Treatment of Drug-Susceptible Pulmonary Tuberculosis in HIV-uninfected Adults

30/10/2020 Treatment of drug-susceptible pulmonary tuberculosis in HIV-uninfected adults - UpToDate
Official reprint from UpToDate®

www.uptodate.com ©2020 UpToDate, Inc. and/or its affiliates. All Rights Reserved.
Treatment of drug-susceptible pulmonary tuberculosis in HIV-uninfected adults

Author: Timothy R Sterling, MD
Section Editor: John Bernardo, MD
Deputy Editor: Elinor L Baron, MD, DTMH
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Sep 2020. | This topic last updated: Oct 19, 2020.
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 TB is a key summary of treatment guidelines in the United States [1]. The World Health Organization and the
International Standards for Tuberculosis Care provides important treatment recommendations for international settings [4,6,7].
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".)
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 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".)
ANTITUBERCULOUS THERAPY
Clinical approach — The approach to treatment of patients with pulmonary 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)
[1]; most patients receive six months of treatment (intensive phase of two months and continuation phase of four months) [8].
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]. 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 [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 [9].
First-line drugs include isoniazid, rifampin, pyrazinamide, and ethambutol (sometimes referred to as "RIPE therapy"). Drug doses are
summarized in the table ( table 2) [10,11]. 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) [6]. 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".)
In August 2020, the US Food and Drug Administration announced detection of nitrosamine impurities in samples of rifampin and rifapentine
[12]. Some such compounds have been implicated as possible carcinogens in long-term animal studies, with toxicity largely related to
cumulative exposure. For treatment of TB disease, we favor continued use of rifampin if acceptable to the patient, as the risk of not taking
rifampin likely outweighs any potential risk from nitrosamine impurities. This is consistent with updated United States Centers for Disease
Control and Prevention guidance in September 2020 [13].
Individual case management with directly observed therapy (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
https://www-uptodate-com.aure.unab.edu.co/contents/treatment-of-drug-susceptible-pulmonary-tuberculosis-in-hiv-uninfected-adults/print?searc… 1/12
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'.)
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 [14-20]. 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.
Treatment of drug-susceptible TB with standard four-drug treatment is often successful; however, relapse occurs in approximately 5 percent
of patients after six months of first-line therapy [21]. Minimum inhibitory concentration (MIC) readouts are not used routinely for drug
susceptibility testing by clinical or public health laboratories; rather, drug resistance is determined by assessing growth of an inoculum in
the presence of a "critical concentration" of drug (defined as the lowest concentration of drug that inhibit 95 percent of "wild-type strains"
but not inhibiting strains from patients unresponsive to therapy and considered resistant) [22]. In a retrospective analysis of pretreatment
isolates from 117 patients with TB treated with standard four-drug treatment (54 relapsed; 63 were cured), the MIC was measured with
gradations below standard resistance breakpoints; higher pretreatment MICs for isoniazid or rifampin were associated with an increased
risk of relapse [23]. Prospective studies in larger cohorts with MIC testing of pretreatment isolates are needed to validate these findings.
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 [24-27]. In a randomized trial including more than 190 patients from South Africa in which patients with TB (90 percent of
whom were smear positive and 70 percent of whom were HIV infected) were treated with a standard regimen or a regimen in which
moxifloxacin was substituted for ethambutol, the rates of culture conversion at eight weeks and treatment success were comparable;
however, the rate of serious adverse events was higher in the moxifloxacin group (29 versus 12 percent) [28].
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) [29]. 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) [1,20].
If pyrazinamide must be excluded from the intensive phase of treatment (eg, due to hepatotoxicity, 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) [1]. 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 [30]. 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 [1]:
● 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 months of twice-weekly isoniazid and rifampin [31].
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 [32].
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 TB 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'.)
During treatment of pulmonary TB, sputum should be obtained for AFB smear and culture at monthly intervals until two consecutive
cultures are negative [1]. 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 TB treatment have low sensitivity and modest specificity for predicting
failure and relapse; better markers are needed [33,34].
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 [35]. (See "Diagnosis of pulmonary tuberculosis in 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 [1].
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 3).
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 [36]. 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 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 'Manifestations and their management'.)
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 TB disease due to susceptible strains in the setting of drug intolerance include [1]:
● 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 [18,20,37]. Alternatively, rifampin and ethambutol may be given for 12 months, preferably with pyrazinamide during at
least the initial two months [18,38].
● 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 [39,40]. 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) [41].
● 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, rifampin, 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'.)
An asymptomatic increase in aspartate transaminase 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 [42].
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 (or, in individuals with symptoms of hepatitis, serum
transaminases more than three times the upper limit of normal) [1]. 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 [42,43]. 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 [1,44]; however, the benefit of a shorter treatment course may not outweigh the risk of severe hepatotoxicity from
pyrazinamide rechallenge.
SPECIAL CIRCUMSTANCES
Pulmonary TB with complications — Complications of pulmonary 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 [45-47].
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 [48-51]. (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 [52-54]. One retrospective study found that corticosteroid
use may reduce the 90-day mortality rate in patients with pulmonary TB and acute respiratory failure [55].
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: An overview" and "Bone and joint tuberculosis".)
Adjunctive corticosteroids are warranted in patients with tuberculous meningitis [1], 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 — 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 acid-fast bacillus smear or caseating granulomas on pathology).
In the United States in 2014, 23 percent of TB cases were culture negative [56].
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 [1,57].
Treatment failure and relapse — Treatment failure refers to positive cultures after four months of antituberculous therapy [1]. 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 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 [58,59]; molecular test results for
drug resistance must be confirmed using culture-based methods. (See "Diagnosis of pulmonary tuberculosis in 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 for drug-resistant TB'.)
Risk factors for treatment failure and relapse include [31,60-62]:
● Inadequate adherence to treatment

