in the treatment of active tuberculosis.

Mechanism of action:
 Inhibits synthesis of Fig: One of several recommended multidrug
mycolic acids, which are essential schedules for the treatment of tuberculosis.

components of mycobacterial cell walls.

 INH is a prodrug that is activated by KatG (the mycobacterial catalase-
peroxidase).
 At least two different target enzymes for isoniazid which are involved in the
production of mycolic acids. The activated drug covalently binds to and
inhibits these enzymes, which are essential for the synthesis of mycolic acid.
 Decreased mycolic acid synthesis corresponds with the loss of acid-fastness
after exposure to isoniazid.
[Acid-fastness is a physical property of some bacteria referring to their resistance to decolorization by
acids during staining procedures.]

Antibacterial spectrum:
 For bacilli in the stationary phase, INH is bacteriostatic
 But for rapidly dividing organisms, it is bactericidal.
 It is effective against intracellular bacteria.
 Isoniazid inhibits most tubercle bacilli in a concentration of 0.2 µg/mL or less.
 Penetrates into macrophages and is active against both extracellular and
intracellular organisms.

Resistance:
 Treatment with INH alone leads to development of resistance, occurs within
a few weeks after therapy is started.
 This is associated with several different chromosomal mutations.
 Drug-resistant mutants are normally present in susceptible mycobacterial
populations at about 1 bacillus in 106. Since tuberculous lesions often contain
more than 108 tubercle bacilli, resistant mutants are readily selected out if
isoniazid or any other drug is given as a single agent.

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  The use of two independently acting drugs in combination is much more
effective. The probability that a bacillus is resistant to both drugs is
approximately 1 in 106 x 106, or 1 in 1012.

Pharmacokinetics
 Isoniazid is readily absorbed from the gastrointestinal tract.
 A 300-mg oral dose (5 mg/kg in children) achieves peak plasma
concentrations of 3-5 µg/mL within 1-2 hours.
 Isoniazid diffuses readily into all body fluids and tissues.
 Metabolism of isoniazid, especially acetylation by liver N-acetyltransferase, is
genetically determined.
 Subtherapeutic concentrations may occur if drug is administered as a once-
weekly dose or if there is malabsorption.
 Metabolites and a small amount of unchanged drug are excreted mainly in
the urine.

Clinical Uses
 Usual dosage of isoniazid is 5 mg/kg/d; a typical adult dose is 300 mg given
once daily.
 Up to 10 mg/kg/d may be used for serious infections or if malabsorption is a
problem.
 A 15 mg/kg dose, or 900 mg, may be used in a twice-weekly dosing regimen
in combination with a second antituberculous agent (eg, rifampin 600 mg).

Adverse effects:
Adverse effects are related to the dosage and duration of administration.
1. Peripheral neuritis:
Peripheral neuritis is one of the most common adverse effects, 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).
[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.]

2. Hepatitis and idiosyncratic hepatotoxicity:

Potentially fatal hepatitis is the most severe side effect associated with
isoniazid. It has been suggested that this is caused by formation of toxic
metabolite during the metabolism of isoniazid. Its incidence increases among
patients with increasing age, among patients who also take rifampin, or
among those who drink alcohol daily.

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 3. Drug interactions: Because isoniazid inhibits metabolism of phenytoin,
isoniazid can potentiate the adverse effects of that drug.

4. Other adverse effects:

Mental abnormalities, convulsions in patients prone to seizures, optic neuritis
have been observed. Hypersensitivity reactions include rashes and fever.
Hematologic abnormalities, provocation of pyridoxine deficiency anemia,
tinnitus, and gastrointestinal discomfort etc are also.

Rifampin

Rifampin is a semisynthetic derivative of rifamycin, an antibiotic produced by

Streptomyces mediterranei.

Mechanism of action & resistance:

 Rifampin binds to the β subunit of bacterial DNA-dependent RNA
polymerase and thereby inhibits RNA synthesis.
 Resistance results from any one of several possible point mutations in the
gene for the β subunit of RNA polymerase. These mutations result in reduced
binding of rifampin to RNA polymerase.
 Human RNA polymerase does not bind rifampin and is not inhibited by it.

