© 2003 American Thoracic Society
American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of AmericaTreatment of TuberculosisThis Official Joint Statement of the American Thoracic Society, Centers for Disease Control and Prevention, and the Infectious Diseases Society of America was approved by the ATS Board of Directors October 2002, The Centers for Disease Control and Prevention October 2002, and the Council of the IDSA October 2002.CONTENTS
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
SUMMARY
Responsibility for Successful Treatment
Organization and Supervision of Treatment 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
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 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, 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 regimen.
Baseline and Follow-Up Evaluations 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 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 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 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 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. 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%. Although most treatment studies in children have used daily drug administration for the first 2 weeks to 2 months, it appears that a three times weekly regimen from the beginning is equally efficacious. 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.
Culture-negative pulmonary tuberculosis and radiographic evidence of prior pulmonary tuberculosis. 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.
Liver disease. In all patients with preexisting liver disease, frequent clinical and laboratory monitoring should be performed to detect drug-induced hepatic injury.
Pregnancy and breastfeeding. 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 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 the Centers for Disease Control and Prevention. 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 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 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- 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. Committee This document was written by a joint committee of the American Thoracic Society (ATS), the Infectious Diseases Society of America (IDSA), and the Centers for Disease Control and Prevention (CDC). The committee members are as follows*:
*Charles Peloquin, Pharm.D., also made substantial contributions to the document. Acknowledgments The Committee thanks Elisha Malanga of the American Thoracic Society for excellent administrative support. The Committee also thanks the members of an ad hoc rerview panel convened by the Division of Tuberculosis Elimination, Centers for Disease Control and Prevention, for their thorough review and helpful comments. The members of this panel were as follows: Noami Bock, M.D., James Burns, M.D., Mike Holcombe, M.P.P.A., James Lamberti, M.D., Evelyn Lancaster, R.N., Kathleen Moser, M.D., M.P.H., James McDaniel, M.D., F.A.C.P., Sonal Munsiff, M.D., Margaret Oxtoby, M.D., Carol Pozsik, R.N., M.P.H., Susan Ray, M.D., Jon Tillinghast, M.D., M.P.H., Victor Tomlinson, Jr., M.D., and Charles Wallace, Ph.D. FOOTNOTES Members of the adhoc statement committee have disclosed any direct commercial associations (financial relationships or legal obligations) related to the preparation of this statement. This information is kept on file at the ATS Headquarters. Am J Respir Crit Care Med Vol 167. pp 603–662, 2003
1. INTRODUCTION AND BACKGROUND Since 1971 the American Thoracic Society (ATS) and the Centers for Disease Control and Prevention (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 in the boxed insert 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).
PROVIDER RESPONSIBILITY Treatment of tuberculosis benefits both the community as a whole and the individual patient; thus, any public health program or private provider (or both in a defined arrangement by which management is shared) undertaking to treat a patient with tuberculosis is assuming a public health function that includes not only prescribing an appropriate regimen but also ensuring adherence to the regimen until treatment is completed. 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 OF 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
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 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.
WHAT'S DOT? Direct observation of therapy (DOT) involves providing the antituberculosis drugs directly to the patient and watching as he/she swallows the medications. It is the preferred core management strategy for all patients with tuberculosis.
2.2. Promoting Adherence 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 metaanalysis 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 potential 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.
TRACKING TUBERCULOSIS Inter- and intrastate notifications constitute the key patient-tracking systems for patients moving within the United States. International notifications can also be made, although specific tracking programs vary by country. Currently there are two formal patient-tracking systems in operation for patients moving across the United States–Mexico boarder: TB Net, operated by the Migrant Clinician Network based in Austin, Texas (www.migrantclinician.org; telephone, 512-327-2017) and Cure TB, managed by the San Diego County, California, Division of Tuberculosis Control (www.curetb.org; telephone, 619-692-5719). 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.
LEGAL ACTION FOR TUBERCULOSIS IN NEW YORK CITY: 1993–1999
REFERENCES
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RPT should not be used in HIV-infected patients with tuberculosis or in patients with extrapulmonary tuberculosis. 
Therapy should be extended to 9 months if 2-month culture is positive. CXR = chest radiograph; EMB = ethambutol; INH = isoniazid; PZA = pyrazinamide; RIF = rifampin; RPT = rifapentine.
and interleukin-2, and nutritional supplements, especially vitamin A and zinc. 
