Summary. For most patients, the initial regimen for treating TB diseaseshould include four drugs: isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin. The regimen can be adjusted when drug susceptibility results become available. In areas where the rate of isoniazid resistance is documented to be less than 4%, three drugs (isoniazid, rifampin, and pyrazinamide) may be adequate for the initial regimen. A four-drug, 6-month regimen is effective even when the infecting organism is resistant to isoniazid. Alternatively, a 9-month regimen of isoniazid and rifampin is acceptable for persons who cannot or should not take pyrazinamide. Ethambutol or streptomycin should also be included in this regimen until the results of drug susceptibility studies are available, unless there is little possibility of drug resistance. The recommendations for duration of TB treatment in HIV-infected persons are the same as for persons not infected with HIV. The major determinant of the outcome of treatment is patient adherence to the drug regimen. Thus, careful attention should be paid to measures designed to foster adherence, and consideration should be given to treating all patients with DOT. Nearly all the treatment regimens may be given intermittently if they are directly observed. Multidrug-resistant TB (e.g., TB resistant to at least isoniazid and rifampin) presents difficult treatment problems, often requiring expert consultation.
TB must be treated for a long time (6-24 months) compared with many other infectious diseases. If treatment is not continued for a sufficient length of time, some tubercle bacilli may survive, and the patient may become ill and infectious again.
Regimens for the treatment of TB must contain multiple drugs to which the organisms are susceptible. The administration of a single drug can lead to the development of a bacterial population resistant to that drug. Likewise, the addition of a single drug to a failing regimen can lead to resistance to that drug. When two or more drugs are used simultaneously, each helps prevent the emergence of tubercle bacilli resistant to the others.
The initial phase of treatment is crucial for preventing the emergence of drug resistance and for determining the ultimate outcome of the regimen. Four drugs--isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin--should be included in the initial treatment regimen until the results of drug susceptibility tests are available. If there is little possibility of drug resistance (i.e., less than 4% primary resistance to isoniazid in the community and the patient has had no previous treatment with TB drugs, is not from a country with a high prevalence of drug resistance, and has no known exposure to a patient with drug-resistant disease), three drugs (isoniazid, rifampin, and pyrazinamide) may be adequate for the initial regimen.
There are several options for daily and intermittent therapy, but the aim of treatment should be to provide the safest and most effective therapy in the shortest period of time. Given adequate treatment, almost all patients will become bacteriologically negative, recover, and remain well.
For each new case of TB, a specific treatment and monitoring plan should be developed in collaboration with the local health department within 1 week of the presumptive diagnosis. This plan should include a description of the treatment regimen, the methods of assessing and ensuring adherence, and the methods of monitoring for adverse reactions.
Nonadherence is a major problem in TB control. On average, 25% of persons receiving treatment for TB disease do not complete a recommended regimen within 12 months. Inadequate treatment can lead to relapse, continued transmission, and the development of drug resistance.
Most health departments have public health nurses or community outreach workers who can work with patients and clinicians to help patients adhere to a prescribed regimen. Whenever possible, a worker who has the same cultural and linguistic background as the patient should be assigned to help develop an individualized treatment adherence plan.
One way to ensure that patients adhere to therapy is to use directly observed therapy (DOT). DOT means that a health care worker or another designated person watches the patient swallow each dose of TB medication. DOT should be considered for all patients because clinicians are often inaccurate in predicting which patients will adhere to medication on their own.
In many areas, patients are routinely given DOT. DOT has been shown to be cost-effective when intermittent regimens are used. Nearly all the treatment regimens for TB can be given intermittently if they are directly observed; using intermittent regimens reduces the total number of doses a patient must take, as well as the total number of encounters with the health care provider or outreach worker. Furthermore, DOT can significantly reduce the frequency of acquired drug resistance and relapse.
It is important that DOT be carried out at times and in locations that are as convenient as possible for the individual patient. Therapy may be directly observed in the office or clinic setting but also can be observed by an outreach worker in the field (i.e., the patient's home, place of employment, school, or other mutually agreed-upon place). In some situations, staff of correctional facilities, drug treatment programs, home health care workers, maternal and child health staff, or a responsible community or family member may provide DOT.
