Treatment of Tuberculosis

American Thoracic Society, CDC, and Infectious Diseases Society of America

Please note: An erratum has been published for this article. To view the erratum, please click here.

This Official Joint Statement of the American Thoracic Society, CDC, and the Infectious Diseases Society of America was approved by the ATS Board of Directors, by CDC, and by the Council of the IDSA in October 2002. This report appeared in the American Journal of Respiratory and Critical Care Medicine (2003;167:603--62) and is being reprinted as a courtesy to the American Thoracic Society, the Infectious Diseases Society of America, and the MMWR readership.

Purpose

The recommendations in this document are intended to guide the treatment of tuberculosis in settings where mycobacterial cultures, drug susceptibility testing, radiographic facilities, and second-line drugs are routinely available. In areas where these resources are not available, the recommendations provided by the World Health Organization, the International Union against Tuberculosis, or national tuberculosis control programs should be followed.

What's New In This Document

• The responsibility for successful treatment is clearly assigned to the public health program or private provider, not to the patient.
• It is strongly recommended that the initial treatment strategy utilize patient-centered case management with an adherence plan that emphasizes direct observation of therapy.
• Recommended treatment regimens are rated according to the strength of the evidence supporting their use. Where possible, other interventions are also rated.
• Emphasis is placed on the importance of obtaining sputum cultures at the time of completion of the initial phase of treatment in order to identify patients at increased risk of relapse.
• Extended treatment is recommended for patients with drug-susceptible pulmonary tuberculosis who have cavitation noted on the initial chest film and who have positive sputum cultures at the time 2 months of treatment is completed.
• The roles of rifabutin, rifapentine, and the fluoroquinolones are discussed and a regimen with rifapentine in a once-a-week continuation phase for selected patients is described.
• Practical aspects of therapy, including drug administration, use of fixed-dose combination preparations, monitoring and management of adverse effects, and drug interactions are discussed.
• Treatment completion is defined by number of doses ingested, as well as the duration of treatment administration.
• Special treatment situations, including human immunodeficiency virus infection, tuberculosis in children, extrapulmonary tuberculosis, culture-negative tuberculosis, pregnancy and breastfeeding, hepatic disease and renal disease are discussed in detail.
• The management of tuberculosis caused by drug-resistant organisms is updated.
• These recommendations are compared with those of the WHO and the IUATLD and the DOTS strategy is described.
• The current status of research to improve treatment is reviewed.

Summary

Responsibility for Successful Treatment

The overall goals for treatment of tuberculosis are 1) to cure the individual patient, and 2) to minimize the transmission of Mycobacterium tuberculosis to other persons. Thus, successful treatment of tuberculosis has benefits both for the individual patient and the community in which the patient resides. For this reason the prescribing physician, be he/she in the public or private sector, is carrying out a public health function with responsibility not only for prescribing an appropriate regimen but also for successful completion of therapy. Prescribing physician responsibility for treatment completion is a fundamental principle in tuberculosis control. However, given a clear understanding of roles and responsibilities, oversight of treatment may be shared between a public health program and a private physician.

Organization and Supervision of Treatment

Treatment of patients with tuberculosis is most successful within a comprehensive framework that addresses both clinical and social issues of relevance to the patient. It is essential that treatment be tailored and supervision be based on each patient's clinical and social circumstances (patient-centered care). Patients may be managed in the private sector, by public health departments, or jointly, but in all cases the health department is ultimately responsible for ensuring that adequate, appropriate diagnostic and treatment services are available, and for monitoring the results of therapy.

It is strongly recommended that patient-centered care be the initial management strategy, regardless of the source of supervision. This strategy should always include an adherence plan that emphasizes directly observed therapy (DOT), in which patients are observed to ingest each dose of antituberculosis medications, to maximize the likelihood of completion of therapy. Programs utilizing DOT as the central element in a comprehensive, patient-centered approach to case management (enhanced DOT) have higher rates of treatment completion than less intensive strategies. Each patient's management plan should be individualized to incorporate measures that facilitate adherence to the drug regimen. Such measures may include, for example, social service support, treatment incentives and enablers, housing assistance, referral for treatment of substance abuse, and coordination of tuberculosis services with those of other providers.

Recommended Treatment Regimens

The recommended treatment regimens are, in large part, based on evidence from clinical trials and are rated on the basis of a system developed by the United States Public Health Service (USPHS) and the Infectious Diseases Society of America (IDSA). The rating system includes a letter (A, B, C, D, or E) that indicates the strength of the recommendation and a roman numeral (I, II, or III) that indicates the quality of evidence supporting the recommendation (Table 1).

There are four recommended regimens for treating patients with tuberculosis caused by drug-susceptible organisms. Although these regimens are broadly applicable, there are modifications that should be made under specified circumstances, described subsequently. Each regimen has an initial phase of 2 months followed by a choice of several options for the continuation phase of either 4 or 7 months. The recommended regimens together with the number of doses specified by the regimen are described in Table 2. The initial phases are denoted by a number (1, 2, 3, or 4) and the continuation phases that relate to the initial phase are denoted by the number plus a letter designation (a, b, or c). Drug doses are shown in Tables 3, 4, and 5.

The general approach to treatment is summarized in Figure 1. Because of the relatively high proportion of adult patients with tuberculosis caused by organisms that are resistant to isoniazid, four drugs are necessary in the initial phase for the 6-month regimen to be maximally effective. Thus, in most circumstances, the treatment regimen for all adults with previously untreated tuberculosis should consist of a 2-month initial phase of isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB) (Table 2, Regimens 1--3). If (when) drug susceptibility test results are known and the organisms are fully susceptible, EMB need not be included. For children whose visual acuity cannot be monitored, EMB is usually not recommended except when there is an increased likelihood of the disease being caused by INH-resistant organisms (Table 6) or when the child has "adult-type" (upper lobe infiltration, cavity formation) tuberculosis. If PZA cannot be included in the initial phase of treatment, or if the isolate is resistant to PZA alone (an unusual circumstance), the initial phase should consist of INH, RIF, and EMB given daily for 2 months (Regimen 4). Examples of circumstances in which PZA may be withheld include severe liver disease, gout, and, perhaps, pregnancy. EMB should be included in the initial phase of Regimen 4 until drug susceptibility is determined.

The initial phase may be given daily throughout (Regimens 1 and 4), daily for 2 weeks and then twice weekly for 6 weeks (Regimen 2), or three times weekly throughout (Regimen 3). For patients receiving daily therapy, EMB can be discontinued as soon as the results of drug susceptibility studies demonstrate that the isolate is susceptible to INH and RIF. When the patient is receiving less than daily drug administration, expert opinion suggests that EMB can be discontinued safely in less than 2 months (i.e., when susceptibility test results are known), but there is no evidence to support this approach.

Although clinical trials have shown that the efficacy of streptomycin (SM) is approximately equal to that of EMB in the initial phase of treatment, the increasing frequency of resistance to SM globally has made the drug less useful. Thus, SM is not recommended as being interchangeable with EMB unless the organism is known to be susceptible to the drug or the patient is from a population in which SM resistance is unlikely.

The continuation phase (Table 2) of treatment is given for either 4 or 7 months. The 4-month continuation phase should be used in the large majority of patients. The 7-month continuation phase is recommended only for three groups: patients with cavitary pulmonary tuberculosis caused by drug-susceptible organisms and whose sputum culture obtained at the time of completion of 2 months of treatment is positive; patients whose initial phase of treatment did not include PZA; and patients being treated with once weekly INH and rifapentine and whose sputum culture obtained at the time of completion of the initial phase is positive. 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). For human immunodeficiency virus (HIV)-seronegative patients with noncavitary pulmonary tuberculosis (as determined by standard chest radiography), and negative sputum smears at completion of 2 months of treatment, the continuation phase may consist of rifapentine and INH given once weekly for 4 months by DOT (Regimens 1c and 2b) (Figure 1). If the culture at completion of the initial phase of treatment is positive, the once weekly INH and rifapentine continuation phase should be extended to 7 months. All of the 6-month regimens, except the INH--rifapentine once weekly continuation phase for persons with HIV infection (Rating EI), are rated as AI or AII, or BI or BII, in both HIV-infected and uninfected patients. The once-weekly continuation phase is contraindicated (Rating EI) in patients with HIV infection because of an unacceptable rate of failure/relapse, often with rifamycin-resistant organisms. For the same reason twice weekly treatment, either as part of the initial phase (Regimen 2) or continuation phase (Regimens 1b and 2a), is not recommended for HIV-infected patients with CD4⁺ cell counts <100 cells/µl. These patients should receive either daily (initial phase) or three times weekly (continuation phase) treatment. Regimen 4 (and 4a/4b), a 9-month regimen, is rated CI for patients without HIV infection and CII for those with HIV infection.

Deciding To Initiate Treatment

The decision to initiate combination antituberculosis chemotherapy should be based on epidemiologic information; clinical, pathological, and radiographic findings; and the results of microscopic examination of acid-fast bacilli (AFB)--stained sputum (smears) (as well as other appropriately collected diagnostic specimens) and cultures for mycobacteria. A purified protein derivative (PPD)-tuberculin skin test may be done at the time of initial evaluation, but a negative PPD-tuberculin skin test does not exclude the diagnosis of active tuberculosis. However, a positive PPD-tuberculin skin test supports the diagnosis of culture-negative pulmonary tuberculosis, as well as latent tuberculosis infection in persons with stable abnormal chest radiographs consistent with inactive tuberculosis (see below).

If the suspicion of tuberculosis is high or the patient is seriously ill with a disorder, either pulmonary or extrapulmonary, that is thought possibly to be tuberculosis, combination chemotherapy using one of the recommended regimens should be initiated promptly, often before AFB smear results are known and usually before mycobacterial culture results have been obtained. A positive AFB smear provides strong inferential evidence for the diagnosis of tuberculosis. If the diagnosis is confirmed by isolation of M. tuberculosis or a positive nucleic acid amplification test, treatment can be continued to complete a standard course of therapy (Figure 1). When the initial AFB smears and cultures are negative, a diagnosis other than tuberculosis should be considered and appropriate evaluations undertaken. If no other diagnosis is established and the PPD-tuberculin skin test is positive (in this circumstance a reaction of 5 mm or greater induration is considered positive), empirical combination chemotherapy should be initiated. If there is a clinical or radiographic response within 2 months of initiation of therapy and no other diagnosis has been established, a diagnosis of culture-negative pulmonary tuberculosis can be made and treatment continued with an additional 2 months of INH and RIF to complete a total of 4 months of treatment, an adequate regimen for culture-negative pulmonary tuberculosis (Figure 2). If there is no clinical or radiographic response by 2 months, treatment can be stopped and other diagnoses including inactive tuberculosis considered.

If AFB smears are negative and suspicion for active tuberculosis is low, treatment can be deferred until the results of mycobacterial cultures are known and a comparison chest radiograph is available (usually within 2 months) (Figure 2). In low-suspicion patients not initially being treated, if cultures are negative, the PPD-tuberculin skin test is positive (5 mm or greater induration), and the chest radiograph is unchanged after 2 months, one of the three regimens recommended for the treatment of latent tuberculosis infection could be used. These include (1) INH for a total of 9 months, (2) RIF with or without INH for a total of 4 months, or (3) RIF and PZA for a total of 2 months. Because of reports of an increased rate of hepatotoxicity with the RIF--PZA regimen, it should be reserved for patients who are not likely to complete a longer course of treatment, can be monitored closely, and do not have contraindications to the use of this egimen.

