Up To Date. Tuberculosis Treatment

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Official reprint from UpToDate®

www.uptodate.com © 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved.
Treatment of drug-susceptible pulmonary tuberculosis in

nonpregnant adults without HIV infection
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: Feb 2023. | This topic last updated: Mar 14, 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-
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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.)
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● 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
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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
• 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".)
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• 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.)
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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
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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:
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• 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
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● 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
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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.
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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 — 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.
Administration logistics
Drug dosing and administration — Drug doses are summarized in the table ( table 2
and table 3) [37,38]. The drugs should be administered simultaneously to synchronize peak
serum concentrations and optimize killing; if feasible, use of fixed-drug combination tablets is
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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
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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 [39].
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.
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• The choice of which drug to resume may be guided by clinical circumstances

( algorithm 4 and algorithm 5) [39,40]:
- 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 [1,41];
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 [1,13,24,42,43]; 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
[24,44].
● 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
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two months [45,46]. 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) [47].
● 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 [48].
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) [26,49-52].
Among patients treated with rifamycin-containing regimens using DOT, relapse

generally occurs with susceptible organisms. If initial drug susceptibility testing was
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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 [14,53-55]:
• 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") [56]. In the
United States, specimens may be forwarded to the CDC for molecular testing with
relatively rapid turnaround time [57,58]. (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 [59-61].
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● 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 [62-65]. (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 [66].
● 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 [1,67].
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.)
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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 [68];
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 [69].
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
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calorie or protein intake if needed [70]. (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 [71-74].
Other studies have observed no effect on mortality or other outcomes [75-78]. These
discordant findings may be related to differences in the types of micronutrients
supplemented, sex, age, and other factors [79].
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 [70].
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 [80].
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
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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 [81]. (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 [3,6,82].
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) [83-85].
Globally, the World Health Organization estimates a treatment success rate of 85 percent and a
mortality rate of 15 percent [86]. 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) [87].
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".)
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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:
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- Sputum AFB culture negative at two months, no cavitary disease on initial chest
- Sputum AFB culture negative at two months, with cavitary disease on initial chest
- 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.)
Use of UpToDate is subject to the Terms of Use.
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76. Semba RD, Kumwenda J, Zijlstra E, et al. Micronutrient supplements and mortality of HIV-
infected adults with pulmonary TB: a controlled clinical trial. Int J Tuberc Lung Dis 2007;
11:854.
77. Wejse C, Gomes VF, Rabna P, et al. Vitamin D as supplementary treatment for tuberculosis:
a double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med 2009;
179:843.
78. Daley P, Jagannathan V, John KR, et al. Adjunctive vitamin D for treatment of active
tuberculosis in India: a randomised, double-blind, placebo-controlled trial. Lancet Infect Dis
2015; 15:528.
79. Benn CS, Friis H, Wejse C. Should micronutrient supplementation be integrated into the
case management of tuberculosis? J Infect Dis 2008; 197:1487.
80. Koethe JR, von Reyn CF. Protein-calorie malnutrition, macronutrient supplements, and
tuberculosis. Int J Tuberc Lung Dis 2016; 20:857.
81. Boehme CC, Nabeta P, Hillemann D, et al. Rapid molecular detection of tuberculosis and
rifampin resistance. N Engl J Med 2010; 363:1005.
82. International Union Against Tuberculosis and Lung Disease. Management of tuberculosis:
A guide to the essential of good practice, 6th ed, 2010.
3/30/23, 2:45 AM 8015
83. Lin CH, Lin CJ, Kuo YW, et al. Tuberculosis mortality: patient characteristics and causes. BMC
Infect Dis 2014; 14:5.
84. Fox GJ, Nguyen VN, Dinh NS, et al. Post-treatment Mortality Among Patients With
Tuberculosis: A Prospective Cohort Study of 10 964 Patients in Vietnam. Clin Infect Dis
2019; 68:1359.
85. Chidambaram V, Tun NL, Majella MG, et al. Male Sex Is Associated With Worse
Microbiological and Clinical Outcomes Following Tuberculosis Treatment: A Retrospective
Cohort Study, a Systematic Review of the Literature, and Meta-analysis. Clin Infect Dis 2021;
73:1580.
86. World Health Organization. Global tuberculosis report 2019. https://www.who.int/tb/public
ations/global_report/en/ (Accessed on October 28, 2019).
87. Centers for Disease Control and Prevention. Trends in Tuberculosis, 2018. https://www.cdc.
gov/tb/publications/factsheets/statistics/tbtrends.htm (Accessed on June 04, 2019).
Topic 8015 Version 71.0
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GRAPHICS
Treatment of drug-susceptible pulmonary tuberculosis in HIV-uninfected