Antibacterial spectrum:
 Rifampin is bactericidal for both intracellular and extracellular mycobacteria,
including M. tuberculosis, and atypical mycobacteria, such as M. kansasii.
 Effective against many gram-positive and gram-negative organisms.
 Frequently used prophylactically for individuals exposed to meningitis
caused by meningococci or Haemophilus influenzae.
 Rifampin is the most active antileprosy drug at present, but to delay the
emergence of resistant strains, it is usually given in combination with other
drugs.

Pharmacokinetics:
 Rifampin is well absorbed after oral administration and excreted mainly
through the liver into bile.
 It then undergoes enterohepatic recirculation, with the bulk excreted in feces
and a small amount in the urine.
 Distributed widely in body fluids and tissues. It is relatively highly protein-
bound, and adequate cerebrospinal fluid concentrations are achieved only in
the presence of meningeal inflammation.

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Clinical Uses
 Rifampin, usually 600 mg/d (10 mg/kg/d) orally, must be administered with
isoniazid or other antituberculous drugs to patients with active tuberculosis to
prevent emergence of drug-resistant mycobacteria.
 In some short-course therapies, 600 mg of rifampin are given twice weekly.
 Rifampin 600 mg daily or twice weekly for 6 months also is effective in
combination with other agents in some atypical mycobacterial infections and
in leprosy.
 Rifampin, 600 mg daily for 4 months as a single drug, is an alternative to
isoniazid prophylaxis for patients with latent tuberculosis only who are
unable to take isoniazid or who have had exposure to a case of active
tuberculosis caused by an isoniazid-resistant, rifampin-susceptible strain.

Adverse Reactions
1. Rifampin imparts a harmless orange color to urine, sweat, tears, and contact
lenses (soft lenses may be permanently stained).
2. Occasional adverse effects include rashes, thrombocytopenia, and nephritis.
3. May cause cholestatic jaundice and occasionally hepatitis.
4. Commonly causes light-chain proteinuria.
5. If administered less often than twice weekly, rifampin causes a flu-like
syndrome characterized by fever, chills, myalgias, anemia, and
thrombocytopenia and sometimes is associated with acute tubular necrosis.
6. Strongly induces most cytochrome P450 isoforms which increases the
elimination of numerous other drugs including methadone, anticoagulants,
cyclosporine, some anticonvulsants, protease inhibitors, some nonnucleoside
reverse transcriptase inhibitors, contraceptives, and a host of others.
7. Should be used with caution in patients who are alcoholic, elderly, or have
chronic liver disease due to the increased incidence of severe hepatic
dysfunction when rifampin is administered alone or concomitantly with
isoniazid.

Ethambutol

 Ethambutol is a synthetic, water-soluble, heat-stable compound.

Antibacterial spectrum:
 Susceptible strains of Mycobacterium tuberculosis and other mycobacteria are
inhibited in vitro by ethambutol, 1-5 µg/mL.

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Mechanism of action & resistance:
 Ethambutol inhibits mycobacterial arabinosyl transferases, involved in the
polymerization reaction of arabinoglycan, an essential component of the
mycobacterial cell wall.
 Resistance to ethambutol is due to mutations.

Pharmacokinetics :
 Ethambutol is well absorbed from the gut. After ingestion of 25 mg/kg, a
blood level peak of 2-5 mcg/mL is reached in 2-4 hours.
 About 20% of the drug is excreted in feces and 50% in urine in unchanged
form.
 Ethambutol accumulates in renal failure, and the dose should be reduced by
half if creatinine clearance is less than 10 mL/min.
 Ethambutol crosses the blood-brain barrier only if the meninges are inflamed.

Clinical Use
 Ethambutol hydrochloride, 15-25 mg/kg, is usually given as a single daily
dose in combination with isoniazid or rifampin.
 The higher dose is recommended for treatment of tuberculous meningitis.
 The dose of ethambutol is 50 mg/kg when a twice-weekly dosing schedule is
used.

Adverse Reactions
 The most common serious adverse event is retrobulbar neuritis, resulting in
loss of visual acuity and red-green color blindness. This dose-related side
effect is more likely to occur at doses of 25 mg/kg/d continued for several
months.
 At 15 mg/kg/d or less, visual disturbances are very rare. Periodic visual
acuity testing is desirable if the 25 mg/kg/d dosage is used.
 Ethambutol is relatively contraindicated in children too young to permit
assessment of visual acuity and red-green color discrimination.

Pyrazinamide
 Pyrazinamide (PZA) is a relative of nicotinamide, stable, and slightly soluble
in water.
 Inactive at neutral pH, but at pH 5.5 it inhibits tubercle bacilli and some other
mycobacteri .
 The drug is taken up by macrophages and exerts its activity against
mycobacteria residing within the acidic environment of lysosomes.

