Version December 2023
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 (CDC), and Infectious Disease Society of America 2016 statement on the treatment of TB is a key summary of treatment guidelines in the United States [1]. The CDC subsequently issued interim guidance regarding use of a shortened four-month regimen in 2022 [2]. The World Health Organization and the International Standards for Tuberculosis Care provides important treatment recommendations for international settings [3].
Issues related to treatment of pulmonary TB in human immunodeficiency virus (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 patients with HIV infection are discussed separately, as are issues related to treatment of drug-resistant TB. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults with HIV infection: Initiation of therapy" and "Treatment of drug-resistant pulmonary tuberculosis in adults".)
Issues related to TB transmission and control are discussed separately. (See "Tuberculosis transmission and control in health care settings".)
DIAGNOSTIC EVALUATION — Issues related to clinical manifestations and diagnosis of TB are discussed separately. (See "Clinical manifestations and complications of pulmonary tuberculosis" and "Diagnosis of pulmonary tuberculosis in adults".)
Individuals with known or suspected TB who are not known to be HIV infected should undergo HIV counseling and testing. (See "Screening and diagnostic testing for HIV infection".)
ANTITUBERCULOUS THERAPY
Pulmonary TB
Regimen selection
●Our approach – For treatment of drug-susceptible pulmonary TB, options include the traditional regimen (≥6 months) or a shortened rifapentine-moxifloxacin (four-month) regimen. The traditional regimen remains standard of care; the shortened regimen may be used in a subset of patients who fulfill specific criteria as described below. (See 'Rifapentine-moxifloxacin-based four-month regimen' below.)
●Regimens – TB treatment regimens include:
•Traditional regimen (≥6 months) – The traditional regimen (intensive phase of two months and continuation phase of at least four months) includes the drugs isoniazid, rifampin, pyrazinamide, and ethambutol (sometimes referred to as "RIPE therapy"; outside the United States, this regimen is known as 2HRZE/4HR) (table 1 and table 2) [7]. (See 'Traditional regimen (≥6 months)' below.)
•Rifapentine-moxifloxacin four-month regimen – A shortened, four-month regimen (intensive phase of eight weeks and continuation phase of nine weeks) includes the drugs isoniazid, rifapentine, moxifloxacin, and pyrazinamide (table 3) [2,8]. (See 'Rifapentine-moxifloxacin-based four-month regimen' below.)
●Treatment phases – In general, TB treatment regimens consists of two phases: an intensive phase (administration of four drugs for two months) followed by a continuation phase (administration of two or three drugs for two to seven months) [1,2].
●Rifamycin nitrosamine impurities – In August 2020, the US Food and Drug Administration (FDA) announced detection of nitrosamine impurities in samples of rifampin and rifapentine [9]. Some such compounds have been implicated as possible carcinogens in long-term animal studies, with toxicity largely related to cumulative exposure. To preserve availability of rifampin and rifapentine for TB treatment, the FDA temporarily increased the maximum daily limits of these contaminants.
We favor continued use of rifampin or rifapentine if acceptable to the patient, as the risk of not taking rifampin or rifapentine for TB treatment likely outweighs any potential risk from nitrosamine impurities; this approach is consistent with the United States Centers for Disease Control and Prevention (CDC) guidance issued in September 2020 [10]. Precise levels of contamination for a given lot of drug are not provided to the consumer. However, the nitrosamine exposure is likely to be greater for the four-month rifapentine-moxifloxacin regimen than for the traditional regimen, given daily high dose, administration with a greater allowable limit for rifapentine [11].
Elevated levels of nitrosamine impurities have not been reported for rifabutin.
Traditional regimen (≥6 months)
Intensive and continuation phases
Considerations during the intensive phase include:
●Treatment structure – The traditional intensive phase usually consists of four drugs (isoniazid, rifampin, pyrazinamide, and ethambutol) administered for two months (table 2). 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) [12]. 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) [1,13].
●If pyrazinamide must be excluded – If pyrazinamide must be excluded from the intensive phase of treatment (eg, due to hepatotoxicity, gout, or [in the United States] 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).