adults: Traditional regimen (minimum six months)
Intensive phase* Continuation phase ¶ Range of Comments Δ◊

total doses
Drugs Interval and Drugs Interval and
(minimal
doses § doses §
duration)
(minimal (minimal
duration) duration)
Regimen 1
INH Daily for 8 INH 7 days per 182 to 130 (26 This is the
weeks week for 126 weeks) preferred
RIF RIF
doses (18 regimen for
7 days per
PZA weeks), or patients with
week for 56
EMB newly
doses (8 5 days per
diagnosed
weeks), or week for 90
pulmonary
doses (18
5 days per tuberculosis.
weeks)
week for 40
doses (8
weeks) ¥
Regimen 2
INH Daily for 8 INH Three times 110 to 94 (26 Preferred

weeks weekly for 54 weeks) alternative
RIF RIF
doses (18 regimen in
7 days per
PZA weeks) situations in
week for 56
EMB which more
doses (8
frequent DOT
weeks), or
during
5 days per continuation
week for 40 phase is difficult
doses (8 to achieve.
weeks) ¥
Regimen 3
INH Three times INH Three times 78 (26 weeks) Use regimen
weekly for 8 weekly for 54 with caution in
RIF RIF
weeks doses (18 patients with
PZA weeks) HIV and/or
Three times
EMB cavitary disease.
weekly for 24
Missed doses
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doses (8 can lead to

weeks) treatment
failure, relapse,
and acquired
drug resistance.
Regimen 4
INH Daily for 2 INH Twice weekly 62 (26 weeks) Do not use
weeks, then for 36 doses twice-weekly
RIF RIF
twice weekly (18 weeks) regimens in HIV-
PZA for 6 weeks infected
EMB patients or
7 days per
patients with
week for 14
smear-positive
doses (2
and/or cavitary
weeks), then
disease. If doses
twice weekly
are missed, then
for 12 doses ‡
therapy is
equivalent to
once weekly,
which is inferior.
INH: isoniazid; RIF: rifampin; RPT: rifapentine; PZA: pyrazinamide; EMB: ethambutol; DOT: directly
observed therapy; HIV: human immunodeficiency virus.
* Daily therapy is preferred over intermittent therapy to reduce risk of relapse and drug resistance;
this is particularly important during the intensive phase of treatment.
¶ During the continuation phase of treatment, daily treatment is preferred over intermittent
therapy; if daily therapy is not feasible, thrice-weekly dosing is preferred over twice-weekly dosing.
Δ 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.
◊ 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.
§ 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.
¥ 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.
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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/.
Graphic 50102 Version 24.0
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Dosing of first-line drugs for treatment of drug-susceptible tuberculosis

(traditional regimen; minimum six months) in adults*
Doses ¶
Drug Preparations
Daily 3x/week 2x/week 1x/week
First-line drugs
Isoniazid Δ Tablets (50 mg, 5 mg/kg 15 mg/kg 15 mg/kg 15 mg/kg

100 mg, 300 (usual (usual (usual (usual
mg); elixir (50 maximum maximum maximum maximum
mg/5 mL); dose 300 dose 900 mg) dose 900 mg) dose 900
aqueous mg) mg)
solution (100
mg/mL) for
intravenous or
intramuscular
injection
Rifampin Capsules (150 10 mg/kg 10 mg/kg 10 mg/kg –

(rifampicin) ◊ mg, 300 mg); (usual (usual (usual
capsule maximum maximum maximum
contents may dose 600 dose 600 mg) dose 600 mg)
be suspended mg)
for oral
administration;
aqueous
solution for
intravenous
injection
Rifabutin ◊ Capsule (150 5 mg/kg Not Not –

mg) (usual recommended recommended
maximum
dose 300
mg)
Rifapentine ◊ Tablet (150 mg, – – – 10 to 20

film coated) mg/kg once
weekly
during
continuation
phase of
treatment §
Pyrazinamide ¥ Tablet (500 mg, Patient weight 40 to 55 kg ‡

scored)
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1000 1500 mg (27.3 2000 mg (36.4 –

mg to 37.5 mg/kg) to 50 mg/kg)
(18.2 to
25
mg/kg)
Patient weight 56 to 75 kg ‡
1500 2500 mg (33.3 3000 mg (40 –

mg (20 to 44.6 mg/kg) to 53.6 mg/kg)
to 26.8
mg/kg)
Patient weight 76 to 90 kg ‡†
2000 3000 mg** 4000 mg** –

mg** (33.3 to 39.5 (44.4 to 52.6
(22.2 to mg/kg) mg/kg)
26.3
mg/kg)
Ethambutol ¶¶ Tablets (100 Patient weight 40 to 55 kg ‡

