Tuberculosis responds well to long-term treatment with a combina-tion of three or more antitubercular drugs.Antitubercular drugs are used to treat active cases of tuberculosis and as a prophylactic to prevent the spread of tuberculosis. The drugs used to treat tuberculosis do not “cure” the disease, but they render the patient nonin- fectious to others.
Antitubercular drugs are classified as primary and second-line drugs. Primary (first-line) drugs provide the foundation for treatment. Second-line or secondary drugs are less effective and more toxic than primary drugs.
These drugs are used in various combinations to treat tuberculosis. Sensitivity testing may be done to determine the most effective combination treatment,especially in areas of the country showing resistance.Second-line drugs are used to treat extrapulmonary tuberculosis or drug-resistant organisms. The primary antitubercular drugs are discussed in this chapter. Both primary and second-line antitubercular drugs fluoroquinolones such as ciprofloxacin, ofloxacin, levofloxacin, and sparfloxacin have proven effective against tuberculosis and are considered second line drugs.
ACTIONS
Most antitubercular drugs are bacteriostatic (slow or retard the growth of bacteria) against the M. tuberculosis bacillus. These drugs usually act to inhibit bacterial cell wall synthesis, which slows the multiplication rate of the bacteria. Only isoniazid is bactericidal, with rifampin and streptomycin having some bactericidal activity.
USES
Antitubercular drugs are used in combination with other antitubercular drugs to treat active tuberculosis.Isoniazid (INH) is the only antitubercular drug used alone. While isoniazid is used in combination with other drugs for the treatment of primary tuberculosis, a primary use is in preventive therapy (prophylaxis)
against tuberculosis. For example, when a diagnosis of tuberculosis is present, family members of the infected individual must be given prophylactic treatment with isoniazid for 6 months to 1 year.
RESISTANCE TO THE
ANTITUBERCULAR DRUGS
Of increasing concern is the development of mutant strains of tuberculosis that are resistant to many of the antitubercular drugs currently in use. Bacterial resistance develops, sometimes rapidly, with the use of anti-tubercular drugs. Treatment is individualized and based on laboratory studies identifying the drugs to
which the organism is susceptible. To slow the devel-opment of bacterial resistance, the Centers for Disease Control (CDC) recommends the use of three or more drugs with initial therapy, as well as in retreatment.Using a combination of drugs slows the development of bacterial resistance.Tuberculosis caused by drug-resistant organisms should be considered in patients who have no response to therapy and in patients who have been treated in the past.
STANDARD TREATMENT
Standard treatment for tuberculosis is divided into two phases: the initial phase followed by a continuing phase.During the initial phase, drugs are used to kill the rapidly multiplying M. tuberculosis and to prevent drug resist-ance. The initial phase lasts approximately 2 months and the continuing phase approximately 4 months, with the total treatment regimen lasting for 6 to 9 months,
depending on the patient’s response to therapy.The initial phase must contain three or more of the following drugs: isoniazid, rifampin, and pyrazin-amide, along with either ethambutol or streptomycin.The CDC recommends treatment to begin as soon as possible after the diagnosis of tuberculosis. The treatment recommendation regimen is for the administra-tion of rifampin, isoniazid, and pyrazinamide for a minimum of 2 months (8 weeks), followed by rifampin and isoniazid for 4 months (16 weeks) in areas with a low incidence of tuberculosis. In areas of high incidence of tuberculosis, the CDC recommends the addi-tion of streptomycin or ethambutol for the first 2 months.
RETREATMENT
At times treatment fails due to noncompliance with the drug regimen or to inadequate initial drug treatment.When treatment fails, retreatment is necessary.
Retreatment generally includes the use of four or more antitubercular drugs. Retreatment drug regimens most often consist of the secondary drugs ethionamide,aminosalicylic acid, cycloserine, and capreomycin.Ofloxacin and ciprofloxacin may also be used in retreat-ment. At times during retreatment, as many as seven or more drugs may be used, with the ineffective drugs dis-continued when susceptibility test results are available.
ETHAMBUTOL
Optic neuritis (a decrease in visual acuity and changes in color perception), which appears to be related to the dose given and the duration of treatment, has occurred in some patients receiving ethambutol. Usually, this adverse reaction disappears when the drug is discontinued. Other adverse reactions are dermatitis, pruritus, anaphylac-toid reactions (unusual or exaggerated allergic reactions), joint pain, anorexia, nausea, and vomiting.