Baseline and Follow-Up Evaluations

Patients suspected of having tuberculosis should have appropriate specimens collected for microscopic examination and mycobacterial culture. When the lung is the site of disease, three sputum specimens should be obtained. Sputum induction with hypertonic saline may be necessary to obtain specimens and bronchoscopy (both performed under appropriate infection control measures) may be considered for patients who are unable to produce sputum, depending on the clinical circumstances. Susceptibility testing for INH, RIF, and EMB should be performed on a positive initial culture, regardless of the source of the specimen. Second-line drug susceptibility testing should be done only in reference laboratories and be limited to specimens from patients who have had prior therapy, who are contacts of patients with drug-resistant tuberculosis, who have demonstrated resistance to rifampin or to other first-line drugs, or who have positive cultures after more than 3 months of treatment.

It is recommended that all patients with tuberculosis have counseling and testing for HIV infection, at least by the time treatment is initiated, if not earlier. For patients with HIV infection, a CD4⁺ lymphocyte count should be obtained. Patients with risk factors for hepatitis B or C viruses (e.g., injection drug use, foreign birth in Asia or Africa, HIV infection) should have serologic tests for these viruses. For all adult patients baseline measurements of serum amino transferases (aspartate aminotransferase [AST], alanine aminotransferase [ALT]), bilirubin, alkaline phosphatase, and serum creatinine and a platelet count should be obtained. Testing of visual acuity and red-green color discrimination should be obtained when EMB is to be used.

During treatment of patients with pulmonary tuberculosis, a sputum specimen for microscopic examination and culture should be obtained at a minimum of monthly intervals until two consecutive specimens are negative on culture. More frequent AFB smears may be useful to assess the early response to treatment and to provide an indication of infectiousness. For patients with extrapulmonary tuberculosis the frequency and kinds of evaluations will depend on the site involved. In addition, it is critical that patients have clinical evaluations at least monthly to identify possible adverse effects of the antituberculosis medications and to assess adherence. Generally, patients do not require follow-up after completion of therapy but should be instructed to seek care promptly if signs or symptoms recur.

Routine measurements of hepatic and renal function and platelet count are not necessary during treatment unless patients have baseline abnormalities or are at increased risk of hepatotoxicity (e.g., hepatitis B or C virus infection, alcohol abuse). At each monthly visit patients taking EMB should be questioned regarding possible visual disturbances including blurred vision or scotomata; monthly testing of visual acuity and color discrimination is recommended for patients taking doses that on a milligram per kilogram basis are greater than those listed in Table 5 and for patients receiving the drug for longer than 2 months.

Identification and Management of Patients at Increased Risk of Treatment Failure and Relapse

The presence of cavitation on the initial chest radiograph combined with having a positive sputum culture at the time the initial phase of treatment is completed has been shown in clinical trials to identify patients at high risk for adverse outcomes (treatment failure, usually defined by positive cultures after 4 months of treatment, or relapse, defined by recurrent tuberculosis at any time after completion of treatment and apparent cure). For this reason it is particularly important to conduct a microbiological evaluation 2 months after initiation of treatment (Figure 1). Approximately 80% of patients with pulmonary tuberculosis caused by drug-susceptible organisms who are started on standard four-drug therapy will have negative sputum cultures at this time. Patients with positive cultures after 2 months of treatment should undergo careful evaluation to determine the cause. For patients who have positive cultures after 2 months of treatment and have not been receiving DOT, the most common reason is nonadherence to the regimen. Other possibilities, especially for patients receiving DOT, include extensive cavitary disease at the time of diagnosis, drug resistance, malabsorption of drugs, laboratory error, and biological variation in response.

In USPHS Study 22, nearly 21% of patients in the control arm of the study (a continuation phase of twice weekly INH and RIF) who had both cavitation on the initial chest radiograph and a positive culture at the 2-month juncture relapsed. Patients who had only one of these factors (either cavitation or a positive 2-month culture) had relapse rates of 5--6% compared with 2% for patients who had neither risk factor. In view of this evidence, it is recommended that, for patients who have cavitation on the initial chest radiograph and whose 2-month culture is positive, the minimum duration of treatment should be 9 months (a total of 84--273 doses depending on whether the drugs are given daily or intermittently) (Figure 1 and Table 2). The recommendation to lengthen the continuation phase of treatment is based on expert opinion and on the results of a study of the optimal treatment duration for patients with silicotuberculosis showing that extending treatment from 6 to 8 months greatly reduced the rate of relapse (Rating AIII). The recommendation is also supported by the results of a trial in which the once weekly INH--rifapentine continuation phase was extended to 7 months for patients at high risk of relapse. The rate of relapse was reduced significantly compared with historical control subjects from another trial in which the continuation phase was 4 months.

For patients who have either cavitation on the initial film or a positive culture after completing the initial phase of treatment (i.e., at 2 months), the rates of relapse were 5--6%. In this group decisions to prolong the continuation phase should be made on an individual basis.

Completion of Treatment

A full course of therapy (completion of treatment) is determined more accurately by the total number of doses taken, not solely by the duration of therapy. For example, the "6-month" daily regimen (given 7 days/week; see below) should consist of at least 182 doses of INH and RIF, and 56 doses of PZA. Thus, 6 months is the minimum duration of treatment and accurately indicates the amount of time the drugs are given only if there are no interruptions in drug administration. In some cases, either because of drug toxicity or nonadherence to the treatment regimen, the specified number of doses cannot be administered within the targeted period. In such cases the goal is to deliver the specified number of doses within a recommended maximum time. For example, for a 6-month daily regimen the 182 doses should be administered within 9 months of beginning treatment. If treatment is not completed within this period, the patient should be assessed to determine the appropriate action to take---continuing treatment for a longer duration or restarting treatment from the beginning, either of which may require more restrictive measures to be used to ensure completion.

Clinical experience suggests that patients being managed by DOT administered 5 days/week have a rate of successful therapy equivalent to those being given drugs 7 days/week. Thus, "daily therapy" may be interpreted to mean DOT given 5 days/week and the required number of doses adjusted accordingly. For example, for the 6-month "daily" regimen given 5 days/week the planned total number of doses is 130. (Direct observation of treatment given 5 days/week has been used in a number of clinical trials, including USPHS Study 22, but has not been evaluated in a controlled trial; thus, this modification should be rated AIII.) As an option, patients might be given the medications to take without DOT on weekends.

Interruptions in treatment may have a significant effect on the duration of therapy. Reinstitution of treatment must take into account the bacillary load of the patient, the point in time when the interruption occurred, and the duration of the interruption. In general, the earlier in treatment and the longer the duration of the interruption, the more serious the effect and the greater the need to restart therapy from the beginning.

Practical Aspects of Patient Management During Treatment

The first-line antituberculosis medications should be administered together; split dosing should be avoided. Fixed-dose combination preparations may be administered more easily than single drug tablets and may decrease the risk of acquired drug resistance and medication errors. Fixed-dose combinations may be used when DOT is given daily and are especially useful when DOT is not possible, but they are not formulated for use with intermittent dosing. It should be noted that for patients weighing more than 90 kg the dose of PZA in the three-drug combination is insufficient and additional PZA tablets are necessary. There are two combination formulations approved for use in the United States: INH and RIF (Rifamate^®) and INH, RIF, and PZA (Rifater^®).

Providers treating patients with tuberculosis must be especially vigilant for drug interactions. Given the frequency of comorbid conditions, it is quite common for patients with tuberculosis to be taking a variety of other medications, the effects of which may be altered by the antituberculosis medications, especially the rifamycins. These interactions are described in Section 7, Drug Interactions.

Adverse effects, especially gastrointestinal upset, are relatively common in the first few weeks of antituberculosis therapy; however, first-line antituberculosis drugs, particularly RIF, must not be discontinued because of minor side effects. Although ingestion with food delays or moderately decreases the absorption of antituberculosis drugs, the effects of food are of little clinical significance. Thus, if patients have epigastric distress or nausea with the first-line drugs, dosing with meals or changing the hour of dosing is recommended. Administration with food is preferable to splitting a dose or changing to a second-line drug.

Drug-induced hepatitis, the most serious common adverse effect, is defined as a serum AST level more than three times the upper limit of normal in the presence of symptoms, or more than five times the upper limit of normal in the absence of symptoms. If hepatitis occurs INH, RIF, and PZA, all potential causes of hepatic injury, should be stopped immediately. Serologic testing for hepatitis viruses A, B, and C (if not done at baseline) should be performed and the patient questioned carefully regarding exposure to other possible hepatotoxins, especially alcohol. Two or more antituberculosis medications without hepatotoxicity, such as EMB, SM, amikacin/kanamycin, capreomycin, or a fluoroquinolone (levofloxacin, moxifloxacin, or gatifloxacin), may be used until the cause of the hepatitis is identified. Once the AST level decreases to less than two times the upper limit of normal and symptoms have significantly improved, the first-line medications should be restarted in sequential fashion. Close monitoring, with repeat measurements of serum AST and bilirubin and symptom review, is essential in managing these patients.

Treatment in Special Situations

HIV infection

Recommendations for the treatment of tuberculosis in HIV-infected adults are, with a few exceptions, the same as those for HIV-uninfected adults (Table 2). The INH--rifapentine once weekly continuation phase (Regimens 1c and 2b) is contraindicated in HIV-infected patients because of an unacceptably high rate of relapse, frequently with organisms that have acquired resistance to rifamycins. The development of acquired rifampin resistance has also been noted among HIV-infected patients with advanced immunosuppression treated with twice weekly rifampin- or rifabutin-based regimens. Consequently, patients with CD4⁺ cell counts <100/µl should receive daily or three times weekly treatment (Regimen 1/1a or Regimen 3/3a). DOT and other adherence-promoting strategies are especially important for patients with HIV-related tuberculosis.

Management of HIV-related tuberculosis is complex and requires expertise in the management of both HIV disease and tuberculosis. Because HIV-infected patients are often taking numerous medications, some of which interact with antituberculosis medications, it is strongly encouraged that experts in the treatment of HIV-related tuberculosis be consulted. A particular concern is the interaction of rifamycins with antiretroviral agents and other antiinfective drugs. Rifampin can be used for the treatment of tuberculosis with certain combinations of antiretroviral agents. Rifabutin, which has fewer problematic drug interactions, may also be used in place of rifampin and appears to be equally effective although the doses of rifabutin and antiretroviral agents may require adjustment. As new antiretroviral agents and more pharmacokinetic data become available, these recommendations are likely to be modified.

On occasion, patients with HIV-related tuberculosis may experience a temporary exacerbation of symptoms, signs, or radiographic manifestations of tuberculosis while receiving antituberculosis treatment. This clinical or radiographic worsening (paradoxical reaction) occurs in HIV-infected patients with active tuberculosis and is thought to be the result of immune reconstitution as a consequence of effective antiretroviral therapy. Symptoms and signs may include high fevers, lymphadenopathy, expanding central nervous system lesions, and worsening of chest radiographic findings. The diagnosis of a paradoxical reaction should be made only after a thorough evaluation has excluded other etiologies, particularly tuberculosis treatment failure. Nonsteroidal antiinflammatory agents may be useful for symptomatic relief. For severe paradoxical reactions, prednisone (1--2 mg/kg per day for 1--2 weeks, then in gradually decreasing doses) may be used, although there are no data from controlled trials to support this approach (Rating CIII).