mg, 400 mg)
800 mg 1200 mg (21.8 2000 mg (36.4 –
(14.5 to to 30 mg/kg) to 50 mg/kg)
20
mg/kg)
1200 2000 mg (26.7 2800 mg (37.3 –

mg (16 to 35.7 mg/kg) to 50 mg/kg)
to 21.4
mg/kg)
1600 2400 mg** 4000 mg** –

mg** (26.7 to 31.6 (44.4 to 52.6
(17.8 to mg/kg) mg/kg)
21.1
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
3/30/23, 2:45 AM 8015
aminoglycoside doses. Because tuberculosis drug dosing for obese patients has not been
established, therapeutic drug monitoring may be considered for such patients.
¶ Daily therapy is preferred over intermittent therapy to reduce risk of relapse and drug resistance;
this is particularly important during the intensive phase of treatment. During the continuation phase
of treatment, daily treatment is preferred over intermittent therapy; if daily therapy is not feasible,
thrice-weekly dosing is preferred over twice-weekly dosing.
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.
◊ 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.
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.
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Drug dosing for treatment of drug-susceptible tuberculosis (rifapentine-

moxifloxacin-based regimen) in patients ≥12 years
Daily dose
Drug Preparations (administered as a single
dose)
Isoniazid* Oral: 300 mg

Tablet: 100 mg, 300 mg
Oral solution: 50 mg/5 mL
IM, IV:
Solution for injection: 100
mg/mL
Rifapentine Oral: 1.2 g

Tablet: 150 mg
Moxifloxacin Oral: 400 mg

Tablet: 400 mg
IV:
Solution for injection: 400
mg/250 mL
Pyrazinamide Oral: Dosing based on patient

Tablet: 500 mg weight: ¶
≥40 to 55 kg: 1 g
≥55 to 75 kg: 1.5 g
>75 kg: 2 g
The regimen summarized in this table is intended for patients with age ≥12 years, weight ≥40
kg, and CrCl ≥30 mL/min.
Antituberculous agents are used in multidrug combination regimens. The shortened 4-month
regimen consists of an intensive phase (8 weeks of rifapentine, isoniazid, pyrazinamide, and
moxifloxacin administered once daily), followed by a continuation phase (9 weeks of rifapentine,
isoniazid, and moxifloxacin administered once daily). Refer to the UpToDate clinical topic for
discussion.
IM: intramuscular; IV: intravenous; CrCl: creatinine clearance.
* Pyridoxine (vitamin B6) 25 to 50 mg/day is given with isoniazid to individuals at risk for neuropathy
(eg, pregnant women, 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.
3/30/23, 2:45 AM 8015
¶ Based on actual body weight [1] . Some experts dose based on estimated lean body weight [2] . A
calculator for estimating lean body weight is available separately in UpToDate.
Data from:
1. Dorman SE, Nahid P, Kurbatova EV, et al. Four-Month Rifapentine Regimens with or without Moxifloxacin for
Tuberculosis. N Engl J Med 2021; 384:1705.
Prevention/Infectious Diseases Society of American clinical practice guidelines: Treatment of drug-susceptible
tuberculosis. Clin Infect Dis 2016; 63:e147.
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Management of drug-susceptible pulmonary tuberculosis in HIV-uninfected ad

(traditional regimen) at 2-month juncture: sputum AFB culture negative, no cav
disease on initial chest radiograph
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Drug dosing is summarized separately (refer to text and related tables).