CONTRAINDICATIONS, PRECAUTIONS
AND INTERACTIONS
Ethambutol is contraindicated in patients with a history of hypersensitivity to the drug. Ethambutol is not rec-ommended for children younger than 13 years. The drug is used with caution during lactation, in patients with hepatic and renal impairment, and during preg-nancy (Category B). Because of the danger of optic neuritis, the drug is used cautiously in patients with dia-betic retinopathy or cataracts.
ISONIAZID
ADVERSE REACTIONS
The incidence of adverse reactions appears to be higher when larger doses of isoniazid are prescribed. Adverse reactions include hypersensitivity reactions, hemato-logic changes, jaundice, fever, skin eruptions, nausea,vomiting, and epigastric distress. Severe, and some-times fatal, hepatitis has been associated with isoniazid therapy and may appear after many months of treat-ment. Peripheral neuropathy (numbness and tin-gling of the extremities) is the most common symptom of toxicity.
CONTRAINDICATIONS, PRECAUTIONS,
AND INTERACTIONS
Isoniazid is contraindicated in patients with a history of hypersensitivity to the drug. The drug is used with caution during lactation, in patients with hepatic and renal impairment, and during pregnancy (Category C). Daily consumption of alcohol when taking isoni-azid may result in a higher incidence of drug-related
hepatitis. Aluminum salts may reduce the oral absorption of isoniazid. The action of the anticoagu-lants may be enhanced when taken with isoniazid.There is a possibility of increased serum levels of phenytoin with concurrent use of isoniazid. When isoniazid is taken with foods containing tyramine,such as aged cheese and meats, bananas, yeast prod-ucts, and alcohol, an exaggerated sympathetic-type response can occur (eg, hypertension, increased heart rate, palpitations).
PYRAZINAMIDE
ADVERSE REACTIONS
Hepatotoxicity is the principal adverse reaction seen with pyrazinamide use. Symptoms of hepatotoxicity may range from none (except for slightly abnormal hepatic function tests) to a more severe reaction such as jaundice. Nausea, vomiting, diarrhea, myalgia, and rashes also may be seen.
CONTRAINDICATIONS, PRECAUTIONS,
AND INTERACTIONS
Pyrazinamide is contraindicated in patients with a his-tory of hypersensitivity to the drug. The drug is also contraindicated in patients with acute gout (a metabolic disorder resulting in increased levels of uric acid)and in patients with severe hepatic damage. The drug is used with caution during lactation, in patients with hepatic and renal impairment, and during pregnancy (Category C). Pyrazinamide is used cautiously in patients infected with human immunodeficiency virus,who may require longer treatment, and in patients with diabetes mellitus, in whom management is more diffi-cult. Pyrazinamide decreases the effects of allopurinol,colchicines, and probenecid.
RIFAMPIN
ADVERSE REACTIONS
Nausea, vomiting, epigastric distress, heartburn,fatigue, dizziness, rash, hematologic changes, and renal insufficiency may be seen with administration of rifampin. Rifampin may also cause a reddish-orange dis-coloration of body fluids, including urine, tears, saliva,sweat, and sputum.
CONTRAINDICATIONS, PRECAUTIONS,
AND INTERACTIONS
Rifampin is contraindicated in patients with a history of hypersensitivity to the drug. The drug is used with cau-tion during lactation, in patients with hepatic and renal impairment, and during pregnancy. Serum concentra-tions of digoxin may be decreased by rifampin. Isoniazid and rifampin administered concurrently may result in a higher risk of hepatotoxicity than when either drug is used alone. The use of rifampin with the oral anticoagu-lants or oral hypoglycemics may decrease the effects of the anticoagulant or hypoglycemic drug. There is a decrease in the effect of the oral contraceptives, chloram-phenicol, phenytoin, and verapamil when these agents are administered concurrently with rifampin.
STREPTOMYCIN
ADVERSE REACTIONS
Nephrotoxicity (damage to the kidneys), ototoxicity (damage to the organs of hearing by a toxic substance),numbness, tingling, tinnitus (ringing in the ears), nau-sea, vomiting, vertigo (dizziness), and circumoral (around the mouth) paresthesia may be noted with the administration of streptomycin. Soreness at the injection site may also be noted, especially when the drug is given for a long time.
CONTRAINDICATIONS, PRECAUTIONS,
AND INTERACTIONS
Streptomycin is contraindicated in patients with a his- tory of hypersensitivity to the drug or any other aminoglycoside. Streptomycin is a Pregnancy Category D drug and can cause fetal harm when administered to a preg-nant woman. This drug is used cautiously in patients with preexisting hearing difficulty or tinnitus and in patients with renal insufficiency. The ototoxic effects of streptomycin are potentiated when administered with ethacrynic acid, furosemide, and mannitol.
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