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ANTIMYCOBACTERIALS II
PHARMACOLOGY IV
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Antimicrobials
Used in the Treatment of Tuberculosis
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Rifamycins:
Rifampin, rifabutin and rifapentine
Rifampin, rifabutin, and rifapentine are all considered to be
rifamycins, a group of structurally similar macrocyclic antibiotics,
which are first-line drugs for tuberculosis.

Any of these rifamycins must always be used in conjunction with

at least one other antituberculosis drug to which the isolate is
susceptible.
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Rifampin
Rifampin, which is derived from the soil mold Streptomyces, has
a broader antimicrobial activity than isoniazid and has found
application in the treatment of a number of different bacterial
infections.
Because resistant strains rapidly emerge during therapy, it is
never given as a single agent in the treatment of active
tuberculosis.
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Mechanism of action
Rifampin blocks transcription by interacting with the β subunit
of bacterial, inhibit DNA dependent RNA polymerase in
Mycobacterium tuberculosis and many other microorganism.

[Note: The drug is specific for prokaryotes.]

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Antimicrobial spectrum
Rifampin is bactericidal for both intracellular and extracellular
mycobacteria, including M. tuberculosis, and atypical
mycobacteria, such as M. kansasii.
It is effective against many gram-positive and gram-negative
organisms and is used prophylactically for individuals
exposed to meningitis caused by meningococci or
Haemophilus influenzae.
Rifampin is the most active anti-leprosy drug at present, but
to delay the emergence of resistant strains, it is usually given in
combination with other drugs.
Rifabutin, an analog of rifampin, has some activity against
Mycobacterium avium-intracellulare complex, but is less
active against tuberculosis.
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Resistance
Resistance to rifampin can be caused by a mutation in the
affinity of the bacterial DNA-dependent RNA polymerase for the
drug, or by decreased permeability.
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Pharmacokinetics
Absorption is adequate after oral administration.
Distribution of rifampin occurs to all body fluids and organs.
Adequate levels are attained in the CSF even in the absence of
inflammation.
The drug is taken up by the liver and undergoes enterohepatic
cycling. Rifampin itself can induce the hepatic mixed-
function oxidases , leading to a shortened half-life and
numerous drug interactions.
Elimination of metabolites and the parent drug is via the bile
into the feces or via the urine .
Urine and feces, as well as, other secretions have an
orange-red color. Tears may permanently stain soft contact
lenses orange-red.
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Adverse effects
Rifampin is generally well tolerated.
The most common adverse reactions include nausea, vomiting,
and rash.
Hepatitis and death due to liver failure is rare; however, the
drug 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.
Often, when rifampin is dosed intermittently, or in daily doses of
1.2 grams or greater, a flu-like syndrome is associated with
fever, chills, and myalgia and sometimes is associated with
acute renal failure, hemolytic anemia, and shock.
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Drug interactions
• Because rifampin can induce a number of cytochrome P450
enzymes , it can decrease the half-lives of other drugs that are
coadministered and metabolized by this system .
• This may lead to higher dosage requirements for these agents.
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Rifabutin
Rifabutin a derivative of rifampin, is the preferred drug for use in
tuberculosis infected with the human immunodeficiency virus
(HIV) patients who are concomitantly treated with protease
inhibitors or non-nucleoside reverse transcriptase inhibitors,
because it is a less potent inducer of cytochrome P450 enzymes.

