Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.
INTRODUCTION — Goals of tuberculosis (TB) treatment include eradication of Mycobacterium tuberculosis infection, preventing transmission, preventing relapse of disease, and preventing development of drug resistance [1-6].
Management consists of a patient-centered approach in which the patient, provider, public health, and laboratory enter into a relationship that assures that the goals of treatment are met.
The American Thoracic Society, United States Centers for Disease Control and Prevention, and Infectious Disease Society of America statement on the treatment of tuberculosis is a key summary of treatment guidelines in the United States . The World Health Organization and the International Standards for Tuberculosis Care provides important treatment recommendations for international settings [4,6].
Individuals with known or suspected tuberculosis who are not known to be HIV-infected should undergo human immunodeficiency virus (HIV) counseling and testing. (See "Screening and diagnostic testing for HIV infection".)
Issues related to treatment of pulmonary TB in HIV-uninfected adults caused by organisms known or presumed to be drug susceptible (ie, in areas where the incidence of drug-resistant TB is low) will be reviewed here.
Issues related to treatment of pulmonary TB in HIV-infected patients are discussed separately, as are issues related to treatment of drug-resistant TB. (See "Treatment of pulmonary tuberculosis in HIV-infected adults: Initiation of therapy" and "Treatment of drug-resistant pulmonary tuberculosis in adults".)
Clinical approach — The approach to treatment of patients with pulmonary tuberculosis (TB) caused by organisms known or presumed to be drug susceptible is summarized in the algorithm (algorithm 1). Treatment regimens are outlined in the table (table 1). In general, antituberculous regimens consists of two phases: an intensive phase (two months), followed by a continuation phase (four to seven months) ; most patients receive six months of treatment (intensive phase of two months and continuation phase of four months) .
Daily therapy is preferred over intermittent therapy to reduce risk of relapse and drug resistance; this is particularly important during the intensive phase of treatment . During the continuation phase of treatment, daily treatment is preferred over intermittent therapy; if daily therapy is not feasible, thrice-weekly dosing is preferred over twice-weekly dosing . This approach is supported by a systematic review and meta-analysis (including 56 randomized trials) in which intermittent dosing was associated with worse treatment outcomes (eg, relapse, failure, and acquired drug resistance) than daily dosing .
First-line drugs include isoniazid, rifampin, pyrazinamide, and ethambutol. Drug doses are summarized in the tables (table 2 and table 3 and table 4) [9,10]. The drugs should be administered simultaneously to synchronize peak serum concentrations and optimize killing; if feasible, use of fixed-drug combination tablets are preferred over separate drug formulations . The drugs should be administered on an empty stomach if tolerated, but dosing with food is acceptable to ameliorate gastrointestinal upset and is preferable to dividing doses or changing to second-line agents. Issues related to antituberculous drugs are discussed further separately. (See "Antituberculous drugs: An overview".)
Individual case management with directly observed therapy (DOT) is preferred for all patients to ensure adherence and prevent emergence of drug resistance. DOT involves assigning a trained nurse or other health worker to provide the antituberculous medication directly to the patient and observe as the patient swallows the medication. This process ensures the appropriate medication is taken as prescribed and provides an opportunity to assess medication side effects at each dose and to follow clinical response closely. Evidence supporting DOT is summarized separately. (See "Adherence to tuberculosis treatment", section on 'Directly observed therapy'.)
Several trials conducted in the 1970s and 1980s by the British Medical Research Council, British Thoracic Association, and Hong Kong Chest Service evaluated the optimal combination and duration of antituberculosis therapy [11-17]. These studies established that the efficacy of short-course (six-month) regimens with addition of rifampin and pyrazinamide to a base regimen of daily isoniazid and streptomycin, that ethambutol was roughly as effective as streptomycin (allowing an all-oral regimen), and that pyrazinamide and ethambutol were necessary only for the first two months of a six-month regimen using isoniazid and rifampin throughout.
Fluoroquinolones are alternative antituberculous agents that should be used only for patients with drug intolerance or resistance to first-line agents [1,6]. Several clinical trials have demonstrated that shorter fluoroquinolone-containing regimens are inferior to standard six-month therapy [18-21].
Intensive phase — The intensive phase usually consists of four drugs (isoniazid, rifampin, pyrazinamide, and ethambutol) administered for two months. The use of this regimen is intended to minimize the likelihood of developing secondary resistance to rifampin in regions with a high rate of primary resistance to isoniazid (≥4 percent) . If susceptibility data become available before the end of the intensive phase and demonstrate that the isolate is sensitive to isoniazid, rifampin, and pyrazinamide, ethambutol may be discontinued (its inclusion does not affect the overall treatment duration) [1,17].
If pyrazinamide must be excluded from the intensive phase of treatment (eg, due to severe liver disease, gout, or pregnancy), the intensive phase should consist of isoniazid, rifampin, and ethambutol administered daily for two months, and the continuation phase should be extended to seven months (total duration of treatment extended to nine months).
