Download antimycobacterials

ANTIMYCOBACTERIALS
I. OVERVIEW
Mycobacteria are slender, rod-shaped bacteria with lipid-rich cell walls that stain poorly with the Gram
stain, but once stained, the walls cannot be easily decolorized by treatment with acidified organic
solvents. Hence, they are termed “acid-fast.” The most widely encountered mycobacterial infection is
tuberculosis—the leading cause worldwide of death from infection. Members of the genus Mycobacterium
also cause leprosy, as well as, several tuberculosis-like human infections. Mycobacterial infections are
intracellular and, generally, result in the formation of slow-growing granulomatous lesions that are
responsible for major tissue destruction.
Diagnostic testing for tuberculosis can be accomplished via the standard tuberculin skin test with purified
protein derivative (PPD) or by an interferon-gamma release assay (IGRA) blood test, Quantiferon-TB
Gold, approved by the FDA in 2005. The advantages that the blood test offers is that it requires only a
single test visit, and it is less susceptible to false positive results due to BCG vaccination or to infection
with mycobacteria other than Mycobacterium tuberculosis. However, the cost of the blood test is more
than that of the skin test, yet it reduces the expense of follow-up x-rays and lab tests needed with a
tuberculin skin test.
There are four currently recommended first-line agents utilized for antituberculosis therapy. Second-line
medications are either less effective, more toxic, or have not been studied as extensively. They are useful
in patients who cannot tolerate the first-line drugs or who are infected with mycobacteria that are
resistant to the first-line agents.
DRUGS
USED
TO
TREAT
Capreomycin
TUBERCULOSIS (1st line)
Cycloserine
Ethambutol
Ethionamine
Isoniazid (INH)
Flouroquinolones
Pyrazinamide
Macrolide
Rifampicin
DRUGS USED TO TREAT LEPROSY
DRUGS
USED
TO
TREAT
Clofazimine
TUBERCULOSIS (2nd Line)
Dapsone
Aminoglycosides
Rifampicin
Aminosalicylic acid
II. CHEMOTHERAPY FOR TUBERCULOSIS
Mycobacterium tuberculosis, one of a number of mycobacteria, can lead to serious infections of the
lungs, genitourinary tract, skeleton, and meninges. Treating tuberculosis as well as other mycobacterial
infections presents therapeutic problems. The organism grows slowly; thus, are difficult to culture and
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may have to be treated for 6 months to 2 years. Resistant organisms readily emerge, particularly in
patients who have had prior therapy or who fail to adhere to the treatment protocol. It is currently
estimated that about one-third of the world’s population is infected with M. tuberculosis, with 30 million
people having active disease. Worldwide, 9 million new cases occur, and approximately 2 million people
die of the disease each year (Lippincott, 2012).
A. Strategies for addressing drug resistance
Strains of M. tuberculosis that are resistant to a particular agent emerge during treatment with a single
drug. Therefore, multidrug therapy is employed when treating tuberculosis in an effort to delay or
prevent the emergence of resistant strains. 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. Today, however, 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. 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 and then isoniazid and rifampin for the next 4 months (the
“continuation phase”; Figure 34.3). Before susceptibility data are available, more drugs may be added to
the first-line agents for patients who have previously had tuberculosis or those in whom multidrugresistant tuberculosis is suspected. The added drugs normally include an aminoglycoside ( streptomycin,
kanamycin, or amikacin) or capreomycin (injectable agents), a fluoroquinolone, and perhaps a secondline antituberculosis agent such as cycloserine, ethionamide, or p-aminosalicylic acid. Once susceptibility
data are available, the drug regimen can be individually tailored to the patient. Patient compliance is
often low when multidrug schedules last for 6 months or longer. One successful strategy for achieving
better treatment completion rates is “directly observed therapy,” also known as DOT, in which patients
take their medication while being supervised and observed. DOT has been shown to decrease drug
resistance as well as relapse and mortality rates and to improve cure rates. Most local and state health
departments offer DOT services.
B. Pharmacokinetics
Most antitubercular drugs are administered orally. When administered orally, these drugs are well
absorbed from the GI tract and widely distributed throughout the body. They’re metabolized primarily in
the liver and excreted by the kidneys.
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C. Pharmacodynamics
Antitubercular drugs are specific for mycobacteria. At usual doses, ethambutol and isoniazid are
tuberculostatic, meaning that they inhibit the growth of M. tuberculosis. In contrast, rifampin is
tuberculocidal, meaning that it destroys the mycobacteria. Because bacterial resistance to isoniazid and
rifampin can develop rapidly, they should always be used with other antitubercular drugs.
II. ANTIMYCOBACTERIAL DRUGS
A. Ethambutol
The exact mechanism of action of ethambutol remains unclear, but it may be related to inhibition of cell
metabolism, arrest of multiplication, and cell death. Ethambutol acts only against replicating bacteria.
B. Isoniazid (INH)
Although isoniazid’s exact mechanism of action isn’t known, the drug is believed to inhibit the synthesis
of mycolic acids, important components of the mycobacterium cell wall. This inhibition disrupts the cell
wall. Only replicating, not resting, bacteria appear to be inhibited.
C. Rifampicin
Rifampin inhibits RNA synthesis in susceptible organisms. The drug is effective primarily in replicating
bacteria, but may have some effect on resting bacteria as well.
D. Pyrazinamide
The exact mechanism of action of pyrazinamide isn’t known, but the antimycobacterial activity appears to
be linked to the drug’s conversion to the active metabolite pyrazinoic acid. Pyrazinoic acid, in turn,
creates an acidic environment where mycobacteria can’t replicate.
Pyrazinamide is currently recommended as a first -line TB drug in combination with ethambutol, rifampin,
and isoniazid. Pyrazinamide is a highly specific drug that’s active only against M. tuberculosis. Resistance
to pyrazinamide may develop rapidly when it’s used alone.
III. PHARMACOTHERAPEUTICS
Isoniazid usually is used with ethambutol, rifampin, or pyrazinamide. This is because combination therapy
for TB and other mycobacterial infections can prevent or delay the development of resistance. In
uncomplicated cases, Ethambutol is used with isoniazid and rifampin to treat the patient with
uncomplicated pulmonary TB. It’s also used to treat infections resulting from M. bovis and most strains of
M. kansasii .
Although isoniazid is the most important drug for treating TB, bacterial resistance develops rapidly if it’s
used alone. However, resistance doesn’t pose a problem when isoniazid is used alone to prevent TB in
the patient who has been exposed to the disease, and no evidence exists of cross-resistance between
isoniazid and other antitubercular drugs. Isoniazid is typically given orally, but may be given
intravenously, if necessary.
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Rifampin is a first -line drug for treating pulmonary TB with other antitubercular drugs. It combats many
gram-positive and some gram-negative bacteria, but is seldom used for nonmycobacterial infections
because bacterial resistance develops rapidly. It’s used to treat asymptomatic carriers of Neisseria
meningitidis when the risk of meningitis is high, but it isn’t used to treat N. meningitides infections
because of the potential for bacterial resistance.
IV. ADVERSE REACTIONS TO ANTITUBERCULAR DRUGS
A. Ethambutol
Itching, joint pain, GI distress, malaise, leukopenia, headache, dizziness, numbness and tingling of the
extremities, optic neuritis, and confusion may occur.
Although rare, hypersensitivity reactions to ethambutol may produce rash and fever.
Anaphylaxis may also occur.
B. Isoniazid
Peripheral neuropathy is the most common adverse reaction. Severe and occasionally fatal hepatitis
associated with isoniazid may occur even many months after treatment has stopped. The patient must be
monitored carefully.
C. Rifampin
The most common adverse reactions include epigastric pain, nausea, vomiting, abdominal cramps,
flatulence, anorexia, and diarrhea.
D. Pyrazinamide
Liver toxicity is the major limiting adverse reaction. GI disturbances include nausea, vomiting,
hyperuricemia, arthralgia, and anorexia.
V. DRUG INTERACTIONS
Antitubercular drugs may interact with many other drugs.

