The number of new cases of tuberculosis reported in the United States decreased by an average of 5 percent a year until 1985, when the decrease was negligible (0.2 percent). In 1986, an increase in new cases was noted for the first time since reporting began in 1953. The number of new cases increased by 5 percent in 1989 and by about 10 percent in 1990. Mycobacterium tuberculosis infection in persons with acquired immunodeficiency syndrome is probably responsible for the resurgence of tuberculosis. The increased incidence may soon place the general population at higher risk for this disease.
Tuberculosis can be classified according to the stages of infection and disease.  In class 1, exposure to tuberculosis has occurred, but there is no evidence of infection and the tuberculin skin test is negative. Class 2 is defined as tuberculous infection without disease. The tuberculin skin test is positive, but bacteriologic studies and chest radiographs are negative. Class 3 is defined as clinically active tuberculosis with positive cultures and radiographic studies.
First-line antituberculous drugs are used in initial therapy. Second-line drugs are usually reserved for cases of treatment failure and/or drug resistance, although they are occasionally used when adverse reactions to first-line drugs occur. Isoniazid (Laniazid), one of the first-line drugs, is given to prevent tuberculous infection (class 2) from progressing to clinically active disease (class 3). Combination drug therapy is used for active disease.
In addition to isoniazid, also known as INH, the first-line antituberculous drugs (Table 1) include rifampin (Rifadin, Rimactane), pyrazinamide, streptomycin and ethambutol (Myambutol).
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Isoniazid. This relatively inexpensive drug is bactericidal and well absorbed. The incidence of chemical hepatitis, the major adverse effect of isoniazid, increases with age, particularly after age 35. Peripheral neuropathy can occur as a result of increased urinary pyridoxine excretion, but this adverse effect is uncommon when isoniazid is given in the usual dosage of 300 mg per day.  However, pyridoxine supplementation should be added to the regimen in pregnant women, alcoholics and individuals with seizure disorders.
Drug interactions can occur, particularly with phenytoin (Dilantin). The potential for toxic serum phenytoin levels necessitates monitoring in patients receiving isoniazid along with phenytoin.
Rifampin. This first-line drug is bactericidal and is effective against both multiplying and inactive organisms. The efficacy of rifampin is responsible for the marked reduction in the duration of therapy now given for tuberculosis.
The most common side effect of rifampin is gastrointestinal distress. Skin rashes, hepatitis and, rarely, thrombocytopenia also can occur. Acute renal failure, an influenza-like syndrome, hemolytic anemia and thrombocytopenia have been associated with intermittent administration of rifampin. These adverse effects usually occur only with doses greater than 10 mg per kg.  Orange discoloration of body secretions and excretions, especialy urine, occurs with rifampin therapy; patients should be warned about this effect, which has no other clinical significance. Rifampin accelerates the clearance of many drugs metabolized in the liver, including warfarin (Coumadin), digitalis, oral contraceptives, hypoglycemic agents and anticonvulsants.
Pyrazinamide. This drug is highly effective, particularly against organisms within macrophages. Hepatotoxicity and hyperuricemia are its major adverse effects. Rare cases of gout are reported in patients receiving pyrazinamide.
Streptomycin. The major toxic effect of this parenterally administered drug is ototoxicity, which results in vertigo and/or hearing loss. Because streptomycin can cause nephrotoxicity, the dosage must be reduced in patients with renal failure.
Ethambutol. The most serious adverse effect of this bactriostatic drug is retrobulbar neuritis. Decreased visual acuity and diminished red-green color discrimination are associated symptoms. The optic neuritis is dose-related and has an incidence of less than 1 percent when ethambutol is given in a dosage of 15 mg per kg per day. 