● High burden of clinical disease (presence of cavitary disease, bilateral disease, and/or extrapulmonary disease)
● Drug resistance
● Malabsorption
● Malnourishment
● Alternative diagnosis
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) [30,63-66]. 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 2). To
optimize peak serum concentrations, lengthening the dosing interval is preferable over reducing the dose [1]. 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 removal of the
drugs [67].
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 [68]. (See "Antituberculous drugs: An overview", section on 'Serum drug concentration monitoring'.)
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 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 TB. Patients should be encouraged to
gain weight with the help of dietary supplemental calorie or protein intake if needed [69]. (See "Epidemiology of tuberculosis", section on
'Nutritional status'.)
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 [70-73]. Other studies have observed no effect on mortality or other outcomes [74-77]. These discordant findings may
be related to differences in the types of micronutrients supplemented, gender, age, and other factors [78].
The role of macronutrient supplementation (eg, supplemental calorie or protein intake) in the treatment of TB is uncertain [69]. 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 [79].
Resource-limited settings — 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 [6]. Previously, the WHO did include a thrice-
weekly regimen with directly observed therapy as a possible treatment option [5]; 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 [9].
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 [80]. (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 and 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 [4,6,81].
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)
[82,83].
Globally, the World Health Organization estimates a treatment success rate of 85 percent and a mortality rate of 15 percent [84]. 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) [85].
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
● 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). (See 'Clinical approach' above.)
● In general, antituberculous regimens consists of two phases: an intensive phase followed by a continuation phase ( algorithm 1). We
suggest that the intensive phase consist of four drugs (rather than fewer drugs) (Grade 2C), to minimize the likelihood of development
of resistance; in general, the intensive phase consists of isoniazid, rifampin, ethambutol, and pyrazinamide (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 or video 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 3). 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 (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 2). (See 'Hepatotoxicity'
above.)
● Treatment failure refers to positive cultures after four months of antituberculous therapy. 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 Mycobacterium
tuberculosis isolate should be sent for drug susceptibility testing to first- and second-line agents. (See 'Treatment failure and relapse'
above.)
Use of UpToDate is subject to the Subscription and License Agreement.
Topic 8015 Version 61.0
GRAPHICS
Approach to treatment of drug-susceptible pulmonary tuberculosis in adults
Drug dosing is summarized separately (refer to the UpToDate text and related tables).
The algorithm is designed based on assumption that positive AFB smears and cultures reflect Mycobacterium tuberculosis; identification of non-tuberculous mycobacteria should prompt adjustm
The algorithm is designed based on the assumption that the patient has drug-susceptible disease; drug susceptibility data should be reviewed, and identification of drug resistance should prom
During treatment of pulmonary TB, sputum should be obtained for AFB smear and culture at monthly intervals until two consecutive cultures are negative. Presence of positive sputum cultures
discussion of management).
Directly observed therapy is preferred for all patients to ensure adherence and prevent emergence of drug resistance.
AFB: acid-fast bacilli; HIV: human immunodeficiency virus; TB: tuberculosis.