Children

Because of the high risk of disseminated tuberculosis in infants and children younger than 4 years of age, treatment should be started as soon as the diagnosis of tuberculosis is suspected. In general, the regimens recommended for adults are also the regimens of choice for infants, children, and adolescents with tuberculosis, with the exception that ethambutol is not used routinely in children. Because there is a lower bacillary burden in childhood-type tuberculosis there is less concern with the development of acquired drug resistance. However, children and adolescents may develop "adult-type" tuberculosis with upper lobe infiltration, cavitation, and sputum production. In such situations an initial phase of four drugs should be given until susceptibility is proven. When clinical or epidemiologic circumstances (Table 6) suggest an increased probability of INH resistance, EMB can be used safely at a dose of 15--20 mg/kg per day, even in children too young for routine eye testing. Streptomycin, kanamycin, or amikacin also can be used as the fourth drug, when necessary.

Most studies of treatment in children have used 6 months of INH and RIF supplemented during the first 2 months with PZA. This three-drug combination has a success rate of greater than 95% and an adverse drug reaction rate of less than 2%. Most treatment studies of intermittent dosing in children have used daily drug administration for the first 2 weeks to 2 months. DOT should always be used in treating children.

Because it is difficult to isolate M. tuberculosis from a child with pulmonary tuberculosis, it is frequently necessary to rely on the results of drug susceptibility tests of the organisms isolated from the presumed source case to guide the choice of drugs for the child. In cases of suspected drug-resistant tuberculosis in a child or when a source case isolate is not available, specimens for microbiological evaluation should be obtained via early morning gastric aspiration, bronchoalveolar lavage, or biopsy.

In general, extrapulmonary tuberculosis in children can be treated with the same regimens as pulmonary disease. Exceptions are disseminated tuberculosis and tuberculous meningitis, for which there are inadequate data to support 6-month therapy; thus 9--12 months of treatment is recommended.

The optimal treatment of pulmonary tuberculosis in children and adolescents with HIV infection is unknown. The American Academy of Pediatrics recommends that initial therapy should always include at least three drugs, and the total duration of therapy should be at least 9 months, although there are no data to support this recommendation.

Extrapulmonary tuberculosis

The basic principles that underlie the treatment of pulmonary tuberculosis also apply to extrapulmonary forms of the disease. Although relatively few studies have examined treatment of extrapulmonary tuberculosis, increasing evidence suggests that 6- to 9-month regimens that include INH and RIF are effective. Thus, a 6-month course of therapy is recommended for treating tuberculosis involving any site with the exception of the meninges, for which a 9- 12-month regimen is recommended. Prolongation of therapy also should be considered for patients with tuberculosis in any site that is slow to respond. The addition of corticosteroids is recommended for patients with tuberculous pericarditis and tuberculous meningitis.

Culture-negative pulmonary tuberculosis and radiographic evidence of prior pulmonary tuberculosis

Failure to isolate M. tuberculosis from persons suspected of having pulmonary tuberculosis on the basis of clinical features and chest radiographic examination does not exclude a diagnosis of active tuberculosis. Alternative diagnoses should be considered carefully and further appropriate diagnostic studies undertaken in persons with apparent culture-negative tuberculosis. The general approach to management is shown in Figure 2. A diagnosis of tuberculosis can be strongly inferred by the clinical and radiographic response to antituberculosis treatment. Careful reevaluation should be performed after 2 months of therapy to determine whether there has been a response attributable to antituberculosis treatment. If either clinical or radiographic improvement is noted and no other etiology is identified, treatment should be continued for active tuberculosis. Treatment regimens in this circumstance include one of the standard 6-month chemotherapy regimens or INH, RIF, PZA, and EMB for 2 months followed by INH and RIF for an additional 2 months (4 months total). However, HIV-infected patients with culture-negative pulmonary tuberculosis should be treated for a minimum of 6 months.

Persons with a positive tuberculin skin test who have radiographic evidence of prior tuberculosis (e.g., upper lobe fibronodular infiltrations) but who have not received adequate therapy are at increased risk for the subsequent development of tuberculosis. Unless previous radiographs are available showing that the abnormality is stable, it is recommended that sputum examination (using sputum induction if necessary) be performed to assess the possibility of active tuberculosis being present. Also, if the patient has symptoms of tuberculosis related to an extrapulmonary site, an appropriate evaluation should be undertaken. Once active tuberculosis has been excluded (i.e., by negative cultures and a stable chest radiograph), the treatment regimens are those used for latent tuberculosis infection: INH for 9 months, RIF (with or without INH) for 4 months, or RIF and PZA for 2 months (for patients who are unlikely to complete a longer course and who can be monitored closely) (Figure 2).

Renal insufficiency and end-stage renal disease

Specific dosing guidelines for patients with renal insufficiency and end-stage renal disease are provided in Table 15. For patients undergoing hemodialysis, administration of all drugs after dialysis is preferred to facilitate DOT and to avoid premature removal of drugs such as PZA and cycloserine. To avoid toxicity it is important to monitor serum drug concentrations in persons with renal failure who are taking cycloserine or EMB. There is little information concerning the effects of peritoneal dialysis on clearance of antituberculosis drugs.

Liver disease

INH, RIF, and PZA all can cause hepatitis that may result in additional liver damage in patients with preexisting liver disease. However, because of the effectiveness of these drugs (particularly INH and RIF), they should be used if at all possible, even in the presence of preexisting liver disease. If serum AST is more than three times normal before the initiation of treatment (and the abnormalities are not thought to be caused by tuberculosis), several treatment options exist. One option is to treat with RIF, EMB, and PZA for 6 months, avoiding INH. A second option is to treat with INH and RIF for 9 months, supplemented by EMB until INH and RIF susceptibility are demonstrated, thereby avoiding PZA. For patients with severe liver disease a regimen with only one hepatotoxic agent, generally RIF plus EMB, could be given for 12 months, preferably with another agent, such as a fluoroquinolone, for the first 2 months; however, there are no data to support this recommendation.

In all patients with preexisting liver disease, frequent clinical and laboratory monitoring should be performed to detect drug-induced hepatic injury.

Pregnancy and breastfeeding

Because of the risk of tuberculosis to the fetus, treatment of tuberculosis in pregnant women should be initiated whenever the probability of maternal disease is moderate to high. The initial treatment regimen should consist of INH, RIF, and EMB. Although all of these drugs cross the placenta, they do not appear to have teratogenic effects. Streptomycin is the only antituberculosis drug documented to have harmful effects on the human fetus (congenital deafness) and should not be used. Although detailed teratogenicity data are not available, PZA can probably be used safely during pregnancy and is recommended by the World Health Organization (WHO) and the International Union against Tuberculosis and Lung Disease (IUATLD). If PZA is not included in the initial treatment regimen, the minimum duration of therapy is 9 months.

Breastfeeding should not be discouraged for women being treated with the first-line antituberculosis agents because the small concentrations of these drugs in breast milk do not produce toxicity in the nursing newborn. Conversely, drugs in breast milk should not be considered to serve as effective treatment for tuberculosis or for latent tuberculosis infection in a nursing infant. Pyridoxine supplementation (25 mg/day) is recommended for all women taking INH who are either pregnant or breastfeeding. The amount of pyridoxine in multivitamins is variable but generally less than the needed amount.

Management of Relapse, Treatment Failure, and Drug Resistance

Relapse refers to the circumstance in which a patient becomes and remains culture negative while receiving therapy but, at some point after completion of therapy, either becomes culture positive again or has clinical or radiographic deterioration that is consistent with active tuberculosis. In the latter situation rigorous efforts should be made to establish a diagnosis and to obtain microbiological confirmation of the relapse to enable testing for drug resistance. Most relapses occur within the first 6--12 months after completion of therapy. In nearly all patients with tuberculosis caused by drug-susceptible organisms and who were treated with rifamycin-containing regimens using DOT, relapses occur with susceptible organisms. However, in patients who received self-administered therapy or a nonrifamycin regimen and who have a relapse, the risk of acquired drug resistance is substantial. In addition, if initial drug susceptibility testing was not performed and the patient fails or relapses with a rifamycin-containing regimen given by DOT, there is a high likelihood that the organisms were resistant from the outset.

The selection of empirical treatment for patients with relapse should be based on the prior treatment scheme and severity of disease. For patients with tuberculosis that was caused by drug-susceptible organisms and who were treated under DOT, initiation of the standard four-drug regimen is appropriate until the results of drug susceptibility tests are available. However, for patients who have life-threatening forms of tuberculosis, at least three additional agents to which the organisms are likely to be susceptible should be included.

For patients with relapse who did not receive DOT, who were not treated with a rifamycin-based regimen, or who are known or presumed to have had irregular treatment, it is prudent to infer that drug resistance is present and to begin an expanded regimen with INH, RIF, and PZA plus an additional two or three agents based on the probability of in vitro susceptibility. Usual agents to be employed would include a fluoroquinolone (levofloxacin, moxifloxacin, or gatifloxacin), an injectable agent such as SM (if not used previously and susceptibility to SM had been established), amikacin, kanamycin, or capreomycin, with or without an additional oral drug.

Treatment failure is defined as continued or recurrently positive cultures during the course of antituberculosis therapy. After 3 months of multidrug therapy for pulmonary tuberculosis caused by drug-susceptible organisms, 90--95% of patients will have negative cultures and show clinical improvement. Thus, patients with positive cultures after 3 months of what should be effective treatment must be evaluated carefully to identify the cause of the delayed conversion. Patients whose sputum cultures remain positive after 4 months of treatment should be deemed treatment failures.

Possible reasons for treatment failure in patients receiving appropriate regimens include nonadherence to the drug regimen (the most common reason), drug resistance, malabsorption of drugs, laboratory error, and extreme biological variation in response. If treatment failure occurs, early consultation with a specialty center is strongly advised. If failure is likely due to drug resistance and the patient is not seriously ill, an empirical retreatment regimen could be started or administration of an altered regimen could be deferred until results of drug susceptibility testing from a recent isolate are available. If the patient is seriously ill or sputum AFB smears are positive, an empirical regimen should be started immediately and continued until susceptibility tests are available. For patients who have treatment failure, M. tuberculosis isolates should be sent promptly to a reference laboratory for drug susceptibility testing to both first- and second-line agents.

A fundamental principle in managing patients with treatment failure is never to add a single drug to a failing regimen; so doing leads to acquired resistance to the new drug. Instead, at least two, and preferably three, new drugs to which susceptibility could logically be inferred should be added to lessen the probability of further acquired resistance. Empirical retreatment regimens might include a fluoroquinolone, an injectable agent such as SM (if not used previously and the patient is not from an area of the world having high rates of SM resistance), amikacin, kanamycin, or capreomycin, and an additional oral agent such as p-aminosalicylic acid (PAS), cycloserine, or ethionamide. Once drug-susceptibility test results are available, the regimen should be adjusted according to the results.

Patients having tuberculosis caused by strains of M. tuberculosis resistant to at least INH and RIF (multidrug-resistant [MDR]) are at high risk for treatment failure and further acquired drug resistance. Such patients should be referred to or consultation obtained from specialized treatment centers as identified by the local or state health departments or CDC. Although patients with strains resistant to RIF alone have a better prognosis than patients with MDR strains, they are also at increased risk for treatment failure and additional resistance and should be managed in consultation with an expert.