Second-line antituberculous drugs include aminosalicylate sodium (Sodium P.A.S.), ethionamide (Trecator-SC0, cycloserine (Seromycin), kanamycin (Kantrex, Klebcil) and capreomycin (Capastat). All of these drugs have serious side effects that place major limitations on their clinical use. Aminosalicylate sodium is associated with a high incidence of gastrointestinal upset at the large doses necessary for clinical efficacy. Ethionamide is poorly tolerated, principally because of gastrointestinal symptoms; hepatitis also can occur. Cycloserine can cause convulsions, behavior disturbances and peripheral neuropathy. Like other aminoglycosides, the parenteral agents kanamycin and capreomycin are nephrotoxic and ototoxic.
Tuberculous infection progresses to clinically active disease in approximately 10 percent of cases. Disease progression depends on patient susceptibility and probably occurs in as many as 30 percent of patients infected with human immunodeficiency virus (HIV). 
The lung is the most common site for tuberculosis. Cavitation and nodular infiltration of the apical and posterior segments of the upper lobes and/or superior segments of the lower lobes are the most common findings on chest radiographs.
Diagnosis of tuberculosis depends on sputum smear and culture. For testing, it is best to obtain sputum specimens on three consecutive mornings. A presumptive diagnosis of tuberculosis can be made, and treatment can be initiated, if the sputum smear is positive for acid-fast bacilli. Diagnosis is confirmed by culture of M. tuberculosis.
Treatment of clinically active tuberculosis can be successful if an effective drug regimen is used for a sufficient period of time in a compliant patient. Outpatient therapy is preferred. Hospitalization is not required unless the disease is life-threatening or the patient is unable to take care of himself or herself. Infectivity alone is not an indication for hospitalization. 
To increase the chance of eradicating drug-resistant bacilli, more than one antituberculous drug must be given. Both six- and nine-month drug regimens are effective and have acceptable relapse and failure rates.  The preferred regimen in adults consists of six months of isoniazid (300 mg per day) and rifampin (600 mg per day), with pyrazinamide (15 to 30 mg per kg per day) given during the first two months of therapy. A nine-month regimen of isoniazid and rifampin alone is a less useful but acceptable alternative. All drugs are administered in a single daily dose, with isoniazid and rifampin given as a fixed-dose combination (e.g., Rifamate).
Streptomycin can be used in place of pyrazinamide. A daily intramuscular injection of 15 mg per kg in adults (to a maximum of 1 g per day) is given. The total dose of streptomycin should not exceed 120 g. Outcome is not improved by continuing streptomycin therapy beyond two months.  Parenteral drugs are useful in noncompliant patients. However, substitution of streptomycin for pyrazinamide decreases efficacy.
Ethambutol is added to the regimen when primary isoniazid resistance is suspected, as in the case of immigrants from areas where the incidence of isoniazid resistance is high (e.g., Mexico, Southeast Asia). [3} If drug susceptibility studies confirm isoniazid resistance, ethambutol is given for 12 months; if resistance is not confirmed, ethambutol therapy is discontinued. Pyrazinamide can still be given during the first two months of therapy.
With dosage adjustment, intermittent drug administration may be as effective as daily administration. Intermittent therapy can be used as a technique to increase compliance. The drugs can be given as part of a directly administered program. With this approach, isoniazid, rifampin and pyrazinamide are given daily in their usual doses for two months. Then isoniazid (in higher doses) and rifampin are given twice a week for another four months.
Special Clinical Situations
The treatment of children with tuberculosis is similar to that of adults. Six-and nine-month regimens are used, with the daily doses adjusted to the weight of the child [7,8] (Table 1).
Drug toxicity, including hepatotoxicity, is less common in children than in adults. The difficulty in monitoring ocular toxicity in children precludes the use of ethambutol in this age group. Since sputum samples are difficult to obtain in young children, response to therapy usually has to be determined clinically and radiographically.
Pregnant women are not at increased risk of tuberculosis. Pregnancy does not affect prognosis,  and clinically active disease should be treated at the time of diagnosis. Because of the risk of fetal ototoxicity, streptomycin and other aminoglycosides should not be used. The safety of pyrazinamide in pregnancy has not been established, but no harmful fetal effects have been reported with isoniazid, ethambutol or rifampin. A nine-month course of isoniazid and rifampin with pyridoxine is an acceptable regimen in pregnant women. Breast feeding is not contraindicated during therapy. 