The algorithm is designed based on assumption that positive AFB cultures reflect Mycobacterium tubercul
identification of non-tuberculous mycobacteria should prompt adjustment of therapy accordingly (refer t
UpToDate content on nontuberculous mycobacteria).
The algorithm is designed based on assumption that patient has drug-susceptible disease; drug suscept
data should be reviewed and identification of drug resistance should prompt adjustment of therapy
accordingly (refer to UpToDate content on drug-resistant tuberculosis).
During treatment of pulmonary tuberculosis, sputum should be obtained for AFB smear and culture at
monthly intervals until 2 consecutive cultures are negative. Presence of positive sputum AFB culture afte
months of antituberculous therapy should prompt drug susceptibility testing and review of causes for
reatment failure. Presence of positive sputum cultures after 4 months of antituberculous therapy reflects
treatment failure; refer to text for discussion of management.
Directly observed therapy with individual, patient-centered case management is preferred for all patients
ensure adherence and prevent emergence of drug resistance.
AFB: acid-fast bacilli.
* Pyrazinamide may be discontinued after it has been taken for 2 months (56 daily doses).
¶ Ethambutol may be discontinued when results of drug susceptibility testing indicate no drug resistance to
line agents.
Δ Worsening chest radiograph findings or clinical manifestations prior to initiation of continuation phase sh
prompt consideration of drug-resistant tuberculosis or alternate diagnosis; refer to text for further discussio
◊ Use of once-weekly therapy with isoniazid and rifapentine in the continuation phase, or twice-weekly ther
with isoniazid and rifampin in the continuation phase are no longer recommended except for unusual
circumstances to facilitate directly observed therapy. In addition, rifapentine should not be used in patients
extrapulmonary tuberculosis.
§ If rifampin and pyrazinamide were included in the treatment regimen for at least 2 months, no further
treatment for latent tuberculosis is needed; otherwise a regimen for treatment of latent tuberculosis should
completed with rifampin and/or isoniazid (refer to UpToDate topic on treatment of latent tuberculosis infect
for further disucssion).
¥ Patients with drug-resistant isolates should be treated as discussed separately (refer to UpToDate topics
treatment of pulmonary tuberculosis and drug-resistant tuberculosis).
References:
1. Nahid P, Dorman SE, Alipanah N, et al. Official American Thoracic Society/Centers for Disease Control and Prevention/Infectiou
Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis. Clin Infect Dis 2016; 63:e1
2. Centers for Disease Control and Prevention. Treatment of Tuberculosis, American Thoracic Society, CDC, and Infectious Disease
Society of America. MMWR 2003;52(No. RR-11).
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Management of drug-susceptible pulmonary tuberculosis in HIV-uninfected ad

(traditional regimen) at 2-month juncture: sputum AFB culture negative, with c
disease on initial chest radiograph
3/30/23, 2:45 AM 8015

The algorithm is designed based on assumption that positive AFB cultures reflect Mycobacterium tubercul
identification of non-tuberculous mycobacteria should prompt adjustment of therapy accordingly (refer t
UpToDate content on nontuberculous mycobacteria).
The algorithm is designed based on assumption that patient has drug-susceptible disease; drug suscept
data should be reviewed and identification of drug resistance should prompt adjustment of therapy acco
(refer to UpToDate content on drug-resistant tuberculosis).
During treatment of pulmonary tuberculosis, sputum should be obtained for AFB smear and culture at m
intervals until 2 consecutive cultures are negative. Presence of positive sputum AFB culture after 3 month
antituberculous therapy should prompt drug susceptibility testing and review of causes for reatment fail
Presence of positive sputum cultures after 4 months of antituberculous therapy reflects treatment failure
to text for discussion of management.
Directly observed therapy with individual, patient-centered case management is preferred for all patients
ensure adherence and prevent emergence of drug resistance.
* Pyrazinamide may be discontinued after it has been taken for 2 months (56 doses).
¶ Ethambutol may be discontinued when results of drug susceptibility testing indicate no drug resistance to
line agents.
Δ Worsening chest radiograph findings or clinical manifestations prior to initiation of continuation phase sh
prompt consideration of drug-resistant tuberculosis or alternate diagnosis; refer to text for further discussio
◊ Use of once-weekly therapy with isoniazid and rifapentine in the continuation phase, or twice-weekly ther
isoniazid and rifampin in the continuation phase are no longer recommended except for unusual circumsta
facilitate directly observed therapy. In addition, rifapentine should not be used in patients with extrapulmon
tuberculosis.
§ Some experts would also extend the continuation phase for patients >10% below ideal body weight, or wit
current tobacco use, diabetes, HIV infection, other immunocompromising condition, and/or extensive disea
chest radiograph [1] . ¥ Patients with drug-resistant isolates should be treated as discussed separately (refer
UpToDate topics treatment of pulmonary tuberculosis and drug-resistant tuberculosis).
References:
Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis. Clin Infect Dis 2016; 63:e147.
2. Centers for Disease Control and Prevention. Treatment of Tuberculosis, American Thoracic Society, CDC, and Infectious Disease
of America. MMWR 2003;52(No. RR-11).
3/30/23, 2:45 AM 8015
Management of drug-susceptible pulmonary tuberculosis in adults