Definitive randomized or controlled studies have not been performed to establish optimum regimens for treating patients with the various patterns of drug-resistant tuberculosis; thus, treatment recommendations are based on expert opinion, guided by a set of general principles specified in Section 9, Management of Relapse, Treatment Failure, and Drug Resistance. Table 16 contains treatment regimens suggested for use in patients with various patterns of drug-resistant tuberculosis (all are rated AIII).

The role of resectional surgery in the management of patients with extensive pulmonary MDR tuberculosis has not been established in randomized studies and results have been mixed. Surgery should be performed by surgeons with experience in these situations and only after the patient has received several months of intensive chemotherapy. Expert opinion suggests that chemotherapy should be continued for 1--2 years postoperatively to prevent relapse.

Treatment of Tuberculosis in Low-Income Countries: Recommendations of the WHO and Guidelines from the IUATLD

To place the current guidelines in an international context it is necessary to have an understanding of the approaches to treatment of tuberculosis in high-incidence, low-income countries. It is important to recognize that the American Thoracic Society/CDC/Infectious Diseases Society of America (ATS/CDC/IDSA) recommendations cannot be assumed to be applicable under all epidemiologic and economic circumstances. The incidence of tuberculosis and the resources with which to confront the disease to an important extent determine the approaches used. Given the increasing proportion of patients in low-incidence countries who were born in high-incidence countries, it is also important for persons managing these cases to be familiar with the approaches used in the countries of origin.

The major international recommendations and guidelines for treating tuberculosis are those of the WHO and of the IUATLD. The WHO document was developed by an expert committee whereas the IUATLD document is a distillation of IUATLD practice, validated in the field.

The WHO and IUATLD documents target, in general, countries in which mycobacterial culture, drug susceptibility testing, radiographic facilities, and second-line drugs are not widely available as a routine. A number of differences exist between these new ATS/CDC/IDSA recommendations, and the current tuberculosis treatment recommendations of the WHO and guidelines of the IUATLD. Both international sets of recommendations are built around a national case management strategy called "DOTS," the acronym for "directly observed therapy, short course," in which direct observation of therapy (DOT) is only one of five key elements. The five components of DOTS are 1) government commitment to sustained tuberculosis control activities, 2) case detection by sputum smear microscopy among symptomatic patients self-reporting to health services, 3) a standardized treatment regimen of 6--8 months for at least all confirmed sputum smear--positive cases, with DOT for at least the initial 2 months, 4) a regular, uninterrupted supply of all essential antituberculosis drugs, and 5) a standardized recording and reporting system that enables assessment of treatment results for each patient and of the tuberculosis control program overall.

A number of other differences exist as well:

• The WHO and the IUATLD recommend diagnosis and classification of tuberculosis cases and assessment of response based on sputum AFB smears. Culture and susceptibility testing for new patients is not recommended because of cost, limited applicability, and lack of facilities.
• Chest radiography is recommended by both the WHO and IUATLD only for patients with negative sputum smears and is not recommended at all for follow-up.
• Both 6- and 8-month treatment regimens are recommended by the WHO. The IUATLD recommends an 8-month regimen with thioacetazone in the continuation phase for HIV-negative patients. For patients suspected of having or known to have HIV infection, ethambutol is substituted for thioacetazone
• The WHO and the IUATLD recommend a standardized 8-month regimen for patients who have relapsed, had interrupted treatment, or have failed treatment. Patients who have failed supervised retreatment are considered "chronic" cases and are highly likely to have tuberculosis caused by MDR organisms. Susceptibility testing and a tailored regimen using second-line drugs based on the test results are recommended by the WHO, if testing and second-line drugs are available. The IUATLD recommendations do not address the issue.
• Neither baseline nor follow-up biochemical testing is recommended by the WHO and the IUATLD. It is recommended that patients be taught to recognize the symptoms associated with drug toxicity and to report them promptly.

A Research Agenda for Tuberculosis Treatment

New antituberculosis drugs are needed for three main reasons: 1) to shorten or otherwise simplify treatment of tuberculosis caused by drug-susceptible organisms, 2) to improve treatment of drug-resistant tuberculosis, and 3) to provide more efficient and effective treatment of latent tuberculosis infection. No truly novel compounds that are likely to have a significant impact on tuberculosis treatment are close to clinical trials. However, further work to optimize the effectiveness of once-a-week rifapentine regimens using higher doses of the drug and using rifapentine in combination with moxifloxacin is warranted, on the basis of experimental data.

New categories of drugs that have shown promise for use in treating tuberculosis include the nitroimidazopyrans and the oxazolidinones. Experimental data also suggest that a drug to inhibit an enzyme, isocitrate lyase, thought to be necessary for maintaining the latent state, might be useful for treatment of latent tuberculosis infection.

A number of other interventions that might lead to improved treatment outcome have been suggested, although none has undergone rigorous clinical testing. These include various drug delivery systems, cytokine inhibitors, administration of "protective" cytokines such as interferon-g and interleukin-2, and nutritional supplements, especially vitamin A and zinc.

Research is also needed to identify factors that are predictive of a greater or lesser risk of relapse to determine optimal length of treatment. Identification of such factors would enable more efficient targeting of resources to supervise treatment. In addition, identification of behavioral factors that identify patients at greater or lesser likelihood of being adherent to therapy would also enable more efficient use of DOT.

1. Introduction and Background

Since 1971 the American Thoracic Society (ATS) and CDC have regularly collaborated to develop joint guidelines for the diagnosis, treatment, prevention, and control of tuberculosis (1). These documents have been intended to guide both public health programs and health care providers in all aspects of the clinical and public health management of tuberculosis in low-incidence countries, with a particular focus on the United States. The most recent version of guidelines for the treatment of tuberculosis was published in 1994 (2).

The current document differs from its predecessor in a number of important areas that are summarized above. The process by which this revision of the recommendations for treatment was developed was modified substantially from the previous versions. For the first time the Infectious Diseases Society of America (IDSA) has become a cosponsor of the statement, together with the ATS and CDC. The IDSA has had representation on prior statement committees but has not previously been a cosponsor of the document. Practice guidelines that serve to complement the current statement have been developed by the IDSA (3). In addition to the IDSA, representatives of the American Academy of Pediatrics (AAP), the (United States) National Tuberculosis Controllers Association (NTCA), the Canadian Thoracic Society (CTS), the IUATLD, and the WHO participated in the revision. By virtue of their different perspectives these committee members served to provide broader input and to help ensure that the guidelines are placed in an appropriate context. It should be emphasized that the current guidelines are intended for areas in which mycobacterial cultures, drug susceptibility tests, radiographic facilities, and second-line drugs are available, either immediately or by referral, on a routine basis.

For this revision of the recommendations essentially all clinical trials of antituberculosis treatment in the English language literature were reviewed and the strength of the evidence they presented was rated according to the IDSA/USPHS rating scale (4).

This revision of the recommendations for treatment of tuberculosis presents a significant philosophic departure from previous versions. In this document the responsibility for successful treatment of tuberculosis is placed primarily on the provider or program initiating therapy rather than on the patient. It is well established that appropriate treatment of tuberculosis rapidly renders the patient noninfectious, prevents drug resistance, minimizes the risk of disability or death from tuberculosis, and nearly eliminates the possibility of relapse. For these reasons, antituberculosis chemotherapy is both a personal and a public health measure that cannot be equated with the treatment of, for example, hypertension or diabetes mellitus, wherein the benefits largely accrue to the patient. Provider responsibility is a central concept in treating patients with tuberculosis, no matter what the source of their care. All reasonable attempts should be made to accommodate the patient so that a successful outcome is achieved. However, interventions such as detention may be necessary for patients who are persistently nonadherent.

The recommendations in this statement are not applicable under all epidemiologic circumstances or across all levels of resources that are available to tuberculosis control programs worldwide. Although the basic principles of therapy described in this document apply regardless of conditions, the diagnostic approach, methods of patient supervision, and monitoring for response and for adverse drug effects, and in some instances the regimens recommended, are quite different in high-incidence, low-income areas compared with low-incidence, high-income areas of the world. A summary of the important differences between the recommendations in this document and those of the IUATLD and the WHO is found in Section 10,Treatment of Tuberculosis in Low-Income Countries: Recommendations of the WHO and the IUTLD.

In the United States there has been a call for the elimination of tuberculosis, and a committee constituted by the Institute of Medicine (IOM) issued a set of recommendations for reaching this goal (5). The IOM committee had two main recommendations related to treatment of tuberculosis; first, that all U.S jurisdictions have health regulations that mandate completion of therapy (treatment until the patient is cured); and second, that all treatment be administered in the context of patient-centered programs that are based on individual patient characteristics and needs. The IOM recommendations emphasize the importance of the structure and organization of treatment services, as well as the drugs that are used, to treat patients effectively. This philosophy is the core of the DOTS strategy (described in Section 10 Treatment of Tuberculosis in Low-Income Countries: Recommendations oof the WHO and the IUTLD), developed by the IUATLD and implemented globally by the WHO. Thus, although there are superficial differences in the approach to tuberculosis treatment between high- and low-incidence countries, the fundamental concern, regardless of where treatment is given, is ensuring patient adherence to the drug regimen and successful completion of therapy (6).

References

1. DuMelle FJ, Hopewell PC. The CDC and the American Lung Association/American Thoracic Society: an enduring public/private partnership. In: Centers for Disease Control and Prevention: a century of notable events in TB control. TB Notes Newslett 2000;1:23--27.
2. American Thoracic Society, Centers for Disease Control and Prevention. Treatment of tuberculosis and tuberculosis infection in adults and children. Am J Respir Crit Care Med 1994;149:1359--1374. Available at http://www.thoracic.org/adobe/statements/tbchild1-16.pdf
3. Horsburgh CR Jr, Feldman S, Ridzon R. Practice guidelines for the treatment of tuberculosis. Clin Infect Dis 2000;31:633--639.
4. Gross PA, Barrett TL, Dellinger EP, Krause PJ, Martone WJ, McGowan JE Jr, Sweet RL, Wenzel RP. Purpose of quality standards for infectious diseases. Clin Infect Dis 1994;18:421.
5. Geiter LJ, editor. Ending neglect: the elimination of tuberculosis in the United States. Institute of Medicine, Committee on Elimination of Tuberculosis in the United States. Washington, DC: National Academy Press; 2000. Available at http://www.nap.edu/catalog/9837.html.
6. World Health Organization. What is DOTS? A guide to understanding the WHO-recommended TB control strategy known as DOTS. WHO/CDS/CPC/TB/99.270. Geneva, Switzerland: World Health Organization; 1999. Available at http://www.who.int/gtb/dots.

2. Organization and Supervision of Treatment

Successful treatment of tuberculosis depends on more than the science of chemotherapy. To have the highest likelihood of success, chemotherapy must be provided within a clinical and social framework based on an individual patient's circumstances. Optimal organization of treatment programs requires an effective network of primary and referral services and cooperation between clinicians and public health officials, between health care facilities and community outreach programs, and between the private and public sectors of medical care. This section describes the approaches to organization of treatment that serve to ensure that treatment has a high likelihood of being successful.

As noted previously, antituberculosis chemotherapy is both a personal health measure intended to cure the sick patient and a basic public health strategy intended to reduce the transmission of Mycobacterium tuberculosis. Typically, tuberculosis treatment is provided by public health departments, often working in collaboration with other providers and organizations including private physicians, community health centers, migrant health centers, correctional facilities, hospitals, hospices, long-term care facilities, and homeless shelters. Private providers and public health departments may cosupervise patients, assuring that the patient completes therapy in a setting that is not only mutually agreeable but also enables access to tuberculosis expertise and resources that might otherwise not be available. In managed care settings delivery of tuberculosis treatment may require a more structured public/private partnership, often defined by a contract, to assure completion of therapy. Regardless of the means by which treatment is provided, the ultimate legal authority for assuring that patients complete therapy rests with the public health system.

