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ATS CLINICAL PRACTICE GUIDELINE:

SUMMARY FOR CLINICIANS


Series Editors: Carey C. Thomson and Kevin C. Wilson

Treatment of Drug-Susceptible Tuberculosis


Charles S. Dela Cruz1, Patrick G. Lyons2, Susan Pasnick3, Tanya Weinstock4,5, Payam Nahid3,
Kevin C. Wilson6, and Carey C. Thomson4,5
1
Section of Pulmonary, Critical Care, and Sleep Medicine, Yale University School of Medicine, New Haven, Connecticut; 2Section of
Pulmonary and Critical Care Medicine, Pritzker School of Medicine, University of Chicago, Chicago, Illinois; 3Division of Pulmonary and
Critical Care Medicine, University of California, San Francisco, California; 4Division of Pulmonary Disease and Critical Care Medicine,
Mount Auburn Hospital, Cambridge, Massachusetts; 5Harvard Medical School, Boston, Massachusetts; and 6Division of Allergy,
Pulmonary, Critical Care, and Sleep Medicine, Boston University Medical Center, Boston, Massachusetts

An official ATS/CDC/IDSA clinical practice recommendation, low certainty in the recommendation, moderate certainty
guideline: Treatment of Drug-Susceptible evidence). in the evidence).
Tuberculosis. Clin Infect Dis 2016;63:e147–e195. d We recommend the use of daily or three
The certainty in the available evidence
times weekly dosing in the continuation
that case management strategies improve
phase of therapy for drug-susceptible
patient outcomes is low. Despite this, there
The American Thoracic Society, the Centers pulmonary tuberculosis (strong
is general support for the involvement of
for Disease Control and Prevention, and the case managers who provide patient education, recommendation, moderate certainty in
Infectious Diseases Society of America counseling, care coordination, reminders, the evidence).
collaborated to develop guidelines (1) that treatment assessment, and home visits. The preferred regimen for adults
are intended to update the prior version A commonly used strategy to ensure with active tuberculosis caused by susceptible
(2). The new guidelines provide adherence to treatment is DOT. Trained organisms consists of an intensive phase of 2
recommendations on clinical and public personnel watch the patient swallow their months of isoniazid, rifampin, pyrazinamide,
health aspects of tuberculosis management medications, and arrangements can be and ethambutol followed by a continuation
in children and adults in well-resourced made with the patient to have DOT
areas. The implementation of these phase of 4 months of isoniazid and rifampin.
provided in a mutually agreeable location. Pyridoxine is administered with isoniazid
guidelines must be undertaken with Patients suspected of having active
individual circumstances always considered to all patients at risk of developing neuropathy.
tuberculosis should undergo smear During both the intensive and the
when deciding on the optimal course of microscopy, mycobacterial culture, and
action. This concise clinical summary is continuation phases of therapy, the
molecular testing of at least one sputum preferred frequency of drug administration
prepared for practicing clinicians. sample. Empiric treatment for active is daily. During the intensive phase, the
tuberculosis should be initiated in all use of three times weekly dosing may be
Treatment Supervision patients with a high likelihood of considered in patients who are not HIV
tuberculosis, even before the results of infected and are at low risk of relapse
Recommendations
these tests are known. (noncavitary pulmonary tuberculosis caused
d We suggest using case management by susceptible organisms and/or smear-
interventions during the treatment of negative patients). During the continuation
patients with tuberculosis (conditional Treatment Regimens phase, three times weekly therapy may be
recommendation, very low certainty Recommendations considered in select populations.
in the evidence). Alternative regimens exist for cases
d We suggest using directly observed therapy d We recommend the use of daily rather of intolerance or monoresistance to first-
(DOT) rather than self-administered than intermittent dosing in the intensive line drugs. If isoniazid or ethambutol
therapy for routine treatment of patients phase of therapy for drug-susceptible cannot be used, a quinolone can be
with all forms of tuberculosis (conditional pulmonary tuberculosis (strong considered. In cases where pyrazinamide

(Received in original form July 24, 2016; accepted in final form August 1, 2016 )
Correspondence and requests for reprints should be addressed to Charles S. Dela Cruz, M.D., Ph.D., Yale University, Pulmonary and Critical Care Medicine, 300
Cedar Street, TAC S441C, New Haven, CT 06513. E-mail: charles.delacruz@yale.edu
CME will be available for this article at www.atsjournals.org
A Maintenance of Certification exercise linked to this summary is available at http://www.atsjournals.org/page/ats_core_curriculum
Ann Am Thorac Soc Vol 13, No 11, pp 2060–2063, Nov 2016
Copyright © 2016 by the American Thoracic Society
DOI: 10.1513/AnnalsATS.201607-567CME
Internet address: www.atsjournals.org