●Expected clinical course – Patients typically demonstrate clinical improvement (with regard to cough, fever, weight loss) within two to three weeks of starting appropriate treatment. Lack of clinical improvement should prompt further evaluation. Radiographic response may lag behind clinical improvement. (See 'Treatment failure or relapse' below.)
●Assessment at completion of intensive phase – At the time of completion of the intensive phase, a repeat clinical assessment should be performed, along with repeat sputum for acid-fast bacilli (AFB) smear and culture (followed by drug susceptibility testing for culture-positive specimens) [1]. Routine chest radiograph is not necessary in patients who are improving clinically. 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.
Considerations during the continuation phase include:
●Treatment structure – The traditional 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 at least six months. The approach to the continuation phase is guided by (1) sputum AFB culture results at two months and (2) presence or absence of cavitary disease on chest radiograph at the time of treatment initiation. This is summarized in the following three algorithms:
•Sputum AFB culture negative at two months, no cavitary disease on initial chest radiograph (algorithm 1)
•Sputum AFB culture negative at two months, with cavitary disease on initial chest radiograph (algorithm 2)
•Sputum AFB culture positive at two months (algorithm 3)
●Sputum monitoring – The approach to sputum monitoring is as follows [1]:
•Sputum should be obtained for AFB smear and culture at monthly intervals until two consecutive cultures are negative.
•A positive sputum culture at two months should prompt drug susceptibility testing of that isolate; patients with drug-resistant isolates should be treated as discussed separately. (See "Treatment of drug-resistant pulmonary tuberculosis in adults".)
•For patients with both delayed sputum culture conversion (beyond two months) and cavitation on initial chest radiograph, the continuation phase should be continued for seven months (total duration of therapy nine months) (algorithm 3).
•For patients with either delayed sputum culture conversion (beyond two months) or cavitation on initial chest radiograph, a continuation phase of four months (total duration of therapy six months) is acceptable; however, if medications are well tolerated, some experts would extend the continuation phase to seven months (total duration of therapy nine months). Some experts would also extend the continuation phase for patients >10 percent below ideal body weight, or with current tobacco use, diabetes, HIV infection, other immunocompromising condition, and/or extensive disease on chest radiograph [1] (algorithm 2 and algorithm 3).
•For patients with positive sputum culture after three months of antituberculous therapy, further investigation including drug susceptibility testing and review for causes of treatment failure is warranted (eg, nonadherence, malabsorption, coincident diagnosis).
•For patients with positive sputum culture after four months of antituberculous therapy, treatment failure should be presumed. (See 'Treatment failure or relapse' below.)
The above approach is supported by a randomized trial including 1004 patients with TB who received continuation phase treatment with isoniazid plus rifapentine; characteristics associated with increased risk of failure/relapse included cavitation on initial chest radiograph, positive sputum culture at two-month juncture, being underweight, and bilateral pulmonary involvement [14].
●Limitations of sputum monitoring – Use of sputum AFB smear and culture as monitoring tools during TB treatment have low sensitivity and modest specificity for predicting failure and relapse; better markers are needed [15,16]. The Xpert MTB/RIF assay is an automated NAA test that can be used to establish an initial diagnosis of TB but not for subsequent clinical evaluation [17]. (See "Diagnosis of pulmonary tuberculosis in adults".)
●When to shorten the continuation phase – The continuation phase may be shortened to two months (total duration of treatment four months) for patients without HIV infection with evidence for TB infection but negative sputum cultures, with symptomatic and/or radiographic improvement in the absence of an alternative diagnosis (algorithm 1); in such cases, culture-negative TB may be inferred, and the continuation phase consists of isoniazid and rifampin for two months. (See 'Culture-negative TB' below.)
Treatment frequency — 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 [1,3]. During the continuation phase of treatment, daily treatment is preferred over intermittent therapy [3]; if daily therapy is not feasible, thrice-weekly dosing is preferred over twice-weekly dosing [1].
Use of once-weekly therapy with isoniazid and rifapentine in the continuation phase or twice-weekly therapy with isoniazid and rifampin in the continuation phase are no longer recommended except for unusual circumstances to facilitate directly observed therapy (DOT) [1]. 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 [18].