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  Pyrazinamide is converted to pyrazinoic acid, the active form of the drug by
mycobacterial pyrazinamidase.
 The drug target and mechanism of action are unknown.
 Resistance may be due to impaired uptake of pyrazinamide or mutations that
impair conversion of pyrazinamide to its active form.

Pharmacokinetics:
 Pyrazinamide is well absorbed from the gastrointestinal tract and widely
distributed in body tissues, including inflamed meninges.
 The half-life is 8-11 hours.
 Metabolized by the liver, but metabolites are renally cleared; therefore,
pyrazinamide should be administered at 25-35 mg/kg three times weekly
(not daily) in hemodialysis patients and those in whom the creatinine
clearance is less than 30 mL/min.
 In patients with normal renal function, a dose of 40-50 mg/kg is used for
thrice-weekly or twice-weekly treatment regimens.
 Pyrazinamide is an important front-line drug used in conjunction with
isoniazid and rifampin in short-course (ie, 6-month) regimens as a "sterilizing"
agent active against residual intracellular organisms that may cause relapse.

Adverse Reactions
 Major adverse effects of pyrazinamide include hepatotoxicity (in 1-5% of
patients), nausea, vomiting, drug fever, and hyperuricemia (level of uric acid
in the blood that is abnormally high).
 The latter occurs uniformly and is not a reason to halt therapy.
 Hyperuricemia may provoke acute gouty arthritis.

Streptomycin

 First clinically effective drug to become available for the treatment of TB.
 Irreversible inhibitors of protein synthesis.
 Protein synthesis is inhibited by aminoglycosides in at least three ways (1)
interference with the initiation complex of peptide formation; (2) misreading
of mRNA, which causes incorporation of incorrect amino acids into the
peptide, resulting in a nonfunctional or toxic protein; and (3) breakup of
polysomes into nonfunctional monosomes.
 Most tubercle bacilli are inhibited by streptomycin, 1-10 µg/mL, in vitro.
 Nontuberculosis species of mycobacteria other than Mycobacterium avium
complex (MAC) and Mycobacterium kansasii are resistant.

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  All large populations of tubercle bacilli contain some streptomycin-resistant
mutants. On average, 1 in 108 tubercle bacilli can be expected to be resistant to
streptomycin at levels of 10-100 µg/mL.
 Resistance is due to a point mutation in either the gene encoding the S12
ribosomal protein gene or the gene encoding 16S ribosomal rRNA, which
alters the ribosomal binding site.
 Streptomycin penetrates into cells poorly and is active mainly against
extracellular tubercle bacilli.
 Streptomycin crosses the blood-brain barrier and achieves therapeutic
concentrations with inflamed meninges.

Clinical Use in Tuberculosis

 Streptomycin sulfate is used when an injectable drug is needed or desirable,
principally in individuals with severe, possibly life-threatening forms of
tuberculosis, eg, meningitis and disseminated disease, and in treatment of
infections resistant to other drugs.
 The usual dosage is 15 mg/kg/d intramuscularly or intravenously daily for
adults (20-40 mg/kg/d, not to exceed 1-1.5 g for children) for several weeks,
followed by 1-1.5 g two or three times weekly for several months.
 Serum concentrations of approximately 40 µg/mL are achieved 30-60 minutes
after intramuscular injection of a 15 mg/kg dose.
 Other drugs are always given in combination to prevent emergence of
resistance.

Adverse Reactions
 Streptomycin is ototoxic and nephrotoxic.
 Vertigo and hearing loss are the most common side effects and may be
permanent.
 Toxicity is dose-related, and the risk is increased in the elderly. As with all
aminoglycosides, the dose must be adjusted according to renal function.
 Toxicity can be reduced by limiting therapy to no more than 6 months
whenever possible.

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 Chemotherapy for Leprosy

 Caused by Mycobacterium leprae

 Approximately 70 percent of all cases in the world are located in India.
 Bacilli from skin lesions or nasal discharges of infected patients enter
susceptible individuals via abraded skin or the respiratory tract.
 The World Health Organization recommends the triple-drug regimen of
dapsone, clofazimine, and rifampin for 6 to 24 months.

Types of leprosy:
1. Tuberculoid
2. Lepromatous
3. The in-between or borderline.