* Ethambutol may be discontinued when results of drug susceptibility testing indicate no drug resistance to first-line agents.
¶ Pyrazinamide may be discontinued after it has been taken for two months (56 doses).
Δ Worsening chest radiograph findings or clinical manifestations prior to initiation of continuation phase should prompt consideration of drug-resistant TB or alternate diagnosis (refer to the UpToDate text for
◊ During treatment of pulmonary TB, sputum should be obtained for AFB smear and culture at monthly intervals until two consecutive cultures are negative. Positive sputum culture should prompt drug suscep
Patients with drug-resistant isolates should be treated as discussed separately (refer to the UpToDate content on drug-resistant TB).
§ Rifapentine should not be used in patients with extrapulmonary TB.
¥ TB is unlikely if initial sputum culture is negative.
‡ If rifampin and pyrazinamide were included in the treatment regimen for at least two months, no further treatment for latent TB is needed; otherwise, a regimen for treatment of latent TB should be complet
† The continuation phase may warrant extension to seven months (total duration nine months) in patients with additional risk factors for relapse, including those who have bilateral pulmonary disease or are u
Adapted from: American Thoracic Society; CDC; Infectious Diseases Society of America. Treatment of tuberculosis. MMWR Recomm Rep 2003; 52:1.
Graphic 109259 Version 3.0
Regimens for treatment of drug-susceptible pulmonary tuberculosis in HIV-uninfected adults
Range of
Intensive phase Continuation phase
total
doses Comments ¶Δ
Interval and doses* (minimal Interval and doses* (minimal
Drugs Drugs
duration) (minimal duration)
duration)
Regimen 1
INH Daily for 8 weeks INH 7 days per week for 182 to 130 This is the preferred regimen for patients with newly diagnosed pulmonary tuberculosis.
RIF 7 days per week for 56 doses (8 RIF 126 doses (18 weeks), (26 weeks)
weeks), or or
PZA
5 days per week for 40 doses (8 5 days per week for
EMB
weeks) ◊ 90 doses (18 weeks)
Regimen 2
INH Daily for 8 weeks INH Three times weekly 110 to 94 Preferred alternative regimen in situations in which more frequent DOT during continuation
RIF 7 days per week for 56 doses (8 RIF for 54 doses (18 (26 weeks) phase is difficult to achieve.
weeks), or weeks)
PZA
EMB 5 days per week for 40 doses (8
weeks) ◊
Regimen 3
INH Three times weekly for 8 weeks INH Three times weekly 78 (26 Use regimen with caution in patients with HIV and/or cavitary disease. Missed doses can lead to
RIF Three times weekly for 24 doses (8 RIF for 54 doses (18 weeks) treatment failure, relapse, and acquired drug resistance.
weeks) weeks)
PZA
EMB
Regimen 4
INH Daily for 2 weeks, then twice INH Twice weekly for 36 62 (26 Do not use twice-weekly regimens in HIV-infected patients or patients with smear-positive and/or
RIF weekly for 6 weeks RIF doses (18 weeks) weeks) cavitary disease. If doses are missed, then therapy is equivalent to once weekly, which is inferior.
PZA 7 days per week for 14 doses (2