All patients should be educated about TB, the dosing of medications, the possible adverse reactions of the medications, and the importance of taking their medication. Health care workers must take the time to explain clearly to patients when the medication should be taken, how much, and how often, especially if the patient is not receiving DOT. Written instructions should also be provided.
Patients who are not receiving DOT should be asked routinely about adherence at follow-up visits. Pill counts should be taken routinely, and urine tests can be used periodically to check for the presence of drug metabolites. In addition, the patient's response to treatment (bacteriologic conversion to negative) should be monitored closely. If the patient's sputum remains positive after 2 months of treatment, DOT should be considered for the remainder of treatment.
Incentives should be used to enhance adherence to therapy. An incentive may be as simple as offering a cup of coffee and talking with a patient who is waiting in the clinic or as complex as providing food and housing for a homeless patient.
Health care professionals, including private practitioners, who note that a particular TB patient has demonstrated an inability or an unwillingness to adhere to a prescribed treatment regimen should consult the health department. The TB control program in the health department should assist in evaluating the patient for causes of nonadherence and should provide additional services, such as the services of outreach workers, to enable the patient to complete the recommended therapy. If these efforts are unsuccessful, the health department should take appropriate action, such as seeking court-ordered DOT or the detention of a patient who is unwilling or unable to complete treatment and who is infectious, at risk of becoming infectious, or at risk for drug-resistant TB.
When therapy is self-administered, the use of fixed-dose combination capsules or tablets may enhance patient adherence and reduce the risk of inappropriate monotherapy; it may also prevent the development of acquired drug resistance. For this reason, the use of such fixed-dose combinations is strongly encouraged for adults prescribed a self-administered regimen. In the United States, the Food and Drug Administration has licensed fixed-dose combinations of isoniazid and rifampin (Rifamate) and of isoniazid, rifampin, and pyrazinamide (Rifater). Clinicians should become familiar with these fixed-dose combination drugs.
The duration of therapy depends on the drugs used, the drug susceptibility test results, and the patient's response to therapy. Most patients with previously untreated pulmonary TB can be treated with either a 6-month or a 9-month regimen, although the 6-month regimen is preferred. Both the 6-month and 9-month regimens are referred to as short-course regimens. All regimens of 9 months or less must contain isoniazid and rifampin; all 6-month regimens must contain isoniazid, rifampin, and, initially, pyrazinamide.
For adults with smear- or culture-positive pulmonary TB, the initial phase of a 6-month regimen should consist of a 2-month period of isoniazid, rifampin, and pyrazinamide. Ethambutol or streptomycin should be included in the initial regimen until the results of drug susceptibility studies are available, unless there is little possibility of drug resistance (i.e., less than 4% primary drug resistance to isoniazid in the community, and the patient has had no previous treatment with TB drugs, is not from a country with a high prevalence of drug resistance, and has no known exposure to a person with drug resistant TB).
The initial use of a four-drug regimen is recommended to prevent the development of multidrug-resistant TB in areas where primary isoniazid resistance is increased. If susceptibility to isoniazid and rifampin is demonstrated, the second phase of treatment should consist of isoniazid and rifampin for 4 months.
If DOT is used, medications may be dosed intermittently. Several options exist for 6-month, intermittent regimens:
Because intermittent therapy is easier to supervise than daily therapy, intermittent therapy provides an effective tool with which to ensure adherence in the treatment of outpatients.
When isoniazid, pyrazinamide, and ethambutol or streptomycin are given two or three times a week instead of every day, the dose must be increased. However, the dose of rifampin is the same whether the drug is given daily or intermittently.
Alternatively, a 9-month regimen of isoniazid and rifampin is acceptable for persons who cannot or should not take pyrazinamide. Again, ethambutol or streptomycin should be included initially unless there is little possibility of drug resistance (patient has no individual risk factors for drug resistance and resides in an area where the prevalence of isoniazid-resistant TB <4%). If susceptibility to isoniazid and rifampin is demonstrated, isoniazid and rifampin may be given twice weekly after an initial 1 or 2 months of daily treatment.