At the time of completion of the intensive phase, a repeat clinical assessment should be performed along with repeat chest radiograph and repeat sputum for acid-fast bacilli (AFB) smear and culture (followed by drug susceptibility testing for culture-positive specimens) . Nucleic acid amplification (NAA) testing should NOT be used to monitor treatment; these are qualitative tests that detect presence of M. tuberculosis nucleic acid in sputum but provide no indication of organism viability.
Patients typically demonstrate clinical improvement within days to weeks of starting appropriate treatment. Lack of clinical improvement should prompt further evaluation. (See 'Treatment failure and relapse' below.)
Continuation phase — The continuation phase (regimen beyond the first two months) usually consists of two drugs (isoniazid and rifampin) administered for at least four additional months, for a total of six months. The use of a six-month rifampin-based regimen for treatment of drug-susceptible TB is supported by a randomized trial including 1451 patients with pulmonary TB comparing the efficacy of six months of isoniazid and rifampin (plus pyrazinamide for the first two months) with nine months of isoniazid and rifampin . Patients who received the six-month regimen were more likely to complete therapy (61 versus 51 percent); relapse rates two years after completing therapy were similar in the two groups (3.5 and 2.8 percent).
The continuation phase should be extended to seven months (total duration of treatment nine months) for patients in the following circumstances :
●Patients with both cavitary pulmonary TB on initial chest radiograph and positive sputum culture after the two month intensive-phase treatment. The decision to prolong the continuation phase for patients with either cavitation or positive cultures (but not both) should be made on an individual basis.
●Patients whose intensive phase of treatment did not include two months of pyrazinamide.
Extension of the continuation phase to seven months (total duration of treatment nine months) is supported by a randomized trial including 1004 patients with TB, which noted a relapse rate of 21 percent among patients who had cavitation on initial chest radiograph, positive culture at the two month juncture, and whose continuation phase consisted of four moths of twice-weekly isoniazid and rifampin . Patients with only one of these factors (either cavitation or positive culture at two months) had relapse rates of 5 to 6 percent; patients with neither risk factor had relapse rates of 2 percent. A prolonged continuation phase for patients with cavitation and positive cultures at two months is also supported by a study of patients with silicotuberculosis in whom extending treatment to eight months reduced the rate of relapse from 22 percent to 7 percent .
The continuation phase should be shortened to two months (total duration of treatment four months) for HIV-uninfected patients with negative sputum cultures and symptomatic and/or radiographic improvement in the absence of an alternative diagnosis; in such cases, culture-negative tuberculosis may be inferred, and the continuation phase consists of isoniazid and rifampin for two months. (See 'Culture-negative TB' below.)
Clinical monitoring — Patient education regarding symptoms of hepatitis and other possible drug toxicities should be reinforced at each return visit, at least monthly. Patients should be instructed to report signs or symptoms of toxicity to their provider immediately and stop medications until advised to resume treatment. Issues related to laboratory monitoring for patients on antituberculous drugs are discussed separately. (See "Antituberculous drugs: An overview", section on 'Clinical and laboratory monitoring for adverse effects'.)
During treatment of pulmonary tuberculosis, sputum should be obtained for AFB smear and culture at monthly intervals until two consecutive cultures are negative . Sputum AFB smear and culture at the end of the intensive phase (after two months of treatment) is particularly important for assessing relapse risk and for determining the duration of the continuation phase (algorithm 1). Positive sputum culture at two months should prompt drug susceptibility testing of that isolate, and patients with drug-resistant isolates should be treated as discussed separately. (See "Treatment of drug-resistant pulmonary tuberculosis in adults".)
Use of sputum AFB smear and culture as monitoring tools during tuberculosis treatment have low sensitivity and modest specificity for predicting failure and relapse; better markers are needed [26,27].
The Xpert MTB/RIF assay is an automated NAA test that can be used to establish an initial diagnosis of tuberculosis but not for subsequent clinical evaluation . (See "Diagnosis of pulmonary tuberculosis in HIV-uninfected adults".)
Completion of therapy — Completion of treatment is determined by the duration of therapy and the total number of doses administered. In general, all of the doses for the intensive phase (60 doses with daily therapy) should be administered within three months, all of the doses for a four-month continuation phase should be delivered within six months, and all of the doses for a six-month continuation phase should be completed within nine months .
At the time of completion of the continuation phase of treatment, a chest radiograph may be obtained to provide a baseline against which subsequent examinations can be compared.
Interrupted therapy — In some cases, the specified number of doses cannot be administered within the targeted time period (eg, due to problems with drug toxicity or adherence). In such cases, a determination should be made regarding whether to extend the duration of treatment or restart treatment from the beginning. This decision must take into account the burden of disease, the point when the interruption occurred, and the duration of the interruption (table 5).
In general, continuous treatment is more important in the intensive phase of therapy when the organism burden is highest and the chance of developing drug resistance is greatest . The earlier in the treatment course the interruption occurred and the longer the duration of interruption, the more significant the effect of the interruption on treatment outcome and the more important the consideration to restart therapy from the beginning. Consultation with an expert in tuberculosis should be sought if the clinical approach is uncertain.
Regimen adjustments for drug intolerance — Antituberculous drugs are associated with a broad array of adverse effects; these are discussed separately. (See "Antituberculous drugs: An overview", section on 'Adverse effects'.)