weeks), then twice weekly for 12
EMB
doses §
INH: isoniazid; RIF: rifampin; RPT: rifapentine; PZA: pyrazinamide; EMB: ethambutol; DOT: directly observed therapy; HIV: human immunodeficiency virus.
* When DOT is used, drugs may be given five days per week and the necessary number of doses adjusted accordingly. Although there are no studies that compare five with seven daily doses, extensive
experience indicates that this is an effective practice. DOT should be used when drugs are administered <7 days per week.
¶ Based on expert opinion, patients with cavitation on initial chest radiograph and positive cultures at completion of two months of therapy should receive a seven-month (31-week) continuation phase.
Δ 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). For patients with peripheral neuropathy, experts recommend increasing pyridoxine dose to 100 mg/day.
◊ Five-day-a-week administration is always given by DOT.
§ Alternatively, some United States tuberculosis control programs have administered intensive-phase regimens 5 days per week for 15 doses (3 weeks), then twice weekly for 12 doses.
Reproduced from: 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(7):e147-e195. By permission of Oxford University Press on behalf of the Infectious Diseases Society of America. Copyright © 2016.
https://www.idsociety.org/practice-guideline/treatment-of-drug-susceptible-tb/.
Dosing of first-line antituberculosis drugs in adults*
Doses
Drug Preparations
Daily 3x/week 2x/week 1x/week
First-line drugs
Isoniazid ¶ Tablets (50 mg, 100 mg, 300 5 mg/kg (usual maximum 15 mg/kg (usual maximum 15 mg/kg (usual maximum 15 mg/kg (usual maximum
mg); elixir (50 mg/5 mL); dose 300 mg) dose 900 mg) dose 900 mg) dose 900 mg)
aqueous solution (100
mg/mL) for intravenous or
intramuscular injection
Rifampin (rifampicin) Δ Capsules (150 mg, 300 mg); 10 mg/kg (usual maximum 10 mg/kg (usual maximum 10 mg/kg (usual maximum –
capsule contents may be dose 600 mg) dose 600 mg) dose 600 mg)
suspended for oral
administration; aqueous
solution for intravenous
injection
Rifabutin Δ Capsule (150 mg) 5 mg/kg (usual maximum Not recommended Not recommended –
dose 300 mg)
Rifapentine Δ Tablet (150 mg, film coated) – – – 10 to 20 mg/kg once weekly

during continuation phase of
treatment ◊
Pyrazinamide § Tablet (500 mg, scored) Patient weight 40 to 55 kg ¥
1000 mg (18.2 to 25 1500 (27.3 to 37.5 mg/kg) 2000 mg (36.4 to 50 mg/kg) –

mg/kg)
Patient weight 56 to 75 kg ¥
1500 mg (20 to 26.8 2500 (33.3 to 44.6 mg/kg) 3000 mg (40 to 53.6 mg/kg) –
mg/kg)
Patient weight 76 to 90kg ¥‡
2000 mg † (22.2 to 26.3 3000 mg † (33.3 to 39.5 4000 mg † (44.4 to 52.6 –

mg/kg) mg/kg) mg/kg)
Ethambutol** Tablets (100 mg, 400 mg) Patient weight 40 to 55kg ¥
800 mg (14.5 to 20 mg/kg) 1200 mg (21.8 to 30 mg/kg) 2000 mg (36.4 to 50 mg/kg) –
1200 mg (16 to 21.4 2000 mg (26.7 to 35.7 mg/kg) 2800 mg (37.3 to 50 mg/kg) –
mg/kg)
1600 mg † (17.8 to 21.1 2400 mg † (26.7 to 31.6 4000 mg † (44.4 to 52.6 –