(traditional regimen) at 2-month juncture: sputum AFB culture positive

The algorithm is designed based on assumption that positive AFB cultures reflect Mycobacterium
tuberculosis; identification of non-tuberculous mycobacteria should prompt adjustment of therapy
accordingly (refer to UpToDate content on nontuberculous mycobacteria).
The algorithm is designed based on assumption that patient has drug-susceptible disease; drug
susceptibility data should be reviewed and identification of drug resistance should prompt
adjustment of therapy accordingly (refer to UpToDate content on drug-resistant tuberculosis).
3/30/23, 2:45 AM 8015
During treatment of pulmonary tuberculosis, sputum should be obtained for AFB smear and
culture at monthly intervals until 2 consecutive cultures are negative. Presence of positive sputum
AFB culture after 3 months of antituberculous therapy should prompt drug susceptibility testing
and review of causes for reatment failure. Presence of positive sputum cultures after 4 months of
antituberculous therapy reflects treatment failure; refer to text for discussion of management.
Directly observed therapy with individual, patient-centered case management is preferred for all
patients, to ensure adherence and prevent emergence of drug resistance.
* Pyrazinamide may be discontinued after it has been taken for 2 months (56 doses).
¶ Ethambutol may be discontinued when results of drug susceptibility testing indicate no drug
resistance to first-line agents.
Δ Worsening chest radiographi findings or clinical manifestations prior to initiation of continuation

phase should prompt consideration of drug-resistant tuberculosis or alternate diagnosis; refer to text
for further discussion.
◊ 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. In addition, rifapentine should
not be used in patients with extrapulmonary tuberculosis.
§ Patients with drug-resistant isolates should be treated as discussed separately (refer to UpToDate
topics treatment of pulmonary tuberculosis and drug-resistant tuberculosis).
References:
Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible
Tuberculosis. Clin Infect Dis 2016; 63:e147.
2. Centers for Disease Control and Prevention. Treatment of Tuberculosis, American Thoracic Society, CDC, and Infectious
Diseases Society of America. MMWR 2003;52(No. RR-11).
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Management of treatment interruptions* table
Time point of
Details of interruption Approach
interruption
During intensive Lapse is <14 days in duration Continue treatment to complete

phase 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 Received ≥80 percent of doses and Further therapy may not be
continuation sputum was AFB smear negative on necessary
phase initial testing
Received ≥80 percent of doses and Continue therapy until all doses are
sputum was AFB smear positive on completed
initial testing
Received <80 percent of doses and Continue therapy until all doses are
accumulative lapse is <3 months in 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 Restart therapy from the beginning,
lapse is ≥3 months in duration new intensive and continuation
phases (ie, restart intensive phase,
to be followed by continuation
phase)
* 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.
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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/.
3/30/23, 2:45 AM 8015
Some reported causes and potentiators of the long QT syndrome*
Congenital
Jervell and Lange-Nielsen syndrome (including "channelopathies")

Romano-Ward syndrome
Idiopathic
Acquired
Metabolic disorders
Hypokalemia
Hypomagnesemia
Hypocalcemia
Starvation
Anorexia nervosa
Liquid protein diets
Hypothyroidism
Bradyarrhythmias
Sinus node dysfunction
AV block: Second or third degree
Analgesic, anesthetic, and sedative drugs

Anesthetic/sedative:
Moderate risk: Propofol
Low risk: Dexmedetomidine ¶
Opioids:
High risk: Methadone
Low risk: Buprenorphine Δ
Androgen deprivation therapy (GnRH agonist/antagonist therapy or bilateral surgical orchiectomy)
Antianginal drugs
Low risk: Ranolazine (due to bradycardia)
Antiarrhythmic drugs
High risk: Amiodarone ◊ , disopyramide, dofetilide, dronedarone, ibutilide, procainamide,
quinidine, sotalol, vernakalant §
Moderate risk: Flecainide, pilsicainide § , propafenone
Anticholinergic drugs (antimuscarinics)

Low risk: Solifenacin
Antihistamines
High risk: Astemizole ¥ , terfenadine ¥
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Lower risk: Bilastine § , hydroxyzine
Antimicrobials
Antimalarial:
High risk: Delamanid § , quinidine, quinine
Moderate risk: Chloroquine, halofantrine, piperaquine
Lower risk: Artemether-lumefantrine, hydroxychloroquine (rare reports, noted in labeling)
Antiparasitic and antiprotozoal:
Moderate risk: Fexinidazole, meglumine antimoniate
Antituberculous:
High risk: Bedaquiline
Azole antifungals:
Moderate risk: Fluconazole, voriconazole
Low to moderate risk: Itraconazole, ketoconazole (systemic)
Clofazimine (moderate risk)
Fluoroquinolones (systemic):
Moderate risk: Gemifloxacin § , levofloxacin, moxifloxacin, sparfloxacin §
Low to moderate risk: Ciprofloxacin, norfloxacin, ofloxacin
Foscarnet (low to moderate risk)
HIV antiretrovirals:
Moderate risk: Saquinavir
Low to moderate risk: Efavirenz, fostemsavir, lopinavir-ritonavir, rilpivirine
Macrolide antibiotics:
Moderate risk: Azithromycin, clarithromycin, erythromycin
Low to moderate risk: Roxithromycin, telithromycin
Metronidazole (low to moderate risk)
Pentamidine (IV) (moderate risk)
Telavancin (low to moderate risk)
Triclabendazole (low to moderate risk)
Antineoplastic drugs
High risk: Adagrasib, arsenic trioxide, ivosidenib, lenvatinib, mobocertinib, selpercatinib,
vandetanib
Moderate risk: Capecitabine, ceritinib, crizotinib, dabrafenib, dasatinib, encorafenib, floxuridine,
fluorouracil (systemic), gilteritinib, inotuzumab ozogamicin, midostaurin, nilotinib, osimertinib,
pazopanib, ribociclib, sunitinib, toremifene, vemurafenib
Lower risk: Bosutinib, eribulin, glasdegib, lapatinib, oxaliplatin, pacritinib, panobinostat,
romidepsin, sorafenib, tamoxifen, vorinostat
Bronchodilators (beta-2 agonists)