Hepatotoxicity is an important adverse effect that warrants careful clinical attention. More than one antituberculous drug in a treatment regimen may be associated with hepatotoxicity, and in some cases the most significant contributor may be identified and eliminated without loss of the other drugs in the regimen. Among the first-line antituberculous drugs, hepatotoxicity may be caused by isoniazid, rifampin, or pyrazinamide. (See 'Hepatotoxicity' below.)
For circumstances in which a regimen must be adjusted because of drug intolerance, drug susceptibility data should be reviewed carefully, and expert consultation should be sought.
Alternative regimens for treatment of tuberculosis disease due to susceptible strains in the setting of drug intolerance include :
●For patients who cannot tolerate isoniazid, a regimen of rifampin, pyrazinamide, and ethambutol may be administered for six months. This regimen is nearly as efficacious as an isoniazid-containing regimen, though it may be poorly tolerated given prolonged use of pyrazinamide [15,17,30]. Alternatively, rifampin and ethambutol may be given for 12 months, preferably with pyrazinamide during at least the initial two months [15,31].
●For patients who cannot tolerate rifampin, isoniazid and ethambutol may be given for 12 to 18 months, with pyrazinamide during at least the first two months [32,33]. An injectable agent may be added for the first two to three months for individuals with extensive disease or to shorten the overall treatment duration to 12 months.
●For patients who cannot tolerate pyrazinamide, isoniazid and rifampin should be administered for nine months (supplemented by ethambutol until isoniazid and rifampin susceptibility are demonstrated) .
●For patients who require a regimen with no hepatotoxic agents, potential agents include ethambutol, levofloxacin or moxifloxacin, an injectable agent, and other second-line oral drugs. The optimal choice of agents and duration of treatment (at least 18 to 24 months) is uncertain. (See "Antituberculous drugs: An overview", section on 'Second-line agents'.)
Hepatotoxicity — The first-line antituberculous drugs associated with hepatotoxicity are isoniazid, rifampin, and pyrazinamide. There is overlap in the pattern of liver injury caused by rifampin, isoniazid, and pyrazinamide; all individually or in combination may contribute to hepatotoxicity. Rifampin may be associated with a cholestatic pattern, with elevations in serum bilirubin and alkaline phosphatase concentrations; isoniazid and pyrazinamide may be associated with elevations in serum transaminase concentrations.
Patients receiving antituberculous therapy should undergo baseline measurement of liver function tests (serum bilirubin, alkaline phosphatase, and transaminases). Issues related to laboratory monitoring for patients on antituberculous drugs are discussed separately. (See "Antituberculous drugs: An overview", section on 'Clinical and laboratory monitoring for adverse effects'.)
An asymptomatic increase in aspartate transaminase (AST) concentration occurs in approximately 20 percent of patients treated with the standard four-drug regimen; in most patients, asymptomatic aminotransferase elevations resolve spontaneously over days to weeks .
Drug-induced hepatitis is a diagnosis of exclusion. Other potential causes of abnormal liver function tests should be assessed, such as alcohol, acetaminophen, viral hepatitis, gallstones, and biliary obstruction. (See "Approach to the patient with abnormal liver biochemical and function tests".)
In general, hepatitis attributed to antituberculous drugs should prompt discontinuation of all hepatotoxic drugs if the serum bilirubin is ≥3 mg/dL or serum transaminases are more than five times the upper limit of normal . Thereafter, once liver function tests return to baseline (or fall to less than twice normal), potentially hepatotoxic drugs can be restarted one at a time with careful monitoring between resumption of each agent (algorithm 2).
The optimal approach to resumption of antituberculous therapy is uncertain, and expert consultation should be obtained. In general, in cases where there should be no interruption in therapy (such as severe disease with progressive loss of pulmonary function or current smear-positive disease), three drugs (eg, ethambutol, a fluoroquinolone [eg, levofloxacin], and an injectable agent) could be started until the transaminase concentration returns to less than two to three times the upper limit of normal (or to near baseline levels).
Thereafter, the first-line medications can be restarted one at a time; the choice of specific drug to start with might be suggested by the clinical picture (for example, if laboratory studies suggest a cholestatic-type picture seen more often with rifamycins, isoniazid or pyrazinamide might be restarted first). In the absence of cholestasis, rifampin may be restarted first; if there is no increase in hepatic transaminases after one to two weeks, isoniazid may be resumed [35,36]. If symptoms recur or hepatic transaminases increase, the last drug added should be stopped. For those who have experienced prolonged or severe hepatotoxicity but tolerate reintroduction with rifampin and isoniazid, rechallenge with pyrazinamide may be hazardous. In this circumstance, pyrazinamide may be permanently discontinued with extension of treatment to nine months.
In milder cases of hepatotoxicity, pyrazinamide can be introduced, and a regimen of rifampin, pyrazinamide, and ethambutol can be given for six months [1,37]; however, the benefit of a shorter treatment course may not outweigh the risk of severe hepatotoxicity from pyrazinamide rechallenge.
Pulmonary TB with complications — Complications of pulmonary tuberculosis (TB) include endobronchial disease, laryngeal disease, tuberculoma, and others. Issues related to complications of pulmonary TB are discussed further separately. (See "Clinical manifestations and complications of pulmonary tuberculosis".)