2.1. Role of the Health Department

The responsibility of the health department in the control of tuberculosis is to ensure that all persons who are suspected of having tuberculosis are identified and evaluated promptly and that an appropriate course of treatment is prescribed and completed successfully (1,2). A critical component of the evaluation scheme is access to proficient microbiological laboratory services, for which the health department is responsible.

The responsibilities of the health department may be accomplished indirectly by epidemiologic surveillance and monitoring of treatment decisions and outcome, applying generally agreed-on standards and guidelines, or more directly by provision of diagnostic and treatment services, as well as by conducting epidemiologic investigations. Given the diverse sociodemographic characteristics of patients with tuberculosis and the many mechanisms by which health care is delivered, the means by which the goals of the health department are accomplished may be quite varied.

In dealing with individual patients, approaches that focus on each person's needs and characteristics should be used to determine a tailored treatment plan that is designed to ensure completion of therapy (3). Such treatment plans are developed with the patient as an active participant together with the physician and/or nurse, outreach workers, social worker (when needed), and others as appropriate. Given that one-half the current incident cases of tuberculosis in the United States were born outside the United States (similar circumstances prevail in most other low-incidence countries), translation of materials into the patient's primary language is often necessary to ensure his/her participation in developing the treatment plan. Ideally, a specific case manager is assigned individual responsibility for assuring that the patient completes therapy. The treatment plan is reviewed periodically and revised as needed. These reviews may be accomplished in meetings between the patient and the assigned provider, as well as more formally through case and cohort evaluations. The treatment plan is based on the principle of using the least restrictive measures that are likely to achieve success. The full spectrum of measures that may be employed ranges from, at an absolute minimum, monthly monitoring of the patient in the outpatient setting to legally mandated hospitalization (4). Directly observed therapy (DOT) is the preferred initial means to assure adherence. For nonadherent patients more restrictive measures are implemented in a stepwise fashion. Any approach must be balanced, ensuring that the needs and rights of the patient, as well as those of the public, are met. Care plans for patients being managed in the private sector should be developed jointly by the health department and the private provider, and must address identified and anticipated barriers to adherence.

2.2. Promoting Adherence

Louis Pasteur once said, "The microbe is nothing...the terrain everything" (5). Assuming appropriate drugs are prescribed, the terrain (the circumstances surrounding each patient that may affect his or her ability to complete treatment) becomes the most important consideration in completion of tuberculosis treatment. Many factors may be part of this terrain. Factors that interfere with adherence to the treatment regimen include cultural and linguistic barriers to cooperation, lifestyle differences, homelessness, substance abuse, and a large number of other conditions and circumstances that, for the patient, are priorities that compete with taking treatment for tuberculosis (6). Barriers may be patient related, such as conflicting health beliefs, alcohol or drug dependence, or mental illness, or they may be system related, such as lack of transportation, inconvenient clinic hours, and lack of interpreters (7). Effective tuberculosis case management identifies and characterizes the terrain and determines an appropriate care plan based on each of the identified factors. Additional advantages of the patient-centered approach are that, by increasing communication with the patient, it provides opportunities for further education concerning tuberculosis and enables elicitation of additional information concerning contacts.

To maximize completion of therapy, patient-centered programs identify and utilize a broad range of approaches based on the needs and circumstances of individual patients. Among these approaches, DOT is the preferred initial strategy and deserves special emphasis. Although DOT itself has not been subjected to controlled trials in low-incidence areas (and, thus, is rated AII), observational studies and a meta-analysis in the United States strongly suggest that DOT, coupled with individualized case management, leads to the best treatment results (8--10). To date there have been three published studies of DOT in high-incidence areas, two of which (11,12) showed no benefit and one (13) in which there was a significant advantage for DOT. What is clear from these studies is that DOT cannot be limited merely to passive observation of medication ingestion; there must be aggressive interventions when patients miss doses. Using DOT in this manner can only improve results.

DOT can be provided daily or intermittently in the office, clinic, or in the "field" (patient's home, place of employment, school, street corner, bar, or any other site that is mutually agreeable) by appropriately trained personnel. DOT should be used for all patients residing in institutional settings such as hospitals, nursing homes, or correctional facilities, or in other settings, such as methadone treatment sites, that are conducive to observation of therapy (14). However, even in such supervised settings careful attention must be paid to ensuring that ingestion of the medication is, in fact, observed. It is essential that all patients being treated with regimens that use intermittent drug administration have all doses administered under DOT because of the potentially serious consequences of missed doses. DOT also enables early identification of nonadherence, adverse drug reactions, and clinical worsening of tuberculosis. DOT provides a close connection to the health care system for a group of patients at high risk of other adverse health events and, thus, should facilitate identification and management of other conditions.

The use of DOT does not guarantee ingestion of all doses of every medication (15). Patients may miss appointments, may not actually swallow the pills, or may deliberately regurgitate the medications. Consequently, all patients, including those who are being treated by DOT, should continue to be monitored for signs of treatment failure. DOT is only one aspect of a comprehensive patient-centered program that, in addition, includes incentives and enablers described subsequently (16--20). Patients who are more likely to present a transmission risk to others or are more likely to have problems with adherence (Table 7) should be prioritized for DOT when resources are limited. When DOT is not being used, fixed-dose combination preparations (see Section 6.2, Fixed-Dose Combination Preparations) containing INH and RIF or INH, RIF, and PZA reduce the risk of the patient taking only one drug and may help prevent the development of drug resistance. Combination formulations are easier to administer and also may reduce medication errors.

Depending on the identified obstacles to completion of therapy, the treatment plan may also include enablers and incentives such as those listed in Table 8. Studies have examined the use of a patient-centered approach that utilizes DOT in addition to other adherence-promoting tools (9,21,22). These studies demonstrate, as shown in Figure 3, that "enhanced DOT" (DOT together with incentives and enablers) produces the highest treatment completion rates (in excess of 90% across a range of geographic and socioeconomic settings), and reinforces the importance of patient-related factors in designing and implementing case management (9,23).

Intensive educational efforts should be initiated as soon as the patient is suspected of having tuberculosis. The instruction should be at an educational level appropriate for the patient and should include information about tuberculosis, expected outcomes of treatment, the benefits and possible adverse effects of the drug regimen, methods of supervision, assessment of response, and a discussion of infectiousness and infection control. The medication regimen must be explained in clear, understandable language and the verbal explanation followed with written instructions. An interpreter is necessary when the patient and health care provider do not speak the same language. Materials should be appropriate for the culture, language, age, and reading level of the patient. Relevant information should be reinforced at each visit.

The patient's clinical progress and the treatment plan must be reviewed at least monthly to evaluate the response to therapy and to identify adherence problems. Use of a record system (Figure 4) either manual or computer-based, that quantifies the dosage and frequency of medication administered, indicates AFB smear and culture status, and notes symptom improvement as well as any adverse effects of treatment serves to facilitate the regular reviews and also provides data for cohort analyses. In addition, adherence monitoring by direct methods, such as the detection of drugs or drug metabolites in the patient's urine, or indirect methods, such as pill counts or a medication monitor, should be a part of routine management, especially if the patient is not being given DOT.

Tracking patients is also a critical concern for those charged with assuring completion of treatment. It has been shown that patients who move from one jurisdiction to another before completion of therapy are much more likely to default than patients who do not move (24). Factors that have been shown to be associated with moving/defaulting include diagnosis of tuberculosis in a state correctional facility, drug and alcohol abuse, and homelessness. Communication and coordination of services among different sources of care and different health departments are especially important for patients in these groups as well as for migrant workers and other patients with no permanent home. Such communication may also be necessary across national boundaries, especially the United States--Mexico border, and there are systems in place to facilitate such communication and tracking.

Some patients, for example those with tuberculosis caused by drug-resistant organisms, or who have comorbid conditions, such as HIV infection, alcoholism, or other significant underlying disorders, may need to be hospitalized in a facility where tuberculosis expertise is available and where there are appropriate infection control measures in place. Hospitalization may be necessary for nonadherent patients for whom less restrictive measures have failed (25--27). Public health laws exist in most states that allow the use of detainment under these circumstances, at least for patients who remain infectious (28). Court-ordered DOT has been used successfully in some states as a less costly alternative. The use of these interventions depends on the existence of appropriate laws, cooperative courts, and law enforcement officials, and the availability of appropriate facilities. Health departments must be consulted to initiate legal action when it is necessary.