Moderate risk: Terbutaline
Lower risk: Albuterol, arformoterol, formoterol, indacaterol, levalbuterol, olodaterol, salmeterol,
vilanterol
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Diuretics
Via electrolyte changes (especially hypokalemia or hypomagnesemia)
Gastrointestinal drugs
Antidiarrheal: Loperamide ‡ in overdose (lower risk)
Antiemetics:
Moderate risk: Droperidol, ondansetron (risk with IV use greater than oral)
Low to moderate risk: Amisulpride (IV antiemetic dose), dolasetron, granisetron,
hydroxyzine, tropisetron §
Promotility:
High risk: Cisapride (restricted availability)
Moderate risk: Domperidone §
Low to moderate risk (rare reports): Metoclopramide
Proton pump inhibitors: ‡ Chronic use leading to hypomagnesemia (rare)
Neurologic drugs
Low to moderate risk: Apomorphine, deutetrabenazine, donepezil, ezogabine, fingolimod,
ozanimod † , pimavanserin, ponesimod, tetrabenazine
Oxytocic drugs
Moderate risk: Carbetocin § , oxytocin
Psychotropic drugs
Antidepressants:
Selective serotonin reuptake inhibitors (SSRIs), serotonin modulators, and atypical agents:
Moderate risk: Citalopram, escitalopram
Low to moderate risk: Fluoxetine, sertraline, trazodone
Low risk: Mirtazapine
Tricyclic and tetracyclic antidepressants (TCAs):**
Moderate risk: Clomipramine, doxepin, and imipramine
Antipsychotics:
High risk: Chlorpromazine, IV haloperidol, sertindole § , ziprasidone
Moderate risk: Amisulpride (oral) § , clozapine, flupentixol § , haloperidol (oral), olanzapine,
pimozide, quetiapine, risperidone, thioridazine
Low to moderate risk: Asenapine, iloperidone, paliperidone, periciazine § , pimavanserin
Others:
Low to moderate risk: Atomoxetine
Low risk: Dexmedetomidine sublingual film ¶
Vasodilator drugs
High risk: Bepridil ¥
Other drugs
High risk: Levoketoconazole, papaverine (intracoronary)
Moderate risk: Etelcalcetide, gadobenate dimeglumine, lofexidine, probucol ¥
3/30/23, 2:45 AM 8015
Low to moderate risk: Alfuzosin, anagrelide, cocaine (topical), eliglustat, mifepristone,

pasireotide, voclosporin
Herbs: Cinchona (contains quinine), licorice extract (glycyrrhizin) in overuse leading to electrolyte
abnormalities
Other factors
Myocardial ischemia or infarction, especially with prominent T-wave inversions
Intracranial disease
HIV infection
Hypothermia
Toxic exposure: Organophosphate insecticides
This is not a complete list of all corrected QT interval (QTc)-prolonging drugs and does not include
drugs with either a minor degree or isolated association(s) with QTc prolongation that appear to be
safe in most patients but may need to be avoided in patients with congenital long QT syndrome
depending upon clinical circumstances. A more complete list of such drugs is available at the
CredibleMeds website. For clinical use and precautions related to medications and drug interactions,
refer to the UpToDate topic review of acquired long QT syndrome discussion of medications and the
Lexicomp drug interactions tool.
AV: atrioventricular; IV: intravenous.
* Classifications provided by Lexicomp according to US Food & Drug Administration guidance:

Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythic Potential for Non-
Antiarrhythmic Drugs – Questions and Answers; Guidance for Industry US Food and Drug
Administration, June 2017 (revision 2) available at:
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UC
M073161.pdf with additional data from CredibleMeds QT drugs list [1,2] . The use of other
classification criteria may lead to some agents being classified differently by other sources.
¶ The United States FDA labeling for the sublingual preparation of dexmedetomidine warns against
use in patients at elevated risk for QTc prolongation. Both intravenous (ie, sedative) and sublingual
formulations of dexmedetomidine have a low risk of QTc prolongation and have not been implicated
in TdP.
Δ Rarely associated with significant QTc prolongation at usual doses for treatment of opioid use
disorder, making buprenorphine a suitable alternative for patients with methadone-associated QTc
prolongation. Refer to UpToDate clinical topic reviews.
◊ In contrast with other class III antiarrhythmic drugs, amiodarone is rarely associated with
torsades de pointes; refer to accompanying text within UpToDate topic reviews of acquired long QT
syndrome.
§ Not available in the United States.
¥ Withdrawn from market in most countries due to adverse cardiovascular effects.
‡ Over-the-counter; available without a prescription.
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† Not associated with significant QTc prolongation in healthy persons. Refer to UpToDate clinical
topic for potential adverse cardiovascular (CV) effects in patients with CV disease.
** Other cyclic antidepressants may also prolong the QT interval; refer to UpToDate clinical topic on
cyclic antidepressant pharmacology, side effects, and separate UpToDate topic on tricyclic
antidepressant poisoning.
Data from:
1. Lexicomp Online. Copyright ©1978-2023 Lexicomp, Inc. All Rights Reserved.
2. CredibleMeds QT drugs list website sponsored by Science Foundation of the University of Arizona. Available at
http://crediblemeds.org/.
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Approach to hepatotoxicity caused by first-line antituberculous drugs in adults
3/30/23, 2:45 AM 8015
* First-line antituberculous drugs include isoniazid, rifampin, pyrazinamide, and ethambutol. Isoniazid, rifam
potentially hepatotoxic; ethambutol is not hepatotoxic.
¶ Liver function tests include measurement of serum bilirubin, alkaline phosphatase, and hepatocellular en
and aspartate aminotransferase).
Δ Alternative causes of elevated liver function tests include alcohol, acetaminophen, viral hepatitis, gallstone
◊ Signs and symptoms of hepatotoxicity include nausea, vomiting, malaise, low-grade fever, and anorexia. R
drug-induced liver injury for further discussion.
§ The approach to subsequent monitoring depends on clinical circumstances; some favor checking liver fun
regimen, then every two to four weeks thereafter.
¥ There is overlap in the pattern of liver injury caused by rifampin, isoniazid, and pyrazinamide; all individua
contribute to hepatotoxicity.
‡ Intervals of treatment interruption warranting resumption of therapy from the beginning vary between in
refer to UpToDate text for further discussion.
† Refer to UpToDate content on treatment of tuberculosis for further discussion.
References:
1. Curry International Tuberculosis Center and California Department of Public Health, 2016: Drug-Resistant Tuberculosis: A Surv
Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis. Clin Infect Dis 2016.
3. Nahid P, Mase SR, Migliori GB, et al. Treatment of Drug-Resistant Tuberculosis. An Official ATS/CDC/ERS/IDSA Clinical Practice G
200:e93.
3/30/23, 2:45 AM 8015
Approach to stepwise resumption of tuberculosis treatment in adults

with hepatotoxicity caused by first-line antituberculous drugs*
Refer to separate UpToDate algorithm for initial approach to hepatotoxicity caused by first-line
antituberculous drugs in adults.
* First-line antituberculous drugs include isoniazid, rifampin, pyrazinamide, and ethambutol.

Isoniazid, rifampin, and pyrazinamide are potentially hepatotoxic; ethambutol is not
hepatotoxic.
¶ Rifampin is an uncommon cause of hepatotoxicity. If initiation of rifampin and ethambutol is

not tolerated, we discontinue rifampin and sequentially add other antituberculous agents.
Treatment may be completed with a 3-drug regimen. If isoniazid is tolerated, it can be given
with ethambutol and a fluoroquinolone; if isoniazid is not tolerated, ethambutol, pyrazinamide,
and a fluoroquinolone may be given. If neither isoniazid nor pyrazinamide is tolerated, a
regimen for multidrug-resistant tuberculosis may be used.
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Δ 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.
◊ 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 of hepatotoxicity.
References:
1. Curry International Tuberculosis Center and California Department of Public Health, 2016: Drug-Resistant
Tuberculosis: A Survival Guide for Clinicians, Third Edition.
Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible
Tuberculosis. Clin Infect Dis 2016.
3. Nahid P, Mase SR, Migliori GB, et al. Treatment of Drug-Resistant Tuberculosis. An Official ATS/CDC/ERS/IDSA
Clinical Practice Guideline. Am J Respir Crit Care Med 2019; 200:e93.
3/30/23, 2:45 AM 8015
Contributor Disclosures
Timothy R Sterling, MD No relevant financial relationship(s) with ineligible companies to disclose. John
Bernardo, MD No relevant financial relationship(s) with ineligible companies to disclose. Elinor L Baron,
MD, DTMH No relevant financial relationship(s) with ineligible companies to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.
Conflict of interest policy