Antituberculous therapy for these forms of TB is the same as pulmonary TB.
The role of steroids in the management of endobronchial TB is uncertain; steroids may improve acute inflammatory manifestations but have not been clearly shown to prevent long-term complications such as fibrosis and stenosis [38-40].
Airway stenosis may persist following antituberculous therapy; the optimal approach to management is uncertain. Serial dilation, stenting, electric coagulation, laser treatment, and cryotherapy with balloon dilation have been used with varying success; resection of the involved segment has also been described [41-44]. (See "Clinical presentation, diagnostic evaluation, and management of central airway obstruction in adults".)
Pulmonary TB associated with acute respiratory failure has a high mortality rate [45-47]. One retrospective study found that corticosteroid use may reduce the 90-day mortality rate in patients with pulmonary TB and acute respiratory failure .
Extrapulmonary TB — The choice and duration of antituberculous therapy for extrapulmonary TB is the same as for pulmonary TB, with the exception of central nervous system disease (12 months of therapy) and bone and joint disease (6 to 9 months of therapy). (See "Central nervous system tuberculosis" and "Skeletal tuberculosis".)
Adjunctive corticosteroids are warranted in patients with tuberculous meningitis , patients with constrictive pericarditis, and patients at high risk of constrictive tuberculous pericarditis. These issues are discussed in further detail separately. (See "Central nervous system tuberculosis" and "Tuberculous pericarditis".)
Culture-negative TB — Culture-negative tuberculosis may be inferred for patients with negative sputum cultures and symptomatic and/or radiographic improvement in the absence of an alternative diagnosis. In the United States in 2014, 23 percent of TB cases were culture negative .
Antituberculous therapy for culture-negative TB consists of intensive phase (isoniazid, rifampin, pyrazinamide, and ethambutol administered for two months) followed by continuation phase (isoniazid and rifampin for two months); the total duration of therapy is four months [1,50].
Treatment failure and relapse — Treatment failure refers to positive cultures after four months of antituberculous therapy . Relapse refers to recurrent tuberculosis at any time after completion of treatment with apparent cure.
If treatment failure or relapse is confirmed or suspected, the M. tuberculosis isolate obtained at that time should be sent for drug susceptibility testing to first- and second-line agents. Specimens may be forwarded by your public health laboratory to the United States Centers for Disease Control and Prevention for molecular testing with relatively rapid turnaround time [51,52]; molecular test results for drug resistance must be confirmed using culture-based methods. (See "Diagnosis of pulmonary tuberculosis in HIV-uninfected adults".)
The approach to management of treatment failure and relapse is discussed separately. (See "Treatment of drug-resistant pulmonary tuberculosis in adults", section on 'Empiric treatment'.)
Risk factors for treatment failure and relapse include [24,53-55]:
●Inadequate adherence to treatment
●High burden of clinical disease (presence of cavitary disease, bilateral disease, and/or extrapulmonary disease)
Relapse may occur as a result of relapsed infection due to the same M. tuberculosis strain (more common in low-incidence settings) or due to exogenous reinfection with a new strain (more common in high-incidence settings) [23,56-59]. Most relapses occur within the first 6 to 12 months following completion of therapy. Among patients treated with rifamycin-containing regimens using directly observed therapy (DOT), relapses generally occur with susceptible organisms. For other patients, the risk of acquired drug resistance is substantial. If initial drug susceptibility testing was not performed and the patient fails or relapses with a rifamycin-containing regimen given by DOT, there is high likelihood that the organisms were resistant from the outset.
Drug resistance — Antituberculous regimens need to be modified in areas with a known high prevalence of drug-resistant TB and in treatment of patients with known drug-resistant disease. These issues are discussed in detail separately. (See "Epidemiology and molecular mechanisms of drug-resistant tuberculosis" and "Treatment of drug-resistant pulmonary tuberculosis in adults".)
Renal insufficiency — Antituberculous therapy for patients with renal insufficiency requires careful attention to drug dosing (table 6). To optimize peak serum concentrations, lengthening the dosing interval is preferable over reducing the dose . For patients on hemodialysis, administration of antituberculosis drugs with primary renal metabolism (ethambutol, pyrazinamide, aminoglycosides) immediately after hemodialysis facilitates directly observed therapy and minimizes premature removal of the drugs .
Patients with renal insufficiency may have additional clinical conditions (such as diabetes with associated gastroparesis) that may affect the absorption of antituberculous drugs or may be taking other medications that interact with antituberculous drugs. Therefore, careful clinical and pharmacological assessment is required; in some cases, serum drug concentration monitoring may be warranted to optimize drug dosing . (See "Antituberculous drugs: An overview", section on 'Serum drug concentration monitoring'.)
Hepatic disease — Treatment of tuberculosis in patients with unstable or advanced liver disease is challenging. In such cases, there is increased likelihood of drug-induced hepatitis, and adverse drug effects among patients with marginal hepatic reserve can be life threatening.
In general, standard antituberculosis therapy is usually initiated in patients with underlying hepatic disease, with close monitoring for symptoms of hepatotoxicity and monthly monitoring of liver function tests. In these situations, expert consultation is advised.