2060 AnnalsATS Volume 13 Number 11 | November 2016


ATS CLINICAL PRACTICE GUIDELINE: SUMMARY FOR CLINICIANS

cannot be used, treatment with isoniazid, appropriate interventions to improve rifampin for an additional 3 months
rifampin, and ethambutol for 2 months, gastrointestinal tolerability, if no for a total therapy of 9 months in those
followed by a 7-month continuation phase hepatotoxicity is found. with drug-susceptible pulmonary
is advised. If multiple first-line agents All antituberculous medications can tuberculosis.
cannot be used, regimens similar to those cause a rash. Drugs should be immediately All patients with HIV and tuberculosis
used for drug-resistant tuberculosis should discontinued for fever, generalized coinfection are at increased risk of worse
be considered. erythema, petechiae, or mucous membrane clinical disease and should receive early
Smear microscopy and mycobacterial involvement. Sequential rechallenge, antiretroviral therapy in conjunction with
culture should be obtained monthly until starting with rifampin and then isoniazid, is daily antituberculosis medications, given
two consecutive negative cultures are appropriate once the rash improves. A the reduction in mortality rates and
obtained. The continuation phase of diagnosis of drug fever requires exclusion of decrease in the risk of developing AIDS-
therapy should be extended for 3 months tuberculosis (fever may persist 2 months related conditions. Providers should be
(7 months total) in patients who have into treatment) and exclusion of infection aware of the risk of developing immune
cavitation on initial chest radiograph and due to other organisms. Management reconstitution inflammatory syndrome
positive cultures at the completion of involves sequential rechallenge once the after initiation of therapies, especially for
2 months of intensive therapy, especially patient has been afebrile for 24 hours. those with CD4 cell counts less than 50
in the setting of other important Optic neuritis affects 2% of patients cells/ml (3). For patients who develop this,
comorbidities such as diabetes or receiving ethambutol, and serial vision ibuprofen may be sufficient to address
HIV infection. testing is indicated. mild cases, and for more severe cases
prednisone may be given for 2 to 4 weeks,
with tapering over a period of 6 to
Practical Aspects of Treatment of Tuberculosis with 12 weeks or longer (4).
Drug Therapy HIV Coinfection
Children
Recommendations
Drug Administration and Diagnosis can be challenging in young
Therapeutic Monitoring children (,5 yr), where diagnosis is
d For HIV-infected patients receiving
First-line antituberculous drugs should confirmed microbiologically in only 15 to
antiretroviral therapy, we suggest using
be administered simultaneously on an 50% of cases. In general, it is more
the standard 6-month daily regimen
empty stomach. Therapeutic drug difficult to isolate Mycobacterium
consisting of an intensive phase of
monitoring is not routinely tuberculosis in children, but it is also
2 months of isoniazid, rifampin,
recommended but can be performed if easier to treat than in infected adults.
pyrazinamide, and ethambutol followed
underdosing or drug–drug interactions Systematic reviews by the American
by a continuation phase of 4 months
are suspected. Academy of Pediatrics (5) and the World
of isoniazid and rifampin for the
Health Organization (6, 7) recommend a
treatment of drug-susceptible
Drug–Drug Interactions four-drug regimen for 2 months followed
pulmonary tuberculosis (conditional
Combinations of rifamycin plus isoniazid by a two-drug regimen for 4 months as
recommendation, very low certainty in
generally decrease the concentrations of the preferred regimen for children with
the evidence).
drugs metabolized by the cytochrome P450 suspected or confirmed tuberculosis.
d We recommend initiating antiretroviral
pathway. Antituberculous drugs are
therapy during tuberculosis treatment.
rarely influenced by other medications;
Antiretroviral therapy should ideally
exceptions include rifabutin and the
be initiated within the first 2 weeks of
Treatment in Special
fluoroquinolones, in which concentrations Circumstances
tuberculosis treatment for patients
can be significantly lowered due to drug–
with CD4 cell counts , 50/ml and
drug interactions. Pregnancy and Breastfeeding
within 8 to 12 weeks of tuberculosis
Treatment for tuberculosis is initiated
treatment initiation for patients with CD4
Management of Common Adverse whenever the probability of maternal
cell counts > 50/ml (strong recommendation,
Effects Related to Antituberculous disease is moderate to high because of
high certainty in the evidence).
Drugs the risk of untreated tuberculosis to a
Gastrointestinal symptoms should prompt The recommendation for daily pregnant woman and her fetus. All the
laboratory evaluation for hepatotoxicity. tuberculosis treatment regimens in HIV- antituberculous drugs cross the placenta
Drugs should be held for an alanine infected patients is based on findings that and all are still classified as category C.
transferase level equal to or greater than intermittent tuberculosis treatment Although the inclusion of pyrazinamide is
five times the upper limit of normal, regimens were associated with higher controversial in the United States, expert
abnormal bilirubin, abnormal alkaline rates of relapse and emergence of drug opinion is for its use in pregnant women
phosphatase, or hepatic symptoms. An resistance. In uncommon situations in with tuberculosis and HIV, extrapulmonary
increase in any of these can suggest which HIV-infected patients do not receive tuberculosis, or severe tuberculosis.
hepatotoxicity, for which hepatology antiretroviral therapy during tuberculosis Breastfeeding is encouraged in those
consultation may be helpful. Antacids, treatment, it is recommended to extend the who are deemed noninfectious and being
light snacks, and bedtime dosing are continuation phase with isoniazid and treated.