References

1. CDC Essential components of a tuberculosis prevention and control program. MMWR 1995;44(RR-11):1--16.
2. Simone PM, Fujiwara PI. Role of the health department: legal and public health implications. In: Schlossberg D, editor. Tuberculosis and nontuberculous mycobacterial infections, 4th edition. Philadelphia: W.B. Saunders, 1999:130--9.
3. Etkind SC. The role of the public health department in tuberculosis control. Med Clin North Am 1993;77:1303--14.
4. National Tuberculosis Controllers Association, National TB Nursing Consultant Coalition. Tuberculosis nursing: a comprehensive guide to patient care. Atlanta, GA: National Tuberculosis Controllers Association and National Tuberculosis Nursing Consultant Coalition, 1997:69--84.
5. Delhoume L. De Claude Bernard a d'Arsonval. Paris: J.B. Baillière et Fils, 1939:595.
6. Moss AR, Hahn JA, Tulsky JP, Daley CL, Small PM, Hopewell PC. Tuberculosis in the homeless: a prospective study. Am J Respir Crit Care Med 2000;162:460--4.
7. Sumartojo E. When tuberculosis treatment fails: a social behavioral account of patient adherence. Am Rev Respir Dis 1993;147:1311--20.
8. Chaulk CP, Moore-Rice K, Rizzo R, Chaisson RE. Eleven years of community-based directly observed therapy for tuberculosis. JAMA 1995;274:945--51.
9. Chaulk CP, Kazandjian VA. Directly observed therapy for treatment completion of tuberculosis: census statement of the Public Health Tuberculosis Guidelines Panel. JAMA 1998;279:943--8.
10. Weis SE, Slocum PC, Blais FX, King B, Nunn M, Matney GB, Gomez E, Foresman BH. The effect of directly observed therapy on the rates of drug resistance and relapse in tuberculosis. N Engl J Med 1994;330:1179--84.
11. Zwarenstein M, Schoeman JH, Vundule C, Lombard CJ, Tatley M. Randomised controlled trial of self-supervised and directly observed treatment of tuberculosis. Lancet 1998;352:1340--3.
12. Walley JD, Khan MR, Newell JN, Khan MH. Effectiveness of the direct observation component of DOTS for tuberculosis: a randomised controlled trial in Pakistan. Lancet 2001;357:664--9.
13. Kamolratanakul P, Sawert H, Lertmaharit S, Kasetjaroen Y, Akksilp S, Tulaporn C, Punnachest K, Na-Songkhla S, Payanandana V. Randomized controlled trial of directly observed treatment (DOT) for patients with pulmonary tuberculosis in Thailand. Trans R Soc Trop Med Hyg 1999;5:552--7.
14. Snyder DC, Paz EA, Mohle-Boetani JC, Fallstad R, Balck RL, Chin DP. Tuberculosis prevention in methadone maintenance clinics: effectiveness and cost-effectiveness. Am J Respir Crit Care Med 1999;160:178--85.
15. Burman WJ, Cohn DL, Rietmeijer CA, Judson FN, Sbarbaro JA, Reves RR. Noncompliance with directly observed therapy for tuberculosis: epidemiology and effect on the outcome of treatment. Chest 1997;111:1168--73.
16. Volmink J, Matchaba P, Garner P. Directly observed therapy and treatment adherence. Lancet 2000;355:1345--50.
17. Bayer R, Stayton C, Desvarieux M, Healton C, Landesman S, Tsai W. Directly observed therapy and treatment completion in the United States: is universal supervised therapy necessary? Am J Public Health 1998;88:1052--8.
18. Poszik CJ. Compliance with tuberculosis therapy. Med Clin North Am 1993;77:1289--1300.
19. Lobue PA, Cass R, Lobo D, Moser K, Catanzaro A. Development of housing programs to aid in the treatment of tuberculosis in homeless individuals: a pilot study. Chest 1999;115:218--23.
20. Black B, Bruce ME. Treating tuberculosis: the essential role of social work. Soc Work Health Care 1998;26:51--68.
21. Moore RD, Chaulk CP, Griffiths R, Cavalcante S, Chaisson RE. Cost-effectiveness of directly observed versus self-administered therapy for tuberculosis. Am J Respir Crit Care Med 1996;154:1013--9.
22. Burman WJ, Dalton CB, Cohn DL, Butler RG, Reves RR. A cost-effectiveness analysis of directly observed therapy versus self-administered therapy for treatment of tuberculosis. Chest 1997;112:63--70.
23. Davidson H, Smirnoff M, Klein SJ, Burdick E. Patient satisfaction with care at directly observed therapy programs for tuberculosis in New York City. Am J Public Health 1999;89:1567--70.
24. Cummings KC, Mohle-Boetani J, Royce SE, Chin DP. Movement of tuberculosis patients and the failure to complete antituberculosis treatment. Am J Respir Crit Care Med 1998;157:1249--52.
25. Oscherwitz T, Tulsky JP, Roger S, Sciortino S, Alpers A, Royce S, Lo B. Detention of persistently nonadherent patients with tuberculosis. JAMA 1997;278:843--6.
26. Singleton L, Turner M, Haskal R, Etkind S, Tricarico M, Nardell E. Long term hospitalization for tuberculosis control: experience with a medical--psychosocial inpatient unit. JAMA 1997;278:838--42.
27. Gasner MR, Maw KL, Feldman GE, Fujiwara PI, Frieden TR. The use of legal action in New York City to ensure treatment of tuberculosis. N Engl J Med 1999;340:359--66.
28. Gostin LO. Controlling the resurgent tuberculosis epidemic: a 50 state survey of TB statutes and proposals for reform. JAMA 1993;269:255--61.

3. Drugs in Current Use

Currently, there are 10 drugs approved by the United States Food and Drug Administration (FDA) for treating tuberculosis (Table 9). In addition, the fluoroquinolones, although not approved by the FDA for tuberculosis, are used relatively commonly to treat tuberculosis caused by drug-resistant organisms or for patients who are intolerant of some of the first-line drugs. Rifabutin, approved for use in preventing Mycobacterium avium complex disease in patients with HIV infection but not approved for tuberculosis, is useful for treating tuberculosis in patients concurrently taking drugs that have unacceptable interactions with other rifamycins. Amikacin and kanamycin, nearly identical aminoglycoside drugs used in treating patients with tuberculosis caused by drug-resistant organisms, are not approved by the FDA for tuberculosis.

Of the approved drugs isoniazid (INH), rifampin (RIF), ethambutol (EMB), and pyrazinamide (PZA) are considered first-line antituberculosis agents and form the core of initial treatment regimens. Rifabutin and rifapentine may also be considered first-line agents under the specific situations described below. Streptomycin (SM) was formerly considered to be a first-line agent and, in some instances, is still used in initial treatment; however, an increasing prevalence of resistance to SM in many parts of the world has decreased its overall usefulness. The remaining drugs are reserved for special situations such as drug intolerance or resistance.

The drug preparations available currently and the recommended doses are shown in Tables 3, 4, and 5.

3.1. First-Line Drugs

3.1.1. Isoniazid

Role in treatment regimen. Isoniazid (INH) is a first-line agent for treatment of all forms of tuberculosis caused by organisms known or presumed to be susceptible to the drug. It has profound early bactericidal activity against rapidly dividing cells (1,2).

Dose. See Table 3.

Adults (maximum): 5 mg/kg (300 mg) daily; 15 mg/kg (900 mg) once, twice, or three times weekly.

Children (maximum): 10--15 mg/kg (300 mg) daily; 20--30 mg/kg (900 mg) twice weekly (3).

Preparations. Tablets (50 mg, 100 mg, 300 mg); syrup (50 mg/5 ml); aqueous solution (100 mg/ml) for intravenous or intramuscular injection.

Adverse effects.

Asymptomatic elevation of aminotransferases: Aminotransferase elevations up to five times the upper limit of normal occur in 10--20% of persons receiving INH alone for treatment of latent tuberculosis infection (4). The enzyme levels usually return to normal even with continued administration of the drug.

Clinical hepatitis: (see Table 10.) Data indicate that the incidence of clinical hepatitis is lower than was previously thought. Hepatitis occurred in only 0.1--0.15% of 11,141 persons receiving INH alone as treatment for latent tuberculosis infection in an urban tuberculosis control program (5). Prior studies suggested a higher rate, and a meta-analysis of six studies estimated the rate of clinical hepatitis in patients given INH alone to be 0.6% (6--8). In the meta-analysis the rate of clinical hepatitis was 1.6% when INH was given with other agents, not including RIF. The risk was higher when the drug was combined with RIF, an average of 2.7% in 19 reports (8). For INH alone the risk increases with increasing age; it is uncommon in persons less than 20 years of age but is nearly 2% in persons aged 50--64 years (6). The risk also may be increased in persons with underlying liver disease, in those with a history of heavy alcohol consumption, and, data suggest, in the postpartum period, particularly among Hispanic women (9).

Fatal hepatitis: A large survey estimated the rate of fatal hepatitis to be 0.023%, but more recent studies suggest the rate is substantially lower (10,11). The risk may be increased in women. Death has been associated with continued administration of INH despite onset of symptoms of hepatitis (12).

Peripheral neurotoxicity (13,14): This adverse effect is dose related and is uncommon (less than 0.2%) at conventional doses (15--17). The risk is increased in persons with other conditions that may be associated with neuropathy such as nutritional deficiency, diabetes, HIV infection, renal failure, and alcoholism, as well as for pregnant and breastfeeding women. Pyridoxine supplementation (25 mg/day) is recommended for patients with these conditions to help prevent this neuropathy (18).

Central nervous system effects: Effects such as dysarthria, irritability, seizures, dysphoria, and inability to concentrate have been reported but have not been quantified.

Lupus-like syndrome (19): Approximately 20% of patients receiving INH develop anti-nuclear antibodies. Less than 1% develop clinical lupus erythematosis, necessitating drug discontinuation.

Hypersensitivity reactions: Reactions, such as fever, rash, Stevens-Johnson syndrome, hemolytic anemia, vasculitis, and neutropenia are rare.

Monoamine (histamine/tyramine) poisoning: This has been reported to occur after ingestion of foods and beverages with high monoamine content but is rare (20--22). If flushing occurs, patients should be instructed to avoid foods and drinks, such as certain cheeses and wine, having high concentrations of monoamines.

Diarrhea: Use of the commercial liquid preparation of INH, because it contains sorbitol, is associated with diarrhea.

Use in pregnancy. INH is considered safe in pregnancy, but the risk of hepatitis may be increased in the peripartum period (9,23). Pyridoxine supplementation (25 mg/day) is recommended if INH is administered during pregnancy (18). It should be noted that multivitamin preparations have variable amounts of pyridoxine but generally less than 25 mg/day and, thus, do not provide adequate supplementation.

CNS penetration. Penetration is excellent. Cerebrospinal fluid (CSF) concentrations are similar to concentrations achieved in serum (24).

Use in renal disease. (See Section 8.7: Renal Insufficiency and End-Stage Renal Disease.) INH can be used safely without dose adjustment in patients with renal insufficiency (25) and with end-stage renal isease who require chronic hemodialysis (26).

Use in hepatic disease. (See Section 8.8: Hepatic Disease.) The risk of drug accumulation and drug-induced hepatitis may be increased in the presence of hepatic disease; however, INH may be used in patients with stable hepatic disease. Laboratory and clinical monitoring should be more frequent in such situations.

Monitoring. Routine monitoring is not necessary. However, for patients who have preexisting liver disease or who develop abnormal liver function that does not require discontinuation of the drug, liver function tests should be measured monthly and when symptoms occur. Serum concentrations of phenytoin and carbamazepine may be increased in persons taking INH. However, in combination therapy with RIF the effects of INH on serum concentrations of the anticonvulsants are limited by the decrease caused by RIF. Thus, it is important to measure serum concentrations of these drugs in patients receiving INH with or without RIF and adjust the dose if necessary.

3.1.2. Rifampin

Role in treatment regimen. Rifampin (RIF) is a first-line agent for treatment of all forms of tuberculosis caused by organisms with known or presumed sensitivity to the drug. It has activity against organisms that are dividing rapidly (early bactericidal activity) (1) and against semidormant bacterial populations, thus accounting for its sterilizing activity (27). Rifampin is an essential component of all short-course regimens.

Dose. See Table 3.

Adults (maximum): 10 mg/kg (600 mg) once daily, twice weekly, or three times weekly.

Children (maximum): 10--20 mg/kg (600 mg) once daily or twice weekly.

Preparations. Capsules (150 mg, 300 mg); contents of capsule may also be mixed in an appropriate diluent to prepare an oral suspension; aqueous solution for parenteral administration.

Adverse effects (28).

Cutaneous reactions (29): Pruritis with or without rash may occur in as many as 6% of patients but is generally self-limited (30). This reaction may not represent true hypersensitivity and continued treatment with the drug may be possible. More severe, true hypersensitivity reactions are uncommon, occurring in 0.07--0.3% of patients (17,31,32).

Gastrointestinal reactions (nausea, anorexia, abdominal pain): The incidence is variable, but symptoms are rarely severe enough to necessitate discontinuation of the drug (28--30).

Flulike syndrome: This may occur in 0.4--0.7% of patients receiving 600 mg twice weekly but not with daily administration of the same dose (31--34). Symptoms are more likely to occur with intermittent administration of a higher dose (29,35).

Hepatotoxicity: Transient asymptomatic hyperbilirubinemia may occur in as many as 0.6% of patients receiving the drug. More severe clinical hepatitis that, typically, has a cholestatic pattern may also occur (8,36). Hepatitis is more common when the drug is given in combination with INH (2.7%) than when given alone (nearly 0%) or in combination with drugs other than INH (1.1%) (8).

Severe immunologic reactions: In addition to cutaneous reactions and flulike syndrome, other reactions thought to be immune mediated include the following: thrombocytopenia, hemolytic anemia, acute renal failure, and thrombotic thrombocytopenic purpura. These reactions are rare, each occurring in less than 0.1% of patients (31,32,37).