Up To Date. Tuberculosis Treatment

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Up To Date. Tuberculosis Treatment

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Official reprint from UpToDate®

Treatment of drug-susceptible pulmonary tuberculosis in

Goals of tuberculosis (TB) treatment include eradication of Mycobacterium tuberculosis infection,

Management consists of a patient-centered approach in which the patient, provider, public

Issues related to treatment of pulmonary TB in human immunodeficiency virus (HIV)-uninfected

susceptible pulmonary tuberculosis in nonpregnant adults with HIV infection: Initiation of

● Regimens – TB treatment regimens include:

• Rifapentine-moxifloxacin four-month regimen – A shortened, four-month regimen

● Treatment phases – In general, TB treatment regimens consists of two phases: an

● Rifamycin nitrosamine impurities – In August 2020, the US Food and Drug

Traditional regimen (≥6 months)

Intensive and continuation phases

Considerations during the intensive phase include:

● If pyrazinamide must be excluded – If pyrazinamide must be excluded from the

● Expected clinical course – Patients typically demonstrate clinical improvement (with

● Assessment at completion of intensive phase – At the time of completion of the

Considerations during the continuation phase include:

● Sputum monitoring – The approach to sputum monitoring is as follows [1]:

● Limitations of sputum monitoring – Use of sputum AFB smear and culture as

Treatment frequency — Daily therapy is preferred over intermittent therapy to reduce

● Treatment completion – Completion of treatment is determined by the duration of

● Interrupted treatment – In some cases, the specified number of doses cannot be

In general, continuous treatment is more important in the intensive phase of therapy

beginning. Consultation with an expert in TB should be sought if the clinical approach is

Rifapentine-moxifloxacin-based four-month regimen — The CDC and World Health

● Patients with suspected or confirmed resistance to the medications in the regimen –

● Patients with history of cardiac morbidities (given risk for fluoroquinolone-induced

• History of arrhythmias (especially bradyarrhythmias), uncorrected hypothyroidism, or

• Baseline transaminases >3 times the upper limit of normal

● Pregnant or lactating women

● Patients with incomplete access to medication or inadequate reimbursement to complete

Clinical approach — Our approach to laboratory evaluation, electrocardiogram (EKG)

● Baseline laboratory evaluation – Baseline laboratory evaluation should include:

• Complete blood count (hemoglobin ≥7 g/dL, platelets ≥100,000/microL)

We favor performing baseline EKG prior to starting treatment; we do not use a

● Drug dosing and administration – The rifapentine-moxifloxacin four-month regimen

Therapeutic drug level monitoring may be helpful if there is concern regarding

● Chest radiography – Following initial evaluation, we obtain repeat chest radiograph at

Completing therapy — Patients typically demonstrate clinical improvement (with

Regimen efficacy — Use of the four-month regimen is supported by a study including

● Traditional six-month regimen – Once-daily regimen consisting of rifampin, isoniazid,

● Rifapentine-based four-month regimen – Once-daily regimen in which rifapentine was

● Rifapentine-moxifloxacin four-month regimen – A four-month regimen in which

It is uncertain whether clinical implementation of adaptive treatment (which requires careful

Adverse effect monitoring

● Patient education – Patients on regimens including drugs associated with hepatotoxicity

● Laboratory monitoring – Patients receiving antituberculous therapy should undergo

General principles — Hepatotoxicity due to antituberculous drugs is an important

hepatotoxicity. Rifampin may be associated with a cholestatic pattern, with elevations in

● Differential diagnosis – Drug-induced hepatitis is a diagnosis of exclusion. Other

An asymptomatic increase in aspartate transaminase concentration occurs in

Discontinuing and resuming treatment

• In general, hepatitis attributed to antituberculous drugs should prompt

• The choice of which drug to resume may be guided by clinical circumstances

- If laboratory studies suggest a cholestatic pattern (seen more often with

- In the absence of cholestasis, rifampin may be restarted first; if there is no increase

• Considerations for resuming pyrazinamide:

- In milder cases of hepatotoxicity, pyrazinamide can be introduced, and a regimen

Regimen adjustments for drug intolerance — For circumstances in which a regimen

● Pyrazinamide intolerance – For patients who cannot tolerate pyrazinamide, isoniazid,

Treatment failure or relapse

- For the rifapentine-moxifloxacin four-month regimen, lack of clinical, radiographic,

2000 3000 mg 4000 mg –

1600 2400 mg 4000 mg –