For adults with smear- and culture-negative pulmonary TB, a 4-month regimen of isoniazid and rifampin, combined with pyrazinamide for the first 2 months, may be used when drug resistance is unlikely. However, for adults with smear- and culture-negative pulmonary TB who have individual risk factors for drug resistance or who live in an area where the prevalence of isoniazid-resistant TB is 4% or greater, four drugs (isoniazid, rifampin, pyrazinamide, and ethambutol or streptomycin) should be continued throughout the 4-month regimen.
The recommendations for the duration of TB treatment for HIV-infected persons are the same as for persons not infected with HIV. However, in HIV-infected patients, it is critically important to assess the clinical and bacteriologic response to therapy. Treatment should be prolonged if the response is slow or otherwise suboptimal. Because the effect of patient adherence on the outcome is much more crucial, DOT is strongly recommended for this group.
As a general rule, regimens that are adequate for treating pulmonary TB in adults and children are also effective for treating extrapulmonary disease. However, infants and children who have miliary TB, bone and joint TB, or TB meningitis should receive a minimum of 12 months of therapy.
The use of adjunctive therapies such as surgery and corticosteroids is more commonly required for extrapulmonary TB than for pulmonary disease. Surgery may be necessary to obtain specimens for diagnosis and to treat such processes as constrictive pericarditis and spinal cord compression from Pott's disease. Corticosteroids have been shown to be beneficial in preventing cardiac constriction from tuberculous pericarditis and in decreasing the neurologic sequelae of all stages of TB meningitis, especially when administered early in the course of disease.
In patients with extrapulmonary TB, the type of follow-up examinations should be determined by the site of the disease. Bacteriologic evaluation may be limited by the relative inaccessibility of the site. Thus, the response to treatment must often be judged on the basis of clinical and radiographic findings.
Pregnant women with TB must be given adequate therapy as soon as TB is suspected. The preferred initial treatment regimen is isoniazid, rifampin, and ethambutol (ethambutol may be excluded if primary isoniazid resistance is unlikely). Streptomycin should not be used because it has been shown to have harmful effects on the fetus. In addition, pyrazinamide should not be used routinely because its effect on the fetus is unknown. Because the 6-month treatment regimen cannot be used, a minimum of 9 months of therapy should be given. To prevent peripheral neuropathy, it is advisable to give pyridoxine to pregnant women who are taking isoniazid. See table 3 for information on the use of TB drugs to treat pregnant women.
The small concentrations of TB drugs in breast milk do not have a toxic effect on nursing newborns, and breast feeding should not be discouraged. Conversely, drugs in breast milk should not be considered effective treatment for disease or infection in a nursing infant.
Infants and children with TB should be treated with one of the regimens mentioned in the section Treatment of Pulmonary TB. The specific intermittent regimens have not been studied in children. However, the success of other intermittent regimens in children suggests that these regimens would be effective. Ethambutol is generally not used for young children whose visual acuity cannot be monitored. If ethambutol must be used to treat a young child (e.g., because of drug-resistant TB), the minimum dose should be used.
In infants, TB is much more likely to disseminate; therefore, prompt and vigorous treatment should be started as soon as the diagnosis is suspected.
Sputum specimens collected from children are often inadequate. In these situations, it may be necessary to rely on the results of cultures and susceptibility tests of specimens from the adult source case to confirm the diagnosis in the child and to guide the choice of drugs. When drug-resistant TB is suspected or isolates from a source case are not available, it may be necessary to perform gastric aspiration, bronchoalveolar lavage, or tissue diagnosis.
Furthermore, for children, bacteriologic examinations are less useful for evaluating the response to treatment than for adults; thus, clinical and radiographic examinations are more important for children. However, the chest radiographs of children with hilar adenopathy may not become normal for 2 to 3 years after treatment. In this situation, a normal chest radiograph is not a criterion for discontinuing TB drugs.
In general, extrapulmonary TB in children can be treated with the same regimens as pulmonary TB. The exceptions are bone and joint disease, disseminated (miliary) disease, and meningitis, for which a minimum of 12 months of therapy is recommended.