Cycloserine and ethionamide may produce additive CNS effects, such as drowsiness, dizziness,
headache, lethargy, depression, tremor, anxiety, confusion, and tinnitus (ringing in the ears),
when administered with isoniazid.

Isoniazid may increase levels of phenytoin, carbamazepine, diazepam, ethosuximide, primidone,
theophylline, and warfarin.

When corticosteroids and isoniazid are taken together, the effectiveness of isoniazid is reduced
while the effects of corticosteroids are increased.

Isoniazid may reduce the plasma levels of ketoconazole, itraconazole, and oral antidiabetic
agents.

Oral contraceptives and rifampin taken together may decrease the effectiveness of the oral
contraceptive.
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
When given together, rifampin, isoniazid, ethionamide, and pyrazinamide increase the risk of
hepatotoxicity.

Pyrazinamide combined with phenytoin may increase phenytoin levels.
VI. OTHER ANTITUBERCULAR DRUGS
Several other drugs are used as antitubercular drugs in combination with first -line drugs. Because these
drugs have a greater incidence of toxicity, they’re used primarily for the patient who’s resistant or allergic
to less toxic drugs.
A. Fluoroquinolones
Fluoroquinolones, such as ciprofloxacin and ofloxacin, are effective against Mycobacterium tuberculosis.
Of these two drugs, ofloxacin is more potent and may be an initial choice in retreatment. These drugs are
administered orally and are generally well tolerated. GI adverse reactions are most commonly reported.
However, resistance to fluoroquinolones develops rapidly when these drugs are used alone or in
insufficient doses.
B. Streptomycin
Streptomycin was the first drug recognized as effective in treating tuberculosis. Streptomycin is
administered I.M. only. It appears to enhance the activity of oral antitubercular drugs and is of greatest
value in the early weeks to months of therapy. However, I.M. administration limits its usefulness in longterm therapy. Rapidly absorbed from the I.M. injection site, streptomycin is excreted primarily by the
kidneys as unchanged drug. Most patients tolerate streptomycin well, but those receiving large doses
may exhibit eighth cranial nerve toxicity (ototoxicity).
References:
1. Lippincott’s Pharmacology, 5th Edition, 2012.
2. Clinical Pharmacology Made Easy by Lippincott William and Wilkins, 3rd Edition, 2009.
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