Interrupted treatment
●Treatment completion – 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 [1].
For patients with slow clinical response, a repeat chest radiograph is indicated. At the time of completion of the continuation phase of treatment, a chest radiograph may be obtained to provide a baseline against which subsequent radiographic examinations can be compared.
●Interrupted treatment – 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 4).
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 [19]. The earlier in the treatment course the interruption occurs 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 TB should be sought if the clinical approach is uncertain.
Regimen efficacy — Use of the traditional regimen is supported by the following data:
●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 antituberculous therapy [13,20-25]. These studies established the efficacy of six-month regimens with addition of rifampin and pyrazinamide to a base regimen of daily isoniazid and streptomycin, that ethambutol is roughly as effective as streptomycin (allowing an all-oral regimen), and that pyrazinamide and ethambutol are necessary only for the first two months of a six-month regimen using isoniazid and rifampin throughout.
●In 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) [26].
Rifapentine-moxifloxacin-based four-month regimen — The CDC and World Health Organization issued 2022 guidance for use of a four-month regimen for treatment of drug-susceptible pulmonary TB in which rifapentine is substituted for rifampin and moxifloxacin is substituted for ethambutol [2,3]. Alternative fluoroquinolones (eg, levofloxacin) may not be substituted for moxifloxacin.
Patient selection — The four-month regimen may be used for nonpregnant patients (age ≥12 years, body weight ≥40 kg) with drug-susceptible pulmonary TB, in absence of extrapulmonary involvement.
The four-month regimen should not be used for patients in the following categories [2]:
●Patients with suspected or confirmed resistance to the medications in the regimen – Patients who have not received >5 doses of antimycobacterial therapy in the preceding six months may be started on the four-month regimen while drug susceptibility testing is pending. Rapid drug susceptibility should be available; molecular testing for drug resistance (available from local or state public health laboratory) is advised.
●Patients with history of cardiac morbidities (given risk for fluoroquinolone-induced toxicity), including:
•History of arrhythmias (especially bradyarrhythmias), uncorrected hypothyroidism, or electrolyte imbalances
•History of prolonged QTc or concurrent use of other QTc-prolonging medications (table 5)
•History of ischemic heart disease
•Family history of sudden cardiac death
●Patients with advanced liver disease, renal insufficiency, and/or laboratory abnormalities including:
•Baseline transaminases >3 times the upper limit of normal
•Baseline total bilirubin >2.5 times the upper limit of normal,
•Baseline creatinine >2 mg/dL
•Baseline serum potassium <3.5 mEq/L
●Pregnant or lactating women
●Patients on drugs with potential for interactions with the medications in the regimen; specific interactions may be determined by using the drug interaction tool (Lexi-Interact) included within UpToDate.
●Patients with incomplete access to medication or inadequate reimbursement to complete a full course of treatment
For providers and programs considering use of the four-month regimen, the National TB Controllers Association has developed detailed guidance to help facilitate the decision and to ensure safe completion of treatment [27,28].
Clinical approach — Our approach to laboratory evaluation, electrocardiogram (EKG) monitoring, drug administration, chest radiography, and sputum monitoring is outlined below.
●Baseline laboratory evaluation – Baseline laboratory evaluation should include:
•Complete blood count (hemoglobin ≥7 g/dL, platelets ≥100,000/microL)
•Transaminases, alkaline phosphatase <3 times the upper limit of normal
•Total bilirubin <2.5 times the upper limit of normal
•Creatinine <2 mg/dL
•Serum potassium >3.5 mEq/L
•Serum calcium and magnesium concentrations within normal limits
•Pregnancy testing if indicated
●EKG monitoring – Moxifloxacin is a QT-prolonging agent and has been associated with cardiac arrhythmias which may be fatal.
We favor performing baseline EKG prior to starting treatment; we do not use a fluoroquinolone-based regimen for patients with baseline QTc >450 ms (calculator 1). For patients with normal baseline EKG, we perform subsequent EKG monitoring for QTc prolongation one to two weeks later, then at least monthly thereafter. We stop the regimen if QTc increases to ≥500 ms or increases by ≥60 ms over baseline [29,30]. (See "Fluoroquinolones", section on 'QT interval prolongation' and "Antituberculous drugs: An overview", section on 'QT prolongation'.)