A 6-month regimen of isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin has been demonstrated to be effective for the treatment of TB resistant only to isoniazid. When resistance to isoniazid is documented during the recommended initial four-drug therapy, the regimen should be adjusted by discontinuing isoniazid and continuing the other three drugs for the entire 6 months of therapy. TB resistant only to isoniazid may also be treated with rifampin and ethambutol for 12 months.
When isoniazid resistance is documented in the 9-month regimen without pyrazinamide, isoniazid should be discontinued. If ethambutol was included in the initial regimen, treatment with rifampin and ethambutol should be continued for a minimum of 12 months. If ethambutol was not included initially, susceptibility tests should be repeated, isoniazid should be discontinued, and two drugs (e.g., ethambutol and pyrazinamide) should be added. The regimen can be adjusted when the results of the susceptibility tests become available.
Multidrug-resistant TB (i.e., TB resistant to at least isoniazid and rifampin) presents difficult treatment problems. Treatment must be individualized and based on the patient's medication history and susceptibility studies.
Unfortunately, adequate data are not available on the effectiveness of various regimens and the necessary duration of treatment for patients with organisms resistant to both isoniazid and rifampin. Moreover, many of these patients also have resistance to other first-line drugs (e.g., ethambutol and streptomycin) when drug resistance is discovered. Because of the poor outcome in such cases, it is preferable to give at least three new drugs to which the organism is susceptible. This regimen should be continued until culture conversion is documented, followed by at least 12 months of two-drug therapy. Often, a total of 24 months of therapy is given empirically.
Clinicians who are unfamiliar with the treatment of drug-resistant TB should seek expert consultation. Because second-line drugs can cause serious adverse reactions, patients taking these drugs should be monitored closely throughout the course of treatment. The role of new agents, such as the quinolone derivatives and amikacin, in the treatment of multidrug-resistant disease is not known, although these drugs are commonly being used in such cases.
Surgery seems to offer considerable benefit and a significantly improved cure rate for patients who have multidrug-resistant TB if the bulk of disease can be resected.
A number of medical conditions may alter immune responsiveness and predispose a person to TB. Such disorders include HIV infection, immunosuppressive therapy, hematologic or reticuloendothelial malignancies, chronic renal failure, and malnutrition. These conditions may influence the outcome of therapy. Therapeutic decisions for the impaired host must be individualized.
For patients with partial impairment of renal function, avoid streptomycin, kanamycin, and capreomycin if possible. If renal function is severely impaired, reduced doses or increased dosing intervals of other TB drugs may be necessary (see table 3). Measurement of blood concentrations may be helpful in adjusting dosage.
For patients who may abuse alcohol or who have neuropsychiatric disorders, close supervision--preferably using DOT--is necessary to ensure adherence and monitor for adverse reactions to medications.
Adverse reactions to TB drugs are relatively rare, but in some patients they may be severe. Clinicians who treat TB should be familiar with the methods of monitoring for adverse reactions and response to treatment. In some situations (e.g., drug-resistant TB, pregnant patients, HIV-infected patients), expert consultation may be required.
Adults treated for TB should have baseline measurements of hepatic enzymes, bilirubin, and serum creatinine or blood urea nitrogen, as well as a complete blood and platelet count (or estimate). Serum uric acid should be measured if pyrazinamide is used, and a baseline examination of visual acuity should be obtained for patients for whom ethambutol is prescribed. Audiometry should be performed at the beginning of therapy for patients for whom streptomycin is prescribed. The purpose of these baseline tests is to detect any abnormality that would complicate therapy or require a modified regimen. For children, only baseline vision tests are necessary unless a child has other medical conditions that may complicate therapy.
Monitoring for adverse reactions to TB medications must be individualized. The type and frequency of monitoring should depend on the drugs used in a given regimen and the patient's risk factors for adverse reactions (e.g., age, alcohol use). At a minimum, patients should be seen monthly during therapy and questioned by medical personnel concerning adverse reactions, even if no problems are apparent. Patients should be specifically instructed to look for symptoms associated with the most common reactions to the medications they are taking. They should also be instructed to seek medical attention immediately should these symptoms occur. If the symptoms suggest adverse reactions, appropriate laboratory testing should be performed.