Patients on regimens including drugs associated with hepatotoxicity should be counseled to avoid use of alcohol and drugs associated with hepatotoxicity (such as acetaminophen).
Issues related to hepatotoxicity are discussed above. (See 'Hepatotoxicity' above.)
Malnutrition — Malnutrition is associated with an increased risk of mortality and relapse of active tuberculosis. Patients should be encouraged to gain weight, with the help of dietary supplemental calorie or protein intake if needed . (See "Epidemiology of tuberculosis", section on 'Nutritional status'.)
The role of micronutrient supplementation for patients with tuberculosis is uncertain. Supplementation with a variety of agents (including vitamins A, B complex, C, D, and selenium) has been associated with benefits in some studies including enhanced rate of smear conversion and reduced risk of TB recurrence [63-66]. Other studies have observed no effect on mortality or other outcomes [67-70]. These discordant findings may be related to differences in the types of micronutrients supplemented, gender, age, and other factors .
The role of macronutrient supplementation (eg, supplemental calorie or protein intake) in the treatment of tuberculosis is uncertain . Randomized trials assessing the effects of macronutrient supplementation on the treatment of tuberculosis have demonstrated that supplementation typically produces a 2 to 3 kg improvement in weight gain at two months and may result in improvement in physical function, sputum conversion, and treatment completion, but the trials were not powered to assess effects on mortality or relapse .
Resource-limited settings — In general, the approach to treatment of tuberculosis in resource-limited settings should be as outlined in the preceding sections whenever feasible. We are in agreement with the World Health Organization (WHO), which favors use of daily dosing throughout the entire course of therapy and recommends against use of thrice-weekly dosing . Previously, the WHO did include a thrice-weekly regimen with directly observed therapy as a possible treatment option ; however, a subsequent meta-analysis (including 56 randomized trials) noted intermittent dosing was associated with worse treatment outcomes (eg, relapse, failure, and acquired drug resistance) than daily dosing .
In resource-limited settings, the acid-fast bacilli (AFB) smear is the primary tool for diagnosis of tuberculosis and monitoring response to therapy; access to reliable culture facilities may be limited. Rapid testing with tools such as the Xpert MTB/RIF (a molecular diagnostic test that can detect tuberculosis and resistance to rifampin) is becoming an increasingly important tool in resource-limited settings . (See "Diagnosis of pulmonary tuberculosis in HIV-uninfected adults".)
Drug susceptibility testing is warranted for patients who fail the initial treatment regimen and for those who fail a supervised treatment regimen. (See 'Treatment failure and relapse' above.)
The World Health Organization, the International Union against Tuberculosis and Lung Disease, and the International Standards for Tuberculosis Care have issued guidelines for tuberculosis management in regions where mycobacterial laboratory facilities (for culture and susceptibility testing) and chest radiography may not be readily available [4,6,74].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and treatment of tuberculosis".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)
●Basics topics (see "Patient education: Tuberculosis (The Basics)")
●Beyond the Basics topics (see "Patient education: Tuberculosis (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●The approach to treatment of patients with pulmonary tuberculosis (TB) caused by organisms known or presumed to be drug susceptible is summarized in the algorithm (algorithm 1). Treatment regimens are outlined in the table (table 1). Drug doses are summarized in the tables (table 2 and table 3 and table 4 and table 6). (See 'Clinical approach' above.)
●In general, antituberculous regimens consists of two phases: an intensive phase followed by a continuation phase (algorithm 1). We recommend that the intensive phase consist of four drugs (isoniazid, rifampin, pyrazinamide, and ethambutol) (Grade 1B) administered for two months. The continuation phase usually consists of two drugs (isoniazid and rifampin) administered for at least four months. (See 'Intensive phase' above and 'Continuation phase' above.)
●All patients should have individual case management with directly observed therapy (DOT) to ensure adherence and prevent emergence of drug resistance. DOT involves providing the antituberculosis drugs directly to the patient and watching as the patient swallows the medications. (See 'Clinical approach' above and "Adherence to tuberculosis treatment", section on 'Directly observed therapy'.)
●During treatment of pulmonary TB, sputum should be obtained for acid-fast bacilli (AFB) smear and culture at monthly intervals until two consecutive cultures are negative. Sputum AFB smear and culture at the end of the intensive phase (after two months of treatment) is particularly important for assessing relapse risk and for determining the duration of the continuation phase (algorithm 1). (See 'Clinical monitoring' above.)
●In the setting of interrupted therapy, a determination should be made regarding whether to extend the duration of treatment or restart treatment from the beginning (table 5). In general, continuous treatment is most important in the intensive phase of therapy when the organism burden is highest and the chance of developing drug resistance is greatest. (See 'Interrupted therapy' above.)
●For circumstances in which a regimen must be adjusted because of drug intolerance, drug susceptibility data should be reviewed carefully and expert consultation should be sought. Alternative regimens are summarized above. (See 'Regimen adjustments for drug intolerance' above.)