Rifabutin has adverse effects similar to those of rifampin but

can also cause uveitis (inflammation of uveal tract which lines
the inside of the eye behind the cornea), skin
hyperpigmentation, and neutropenia.
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Rifapentine
Rifapentine has activity comparable to that of rifampin but has a
longer half-life than rifampin and rifabutin, which permits weekly
dosing. However, for the intensive phase (initial 2 months) of the
short-course therapy for tuberculosis, rifapentine is given twice
weekly. In the subsequent phase, rifapentine is dosed once per
week for 4 months.
To avoid resistance issues, rifapentine should not be used alone
but, rather, be included in a three to four-drug regimen.
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Pyrazinamide
Pyrazinamide is a synthetic, orally effective, bactericidal,
antitubercular agent used in combination with isoniazid,
rifampin, and ethambutol.
It is bactericidal to actively dividing organisms, but the
mechanism of its action is unknown.
Pyrazinamide must be enzymatically hydrolyzed to
pyrazinoic acid, which is the active form of the drug.
Pyrazinamide is active against tubercle bacilli in the acidic
environment of lysosomes as well as in macrophages.
Pyrazinamide distributes throughout the body, penetrating the
CSF.
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Pyrazinamide
It undergoes extensive metabolism.
About one to five percent of patients taking isoniazid, rifampin,
and pyrazinamide may experience liver dysfunction.
Urate retention can also occur and may precipitate a gouty
attack.
The most important adverse effects include:
I. myalgia
II. maculopapular rash
III. hepatic dysfunction
IV. porphyria (a group of rare inherited or acquired disorders of certain
enzymes that normally participate in the production of heme)
V. photosensitivity reaction
VI. hyperurecimia usually asymptomatic
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Ethambutol
Ethambutol is bacteriostatic and specific for most strains of
M. tuberculosis and M. kansasii.
Ethambutol inhibits arabinosyl transferase , an enzyme that is
important for the synthesis of the mycobacterial arabinogalactan
cell wall. Resistance is not a serious problem if the drug is
employed with other antitubercular agents.
Ethambutol can be used in combination with pyrazinamide,
isoniazid, and rifampin to treat tuberculosis.
Absorbed on oral administration, ethambutol is well distributed
throughout the body. Penetration into the central nervous system
(CNS) is therapeutically adequate in tuberculous meningitis.
Both parent drug and metabolites are excreted by glomerular
filtration and tubular secretion.
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Ethambutol
The most important adverse effects include:
I. optic neuritis
II. decreased visual acuity
III. red-green blindness
IV. Retinal damage from prolonged use at high doses
V. headache
VI. confusion
VII. peripheral neuritis
VIII. urate excretion is decreased by the drug; thus, gout may be
exacerbated.
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Streptomycin
• This is effective in the treatment of tuberculosis and is
discussed with the aminoglycosides .
• Nontuberculosis species of mycobacteria other than
Mycobacterium avium complex (MAC) and Mycobacterium
kansasii are resistant.
• All large populations of tubercle bacilli contain some
streptomycin-resistant mutants.

• 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.
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Clinical Uses
• Streptomycin is used when an injectable drug is needed or
desirable, principally in individuals with severe, possibly life-
threatening forms of tuberculosis, eg, meningeal and
disseminated (generalized or miliary) TB , and in the treatment
of infections resistant to other drugs.

• Other drugs are always given in combination to prevent

emergence of resistance.
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Adverse effects
• Streptomycin is ototoxic and nephrotoxic.
• Vertigo and hearing loss are the most common adverse 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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Alternate second-line drugs

A number of drugs— para-aminosalicylic acid , ethionamide,
cycloserine, capreomycin, fluoroquinolones, and macrolides—
are considered to be second-line drugs, either because they are
no more effective than the first-line agents and their toxicities are
often more serious, or because they are particularly active
against atypical strains of mycobacteria.

They are useful in patients who cannot tolerate the first-line

drugs or who are infected with myobacteria that are
resistant to the first-line agents.
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Capreomycin
• Capreomycin is a peptide protein synthesis inhibitor
antibiotic obtained from Streptomyces capreolus.
• Capreomycin is primarily reserved for the treatment of
multidrug resistant tuberculosis.
• Capreomycin (15 mg/kg/d) is an important injectable agent for
treatment of drug-resistant tuberculosis.
• Strains of M tuberculosis that are resistant to streptomycin or
amikacin (eg, the multidrug-resistant strain) usually are
susceptible to capreomycin.
• Careful monitoring of the patient is necessary to prevent its
nephrotoxicity and ototoxicity.
• Capreomycin is nephrotoxic and ototoxic. Tinnitus, deafness,
and vestibular disturbances occur. The injection causes
significant local pain, and sterile abscesses may occur.
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Cycloserine
Cycloserine is an orally effective, tuberculostatic agent that
appears to antagonize the steps in bacterial cell wall
synthesis involving D-alanine.
It distributes well throughout body fluids, including the CSF.
Cycloserine is metabolized, and both parent and metaboliteare
excreted in urine.
Accumulation occurs with renal insufficiency.
Adverse effects involve CNS disturbances, and epileptic seizure
activity may be exacerbated.
Peripheral neuropathies are also a problem, but they respond to
pyridoxine.
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Ethionamide
This is a structural analog of isoniazid, but it is not believed to
act by the same mechanism.
Ethionamide can inhibit acetylation of isoniazid .
It is effective after oral administration and is widely distributed
throughout the body, including the CSF.
Metabolism is extensive, and the urine is the main route of
excretion.
Adverse effects that limit its use include gastric irritation,
hepatotoxicity, peripheral neuropathies, and optic neuritis.
Supplementation with vitamin B6 (pyridoxine) may lessen
the severity of the neurologic side effects.
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Fluoroquinolones
They are also active against atypical mycobacteria.
The fluoroquinolones, specifically, ciprofloxacin, moxifloxacin
and levofloxacin have an important place in the treatment of
multidrug-resistant tuberculosis.

Some atypical strains of mycobacteria are also susceptible.

