Antimycobacterial Drugs

Instructor: Racel Trangia- Bactol, RPh

Drugs for Tuberculosis
Major drugs used in
tuberculosis (First line
agents for TB)
• isoniazid (INH), rifampin, ethambutol,
pyrazinamide, and streptomycin.

• For the chemical structure of these agents please

refer to your book
A. Isoniazid
Isoniazid (INH) is a structural congener of pyridoxine.
Mechanism of action
Its mechanism of action involves inhibition of the synthesis
of mycolic acids, essential components of mycobacterial cell
walls.
Mechanism of resistance
High-level resistance is associated with deletion in the katG
gene that codes for a catalase-peroxidase involved in the
bioactivation
of INH.
Low-level resistance occurs via deletions in the inhA gene
that encodes the target enzyme, an acyl carrier protein
reductase.
Resistance can emerge rapidly if the drug is used alone

INH is bactericidal for actively growing tubercle bacilli, but is

less effective against dormant organisms.

Pharmacokinetics
 INH is well absorbed orally and penetrates cells to act on
intracellular mycobacteria.
 The liver metabolism of INH is by acetylation and is under
genetic control.
 Patients may be fast or slow inactivators of the drug. INH half
life in fast acetylators is 60–90 min; in slow acetylators it may
be 3–4 h.
 Fast acetylators may require higher dosage than slow
acetylators for equivalent therapeutic effects.
Clinical Use
INH is the single most important drug used
in tuberculosis and is a component of most drug
combination regimens.
Toxicity and interactions
 Neurotoxic effects are common and include
peripheral neuritis, restlessness, muscle twitching,
and insomnia. (These effects can be alleviated by
administration of pyridoxine 25–50 mg/d orally).
 INH is hepatotoxic and may cause abnormal liver
function tests, jaundice, and hepatitis. Fortunately,
hepatotoxicity is rare in children.
INH may inhibit the hepatic metabolism of drugs
(eg, carbamazepine, phenytoin, warfarin).

Hemolysis has occurred in patients with glucose-6-

phosphate dehydrogenase (G6PDH) deficiency.

A lupus-like syndrome has also been reported.

B. Rifampin
Rifampin, a derivative of rifamycin, is bactericidal
against M tuberculosis.

Mechanism of action
The drug inhibits DNA-dependent RNA polymerase
(encoded by the rpo gene) in M tuberculosis and
many other microorganisms.
Mechanism of resistance
Resistance via changes in drug sensitivity of the
polymerase often emerges rapidly if the drug is used
alone.
Pharmacokinetics—
• When given orally, rifampin is well absorbed and
is distributed to most body tissues, including the
central nervous system (CNS).

• The drug undergoes enterohepatic cycling and is

partially metabolized in the liver.

• Both free drug and metabolites, which are orange-

colored, are eliminated mainly in the feces.
Clinical uses—In the treatment of tuberculosis, rifampin is
almost always used in combination with other drugs

In leprosy, rifampin given monthly delays the emergence of

resistance to dapsone.

Rifampin may be used with vancomycin for infections due

to resistant staphylococci (methicillin-resistant
Staphylococcus aureus [MRSA] strains) or pneumococci
(penicillin-resistant Streptococcus pneumoniae [PRSP]
strains).

Other uses of rifampin include the meningococcal and

staphylococcal carrier states.
Toxicity and interactions—
• Rifampin commonly causes light-chain proteinuria and
may impair antibody responses.
• Occasional adverse effects include skin rashes,
thrombocytopenia, nephritis, and liver dysfunction.
• If given less often than twice weekly, rifampin may
cause a flu-like syndrome and anemia.
• Rifampin strongly induces liver drug-metabolizing
enzymes and enhances the elimination rate of many
drugs, including anticonvulsants, contraceptive
steroids, cyclosporine, ketoconazole, methadone,
terbinafine, and warfarin.
Other rifamycins—
Rifabutin is equally effective as an
antimycobacterial agent and is less likely to cause
drug interactions than rifampin. It is usually
preferred over rifampin in the treatment of
tuberculosis or other mycobacterial infections in
AIDS patients, especially those treated with
cytochrome P450 substrates including protease
inhibitors or efavirenz.
Rifaximin, a rifampin derivative that is not absorbed
from the gastrointestinal tract, has
been used in traveler’s diarrhea.
C. Ethambutol
Mechanism of action
Ethambutol (ETB) inhibits arabinosyltransferases
(encoded by the embCAB operon) involved in the
synthesis of arabinogalactan, a component of
mycobacterial cell walls.

Mechanism of Resistance
Resistance occurs rapidly via mutations in the emb
gene if the drug is used alone.
Pharmacokinetics—
 The drug is well absorbed orally and distributed to
most tissues, including the CNS.
 A large fraction is eliminated unchanged in the
urine.
 Dose reduction is necessary in renal Impairment
Clinical use—
 The main use of ethambutol is in tuberculosis, and
it is always given in combination with other drugs.
Toxicity—
 The most common adverse effects are dose-
dependent visual disturbances, including
decreased visual acuity, red-green color blindness,
optic neuritis, and possible retinal damage (from
prolonged use at high doses). Most of these effects
regress when the drug is stopped.

