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Am Fam Physician. 2003;68(9):1854-1862

The American Thoracic Society (ATS), the Centers for Disease Control and Prevention (CDC), and the Infectious Diseases Society of America (IDSA) recently published a joint statement of recommendations for the treatment of tuberculosis in settings where mycobacterial cultures, radiographic facilities, and drug susceptibility testing are available. The recommendations appeared in the June 20, 2003, issue of the Recommendations and Reports series of Morbidity and Morality Weekly Report (http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5211a1.htm).

Treatment

The goals for treatment of tuberculosis are to cure the individual patient and to minimize the transmission of Mycobacterium tuberculosis. It is the responsibility of the prescribing physician to oversee the successful completion of therapy, because this benefits the individual patient as well as the community in which the patient resides. Treatment should be tailored and supervised based on the clinical and social factors of each patient. This patient-centered approach should emphasize directly observed therapy (DOT), which involves providing the antituberculosis drug directly to the patient and watching as he or she swallows the medication. Additional measures that facilitate adherence to the drug regimen include social service support, housing assistance, coordination of tuberculosis services with those of other providers, referral for treatment of substance abuse, and treatment incentives and enablers.

Recommended Treatment Regimens

There are four recommended treatment regimens for patients with tuberculosis caused by drug-susceptible organisms. Each regimen has an initial two-month phase followed by a four- or seven-month continuation phase as described in Table 1. For most adult patients with previously untreated tuberculosis, the treatment regimen should consist of a two-month initial phase of isoniazid, rifampin, pyrazinamide, and ethambutol. If test results of drug susceptibility are available, ethambutol may not be necessary. The initial phase may be given daily (Regimens 1 and 4), daily for two weeks and then twice weekly for six weeks (Regimen 2), or three times weekly throughout (Regimen 3).

For the majority of patients, the continuation phase should last four months. A seven-month continuation phase is recommended only for the following groups: patients who have cavitary pulmonary tuberculosis caused by drug-susceptible organisms and who had a positive sputum culture obtained at the time of completion of two months of treatment; patients whose initial phase of treatment did not include pyrazinamide; and patients who are receiving isoniazid and rifapentine once weekly and who had a positive sputum culture obtained at the time of completion of two months of treatment. The continuation phase may be given daily (Regimens 1a and 4a), two times weekly by DOT (Regimens 1b, 2a, and 4b), or three times weekly by DOT (Regimen 3a). Doses for first-line antituberculosis drugs are shown in Tables 2 and 3.

Initiation of Treatment

The decision to initiate combination antituberculosis chemotherapy should be based on clinical, pathologic, and radiographic features of the patient, epidemiologic information, results of the initial series of acid-fast bacilli (AFB)-stained sputum smears, and culture for mycobacteria. Treatment with a four-drug regimen should be initiated in patients who are seriously ill and may have tuberculosis. A positive AFB smear provides strong evidence for the diagnosis of tuberculosis. A purified protein derivative (PPD)-tuberculin skin test may be performed at the time of the initial evaluation of the patient. A negative PPD test does not exclude the diagnosis of active tuberculosis, but a positive skin test supports the diagnosis of culture-negative pulmonary tuberculosis or latent tuberculosis infection in patients with stable abnormal chest radiographs consistent with inactive tuberculosis.

If the cultures are negative, the PPD-tuberculin skin test is positive (5 mm or greater induration), and the patient has not responded to treatment, the options include cessation of treatment if rifampin and pyrazinamide have been given for at least two months; continuing treatment with rifampin, with or without isoniazid, for a total of four months; or continuing treatment with isoniazid for a total of nine months.

Initial phaseContinuation phaseRating*(evidence) †
RegimenDrugsInterval and doses‡ (minimal duration)RegimenDrugsInterval and doses† § (minimal duration)Range of total doses (minimal duration)HIV−HIV+
1.Isoniazid, rifampin, pyrazinamide, ethambutolSeven days per week for 56 doses (8 weeks) or 5 days per week for 40 doses (8 weeks)//1aIsoniazid/rifampinSeven days per week for 126 doses (18 weeks) or 5 days per week for 90 doses (18 weeks)//182 to 130 (26 weeks)A (I)A (II)
1bIsoniazid/rifampinTwice weekly for 36 doses (18 weeks)92 to 76 (26 weeks)A (I)A (II)¶
1c#Isoniazid/rifapentineOnce weekly for 18 doses (18 weeks)74 to 58 (26 weeks)B (I)E (I)
2.Isoniazid, rifampin, pyrazinamide, ethambutolSeven days per week for 14 doses (2 weeks), then twice weekly for 12 doses (6 weeks) or 5 days per week for 10 doses (2 weeks),// then twice weekly for 12 doses (6 weeks)2aIsoniazid/rifampinTwice weekly for 36 doses (18 weeks)62 to 58 (26 weeks)A (II)B (II)¶
2b#Isoniazid/rifapentineOnce weekly for 18 doses (18 weeks)44 to 40 (26 weeks)B (I)E (I)
3.Isoniazid, rifampin, pyrazinamide, ethambutolThree times weekly for 24 doses (8 weeks)3aIsoniazid/rifampinThree times weekly for 54 doses (18 weeks)78 (26 weeks)B (I)B (II)
4.Isoniazid, rifampin, ethambutolSeven days per week for 56 doses (8 weeks) or 5 days per week for 40 doses (8 weeks)//4aIsoniazid/rifampinSeven days per week for 217 doses (31 weeks) or 5 days per week for 155 doses (31 weeks)//273 to 195 (39 weeks)C (I)C (II)
4bIsoniazid/rifampinTwice weekly for 62 doses (31 weeks)118 to 102 (39 weeks)C (I)C (II)