Orange discoloration of bodily fluids (sputum, urine, sweat, tears): This is a universal effect of the drug. Patients should be warned of this effect at the time treatment is begun. Soft contact lenses and clothing may be permanently stained.

Drug interactions due to induction of hepatic microsomal enzymes: There are a number of drug interactions (described in Section 7, Drug Interactions, and Table 12) with potentially serious consequences. Of particular concern are reductions, often to ineffective levels, in serum concentrations of common drugs, such as oral contraceptives, methadone, and warfarin. In addition there are important bidirectional interactions between rifamycins and antiretroviral agents. Because information regarding rifamycin drug interactions is evolving rapidly, readers are advised to consult the CDC web site www.cdc.gov/nchstp/tb/ to obtain the most up-to-date information.

Use in pregnancy. RIF is considered safe in pregnancy (38).

CNS penetration. Concentrations in the CSF may be only 10--20% of serum levels, but this is sufficient for clinical efficacy. Penetration may be improved in the setting of meningitis (39).

Use in renal disease. (See Section 8.7: Renal Insufficiency and End-Stage Renal Disease.) RIF can be used safely without dose adjustment in patients with renal insufficiency and end-stage renal disease (26,40).

Use in hepatic disease. (see Section 8.8: Hepatic Disease.) Clearance of the drug may be impaired in the presence of liver disease, causing increased serum levels (40). However, because of the critical importance of rifampin in all short-course regimens, it generally should be included, but the frequency of clinical and laboratory monitoring should be increased.

Monitoring. No routine monitoring tests are required. However, rifampin causes many drug interactions described in Section 7, Drug Interactions, that may necessitate regular measurements of the serum concentrations of the drugs in question.

3.1.3. Rifabutin

Role in treatment regimen. Rifabutin is used as a substitute for RIF in the treatment of all forms of tuberculosis caused by organisms that are known or presumed to be susceptible to this agent. The drug is generally reserved for patients who are receiving any medication having unacceptable interactions with rifampin (41) or have experienced intolerance to rifampin.

Dose. See Table 3.

Adults (maximum): 5 mg/kg (300 mg) daily, twice, or three times weekly. The dose may need to be adjusted when there is concomitant use of protease inhibitors or nonnucleoside reverse transcriptase inhibitors. When rifabutin is used with efavirenz the dose of rifabutin should be increased to 450--600 mg either daily or intermittently. Because information regarding rifamycin drug interactions is evolving rapidly readers are advised to consult the CDC web site, http://www.cdc.gov/nchstp/tb/, to obtain the most up-to-date information.

Children (maximum): Appropriate dosing for children is unknown.

Preparations: Capsules (150 mg) for oral administration.

Adverse effects.

Hematologic toxicity: In a placebo-controlled, double-blind trial involving patients with advanced acquired immunodeficiency syndrome (AIDS) (CD4+ cell counts <200 cells/µl), neutropenia occurred in 25% compared with 20% in patients receiving placebo (p = 0.03). Neutropenia severe enough to necessitate discontinuation of the drug occurred in 2% of patients receiving the drug (product insert B; Adria Laboratories, Columbus, OH). The effect is dose related, occurring more frequently with daily than with intermittent administration of the same dose (42). In several studies of patients with and without HIV infection, neither neutropenia nor thrombocytopenia was associated with rifabutin (43--47).

Uveitis: This is a rare (less than 0.01%) complication when the drug is given alone at a standard (300 mg daily) dose. The occurrence is higher (8%) with higher doses or when rifabutin is used in combination with macrolide antimicrobial agents that reduce its clearance (48). Uveitis may also occur with other drugs that reduce clearance such as protease inhibitors and azole antifungal agents.

Gastrointestinal symptoms: These symptoms occurred in 3% of patients with advanced HIV infection given 300 mg/day (package insert). In subsequent studies no increased incidence of gastrointestinal symptoms was noted among patients taking rifabutin (43,44,46--48).

Polyarthralgias: This symptom occurred in 1--2% of persons receiving a standard 300-mg dose (package insert). It is more common at higher doses (48). Polyarthralgias have not been noted in more recent studies involving both HIV-infected and uninfected patients (43,44,46,47).

Hepatotoxity: Asymptomatic elevation of liver enzymes has been reported at a frequency similar to that of RIF (48). Clinical hepatitis occurs in less than 1% of patients receiving the drug.

Pseudojaundice (skin discoloration with normal bilirubin): This is usually self-limited and resolves with discontinuation of the drug (49).

Rash: Although initially reported to occur in as many as 4% of patients with advanced HIV infection, subsequent studies suggest that rash is only rarely (less than 0.1%) associated with rifabutin (46).

Flulike syndrome: Flulike syndrome is rare (less than 0.1%) in patients taking rifabutin.

Orange discoloration of bodily fluids (sputum, urine, sweat, tears): This is a universal effect of the drug. Patients should be warned of this effect at the time treatment is begun. Soft contact lenses and clothing may be permanently stained.

Use in pregnancy. There are insufficient data to recommend the use of rifabutin in pregnant women; thus, the drug should be used with caution in pregnancy.

CNS penetration. The drug penetrates inflamed meninges (50).

Use in renal disease. (See Section 8.7: Renal Insufficiency and End-Stage Renal Disease.) Rifabutin may be used without dosage adjustment in patients with renal insufficiency and end-stage renal disease (50).

Use in hepatic disease. (See Section 8.8: Hepatic Disease.) The drug should be used with increased clinical and laboratory monitoring in patients with underlying liver disease. Dose reduction may be necessary in patients with severe liver dysfunction (50).

Monitoring. Monitoring is similar to that recommended for rifampin. Although drug interactions are less problematic with rifabutin, they still occur and close monitoring is required.

3.1.4. Rifapentine

Role in treatment regimen. Rifapentine may be used once weekly with INH in the continuation phase of treatment for HIV-seronegative patients with noncavitary, drug-susceptible pulmonary tuberculosis who have negative sputum smears at completion of the initial phase of treatment (51).

Dose. See Table 3.

Adults (maximum): 10 mg/kg (600 mg), once weekly during the continuation phase of treatment. Data have suggested that a dose of 900 mg is well tolerated but the clinical efficacy of this dose has not been established (52).

Children: The drug is not approved for use in children.

Preparation. Tablet (150 mg, film coated).

Adverse effects.

The adverse effects of rifapentine are similar to those associated with RIF. Rifapentine is an inducer of multiple hepatic enzymes and therefore may increase metabolism of coadministered drugs that are metabolized by these enzymes (see Section 7: Drug Interactions).

Use in pregnancy. There is not sufficient information to recommend the use of rifapentine for pregnant women.

CNS penetration. There are no data on CSF concentrations of rifapentine.

Use in renal disease. (See Section 8.7: Renal Insufficiency and End-Stage Renal Disease .) The pharmacokinetics of rifapentine have not been evaluated in patients with renal impairment. Although only about 17% of an administered dose is excreted via the kidneys, the clinical significance of impaired renal function in the disposition of rifapentine is not known.

Use in hepatic disease. (See Section 8.8: Hepatic Disease.) The pharmacokinetics of rifapentine and its 25-desacetyl metabolite were similar among patients with various degrees of hepatic impairment and not different from those in healthy volunteers, even though the elimination of these compounds is primarily via the liver (53). The clinical significance of impaired hepatic function in the disposition of rifapentine and its 25-desacetyl metabolite is not known.

Monitoring. Monitoring is similar to that for RIF. Drug interactions involving rifapentine are being investigated and are likely to be similar to those of RIF.

3.1.5. Pyrazinamide

Role in treatment regimen. Pyrazinamide (PZA) is a first-line agent for the treatment of all forms of tuberculosis caused by organisms with known or presumed susceptibility to the drug. The drug is believed to exert greatest activity against the population of dormant or semidormant organisms contained within macrophages or the acidic environment of caseous foci (54).

Dose. See Tables 3 and 4.

Adults: 20--25 mg/kg per day. Recommended adult dosages by weight, using whole tablets, are listed in Table 4.

Children (maximum): 15--30 mg/kg (2.0 g) daily; 50 mg/kg twice weekly (2.0 g).

Preparations. Tablets (500 mg, scored).

Adverse effects.

Hepatotoxicity: Early studies (55,56) using doses of 40--70 mg/kg per day reported high rates of hepatotoxicity. However, in treatment trials with multiple other drugs, including INH, liver toxicity has been rare at doses of 25 mg/kg per day or less (15,34,57). In one study, however, hepatotoxicity attributable to PZA used in standard doses occurred at a rate of about 1% (58).

Gastrointestinal symptoms (nausea, vomiting): Mild anorexia and nausea are common at standard doses. Vomiting and severe nausea are rare except at high doses (59).

Nongouty polyarthralgia: Polyarthralgias may occur in up to 40% of patients receiving daily doses of PZA. This rarely requires dosage adjustment or discontinuation of the drug (60). The pain usually responds to aspirin or other nonsteroidal antiinflammatory agents. In clinical trials of PZA in the initial intensive phase of treatment, athralgias were not noted to be a significant problem (15,61).

Asymptomatic hyperuricemia: This is an expected effect of the drug and is generally without adverse consequence (15,62).

Acute gouty arthritis: Acute gout is rare except in patients with preexisting gout (63), generally a contraindication to the use of the drug.

Transient morbilliform rash: This is usually self-limited and is not an indication for discontinuation of the drug.

Dermatitis: PZA may cause photosensitive dermatitis (59).

Use in pregnancy. There is little information about the safety of PZA in pregnancy. However, when there are sound reasons to utilize a 6-month course of treatment, the benefits of PZA may outweigh the possible (but unquantified) risk. The WHO and the IUATLD recommend this drug for use in pregnant women with tuberculosis (see Section 10: Treatment of Tuberculosis in Low-Income Countries: Recommendations of the WHO and the IUATLD).

CNS penetration. The drug passes freely into the CSF, achieving concentrations equivalent to those in serum (64).

Use in renal disease. (See Section 8.7: Renal Insufficiency and End-Stage Renal Disease.) PZA is cleared primarily by the liver, but its metabolites are excreted in the urine and may accumulate in patients with renal insufficiency (65). The dose may, therefore, need to be reduced in patients with renal insufficiency. It should be administered at a reduced dose (25--35 mg/kg) three times a week after dialysis in patients with end-stage renal disease (Table 15) (26). The risk of hyperuricemia caused by PZA is increased in patients with renal insufficiency.

Use in hepatic disease. (See Section 8.8: Hepatic Disease.) Although the frequency is slightly lower than with INH or RIF, the drug can cause liver injury that may be severe and prolonged. If the drug is used in patients with underlying liver disease, laboratory and clinical monitoring should be increased.

Monitoring. Serum uric acid measurements are not recommended as a routine but may serve as a surrogate marker for compliance. Liver chemistry monitoring should be performed when the drug is used in patients with underlying liver disease or when it is used with rifampin in treating latent tuberculosis infection.

3.1.6. Ethambutol

Role in treatment regimen. Ethambutol (EMB) is a first-line drug for treating all forms of tuberculosis. It is included in initial treatment regimens primarily to prevent emergence of RIF resistance when primary resistance to INH may be present. Ethambutol is generally not recommended for routine use in children whose visual acuity cannot be monitored. However, if a child has adult-type tuberculosis or disease that is suspected or proven to be caused by organisms that are resistant to either INH or RIF, EMB should be used (see Section 8.2: Children and Adolescents, and Table 6).

Dose. See Tables 3 and 5.