Our approach differs from the CDC, which does not recommend EKG monitoring with the four-month regimen [2].
●Drug dosing and administration – The rifapentine-moxifloxacin four-month regimen consists of an intensive phase (eight weeks of rifapentine, isoniazid, pyrazinamide, and moxifloxacin administered once daily), followed by a continuation phase (nine weeks of rifapentine, isoniazid, and moxifloxacin administered once daily) (table 3) [2,8].
At least five of seven weekly doses should be administered under direct observation. (See 'Directly observed therapy' below.)
Therapeutic drug level monitoring may be helpful if there is concern regarding malabsorption.
●Chest radiography – Following initial evaluation, we obtain repeat chest radiograph at week 8 and at the completion of therapy [2].
●Sputum monitoring – Sputum should be obtained for AFB smear and culture at monthly intervals until two consecutive cultures are negative. A positive sputum culture at two months should prompt drug susceptibility testing of that isolate; patients with drug-resistant isolates should be evaluated for reasons for the emergence of drug resistance (eg, nonadherence, malabsorption). (See 'Treatment failure or relapse' below.)
Completing therapy — Patients typically demonstrate clinical improvement (with regard to cough, fever, weight loss) within two to three weeks of starting appropriate treatment.
Completion of the regimen consists of 119 doses (56 intensive phase doses and 63 continuation phase doses). The intensive phase doses should be administered within 70 days from treatment initiation, and the continuation phase doses should be administered within 84 days from intensive phase completion.
If these targets are not met, the patients should be considered to have interrupted therapy. Further management should be individualized in consultation with a TB expert, and might require switching to the traditional regimen [1,2].
Regimen efficacy — Use of the four-month regimen is supported by a study including more than 2300 patients with TB who were randomly assigned to one of the following regimens [8]:
●Traditional six-month regimen – Once-daily regimen consisting of rifampin, isoniazid, pyrazinamide, and ethambutol for 8 weeks, followed by rifampin and isoniazid for 18 weeks
●Rifapentine-based four-month regimen – Once-daily regimen in which rifapentine was substituted for rifampin (consisting of rifapentine, isoniazid, pyrazinamide, and ethambutol for eight weeks, followed by rifapentine and isoniazid for nine weeks)
●Rifapentine-moxifloxacin four-month regimen – A four-month regimen in which rifapentine was substituted for rifampin and moxifloxacin was substituted for ethambutol, and moxifloxacin was continued for the full course of treatment (consisting of once-daily rifapentine, isoniazid, pyrazinamide, and moxifloxacin for eight weeks, followed by once-daily rifapentine, isoniazid, and moxifloxacin for nine weeks)
The primary efficacy outcome was unfavorable outcome at 12 months from randomization, defined as a positive sputum culture at or after week 17, death or study withdrawal or loss to follow-up during treatment, death from TB during follow-up, or administration of additional TB treatment.
For the primary efficacy outcome, the rifapentine-moxifloxacin regimen was noninferior to the traditional regimen in the microbiologically eligible population (primary outcome occurred in 15.5 versus 14.6 percent of patients, respectively; difference 1.0 percentage point, 95% CI -2.6 to 4.5) and in the assessable population (11.6 versus 9.6 percent; difference 2.0 percentage points, 95% CI -1.1 to 5.1). Unfavorable outcomes related to TB (eg, TB treatment failure or recurrence) occurred in 5.7 versus 3.1 percent of patients, respectively.
Baseline EKGs were not performed and there were very few known cardiac adverse effects; cardiac disorders of grade 3 or higher were reported in three participants (0.4 percent) receiving the four-month regimen.
Similar results were observed among patients with HIV infection, but not among those with smear-positive or cavitary disease or those with a history of tobacco use or diabetes. Noninferiority was not shown for the rifapentine regimen that did not include moxifloxacin. The rate of adverse events (grade 3 or higher) was similar in the three groups (19, 14, and 19 percent, respectively). Subsequently, 18-month follow-up results (a secondary endpoint) were found to be similar to the 12-month results.