mg/kg) mg/kg) mg/kg)
Adult dosing listed in this table is used in patients ≥15 years old or weighing >40 kg.
Antituberculous agents are used in multidrug combination regimens of varying duration, which are described in detail in a separate table (refer to the UpToDate table on regimens for
treatment of drug-susceptible tuberculosis) and in the accompanying text.
* Dosing based on actual weight is acceptable in patients who are not obese. For obese patients (>20% above ideal body weight [IBW]), dosing based on IBW may be preferred for initial doses. Some
clinicians prefer a modified IBW (IBW + [0.40 × (actual weight – IBW)]) as is done for initial aminoglycoside doses. Because tuberculosis drug dosing for obese patients has not been established,
therapeutic drug monitoring may be considered for such patients.
¶ 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). For patients with peripheral neuropathy, experts recommend increasing pyridoxine dose to 100 mg/day.
Δ Rifabutin dose may need to be adjusted when there is concomitant use of protease inhibitors or nonnucleoside reverse transcriptase inhibitors. Refer to the UpToDate topic on treatment of pulmonary
tuberculosis in HIV-infected adults for specific dose adjustments.
◊ Rarely used in practice; it may be an alternative in the continuation phase of treatment in a once-weekly regimen to facilitate directly observed therapy. For further details, refer to the UpToDate topic on
rifamycins.
§ For patients with creatinine clearance <30 mL/min (by Cockroft-Gault equation) or for patients receiving intermittent hemodialysis, pyrazinamide dosing consists of 25 to 35 mg/kg (ideal body weight)
per dose orally 3 times per week (NOT daily); max 2.5 g per dose. On the day of hemodialysis, medications should be administered after hemodialysis. Monitoring of serum drug concentrations should be
considered to ensure adequate drug absorption without excessive accumulation and to assist in avoiding toxicity.
¥ Based on estimated lean body weight.
‡ Patients >90 kg should have serum concentration monitoring. In obese patients, weight-based dosing is likely best based on measurements of ideal (versus total) body weight.
† Maximum dose regardless of weight.
** For patients with creatinine clearance <30 mL/min (by Cockroft-Gault equation) or for patients receiving intermittent hemodialysis, ethambutol dosing consists of 20 to 25 mg/kg (ideal body weight)
per dose orally 3 times per week (NOT daily); max 1.6 g per dose. On the day of hemodialysis, medications should be administered after hemodialysis. Monitoring of serum drug concentrations should be
considered to ensure adequate drug absorption without excessive accumulation and to assist in avoiding toxicity.
Data adapted from:

1. Nahid P, Dorman SE, Alipanah N, et al. Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of American clinical practice guidelines: Treatment of drug-
susceptible tuberculosis. Clin Infect Dis 2016; 63:e147.
2. Curry International Tuberculosis Center and California Department of Public Health, 2016: Drug-Resistant Tuberculosis: A Survival Guide for Clinicians, Third Edition.
https://www-uptodate-com.aure.unab.edu.co/contents/treatment-of-drug-susceptible-pulmonary-tuberculosis-in-hiv-uninfected-adults/print?sear… 10/12
Management of treatment interruptions* table
Time point of interruption Details of interruption Approach
During intensive phase Lapse is <14 days in duration Continue treatment to complete planned total number of doses (as long
as all doses are completed within 3 months)
Lapse is ≥14 days in duration Restart treatment from the beginning
During continuation phase Received ≥80 percent of doses and sputum was AFB smear negative on Further therapy may not be necessary
initial testing
Received ≥80 percent of doses and sputum was AFB smear positive on Continue therapy until all doses are completed
initial testing
Received <80 percent of doses and accumulative lapse is <3 months in Continue therapy until all doses are completed (full course), unless
duration consecutive lapse is >2 months
If treatment cannot be completed within recommended time frame for
regimen, restart therapy from the beginning (ie, restart intensive phase,
to be followed by continuation phase) ¶
Received <80 percent of doses and lapse is ≥3 months in duration Restart therapy from the beginning, new intensive and continuation
phases (ie, restart intensive phase, to be followed by continuation phase)
AFB: acid-fast bacilli.