Follow-Up Evaluations

In patients with suspected tuberculosis, appropriate specimens should be collected for microscopic examination and mycobacterial culture. Three sputum specimens should be obtained if the lung is the site of disease. Susceptibility testing for isoniazid, rifampin, and ethambutol should be conducted on an initial positive culture, regardless of the source.

All patients with tuberculosis should receive counseling and testing for human immunodeficiency virus (HIV) infection. A CD4+ lymphocyte count should be obtained in patients with HIV infection, and patients with risk factors for hepatitis B or C viruses should be tested for these viruses. At baseline, measures should be taken for aspartate transaminase, alanine transaminase, bilirubin, alkaline phosphatase, serum creatinine, and a platelet count in all adult patients.

Doses
DrugPreparationAdults/ChildrenDailyEleven times per weekTwo times per weekThree times per week
IsoniazidTablets (50 mg, 100 mg, 300 mg); elixir(50 mg per 5 mL); aqueous solution (100 mg per mL) for IV or IM injectionAdults (max.)5 mg per kg (300 mg)15 mg per kg (900 mg)15 mg per kg (900 mg)15 mg per kg (900 mg)
Children (max.)10 to 15 mg per kg (300 mg)20 to 30 mg per kg (900 mg)
RifampinCapsule (150 mg, 300 mg); powder may be suspended for oral administration; aqueous solution for IV injectionAdults‡ (max.)10 mg per kg (600 mg)10 mg per kg (600 mg)10 mg per kg (600 mg)
Children (max.)10 to 20 mg per kg (600 mg)10 to 20 mg per kg (600 mg)
RifabutinCapsule (150 mg)Adults‡ (max.)5 mg per kg (300 mg)5 mg per kg (300 mg)5 mg per kg (300 mg)
ChildrenAppropriate dosing for children is unknownAppropriate dosing for children is unknownAppropriate dosing for children is unknownAppropriate dosing for children is unknown
RifapentineTablet (150 mg, film coated)Adults10 mg per kg (continuation phase) (600 mg)
ChildrenThe drug is not approved for use in childrenThe drug is not approved for use in childrenThe drug is notapproved for use in childrenThe drug is not approved for use in children
PyrazinamideTablet (500 mg, scored)AdultsSee Table 3See Table 3See Table 3
Children (max.)15 to 30 mg per kg (2.0 g)50 mg per kg (2 g)
EthambutolTablet (100 mg, 400 mg)AdultsSee Table 3See Table 3See Table 3
Children§ (max.)15 to 20 mg per kg daily (1.0 g)50 mg per kg (2.5 g)

Patients with pulmonary tuberculosis should have a sputum specimen obtained for microscopic examination at least monthly during treatment until at least two consecutive specimens are negative on culture. In patients with extrapulmonary tuberculosis, the frequency and types of examinations will depend on the site involved.

Patients should be assessed at least monthly for adherence to the treatment regimen and any adverse effects. For those receiving ethambutol, visual acuity and color discrimination testing should be performed. It is not necessary to take routine measurements of hepatic and renal function or platelet counts during the course of treatment unless the patient has baseline abnormalities or is at increased risk of hepatotoxicity.

Weight (kg)*
40 to 5556 to 7576 to 90
Pyrazinamide
Daily, mg (mg per kg)1,000 (18.2 to 25.0)1,500 (20.0 to 26.8)2,000† (22.2 to 26.3)
Thrice weekly, mg (mg per kg)1,500 (27.3 to 37.5)2,500 (33.3 to 44.6)3,000† (33.3 to 39.5)
Twice weekly, mg (mg per kg)2,000 (36.4 to 50.0)3,000 (40.0 to 53.6)4,000† (44.4 to 52.6)
Ethambutol
Daily, mg (mg per kg)800 (14.5 to 20.0)1,200 (16.0 to 21.4)1,600† (17.8 to 21.1)
Thrice weekly, mg (mg per kg)1,200 (21.8 to 30.0)2,000 (26.7 to 35.7)2,400† (26.7 to 31.6)
Twice weekly, mg (mg per kg)2,000 (36.4 to 50.0)2,800 (37.3 to 50.0)4,000† (44.4 to 52.6)

Patients who have cavitation on initial chest radiograph and who have a positive culture at the time the initial two-month phase of treatment is completed are at substantially increased risk of relapse. In these patients, the continuation phase of treatment should be prolonged to seven months, making a total treatment period of nine months.