●Hepatotoxicity is an important adverse effect of isoniazid, rifampin, and pyrazinamide. In general, hepatitis attributed to antituberculous drugs should prompt discontinuation of all hepatotoxic drugs if the serum bilirubin is ≥3 mg/dL or serum transaminases are more than five times the upper limit of normal. Thereafter, once liver function tests return to baseline (or fall to less than twice normal), potentially hepatotoxic drugs can be restarted one at a time with careful monitoring between resumption of each agent (algorithm 2). (See 'Hepatotoxicity' above.)
●Treatment failure refers to positive cultures after four months of antituberculous therapy. Relapse refers to recurrent tuberculosis at any time after completion of treatment with apparent cure. If treatment failure or relapse is confirmed or suspected, the Mycobacterium tuberculosis isolate should be sent for drug susceptibility testing to first- and second-line agents. (See 'Treatment failure and relapse' above.)
- Nahid P, Dorman SE, Alipanah N, et al. Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis. Clin Infect Dis 2016; 63:e147.
- Dheda K, Barry CE 3rd, Maartens G. Tuberculosis. Lancet 2016; 387:1211.
- Horsburgh CR Jr, Barry CE 3rd, Lange C. Treatment of Tuberculosis. N Engl J Med 2015; 373:2149.
- Hopewell PC, et al. International standards for tuberculosis care. Diagnosis, Treatment, Public Health. 3d Edition, 2014. http://www.who.int/tb/publications/ISTC_3rdEd.pdf?ua=1 (Accessed on August 26, 2016).
- World Health Organization. Guidelines for treatment of tuberculosis, 4th edition. WHO, Geneva 2010. http://apps.who.int/iris/bitstream/10665/44165/1/9789241547833_eng.pdf?ua=1&ua=1 (Accessed on October 05, 2016).
- World Health Organization. Guidelines for treatment of drug-susceptible tuberculosis and patient care, 2017 update. http://apps.who.int/iris/bitstream/10665/255052/1/9789241550000-eng.pdf?ua=1 (Accessed on June 08, 2017).
- Johnson JL, Hadad DJ, Dietze R, et al. Shortening treatment in adults with noncavitary tuberculosis and 2-month culture conversion. Am J Respir Crit Care Med 2009; 180:558.
- Johnston JC, Campbell JR, Menzies D. Effect of Intermittency on Treatment Outcomes in Pulmonary Tuberculosis: An Updated Systematic Review and Metaanalysis. Clin Infect Dis 2017; 64:1211.
- Small PM, Fujiwara PI. Management of tuberculosis in the United States. N Engl J Med 2001; 345:189.
- Handbook of anti-tuberculosis agents. Introduction. Tuberculosis (Edinb) 2008; 88:85.
- Controlled clinical trial of four short-course (6-month) regimens of chemotherapy for treatment of pulmonary tuberculosis. Second report. Lancet 1973; 1:1331.
- Controlled trial of 6-month and 9-month regimens of daily and intermittent streptomycin plus isoniazid plus pyrazinamide for pulmonary tuberculosis in Hong Kong. The results up to 30 months. Am Rev Respir Dis 1977; 115:727.
- Short-course chemotherapy in pulmonary tuberculosis. A controlled trial by the British Thoracic and Tuberculosis Association. Lancet 1976; 2:1102.
- A controlled trial of six months chemotherapy in pulmonary tuberculosis. Second report: results during the 24 months after the end of chemotherapy. British Thoracic Association. Am Rev Respir Dis 1982; 126:460.
- Five-year follow-up of a controlled trial of five 6-month regimens of chemotherapy for pulmonary tuberculosis. Hong Kong Chest Service/British Medical Research Council. Am Rev Respir Dis 1987; 136:1339.
- Controlled trial of 2, 4, and 6 months of pyrazinamide in 6-month, three-times-weekly regimens for smear-positive pulmonary tuberculosis, including an assessment of a combined preparation of isoniazid, rifampin, and pyrazinamide. Results at 30 months. Hong Kong Chest Service/British Medical Research Council. Am Rev Respir Dis 1991; 143:700.
- Mitchison DA, Nunn AJ. Influence of initial drug resistance on the response to short-course chemotherapy of pulmonary tuberculosis. Am Rev Respir Dis 1986; 133:423.
- Ziganshina LE, Titarenko AF, Davies GR. Fluoroquinolones for treating tuberculosis (presumed drug-sensitive). Cochrane Database Syst Rev 2013; :CD004795.
- Gillespie SH, Crook AM, McHugh TD, et al. Four-month moxifloxacin-based regimens for drug-sensitive tuberculosis. N Engl J Med 2014; 371:1577.
- Jindani A, Harrison TS, Nunn AJ, et al. High-dose rifapentine with moxifloxacin for pulmonary tuberculosis. N Engl J Med 2014; 371:1599.
- Merle CS, Fielding K, Sow OB, et al. A four-month gatifloxacin-containing regimen for treating tuberculosis. N Engl J Med 2014; 371:1588.
- Centers for Disease Control and Prevention. Drug-Resistant TB. http://www.cdc.gov/tb/topic/drtb/ (Accessed on July 18, 2016).
- Combs DL, O'Brien RJ, Geiter LJ. USPHS Tuberculosis Short-Course Chemotherapy Trial 21: effectiveness, toxicity, and acceptability. The report of final results. Ann Intern Med 1990; 112:397.