 Other adverse effects include headache, confusion,

hyperuricemia and peripheral neuritis.
D. Pyrazinamide
Mechanism of action
The mechanism of action of pyrazinamide is
not known; however, its bacteriostatic action appears to require
metabolic conversion via pyrazinamidases (encoded by the
pncA gene) present in M tuberculosis.
Mechanism of Resistance
Resistance occurs via mutations in the gene that encodes
enzymes involved in the bioactivation of pyrazinamide and by
increased expression of drug efflux systems. This develops
rapidly when the drug is used alone, but there is minimal cross-
resistance with other antimycobacterial drugs.
Pharmacokinetics—
 Pyrazinamide is well absorbed orally and penetrates
most body tissues, including the CNS.
 The drug is partly metabolized to pyrazinoic acid, and
both parent molecule and metabolite are excreted in the
urine.
 The plasma half-life of pyrazinamide is increased in
hepatic or renal failure.
Clinical use—
 The combined use of pyrazinamide with other
antituberculous drugs is an important factor in the
success of short course treatment regimens.
Toxicity—
Approximately 40% of patients develop nongouty
polyarthralgia.
Hyperuricemia occurs commonly but is usually
asymptomatic.
Other adverse effects are myalgia, gastrointestinal
irritation, maculopapular rash, hepatic dysfunction,
porphyria, and photosensitivity reactions.
Pyrazinamide should be avoided in pregnancy.
E. Streptomycin
This aminoglycoside is now used more frequently than
before because of the growing prevalence of strains of
M tuberculosis resistant to other drugs.
Streptomycin is used principally in drug combinations
for the treatment of life-threatening tuberculous
disease, including meningitis, miliary dissemination,
and severe
organ tuberculosis.
The pharmacodynamic and pharmacokinetic
properties of streptomycin are similar to those of other
aminoglycosides
F. Alternative Drugs

Several drugs with antimycobacterial activity are

used in cases that are resistant to first-line agents;
they are considered second-line drugs because they
are no more effective, and their toxicities are often
more serious than those of the major drugs.
Amikacin is indicated for the treatment of
tuberculosis suspected to be caused by streptomycin-
resistant or multidrugresistant
mycobacterial strains.
To avoid emergence of resistance, amikacin should
always be used in combination drug
regimens.
Ciprofloxacin and ofloxacin are often active against
strains of M tuberculosis resistant to first-line agents.
The fluoroquinolones should always be used in
combination regimens with two or more other active
agents.
Ethionamide is a congener of INH, but cross-
resistance does not occur.
The major disadvantage of ethionamide is severe
gastrointestinal irritation and adverse neurologic
effects at doses needed to achieve effective plasma
levels.
p-Aminosalicylic acid (PAS) is rarely used because
primary resistance is common.
In addition, its toxicity includes gastrointestinal
irritation, peptic ulceration, hypersensitivity
reactions, and effects on kidney, liver, and thyroid
function.

Other drugs of limited use because of their toxicity

include capreomycin (ototoxicity, renal dysfunction)
and cycloserine (peripheral neuropathy, CNS
dysfunction).
G. Antitubercular
Drug Regimens
Standard regimens—
• For empiric treatment of pulmonary TB (in most
areas of <4% INH resistance), an initial 3-drug
regimen of INH, rifampin, and pyrazinamide is
recommended.
• If the organisms are fully susceptible (and the
patient is HIV-negative), pyrazinamide can be
discontinued after 2 mos. and treatment continued
for a further 4 mo with a 2-drug regimen
Alternative regimens—Alternative regimens in cases of
fully susceptible organisms include INH + rifampin for 9
mo, or INH + ethambutol for 18 mo.
Intermittent (2 or 3 × weekly) high-dose 4-drug regimens are
also effective.
Resistance—If resistance to INH is higher than 4%, the
initial drug regimen should include ethambutol or
streptomycin.
Tuberculosis resistant only to INH (the most common form
of resistance) can be treated for 6 mos with a regimen of
rifampin + pyrazinamide + ethambutol or streptomycin.
Multidrug-resistant organisms (resistant to both INH and
rifampin) should be treated with 3 or more drugs to which
the organism is susceptible for a period of more than 18 mos,
including 12 mos after sputum cultures become negative.
Drugs for Leprosy
A. Sulfones

Dapsone (diaminodiphenylsulfone) remains the

most active drug against M leprae.

The mechanism of action of sulfones may involve

inhibition of folic acid synthesis.

Because of increasing reports of resistance, it is

recommended that the drug be used in combinations
with rifampin and/or clofazimine
Dapsone can be given orally, penetrates tissues well,
undergoes enterohepatic
cycling, and is eliminated in the urine, partly as
acetylated metabolites.

Common adverse effects include gastrointestinal

irritation, fever, skin rashes, and
methemoglobinemia. Hemolysis may occur,
especially in patients with G6PDH deficiency.
Acedapsone is a repository form of dapsone that
provides inhibitory plasma concentrations for several
months.

In addition to its use in leprosy, dapsone is an

alternative drug for the treatment of Pneumocystis
jiroveci pneumonia in AIDS patients
B. Other Agents

Drug regimens usually include combinations of

dapsone with rifampin with or without clofazimine.

Clofazimine, a phenazine dye that may interact with

DNA, causes gastrointestinal irritation and skin
discoloration ranging from red-brown to nearly black
Drugs for Atypical Mycobacterial
Infections
Mycobacterium avium complex (MAC) is a cause of
disseminated infections in AIDS patients.
Currently, clarithromycin or azithromycin
with or without rifabutin is recommended for
primary prophylaxis in patients with CD4 counts less
than 50/μL.
• Treatment of MAC infections requires a
combination of drugs, one favored regimen
consisting of azithromycin or clarithromycin with
ethambutol and rifabutin.

• Infections resulting from other atypical

mycobacteria (eg, M marinum, M ulcerans),
though sometimes asymptomatic, may be treated
with the described antimycobacterial drugs (eg,
ethambutol, INH, rifampin) or other antibiotics
(eg, amikacin, cephalosporins, fluoroquinolones,
macrolides, or tetracyclines).