Completion of Treatment

The completion of therapy is determined by the number of doses taken, not solely the duration of therapy. In some patients, because of drug toxicity or nonadherence to the treatment regimen, the specified number of doses are not administered during the target time period. In these cases, all of the specified number of doses for the initial phase should be delivered within three months and the doses for the four-month continuation phase should be delivered within six months, so that the six-month regimen is completed within nine months.

Interruptions in treatment are common in patients with tuberculosis and may have a significant effect on the duration of therapy. The reinstitution of treatment should take into consideration the duration of the interruption, the point in therapy at which the interruption occurred, and the bacillary load of the patient. The effects of interruptions in therapy are usually more serious if they occur earlier in treatment or are longer in duration; in these cases, the need to restart therapy from the beginning is greater. Continuous treatment is more essential in the initial phase than the continuation phase.

Treatment in Special Situations

HIV INFECTION

Treatment of tuberculosis in patients with HIV infection follows the same principles as treatment of patients without HIV infection. There are two exceptions: (1) once-weekly treatment with isoniazid-rifapentine in the continuation phase should not be used twice weekly in any patient with HIV infection; and (2) isoniazid-rifampin or rifabutin should not be used in patients with CD4+ lymphocyte counts less than 100 per mm3 (100 ×106 per L). The management of HIV-related tuberculosis is complicated because patients with HIV infection are often receiving multiple medications that may interact with tuberculosis medications, especially between the rifamycins and antiretroviral agents.

CHILDREN

Because infants and children younger than four years are at high risk of disseminated tuberculosis, treatment should be initiated as soon as the diagnosis of tuberculosis is suspected. The treatment regimen is the same as that for adults, except for ethambutol, which is not used routinely in children. In most cases, extrapulmonary tuberculosis in children can be treated with the same regimen as pulmonary tuberculosis. Exceptions include disseminated tuberculosis and tuberculosis meningitis, which should be treated for nine to 12 months.

EXTRAPULMONARY TUBERCULOSIS

The treatment of extrapulmonary tuberculosis relies on the same principles of treatment of pulmonary tuberculosis. The report recommends a six-month course of therapy for tuberculosis that involves any site, with the exception of meninges, for which a nine- to 12-month regimen is recommended. Therapy also should be prolonged in patients whose tuberculosis is slow to respond. Corticosteroids may be added to the treatment regimen of patients with tuberculous pericarditis or tuberculous meningitis.

RENAL AND HEPATIC DISEASE

For patients with renal insufficiency who are undergoing hemodialysis, administration of all medications should occur after dialysis to avoid premature removal of drugs such as pyrazinamide and cycloserine. The premature clearing effects of peritoneal dialysis on these drugs is unclear. Although rifampin, pyrazinamide, and isoniazid can cause hepatitis that may result in additional liver damage in patients with pre-existing liver disease, they still should be used if possible because of their effectiveness in the treatment of tuberculosis. In patients with pre-existing liver disease, frequent clinical and laboratory monitoring should be performed to detect drug-induced liver damage.

PREGNANCY AND BREASTFEEDING

Treatment of tuberculosis in pregnant women should be initiated whenever the suspicion of disease is moderate to high, because of the risk of tuberculosis to the fetus. The only antituberculosis medication that has been documented to have harmful effects on the fetus is streptomycin, and it should not be used in women who are pregnant. Women should not be discouraged from breastfeeding while being treated with first-line antituberculosis medications, because the small concentrations of these agents in breast milk do not cause toxicity in the nursing newborn.

Relapse, Treatment Failure, and Drug Resistance

Most relapses occur within six to 12 months after completion of therapy and may occur with drug-resistant or drug-susceptible strains of M. tuberculosis. In cases where a true relapse has been confirmed with microbiologic testing, the selection of treatment should be based on previous treatment and the severity of disease.

Treatment failure is defined as continued or recurrent positive cultures after four months of antituberculosis therapy during which medication ingestion was assured. Reasons for treatment failure in patients receiving appropriate regimens may include drug resistance, nonadherence to the drug regimen, laboratory error, extreme biologic variation in response, or malabsorption of the drugs. A single drug should never be added to a failing regimen, because this may lead to acquired resistance to the new drug. Instead, at least two, and preferably three, new drugs should be added to lessen the probability of further drug resistance.

Treatment of tuberculosis caused by drug-resistant organisms should be managed by or in close consultation with an expert in the management of these difficult cases.

Treatment of Tuberculosis in Low-Income Countries

The authors stress that the recommendations in their report are intended for treatment of tuberculosis in settings where mycobacterial cultures, radiographic facilities, and drug susceptibility testing are available. In areas where these resources are not available, they point toward the recommendations of the World Health Organization, the International Union Against Tuberculosis, or national tuberculosis control programs.

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