- Benator D, Bhattacharya M, Bozeman L, et al. Rifapentine and isoniazid once a week versus rifampicin and isoniazid twice a week for treatment of drug-susceptible pulmonary tuberculosis in HIV-negative patients: a randomised clinical trial. Lancet 2002; 360:528.
- A controlled clinical comparison of 6 and 8 months of antituberculosis chemotherapy in the treatment of patients with silicotuberculosis in Hong Kong. Hong Kong Chest Service/tuberculosis Research Centre, Madras/British Medical Research Council. Am Rev Respir Dis 1991; 143:262.
- Horne DJ, Royce SE, Gooze L, et al. Sputum monitoring during tuberculosis treatment for predicting outcome: systematic review and meta-analysis. Lancet Infect Dis 2010; 10:387.
- Datta S, Sherman JM, Bravard MA, et al. Clinical evaluation of tuberculosis viability microscopy for assessing treatment response. Clin Infect Dis 2015; 60:1186.
- Miotto P, Bigoni S, Migliori GB, et al. Early tuberculosis treatment monitoring by Xpert(R) MTB/RIF. Eur Respir J 2012; 39:1269.
- Mitchison DA. Role of individual drugs in the chemotherapy of tuberculosis. Int J Tuberc Lung Dis 2000; 4:796.
- Reves R, Heilig CM, Tapy JM, et al. Intermittent tuberculosis treatment for patients with isoniazid intolerance or drug resistance. Int J Tuberc Lung Dis 2014; 18:571.
- Bobrowitz ID. Ethambutol-isoniazid versus streptomycin-ethambutol-isoniazid in original treatment of cavitary tuberculosis. Am Rev Respir Dis 1974; 109:548.
- Ziganshina LE, Vizel AA, Squire SB. Fluoroquinolones for treating tuberculosis. Cochrane Database Syst Rev 2005; :CD004795.
- Gosling RD, Uiso LO, Sam NE, et al. The bactericidal activity of moxifloxacin in patients with pulmonary tuberculosis. Am J Respir Crit Care Med 2003; 168:1342.
- Drugs for tuberculosis. Treat Guidel Med Lett 2012; 10:29.
- Steele MA, Burk RF, DesPrez RM. Toxic hepatitis with isoniazid and rifampin. A meta-analysis. Chest 1991; 99:465.
- Saukkonen JJ, Cohn DL, Jasmer RM, et al. An official ATS statement: hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med 2006; 174:935.
- Døssing M, Wilcke JT, Askgaard DS, Nybo B. Liver injury during antituberculosis treatment: an 11-year study. Tuber Lung Dis 1996; 77:335.
- Ip MS, So SY, Lam WK, Mok CK. Endobronchial tuberculosis revisited. Chest 1986; 89:727.
- NEMIR RL, CARDONA J, LACOIUS A, DAVID M. PREDNISONE THERAPY AS AN ADJUNCT IN THE TREATMENT OF LYMPH NODE-BRONCHIAL TUBERCULOSIS IN CHILDHOOD. A DOUBLE-BLIND STUDY. Am Rev Respir Dis 1963; 88:189.
- Chan HS, Sun A, Hoheisel GB. Endobronchial tuberculosis--is corticosteroid treatment useful? A report of 8 cases and review of the literature. Postgrad Med J 1990; 66:822.
- Fu EQ, Nan YD, Jin FG, Ma AQ. Therapeutic effects of sequential therapy by electric coagulation, cryotherapy and balloon dilation with an electronic video bronchoscope. Exp Ther Med 2013; 5:1649.
- Low SY, Hsu A, Eng P. Interventional bronchoscopy for tuberculous tracheobronchial stenosis. Eur Respir J 2004; 24:345.
- Caligiuri PA, Banner AS, Jensik RJ. Tuberculous main-stem bronchial stenosis treated with sleeve resection. Arch Intern Med 1984; 144:1302.
- Sawada S, Fujiwara Y, Furui S, et al. Treatment of tuberculous bronchial stenosis with expandable metallic stents. Acta Radiol 1993; 34:263.
- Penner C, Roberts D, Kunimoto D, et al. Tuberculosis as a primary cause of respiratory failure requiring mechanical ventilation. Am J Respir Crit Care Med 1995; 151:867.
- Kim YJ, Pack KM, Jeong E, et al. Pulmonary tuberculosis with acute respiratory failure. Eur Respir J 2008; 32:1625.
- Ryu YJ, Koh WJ, Kang EH, et al. Prognostic factors in pulmonary tuberculosis requiring mechanical ventilation for acute respiratory failure. Respirology 2007; 12:406.
- Yang JY, Han M, Koh Y, et al. Effects of Corticosteroids on Critically Ill Pulmonary Tuberculosis Patients With Acute Respiratory Failure: A Propensity Analysis of Mortality. Clin Infect Dis 2016; 63:1449.
- Centers for Disease Control and Prevention. Reported Tuberculosis in the United States, 2014. http://www.cdc.gov/tb/statistics/reports/2014/default.htm (Accessed on July 19, 2016).