Prior to the above study, a number of trials demonstrated that shorter fluoroquinolone-containing regimens were inferior to traditional six-month therapy [31-34]. However, those treatment regimens did not also include the substitution of rifapentine for rifampin and different end points were used.
Evaluating shorter regimens
●Adaptive treatment - Use of an adaptive trial design may help accelerate evaluation of shorter TB treatment regimens. In an open-label trial including 675 patients with rifampin-susceptible TB, patients were randomly assigned to treatment with a standard regimen (24 weeks) or an intensified regimen (bedaquiline or high-dose rifampin, each in combination with linezolid, isoniazid, pyrazinamide, and ethambutol) for 8 weeks [35]. Patients with persistent disease (based on symptoms and positive sputum smear) continued treatment for four more weeks, followed by reassessment. A primary-outcome event (death, ongoing treatment, or active disease at week 96) occurred in 3.9 percent of patients in the control group, 11.4 percent in the rifampin-linezolid group, and 5.8 percent in the bedaquiline-linezolid group. Among patients treated with bedaquiline-linezolid, 86 percent received no treatment beyond 8 weeks, and the mean treatment duration in the bedaquiline-linezolid group was shorter than the control group (85 versus 180 days).
It is uncertain whether clinical implementation of adaptive treatment (which requires careful monitoring and considerable resources that may not be available to many TB programs) outside the context of a trial would be feasible; potential benefits include reduced cost and increased patient satisfaction. However, there are also issues related to cost, availability, and tolerability of bedaquiline and linezolid, as well as with potential development of drug resistance [36]. Data for use of bedaquiline, linezolid, isoniazid, pyrazinamide, and ethambutol adaptive treatment are insufficient for routine use at this juncture; further evaluation is warranted.
●Four-month high-dose rifampin regimen – In a trial including more than 600 adults with rifampin-susceptible pulmonary tuberculosis randomly assigned to receive a control regimen (6-month regimen; maximum rifampin dose 600 mg/day), a 4-month regimen including rifampin 1200 mg/day, or a 4-month regimen including rifampin 1800 mg/day, noninferiority was not shown [37]. The high-dose rifampin regimens did not have dose-limiting toxicities or side effects.
Administration logistics
Drug dosing and administration — Drug doses are summarized in the table (table 2 and table 3) [38,39]. The drugs should be administered simultaneously to synchronize peak serum concentrations and optimize killing; if feasible, use of fixed-drug combination tablets is preferred over separate drug formulations (although the level of evidence to support this practice is weak) [3]. 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".)
Directly observed therapy — Individual case management with DOT is preferred for all patients to ensure adherence and safety and to 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 or video observed therapy'.)
Adverse effect monitoring
●Patient education – Patients on regimens including drugs associated with hepatotoxicity should be counseled to avoid use of alcohol and drugs associated with hepatotoxicity.
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'.)
●Laboratory monitoring – 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'.)
Drug-induced hepatotoxicity
General principles — Hepatotoxicity due to antituberculous drugs is an important adverse effect.
●Patterns of liver injury – 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, rifampin, and pyrazinamide may be associated with elevations in serum transaminase concentrations.
●Differential diagnosis – 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".)
An asymptomatic increase in aspartate transaminase concentration occurs in approximately 20 percent of patients treated with the traditional four-drug regimen; in most patients, asymptomatic aminotransferase elevations resolve spontaneously over days to weeks [40].
Discontinuing and resuming treatment
●Discontinuing treatment
•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 (or, in individuals with symptoms of hepatitis, serum transaminases more than three times the upper limit of normal) [1].
•For cases in which there should be no treatment interruption (such as severe disease with progressive loss of pulmonary function or current smear-positive disease), three drugs not associated with hepatoxicity (such as ethambutol, a fluoroquinolone, and an injectable agent) may be administered until the transaminase concentrations return to below two to three times the upper limit of normal (or near baseline levels).