All patients receiving isoniazid, rifampin, or pyrazinamide should be instructed to report immediately any symptoms suggesting hepatitis (nausea, loss of appetite, vomiting, persistently dark urine, yellowish skin, malaise, unexplained elevated temperature for more than 3 days, or abdominal tenderness). Patients receiving rifampin should be monitored for possible manifestations of thrombocytopenia (bleeding tendency, easy bruising, blood in urine) or flu-like syndromes.
Peripheral neuropathy is associated with the use of isoniazid but is uncommon at doses of 5 mg/kg. Persons with conditions in which neuropathy is common (e.g., diabetes, uremia, alcoholism, malnutrition), as well as pregnant women and persons with a seizure disorder, may be given pyridoxine (10-50 mg/day) with isoniazid. As little as 6 mg/day of pyridoxine has been shown to prevent isoniazid-associated neuropathy.
Hyperuricemia may occur in patients receiving pyrazinamide, but acute gout is uncommon. Asymptomatic hyperuricemia is not an indication for discontinuing the drug.
Audiometry should be performed at periodic intervals during streptomycin therapy. If vertigo, dizziness, or ataxia occur in patients taking streptomycin, the drug should be discontinued immediately.
The interaction of isoniazid and phenytoin increases the serum concentration of both drugs. When these drugs are given concomitantly, the serum level of phenytoin should be monitored.
Rifampin may accelerate the clearance of drugs metabolized by the liver. These include methadone, coumadin derivatives, glucocorticoids, estrogens, oral hypoglycemic agents, digitalis, anticonvulsants, ketoconazole, fluconazole, and cyclosporin. For patients who are in a drug treatment program, it may be necessary to increase the methadone dose by as much as 50%. Rifampin may also render oral contraceptives and contraceptive implants (e.g., Norplant) ineffective by accelerating estrogen metabolism. Women taking rifampin should use an alternative birth control method.
Current literature and package inserts should be consulted for other possible drug reactions.
For patients whose sputum cultures are positive before treatment, the best way to measure the effectiveness of therapy is to obtain specimens for culture at least monthly until the cultures convert to negative. Patients whose sputum no longer contains M. tuberculosis after 2 months of treatment should have at least one further sputum smear and culture performed at the completion of therapy. Patients with multidrug-resistant TB should have cultures performed monthly for the entire course of treatment.
Radiographic evaluations during treatment are of less importance than sputum evaluation. However, a chest film at completion of treatment provides a baseline for comparison with any future films.
More than 85% of patients taking isoniazid and rifampin become culture negative within 2 months of starting treatment. Patients whose cultures have not become negative or whose symptoms do not resolve after 2 months of therapy should be reevaluated for drug-resistant disease, as well as for failure to adhere to the regimen. If the patient is receiving self-administered therapy, the remainder of treatment should be directly observed.
While the results of drug susceptibility testing are pending, the original drug regimen may be continued or may be augmented by at least three drugs not given previously. Never add one drug at a time to a failing regimen. This may cause further drug resistance. If drug susceptibility results show resistance to any of the first-line drugs or if the patient remains symptomatic or smear or culture positive after 3 months, consult a TB medical expert.
In patients with negative sputum cultures before treatment, the major indicators of response to therapy are the chest radiograph and the clinical evaluation. The intervals at which chest radiography should be repeated depend on the clinical circumstances and the differential diagnosis that is being considered. If the radiograph does not improve after the patient has received 3 months of treatment, the abnormality may be the result of either previous (not current) TB or another process.
Routine follow-up after therapy is not necessary for patients who have had a satisfactory and prompt bacteriologic response to 6- or 9-month therapy with both isoniazid and rifampin. Patients whose organisms were fully susceptible to the drugs being used should be instructed to report promptly the development of any symptoms, particularly prolonged cough, fever, or weight loss. For patients with organisms resistant to isoniazid or rifampin or both, follow-up evaluation must be individualized.