- Dutt AK, Moers D, Stead WW. Smear- and culture-negative pulmonary tuberculosis: four-month short-course chemotherapy. Am Rev Respir Dis 1989; 139:867.
- Centers for Disease Control and Prevention. Tuberculosis: Laboratory Information. http://www.cdc.gov/tb/topic/laboratory/ (Accessed on June 16, 2016).
- Centers for Disease Control and Prevention. Reference Laboratory Division of TB Elimination Laboratory User Guide for U.S. Public Health Laboratories: Molecular Detection of Drug Resistance (MDDR) in Mycobacterium tuberculosis Complex by DNA Sequencing (Version 2.0), June 2012. CDC, Atlanta, GA 2012. http://www.cdc.gov/tb/topic/laboratory/mddrusersguide.pdf (Accessed on June 16, 2016).
- Sterling TR, Alwood K, Gachuhi R, et al. Relapse rates after short-course (6-month) treatment of tuberculosis in HIV-infected and uninfected persons. AIDS 1999; 13:1899.
- Chang KC, Leung CC, Yew WW, et al. A nested case-control study on treatment-related risk factors for early relapse of tuberculosis. Am J Respir Crit Care Med 2004; 170:1124.
- Korenromp EL, Scano F, Williams BG, et al. Effects of human immunodeficiency virus infection on recurrence of tuberculosis after rifampin-based treatment: an analytical review. Clin Infect Dis 2003; 37:101.
- Verver S, Warren RM, Beyers N, et al. Rate of reinfection tuberculosis after successful treatment is higher than rate of new tuberculosis. Am J Respir Crit Care Med 2005; 171:1430.
- Marx FM, Dunbar R, Enarson DA, et al. The temporal dynamics of relapse and reinfection tuberculosis after successful treatment: a retrospective cohort study. Clin Infect Dis 2014; 58:1676.
- Sonnenberg P, Murray J, Glynn JR, et al. HIV-1 and recurrence, relapse, and reinfection of tuberculosis after cure: a cohort study in South African mineworkers. Lancet 2001; 358:1687.
- Jasmer RM, Bozeman L, Schwartzman K, et al. Recurrent tuberculosis in the United States and Canada: relapse or reinfection? Am J Respir Crit Care Med 2004; 170:1360.
- Ellard GA. Chemotherapy of tuberculosis for patients with renal impairment. Nephron 1993; 64:169.
- Peloquin CA. Using therapeutic drug monitoring to dose the antimycobacterial drugs. Clin Chest Med 1997; 18:79.
- Grobler L, Nagpal S, Sudarsanam TD, Sinclair D. Nutritional supplements for people being treated for active tuberculosis. Cochrane Database Syst Rev 2016; :CD006086.
- Villamor E, Mugusi F, Urassa W, et al. A trial of the effect of micronutrient supplementation on treatment outcome, T cell counts, morbidity, and mortality in adults with pulmonary tuberculosis. J Infect Dis 2008; 197:1499.
- Karyadi E, West CE, Schultink W, et al. A double-blind, placebo-controlled study of vitamin A and zinc supplementation in persons with tuberculosis in Indonesia: effects on clinical response and nutritional status. Am J Clin Nutr 2002; 75:720.
- Range N, Changalucha J, Krarup H, et al. The effect of multi-vitamin/mineral supplementation on mortality during treatment of pulmonary tuberculosis: a randomised two-by-two factorial trial in Mwanza, Tanzania. Br J Nutr 2006; 95:762.
- Martineau AR, Timms PM, Bothamley GH, et al. High-dose vitamin D(3) during intensive-phase antimicrobial treatment of pulmonary tuberculosis: a double-blind randomised controlled trial. Lancet 2011; 377:242.
- Range N, Andersen AB, Magnussen P, et al. The effect of micronutrient supplementation on treatment outcome in patients with pulmonary tuberculosis: a randomized controlled trial in Mwanza, Tanzania. Trop Med Int Health 2005; 10:826.
- Semba RD, Kumwenda J, Zijlstra E, et al. Micronutrient supplements and mortality of HIV-infected adults with pulmonary TB: a controlled clinical trial. Int J Tuberc Lung Dis 2007; 11:854.
- Wejse C, Gomes VF, Rabna P, et al. Vitamin D as supplementary treatment for tuberculosis: a double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med 2009; 179:843.
- Daley P, Jagannathan V, John KR, et al. Adjunctive vitamin D for treatment of active tuberculosis in India: a randomised, double-blind, placebo-controlled trial. Lancet Infect Dis 2015; 15:528.
- Benn CS, Friis H, Wejse C. Should micronutrient supplementation be integrated into the case management of tuberculosis? J Infect Dis 2008; 197:1487.
- Koethe JR, von Reyn CF. Protein-calorie malnutrition, macronutrient supplements, and tuberculosis. Int J Tuberc Lung Dis 2016; 20:857.
- Boehme CC, Nabeta P, Hillemann D, et al. Rapid molecular detection of tuberculosis and rifampin resistance. N Engl J Med 2010; 363:1005.
- International Union Against Tuberculosis and Lung Disease. Management of tuberculosis: A guide to the essential of good practice, 6th ed, 2010.