●Resuming treatment
•More than one antituberculous drug in a treatment regimen may be associated with hepatotoxicity. In some cases, the most significant contributor may be identified and eliminated without loss of the other drugs in the regimen. The optimal approach to resumption of antituberculous therapy is uncertain; expert consultation should be obtained.
•Following drug discontinuation and return of liver function tests to baseline (or less than twice normal), potentially hepatotoxic drugs may be restarted one at a time, with careful monitoring between resumption of each agent.
•The choice of which drug to resume may be guided by clinical circumstances (algorithm 4 and algorithm 5) [40,41]:
-If laboratory studies suggest a cholestatic pattern (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.
-If symptoms recur or hepatic transaminases increase, the last drug added should be stopped. (See 'Regimen adjustments for drug intolerance' below.)
•Considerations for resuming pyrazinamide:
-For patients 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 [1,42]; however, the benefit of a shorter treatment course may not outweigh the risk of severe hepatotoxicity from pyrazinamide rechallenge.
Regimen adjustments for drug intolerance — 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 TB disease due to susceptible strains in the setting of drug intolerance include [1]:
●Isoniazid intolerance – For patients who cannot tolerate isoniazid, a regimen of rifampin, pyrazinamide, ethambutol, and a later-generation fluoroquinolone may be administered for six months. This regimen may be poorly tolerated given prolonged use of pyrazinamide [1,13,24,43,44]; in select cases with a low burden of disease, pyrazinamide may be discontinued after two months [1]. Alternatively, rifampin and ethambutol may be given for 12 months, preferably with pyrazinamide during at least the initial two months [24,45].
●Rifampin intolerance – 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 [46,47]. 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.
●Pyrazinamide intolerance – 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) [48].
●Intolerance to all hepatotoxic agents – For patients who require a regimen with no hepatotoxic agents, potential agents include ethambutol, a fluoroquinolone, 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'.)
Treatment failure or relapse
●Definitions
•Treatment failure
-For the traditional regimen, treatment failure refers to positive sputum cultures after four months of antituberculous therapy [1].
-For the rifapentine-moxifloxacin four-month regimen, lack of clinical, radiographic, or microbiologic improvement at eight weeks of treatment should prompt complete re-evaluation of the patient and treatment regimen.
•Relapse – Relapse refers to recurrent TB at any time after completion of treatment with apparent cure.
Most relapses occur within the first 6 to 12 months following completion of therapy. Among patients with drug-susceptible TB, relapse occurs in approximately 5 percent of cases [49].
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) [26,50-53].
Among patients treated with rifamycin-containing regimens using DOT, relapse generally occurs with susceptible organisms. 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 organism was resistant from the outset.
●Risk factors – Risk factors for treatment failure and relapse include [14,54-56]:
•High burden of disease (presence of cavitary disease, bilateral disease, and/or extrapulmonary disease)
•Drug resistance
•Inadequate treatment adherence
•Malabsorption (if malabsorption is suspected, drug level testing may be useful)
•Malnourishment
•Alternative diagnosis
●Drug susceptibility testing – If treatment failure or relapse is confirmed or suspected, the M. tuberculosis isolate should be sent for drug susceptibility testing to first- and second-line agents. In clinical and public health laboratories, drug resistance is evaluated by assessing growth of in the presence of a "critical concentration" of drug (defined as the lowest concentration of drug that inhibit 95 percent of "wild-type strains") [57]. In the United States, specimens may be forwarded to the CDC for molecular testing with relatively rapid turnaround time [58,59]. (See "Diagnosis of pulmonary tuberculosis in adults", section on 'Microbiologic testing'.)
●Management – 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'.)
Pulmonary TB with complications
●Definitions and approach – Complications of pulmonary TB include endobronchial disease, laryngeal disease, tuberculoma, and others. Antituberculous therapy for these forms of TB is the same as pulmonary TB. Issues related to complications of pulmonary TB are discussed further separately. (See "Clinical manifestations and complications of pulmonary tuberculosis".)