 The tuberculoid is relatively benign and is often self healing. The lepromatous
is a steadily progressing form of the disease. The distinction between two is
difficult as mixed symptoms are always found. The symptoms involve both
skin & nervous system.
 Skin manifestations range from areas of whitening of the skin to massive
nodules.
 Nerve involvement may be pain in certain centres & in serious cases, total loss
of feeling in certain parts of the body.
 The eyes may be affected leading to total blindness.
 Ulcers may occur in mouth & larynx.
 There are tragic cases when fingers fall of the joints leaving only the palms
over which the entire skin starts rotting.

Drugs used for the treatment of leprosy are-

1. Dapsone
2. Rifampin
3. Clofazimine
4. Misc.- ethionamide

Lepra reactions:
After the chemotherapy against leprosy is started, some clinical features called Lepra
Reaction can appear. There are two types-
1. Type-I: It is so called reversible reaction, appears during borderline cases.
There is intensification of skin lesions. Sometimes it is difficult for the
physician to identify whether it is type-I lepra reaction or flaring up of the
disease itself.
2. Type-II: Erythema nodosa leprosum appears during dapsone therapy of
lepromatous leprosy & even the borderline cases. It is manifested as crop of
nodules appearing under the skin.

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 Dapsone

 Several drugs closely related to the sulfonamides have been used effectively
in the long-term treatment of leprosy. The most widely used is dapsone
(diaminodiphenylsulfone).
 Like the sulfonamides, it inhibits folate synthesis.
 Resistance can emerge in large populations of M leprae, eg, in lepromatous
leprosy, if very low doses are given.
 Therefore, the combination of dapsone, rifampin, and clofazimine is
recommended for initial therapy.
 Dapsone may also be used to prevent and treat Pneumocystis jiroveci
pneumonia in AIDS patients.

Pharmacokinetics:
 Sulfones are well absorbed from the gut and widely distributed throughout
body fluids and tissues.
 Dapsone's half-life is 1-2 days, and drug tends to be retained in skin, muscle,
liver, and kidney.
 Skin heavily infected with M leprae may contain several times more drug than
normal skin.
 Excreted into bile and reabsorbed in the intestine.
 Excretion into urine is variable, and most excreted drug is acetylated. In renal
failure, the dose may have to be adjusted.
 The usual adult dosage in leprosy is 100 mg daily. For children, the dose is
proportionately less depending on weight.

Adverse reactions:
 Many patients develop some hemolysis, particularly if they have glucose-6-
phosphate dehydrogenase deficiency.
 Methemoglobinemia is common, but usually is not a problem clinically.
 Gastrointestinal intolerance, fever, pruritus, and various rashes occur.
 During dapsone therapy of lepromatous leprosy, erythema nodosum
leprosum often develops.
 It is sometimes difficult to distinguish reactions to dapsone from
manifestations of the underlying illness.
 Erythema nodosum leprosum may be suppressed by corticosteroids or by
thalidomide.

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 Rifampin

 Rifampin (see earlier discussion) in a dosage of 600 mg daily is highly

effective in lepromatous leprosy.
 Because of the probable risk of emergence of rifampin-resistant M leprae, the
drug is given in combination with dapsone or another antileprosy drug.
 A single monthly dose of 600 mg may be beneficial in combination therapy.

Clofazimine

 Clofazimine is a phenazine dye that can be used as an alternative to dapsone.

 Binds to DNA and prevents it from serving as a template for future DNA
replication.
 Its redox properties may lead to the generation of cytotoxic oxygen radicals
that are also toxic to the bacteria.
 Clofazimine is bactericidal to M. leprae and has some activity against M.
avium-intracellulare complex.

Pharmacokinetics:
 Absorption of clofazimine from the gut is variable, and a major portion of the
drug is excreted in feces.
 Clofazimine is stored widely in reticuloendothelial tissues and skin, and its
crystals can be seen inside phagocytic reticuloendothelial cells.
 It is slowly released from these deposits, so that the serum half-life may be 2
months.

Clinical use:
 Clofazimine is given for sulfone-resistant leprosy or when patients are
intolerant to sulfones.
 A common dosage is 100 mg/d orally.

Adverse effects:
 The most prominent untoward effect is skin discoloration ranging from red-
brown to nearly black.
 Gastrointestinal intolerance occurs occasionally.
 Eosinophilic enteritis has been reported as an adverse effect.

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