Tuberculosis can occurin in HIV-infected individuals and in patients with AIDS. The diagnosis of tuberculosis usually precedes the diagnosis of AIDS. In patients with AIDS, extrapulmonary tuberculosis is more common than pulmonary involvement.  Lymphatic and disseminated (miliary) forms of tuberculosis are particularly common. The typical apical disease with cavity formation is uncommon in AIDS patients with pulmonary involvement. Infiltration can occur in any portion of the lung, often with associated mediastinal and/or hilar adenopathy.
AIDS patients respond to standard antituberculous therapy. The regimen of isoniazid, rifampin and pyrazinamide is used. Ethambutol is added if disseminated or central nervous system disease is suspected. Although the optimal duration of therapy in AIDS patients is not known, a minimum course of nine months, with at least six months of therapy after culture conversion, is strongly suggested. 
Monitoring of Therapy
With all antituberculous drugs, base-line measurements of renal and liver function and a complete blood count are recommended before therapy is started. Other appropriate tests depend on the potential toxicity of the specific drug. Monthly follow-up is necessary to monitor for clinical symptoms of adverse drug effects. The need for further laboratory testing is determined by the patient's symptoms and the degree of risk for adverse effects. Between 10 and 20 percent of patients receiving isoniazid have mild liver function abnormalities, such as a rise in transaminase levels; however, hepatotoxic drugs should be stopped if a threefold increase in transaminase levels occurs and/or symptoms of liver injury develop. 
Routine follow-up of tuberculosis includes monthly sputum smears and cultures until the cultures convert to negative. Cultures become negative within two to three months in about 90 percent of patients.  A sputum specimen should also be obtained at the end of therapy. Without two weeks of starting therapy, a patient can be considered noninfectious. 
Compliance with therapy should be emphasized. Even with only three months of therapy, almost 80 percent of patients will be cured of tuberculosis.  Adherence to the drug regimen is essential.
Compliant patients who respond to therapy show symptomatic improvement, with weight gain, lack of fever and decreased cough. Repeated chest radiographs are not necessary, since sputum culture conversion is more important in monitoring therapeutic success. Chest radiographs in the middle and at the end of therapy are sufficient. After completion of therapy, no mandatory follow-up is required. Patients are advised to return only if symptoms recur.
Treatment failure is defined as the failure of sputum cultures to convert to negative after four to five months of therapy. Acquired drug-resistant organisms are generally present, making future therapy complicated. Treatment failure is usually due to noncompliance. In such cases, patients have stopped taking the medications, have taken them intermittently or have taken only one drug of a regimen.
When initial treatment fails, drug susceptibility testing is indicated to assist in planning the renewed treatment program. The initial regimen can be continued until the results of susceptibility studies are known, or a new retreatment program can be started pending the study results. Patient education is essential, and directly observed, supervised treatment should be considered.
For treatment failure, the patient is given two or preferably three drugs to which M. tuberculosis is known or presumed to be susceptible. When three drugs are used, one drug should be a parenteral agent. Therapy for 12 to 18 months is usually necessary. The duration of therapy and the exact drug combinations are decided on an individual basis. However, treatment failure requires a completely new therapeutic strategy; a single new drug should not be added to a failing regimen. Retreatment usually requires the use of second-line antituberculous drugs, with increased risk of toxicity.
If a course of isoniazid and rifampin has been completed and the patient then relapses, the organisms usually are still susceptible to these drugs, and isoniazid and rifampin can be restarted. 
The most common sites of extrapulmonary tuberculosis are lymph nodes, pericardium, kidneys, skeleton, peritoneum and pleura. Hematogenous spread of the tubercle bacilli results in miliary or disseminated tuberculosis of the lungs and other organs. Associated pulmonary involvement is usual in tuberculous pericarditis and meningitis; it also occurs in a high percentage of cases of tuberculosis of the bone.