●Role of steroids – The role of steroids in the management of pulmonary TB with complications is uncertain. Among patients with endobronchial TB, steroids may improve acute inflammatory manifestations but have not been clearly shown to prevent long-term complications such as fibrosis and stenosis [60-62].
●Airway stenosis – 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 [63-66]. (See "Clinical presentation, diagnostic evaluation, and management of malignant central airway obstruction in adults".)
Extrapulmonary TB
●Antituberculous therapy – The choice and duration of antituberculous therapy for extrapulmonary TB is at least six months; exceptions include central nervous system disease (12 months of therapy) and bone and joint disease (six to nine months of therapy). (See "Bone and joint tuberculosis".).
The rifapentine-moxifloxacin four-month regimen should not be used in patients with extrapulmonary disease [2].
●Role of steroids – Adjunctive corticosteroids are warranted in patients with tuberculous meningitis [1,3], 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: An overview" and "Tuberculous pericarditis".)
Culture-negative TB
●Definition – Culture-negative TB may be inferred for patients with negative sputum cultures and symptomatic and/or radiographic improvement in the absence of an alternative diagnosis. Such patients may also have a positive tuberculin skin test or interferon gamma release assay and pathologic evidence of TB (eg, positive AFB smear or caseating granulomas on pathology). In the United States in 2019, 20.5 percent of TB cases were culture negative [67].
●Antituberculous therapy – Antituberculous therapy for uncomplicated, culture-negative pulmonary 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 [1,68].
The rifapentine-moxifloxacin four-month regimen is an acceptable alternative regimen for treatment of culture-negative TB [2]. (See 'Rifapentine-moxifloxacin-based four-month regimen' above.)
SPECIAL CIRCUMSTANCES
Renal insufficiency
●Drug dosing and monitoring
•Drug dosing – Antituberculous therapy for patients with renal insufficiency requires careful attention to drug dosing (table 2). To optimize peak serum concentrations, lengthening the dosing interval is preferable over reducing the dose [1].
•Comorbid conditions – 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.
•Serum drug concentration monitoring – Serum drug concentration monitoring may be warranted to optimize drug dosing in some patients with renal insufficiency [69]; the indications and approach are discussed separately. (See "Antituberculous drugs: An overview", section on 'Serum drug concentration monitoring'.)
●Hemodialysis – For patients on hemodialysis, administration of antituberculosis drugs with primary renal metabolism (ethambutol, pyrazinamide, aminoglycosides, capreomycin, cycloserine, levofloxacin) immediately after hemodialysis facilitates directly observed therapy and minimizes premature drug removal [70].
The rifapentine-moxifloxacin four-month regimen is not recommended for patients with renal failure.
Hepatic disease — Treatment of TB 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 antituberculous 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.
Issues related to hepatotoxicity are discussed above. (See 'Drug-induced hepatotoxicity' above.)
Malnutrition — Malnutrition is associated with an increased risk of mortality and relapse of active TB. Patients should be encouraged to gain weight with the help of dietary supplemental calorie or protein intake if needed [71]. (See "Epidemiology of tuberculosis", section on 'Nutritional status'.)
●Micronutrient supplementation – The role of micronutrient supplementation for patients with TB 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 [72-75]. Other studies have observed no effect on mortality or other outcomes [76-79]. These discordant findings may be related to differences in the types of micronutrients supplemented, sex, age, and other factors [80].
Pyridoxine (vitamin B6; 25 to 50 mg/day) is given with isoniazid to individuals at risk for neuropathy (eg, pregnant women, breastfeeding infants, and individuals with HIV infection, diabetes, alcoholism, malnutrition, chronic renal failure, or advanced age) (table 1).
●Macronutrient supplementation – The role of macronutrient supplementation (eg, supplemental calorie or protein intake) in the treatment of TB is uncertain [71]. Randomized trials assessing the effects of macronutrient supplementation on the treatment of TB 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 [81].
Pregnancy or lactation — Issues related to treatment of TB in pregnancy are discussed separately. (See "Tuberculosis disease (active tuberculosis) in pregnancy".)
The rifapentine-moxifloxacin four-month regimen should not be used for patients in these groups.
Resource-limited settings
●Treatment approach – In general, the approach to treatment of TB 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 [3].