* According to expert opinion, patients who are lost to follow-up (on treatment) and brought back to therapy, with interim treatment interruption, should have sputum resent for AFB smear, culture, and
drug susceptibility testing.
¶ The recommended time frame for regimen, in tuberculosis control programs in the United States and in several European countries, is to administer all of the specified number of doses for the
intensive phase within 3 months and those for the 4-month continuation phase within 6 months, so that the 6-month regimen is completed within 9 months.
Reproduced from: 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(7):e147-e195. By permission of Oxford University Press on behalf of the Infectious Diseases Society of America. Copyright © 2016. Available at:
https://www.idsociety.org/practice-guideline/treatment-of-drug-susceptible-tb/.
Approach to hepatotoxicity caused by first-line antituberculous drugs in adults*
* First-line antituberculous drugs include isoniazid, rifampin, pyrazinamide, and ethabutol. Isoniazid, rifampin, and pyrazinamide are potentially hepatotoxic; ethambutol is not hepatotoxic.
¶ Liver function tests include measurement of serum bilirubin, alkaline phosphatase, and hepatocellular enzymes (alanine aminotransferase and aspartate aminotransferase).
Δ Alternative causes of elevated liver function tests include alcohol, acetaminophen, viral hepatitis, gallstones, biliary obstruction, and others.
◊ Signs and symptoms of hepatotoxicity include nausea, vomiting, malaise, low-grade fever, and anorexia. Refer to the UpToDate topic on drug-induced liver injury for further discussion.
§ The approach to subsequent monitoring depends on clinical circumstances; some favor checking liver function tests weekly until on a stable regimen, then every two to four weeks thereafter.
¥ There is overlap in the pattern of liver injury caused by rifampin, isoniazid, and pyrazinamide; all individually or in combination may contribute to hepatotoxicity.
‡ Intervals of treatment interruption warranting resumption of therapy from the beginning vary between initiation and continuation phases; refer to text for further discussion.
† Refer to UpToDate content on treatment of tuberculosis for further discussion.
** Fluoroquinolones for treatment of tuberculosis include levofloxacin and moxifloxacin. Moxifloxacin is a more potent agent against Mycobacterium tuberculosis; levofloxacin may be associated with lower risk
References
1. Curry International Tuberculosis Center and California Department of Public Health, 2016: Drug-Resistant Tuberculosis: A Survival Guide for Clinicians, Third Edition.
2. 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-Susceptib
2016.

Treatment of Drug-Susceptible Pulmonary Tuberculosis in HIV-uninfected Adults - UpToDate PDF

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Treatment of Drug-Susceptible Pulmonary Tuberculosis in HIV-uninfected Adults - UpToDate PDF

Uploaded by

Copyright:

Available Formats

30/10/2020 Treatment of drug-susceptible pulmonary tuberculosis in HIV-uninfected adults - UpToDate

Official reprint from UpToDate®

Antituberculous therapy for these forms of TB is the same as pulmonary TB.

Risk factors for treatment failure and relapse include [31,60-62]:

● Inadequate adherence to treatment

Issues related to hepatotoxicity are discussed above. (See 'Hepatotoxicity' above.)

SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

● Basics topic (see "Patient education: Tuberculosis (The Basics)")

SUMMARY AND RECOMMENDATIONS

Use of UpToDate is subject to the Subscription and License Agreement.

Topic 8015 Version 61.0

Approach to treatment of drug-susceptible pulmonary tuberculosis in adults

AFB: acid-fast bacilli; HIV: human immunodeficiency virus; TB: tuberculosis.

Graphic 109259 Version 3.0

Regimens for treatment of drug-susceptible pulmonary tuberculosis in HIV-uninfected adults

PZA 7 days per week for 14 doses (2

Graphic 50102 Version 19.0

Dosing of first-line antituberculosis drugs in adults*

Rifapentine Δ Tablet (150 mg, film coated) – – – 10 to 20 mg/kg once weekly

Pyrazinamide § Tablet (500 mg, scored) Patient weight 40 to 55 kg ¥

1000 mg (18.2 to 25 1500 (27.3 to 37.5 mg/kg) 2000 mg (36.4 to 50 mg/kg) –

Patient weight 76 to 90kg ¥‡

2000 mg † (22.2 to 26.3 3000 mg † (33.3 to 39.5 4000 mg † (44.4 to 52.6 –

Ethambutol** Tablets (100 mg, 400 mg) Patient weight 40 to 55kg ¥

800 mg (14.5 to 20 mg/kg) 1200 mg (21.8 to 30 mg/kg) 2000 mg (36.4 to 50 mg/kg) –

1600 mg † (17.8 to 21.1 2400 mg † (26.7 to 31.6 4000 mg † (44.4 to 52.6 –

Data adapted from:

Graphic 55978 Version 13.0

Management of treatment interruptions* table

Time point of interruption Details of interruption Approach

Lapse is ≥14 days in duration Restart treatment from the beginning

AFB: acid-fast bacilli.

Graphic 109491 Version 9.0

Approach to hepatotoxicity caused by first-line antituberculous drugs in adults*

Graphic 109447 Version 3.0

You might also like