Fluoroquinolones are an important addition to the drugs
available for tuberculosis, especially for strains that are
resistant to first-line agents.
Resistance, develops rapidly if a fluoroquinolone is used as a
single agent; thus, the drug must be used in combination with
two or more other active agents.
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Macrolides
The macrolides, such as azithromycin and clarithromycin, are
part of the regimen that includes ethambutol and rifabutin used
for the treatment of infections by M. avium-intracellulare complex.

Azithromycin is preferred for HIV-infected patients.

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Aminosalicylic Acid (PAS)

• Aminosalicylic acid is a folate synthesis antagonist that is
active almost exclusively against M tuberculosis. It is
structurally similar to p-aminobenzoic acid (PABA) and to the
sulfonamides.
• The drug is widely distributed in tissues and body fluids except
the cerebrospinal fluid.
• Aminosalicylic acid is rapidly excreted in the urine, in part as
active aminosalicylic acid and in part as the acetylated
compound and other metabolic products.
• Very high concentrations of aminosalicylic acid are reached in
the urine, which can result in crystalluria.
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Aminosalicylic Acid (PAS)

• Aminosalicylic acid is used infrequently now because other oral
drugs are better tolerated.
• Gastrointestinal symptoms are common and may be
diminished by giving the drug with meals and with antacids.
• Peptic ulceration and hemorrhage may occur.
• Hypersensitivity reactions manifested by fever, joint pains,
skin rashes, hepatosplenomegaly, hepatitis, adenopathy,
granulocytopenia often occur after 3–8 weeks of aminosalicylic
acid therapy, making it necessary to stop aminosalicylic acid
administration temporarily or permanently.
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Leprosy
• Leprosy is a slowly developing, progressive disease that
damages the skin and nervous system.
• Leprosy is caused by an infection with Mycobacterium leprae
or M. lepromatosis bacteria.
• Early symptoms begin in cooler areas of the body (eg., eyes,
nose, hands) and include loss of sensation.
• Signs of leprosy are painless ulcers, skin lesions of hypo-
pigmented macules (flat, pale areas of skin), and eye damage
(dryness). Later, large ulcerations, loss of digits, skin nodules,
and facial disfigurement may develop.
• The infection is thought to be spread person to person by nasal
secretions or droplets
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CHEMOTHERAPY FOR LEPROSY

Drugs used to treat leprosy
a) Clofazimine
b) Dapsone
c) Rifampin (Rifampicin)

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.
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Dapsone
Dapsone is structurally related to the sulfonamides and
similarly inhibits folate synthesis via dihydropteroate
synthetase inhibiton.
It is bacteriostatic for Mycobacterium leprae.
Resistance can emerge in large populations of M leprae, eg, in
lepromatous leprosy.
Therefore, the combination of dapsone, rifampin, and
clofazimine is recommended for initial therapy.
Dapsone is also employed in the treatment of pneumonia
caused by Pneumocystis jiroveci in patients infected with HIV.
The drug is well absorbed from the gastrointestinal tract and is
distributed throughout the body, with high levels concentrated
in the skin.
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Dapsone
The parent drug enters the enterohepatic circulation and
undergoes hepatic acetylation. Both parent drug and metabolites
are eliminated through the urine.
Adverse reactions include:
I. hemolysis, especially in patients with glucose 6-phosphate
dehydrogenase deficiency
II. methemoglobinemia
III. peripheral neuropathy
IV. erythema nodosum leprosum, (a sever and serious skin
inflammatory complication can be treated with corticosteroids or
thalidomide), it is a hypersensitivity reaction and may occur
with several disease or drugs (e.g, sulfa drugs).
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Clofazimine
Clofazimine binds to DNA and prevents it from serving as a
template for future DNA replication.
Clofazimine is bactericidal to M. leprae and has some activity
against M. avium-intracellulare complex.
Following oral absorption, the drug accumulates in tissues, but
it does not enter the CNS.
Patients may develop a red-brown discoloration of the skin
and gastrointestinal irritation.
The drug also has some anti-inflammatory activity.
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Drugs Active Against Atypical Mycobacteria

• About 10% of mycobacterial infections seen in clinical practice
are caused not by M tuberculosis or M tuberculosis complex
organisms, but by nontuberculous or "atypical" mycobacteria.
• These organisms have specific laboratory characteristics, are
present in the environment, and are not communicable from
person to person.
• As a rule, these mycobacterial species are less susceptible than
M tuberculosis to antituberculous drugs.
• Agents such as erythromycin, sulfonamides, or tetracycline,
which are not active against M tuberculosis, may be effective for
infections caused by atypical strains.
• Emergence of resistance during therapy is also a problem with
these mycobacterial species, and active infection should be
treated with combinations of drugs.
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Clinical Features and Treatment Options for

Infections with Atypical Mycobacteria
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