Previously, the WHO did include a thrice-weekly regimen with directly observed therapy as a possible treatment option [3]; 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 [18].
●Tools for diagnosis and monitoring – In resource-limited settings, the acid-fast bacilli smear is the primary tool for diagnosis of TB 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 TB and resistance to rifampin) is becoming an increasingly important diagnostic tool in resource-limited settings [82]. (See "Diagnosis of pulmonary tuberculosis in 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 or relapse' above.)
The WHO, the International Union against Tuberculosis and Lung Disease, and the International Standards for Tuberculosis Care have issued guidelines for TB management in regions where mycobacterial laboratory facilities (for culture and susceptibility testing) and chest radiography may not be readily available [3,6,83].
PROGNOSIS — The prognosis of TB depends on many variables related to the patient (extent of disease, comorbidities, adherence) and the management (timing of treatment initiation during the course of disease, choice of treatment regimen, supporting infrastructure to facilitate adherence) [84-86].
Globally, the World Health Organization estimates a treatment success rate of 85 percent and a mortality rate of 15 percent [87]. In the United States, the rate of treatment failure or relapse is estimated to be 2.5 to 5 percent. In 2017, there were 515 reported deaths (of 9088 cases; 5.6 percent) [88].
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 email 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 topic (see "Patient education: Tuberculosis (The Basics)")
●Beyond the Basics topic (see "Patient education: Tuberculosis (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Regimen structure – Antituberculous regimens consists of two phases: an intensive phase followed by a continuation phase. We suggest that the intensive phase consist of four drugs (rather than fewer drugs) (Grade 2C), to minimize the likelihood of development of resistance. (See 'Regimen selection' above.)
●Regimen selection – For treatment of drug-susceptible tuberculosis (TB), we suggest the traditional regimen (≥6 months), rather than the shortened rifapentine-moxifloxacin (four-month) regimen (Grade 2C). The shortened regimen may be used for patients who meet all conditions and prefer a shorter regimen. (See 'Regimen selection' above and 'Patient selection' above.)
•Traditional regimen (≥6 months) – The intensive phase consists of isoniazid, rifampin, ethambutol, and pyrazinamide administered for two months (table 1 and table 2).
The continuation phase consists of isoniazid and rifampin administered for at least four months. The approach is guided by (1) sputum acid-fast bacilli (AFB) culture results at two months and (2) presence or absence of cavitary disease on chest radiograph at the time of treatment initiation, as summarized in three algorithms:
-Sputum AFB culture negative at two months, no cavitary disease on initial chest radiograph (algorithm 1)
-Sputum AFB culture negative at two months, with cavitary disease on initial chest radiograph (algorithm 2)
-Sputum AFB culture positive at two months (algorithm 3)
•Rifapentine-moxifloxacin four-month regimen – Intensive phase consisting of rifapentine, isoniazid, pyrazinamide, and moxifloxacin administered for eight weeks, followed by a continuation phase consisting of rifapentine, isoniazid, and moxifloxacin administered for nine weeks (table 3).
●Directly observed therapy (DOT) – All patients should have individual case management with DOT (providing medication directly to the patient and observing the patient swallow it) to ensure adherence and prevent emergence of drug resistance. (See 'Directly observed therapy' above.)
●Drug-induced hepatotoxicity – Hepatotoxicity is an important adverse effect of isoniazid, rifampin, and pyrazinamide. 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 (or, in individuals with symptoms of hepatitis, serum transaminases more than three 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 4 and algorithm 5). (See 'Drug-induced hepatotoxicity' above.)
●Treatment failure and relapse – For the traditional regimen, treatment failure refers to positive sputum cultures after four months of antituberculous therapy; for the rifapentine-moxifloxacin four-month regimen, lack of improvement at eight weeks should prompt re-evaluation of the patient and the treatment regimen. Relapse refers to recurrent TB at any time after completion of treatment with apparent cure. If treatment failure or relapse is confirmed or suspected, the isolate should be sent for drug susceptibility testing to first- and second-line agents. (See 'Treatment failure or relapse' above.)
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