Adults: 15--20 mg/kg per day: Table 5 lists recommended dosages for adults, using whole tablets.

Children (maximum): 15--20 mg/kg per day (2.5 g); 50 mg/kg twice weekly (2.5 g). The drug can be used safely in older children but should be used with caution in children in whom visual acuity cannot be monitored (generally less than 5 years of age) (66). In younger children EMB can be used if there is concern with resistance to INH or RIF (Table 6).

Preparations. Tablets (100 mg, 400 mg) for oral administration.

Adverse effects.

Retrobulbar neuritis: This is manifested as decreased visual acuity or decreased red-green color discrimination that may affect one or both eyes. The effect is dose related, with minimal risk at a daily dose of 15 mg/kg (67). No difference was found in the prevalence of decreased visual acuity between regimens that contained EMB at 15 mg/kg and those not containing the drug (68). The risk of optic toxicity is higher at higher doses given daily (18% of patients receiving more than 30 mg/kg per day) and in patients with renal insufficiency. Higher doses can be given safely twice or three times weekly.

Peripheral neuritis: This is a rare adverse effect (69).

Cutaneous reactions: Skin reactions requiring discontinuation of the drug occur in 0.2--0.7% of patients (68).

Use in pregnancy. EMB is considered safe for use in pregnancy (70--72).

CNS penetration. The agent penetrates the meninges in the presence of inflammation but does not have demonstrated efficacy in tuberculous meningitis (73).

Use in renal disease. (See Section 8.7: Renal Insufficiency and End-Stage Renal Disease.) EMB is cleared primarily by the kidneys. The dose or dosing interval should be adjusted when the creatinine clearance is less than 70 ml/minute (74). EMB should be administered at a dose of 15--20 mg/kg three times a week by DOT after dialysis in patients with end-stage renal disease (Table 15) (26).

Use in hepatic disease. (See Section 8.8: Hepatic Disease.) EMB can be used safely in patients with hepatic disease.

Monitoring. Patients should have baseline visual acuity testing (Snellen chart) and testing of color discrimination (Ishihara tests). At each monthly visit patients should be questioned regarding possible visual disturbances including blurred vision or scotomata. Monthly testing of visual acuity and color discrimination is recommended for patients taking doses greater than 15--25 mg/kg, patients receiving the drug for longer than 2 months, and any patient with renal insufficiency. Patients should be instructed to contact their physician or public health clinic immediately if they experience a change in vision. EMB should be discontinued immediately and permanently if there are any signs of visual toxicity.

3.1.7. Fixed-dose combination preparations

Role in treatment regimen. Two combined preparations, INH and RIF (Rifamate®) and INH, RIF, and PZA (Rifater®), are available in the United States. These formulations are a means of minimizing inadvertent monotherapy, particularly when DOT is not possible, and, therefore, may decrease the risk of acquired drug resistance (75). The use of fixed-dose formulations may reduce the number of pills that must be taken daily. Constituent drugs are combined in proportions compatible with daily treatment regimens. Formulations for intermittent administration are not available in the United States.

Preparations and dose.

Rifamate®: As sold in North America, each capsule contains RIF (300 mg) and INH (150 mg); thus, the daily dose is two capsules (600 mg of RIF and 300 mg of INH). Two capsules of Rifamate® plus two 300-mg tablets of INH are used by some programs for intermittent therapy given twice weekly as DOT.

Rifater®: Each tablet contains RIF (120 mg), INH (50 mg), and PZA (300 mg). The daily dose is based on weight as follows: 44 kg or less, four tablets; 45--54 kg, five tablets; 55 kg or more, six tablets. To obtain an adequate dose of PZA in persons weighing more than 90 kg additional PZA tablets must be given.

Adverse effects. See comments under individual drugs above.

Use in pregnancy. Rifamate® may be used in daily treatment of pregnant women. Rifater® should not be used because it contains PZA.

CNS penetration. See comments under individual drugs above.

Use in renal disease. (See Section 8.7: Renal Insufficiency and End-Stage Renal Disease.) Rifamate® may be used in persons with renal insufficiency. Rifater® should not be used because of the potential need for adjustment of the dose of PZA.

Use in hepatic disease. (See Section 8.8: Hepatic Disease.) In patients with underlying hepatic disease it is advisable to treat with single-drug formulations until safety in an individual patient can be determined and a stable regimen established.

3.2. Second-Line Drugs

3.2.1. Cycloserine

Role in treatment regimen. Cycloserine (76,77) is a second-line drug that is used for treating patients with drug-resistant tuberculosis caused by organisms with known or presumed susceptibility to the agent. It may also be used on a temporary basis for patients with acute hepatitis in combination with other nonhepatotoxic drugs.

Dose. See Table 3.

Adults (maximum): 10--15 mg/kg per day (1,000 mg), usually 500--750 mg/day given in two doses. Clinicians with experience with cycloserine indicate that toxicity is more common at doses over 500 mg/day. Serum concentration measurements aiming for a peak concentration of 20--35 mg/ml are often useful in determining the optimum dose for a given patient. There are no data to support intermittent administration.

Children (maximum): 10--15 mg/kg per day (1.0 g/day).

Preparations. Capsules (250 mg).

Adverse effects.

Central nervous system effects: The central nervous system effects range from mild reactions, such as headache or restlessness, to severe reactions, such as psychosis and seizures. The drug may exacerbate underlying seizure disorders or mental illness. Seizures have been reported to occur in up to 16% of patients receiving 500 mg twice daily but in only 3% when receiving 500 mg once daily (78). Pyridoxine may help prevent and treat neurotoxic side effects and is usually given in a dosage of 100--200 mg/day (79). Rarely, cycloserine may cause peripheral neuritis.

Use in pregnancy. Cycloserine crosses the placenta. There are limited data on safety in pregnancy; thus, it should be used in pregnant women only when there are no suitable alternatives (77).

CNS penetration. Concentrations in CSF approach those in serum (77).

Use in renal disease. (See Section 8.7: Renal Insufficiency and End-Stage Renal Disease.) The drug can accumulate in patients with impaired renal function and should be used cautiously in such patients. Generally, the dose should be reduced and serum concentrations measured. Cycloserine should not be used in patients having a creatinine clearance of less than 50 ml/minute unless the patient is receiving hemodialysis. For patients being hemodialyzed the dose should be 500 mg three times a week or 250 mg daily (Table 15). Serum concentrations of the drug should be measured and the dose adjusted accordingly.

Use in hepatic disease. (See Section 8.8: Hepatic Disease.) There are no precautions except for patients with alcohol-related hepatitis in whom there is an increased risk of seizures (77).

Monitoring. Neuropsychiatric status should be assessed at least at monthly intervals and more frequently if symptoms develop. As noted above, measurements of serum concentrations may be necessary until an appropriate dose is established. For patients taking phenytoin, serum concentrations of phenytoin should be measured.

3.2.2. Ethionamide

Role in treatment. Ethionamide (76,77) is a second-line drug that is used for patients with drug-resistant tuberculosis disease caused by organisms that have demonstrated or presumed susceptibility to the drug.

Dose: See Table 3.

Adults (maximum): 15--20 mg/kg per day (1.0 g/day), usually 500--750 mg/day in a single daily dose or two divided doses. The single daily dose can be given at bedtime or with the main meal. There are no data to support intermittent dosing.

Children (maximum): 15--20 mg/kg per day (1.0 g/day).

Preparations: Tablets (250 mg).

Adverse reactions.

Gastrointestinal effects: Ethionamide commonly causes profound gastrointestinal side effects, including a metallic taste, nausea, vomiting (that is often severe), loss of appetite, and abdominal pain (80). Symptoms may improve if doses are taken with food or at bedtime.

Hepatotoxicity: Ethionamide is similar in structure to INH and may cause similar side effects. Hepatotoxicity occurs in about 2% of patients taking the drug (81,82).

Neurotoxicity: Neurotoxicity, including peripheral neuritis, optic neuritis, anxiety, depression, and psychosis, has been reported in 1--2% of patients taking shorter courses of the drug with higher rates reported with prolonged treatment (83,84).

Endocrine effects: Endocrine disturbances, including gynecomastia, alopecia, hypothyroidism, and impotence, have been described (85,86). Diabetes may be more difficult to manage in patients taking ethionamide (77).

Use in pregnancy. Ethionamide crosses the placenta and is teratogenic in laboratory animals. It should not be used in pregnancy.

CNS penetration. CSF concentrations are equal to those in serum (77).

Use in renal disease. (See Section 8.7: Renal Insufficiency and End-stage Renal Disease.) For patients having a creatinine clearance of less than 30 ml/minute or who are receiving hemodialysis the dose should be reduced to 250--500 mg/day (Table 15).

Use in hepatic disease. (See Section 8.8: Hepatic Disease.) Ethionamide should be used with caution in patients with underlying liver disease.

Monitoring. Liver function tests should be obtained at baseline and, if there is underlying liver disease, at monthly intervals. The studies should be repeated if symptoms occur. Thyroid-stimulating hormone should be measured at baseline and at monthly intervals.

3.2.3. Streptomycin

Role in treatment regimen. Streptomycin (SM) (76,77,87--89) and EMB have been shown to be approximately equivalent when used in the initial phase of treatment with 6-month regimens. However, among patients likely to have acquired M. tuberculosis in a high-incidence country, the relatively high rate of resistance to SM limits its usefulness.

Dose. See Table 3.

Adults (maximum): 15 mg/kg per day (1 g/day) parenterally, usually given as a single daily dose (5--7 days/week) initially, and then reducing to two or three times a week after the first 2--4 months or after culture conversion, depending on the efficacy of the other drugs in the regimen (90). For persons over 59 years of age, the dose should be reduced to 10 mg/kg per day (750 mg). The dosing frequency should be reduced (i.e., 12--15 mg/kg per dose two or three times per week) in persons with renal insufficiency (see below: Use in Renal Disease) (91,92).

Children (maximum): 20--40 mg/kg per day (1 g/day).

Preparations. Aqueous solution in vials of 1 g (93).

Adverse effects.

Ototoxicity: The most important adverse reaction caused by SM is ototoxicity, including vestibular and hearing disturbances. The risk is increased with age (94) or concomitant use of loop-inhibiting diuretics (furosemide, ethacrynic acid). The risk of ototoxicity increases with increasing single doses and with the cumulative dose, especially above 100--120 g.

Neurotoxicity: SM relatively commonly causes circumoral parasthesias immediately after injection. Rarely, it may interact with muscle relaxants to cause postoperative respiratory muscle weakness.

Nephrotoxicity: Nephrotoxicity occurs less commonly with SM than with amikacin, kanamycin, or capreomycin (95). Renal insufficiency requiring discontinuation occurs in about 2% of patients (96).

Use in pregnancy. SM is contraindicated in pregnancy because of the risk of fetal hearing loss (77,97,98).

CNS penetration. There is only slight diffusion of SM into CSF, even in patients with meningitis (77,99)

Use in renal disease. (See Section 8.7: Renal Insufficiency and End-Stage Renal Disease.) SM should be used with caution in patients with renal function impairment because of the increased risk of both ototoxicity and nephrotoxicity. Because clearance is almost exclusively by the kidney, dosing adjustments are essential in patients with underlying renal insufficiency, including the elderly and those undergoing hemodialysis. In such patients, the dosing frequency should be reduced to two or three times weekly, but the milligram dose should be maintained at 12--15 mg/kg per dose to take advantage of the concentration-dependent bactericidal effect (T