Examination of pleural, peritoneal and pericardial fluids may reveal findings suggestive of tuberculosis, but definitive diagnosis requires biopsy, with culture and examination of biopsy specimens. Culture of urine specimens collected on three consecutive mornings is sufficient to diagnose renal tuberculosis. Lung biopsy may be necessary in miliary tuberculosis. When the cerebrospinal fluid findings suggest tuberculous meningitis, therapy is initiated before the culture results are known.
The same therapy is used for extrapulmonary tuberculosis as for pulmonary tuberculosis. The basic six-month regimen of isoniazid, rifampin and pyrazinamide is effective. Extrapulmonary tuberculosis in HIV-infected patients is often treated with a nine-month regimen, as previously described.
Althought efficacy has not been proved, corticosteroids have been used in tuberculous pericarditis to prevent constriction and in tuberculous meningitis to prevent neurologic sequelae.
 American Thoracic Society. Diagnostic standards and classification of tuberculosis. Am Rev Respir Dis 1990;142:725-35 [Published erratum appears in Am Rev Respir Dis 1990; 142(6 Pt1):1470].
 Van Scoy RE, Wilkowske CJ. Antituberculous agents. Mayo Clin Proc 1987;62:1129-36.
 American Thoracic Society. Treatment of tuberculosis and tuberculosis infection in adults and children. Am Rev Respir Dis 1986; 134:355-63.
 Murray JF. The white plague: down and out, or up and coming? Am Rev Respir Dis 1989; 140:1788-95.
 National America College of Chest Physicians Consensus Conference on Tuberculosis. Chest 1985;87(2 Suppl):115S-49S.
 Perez-Stable EJ, Hopewell PC. Current tuberculosis treatment regimens. Choosing the right one for your patient. Clin Chest Med 1989;10:323-39.
 Kendig EL Jr. Evolution of short-course antimicrobial treatment of tuberculosis in children, 1951-1984. Pediatrics 1985;75:684-6.
 Smith MH. Tuberculosis in children and adolescents. Clin Chest Med 1989;10:381-95.
 Snider D. Pregnancy and tuberculosis. Chest 1984;86(3 Suppl):10S-3S.
 Snider DE Jr, Powell KE. Should women taking antituberculosis drugs breast-feed? Arch Intern Med 1984;144:589-90.
 Sunderam G, McDonald RJ, Maniatis T, Oleske J, Kapila R, Reichman LB. Tuberculosis as a manifestation of the acquired immunodeficiency syndrome (AIDS). JAMA 1986;256:362-6.
 Mycobacterioses and the acquired immunodeficiency syndrome. Joint position paper of the American Thoracic Society and the Centers for Disease Control. Am Rev Respir Dis 1987;136:492-6.
 Rouillon A, Perdrizet S, Parrot R. Transmission of tubercle bacilli: the effects of chemotherapy. Tubercle 1976;57:275-99.
 Reichman LB. Compliance in developed nations. Tubercle 1987;68(2 Suppl):25-9.
 Snider DE Jr, Long MW, Cross FS, Farer LS. Six-months isoniazid-rifampin therapy for pulmonary tuberculosis. Report of a United States Public Health Service Cooperative Trial. Am Rev Respir Dis 1984;129:573-9.
GEORGE M. LORDI, M.D. is associate professor of medicine at the University of Medicine and Dentistry of New Jersey (UMDNJ), New Jersey Medical School, Newark. He also serves as vice-chairman in education in the Department of Medicine and as an attending physician in pulmonary medicine at University Hospital, Newark. Dr. Lordi completed an internal medicine residency and pulmonary medicine training at UMDNJ.
LEE B. REICHMAN, M.D., M.P.H. is professor of medicine at UMDNJ, where he serves as director of the pulmonary medicine division and medical director of the cardiorespiratory section. Dr. Reichman completed an internal medicine residency and pulmonary medicine training at Columbia University (Bellevue and Harlem hospitals), New York City. He received his master's degree in public health at Johns Hopkins University School of Hygiene and Public Health, Baltimore.
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