ATS Clinical Practice Guideline: Summary for Clinicians 2061


ATS CLINICAL PRACTICE GUIDELINE: SUMMARY FOR CLINICIANS

Renal and Liver Disease Failure to isolate M. tuberculosis from benefit to corticosteroid use for
Antituberculosis drugs need to be adjusted patients suspected of having pulmonary tuberculous meningitis (10, 11).
according to the creatinine clearance tuberculosis does not exclude a diagnosis of Chemotherapy for tuberculous
and in those receiving hemodialysis. active tuberculosis disease. Bronchoscopy meningitis begins with 2 months
Postdialysis administration of all with bronchoalveolar lavage and biopsy of four-drug therapy followed by
antituberculosis medications is preferred to should be considered before making the 7 to 10 months of isoniazid and
facilitate DOT. The likelihood of drug- diagnosis of culture-negative tuberculosis. rifampin, unless resistance is
induced hepatitis is increased in those with Patients with negative cultures who are identified. Abscess, paresis, and
prior liver disease. Strategies for treating suspected of having pulmonary tuberculosis hydrocephalus require neurosurgical
tuberculosis in the setting of hepatic should have treatment initiated and be consultation.
disease include choosing regimens with followed based on clinical and radiographic
fewer potentially hepatotoxic agents and response. Studies have shown that a Pleural and Peritoneal Tuberculosis
monitoring of liver function tests every 1 to 4-month regimen is adequate for treatment A 6-month regimen is indicated for
4 weeks during treatment. of adults with culture-negative pulmonary tuberculous pleurisy or peritoneal
tuberculosis (8). tuberculosis; adjunctive corticosteroids
Advanced Age are not beneficial. Tuberculous
The risk of drug-induced hepatitis and other empyemas require surgical or
adverse effects increases with age due to Extrapulmonary Manifestations percutaneous drainage on top of
reduced renal and hepatic clearance. Some curative antituberculosis therapy.
Tuberculous Pericarditis
suggest avoiding pyrazinamide, a common
culprit, in patients older than 75 years of age. Recommendation Bone, Joint, and Spine Tuberculosis
An initial regimen would include isoniazid, Bone, joint, and spinal tuberculosis
rifampin, and ethambutol during the d We suggest initial corticosteroid therapy are managed with a 6- to 9-month
intensive phase, with the plan for total NOT be routinely used in patients with standard course of rifampin-containing
duration of treatment extended to 9 months. tuberculous pericarditis (conditional chemotherapy. Surgery should be
recommendation, very low certainty in reserved for symptomatic cord
Other Comorbidities the evidence). compression, spinal instability, or
Treatment of tuberculosis is based on A randomized trial found no benefit of clinical deterioration.
the standard daily 6-month regimen, adjunctive corticosteroids in composite
including for patients with conditions that outcome of mortality, cardiac tamponade, Genitourinary Tuberculosis
alter immune responsiveness. Therapy or constrictive pericarditis for patients Genitourinary tuberculosis is managed with
can be extended to at least 9 months for with tuberculous pericarditis who were 6 months of standard chemotherapy.
those on the basis of disease severity, organ receiving standard chemotherapy (9). Hydronephrosis and ureteral
involvement, and response to treatment. obstruction require nephrostomy
Tumor necrosis factor-a inhibitor therapy or ureteral stenting. Surgery is reserved
is best held if clinically feasible. for abscesses or a damaged kidney
Tuberculous Meningitis
associated with symptoms.
Recommendation
Culture-Negative Tuberculosis Disseminated Tuberculosis and
d We recommend initial adjunctive
Recommendation Lymph Node Tuberculosis
corticosteroid therapy with dexamethasone
A standard 6-month regimen is adequate for
or prednisolone tapered over 6 to 8 weeks
d We suggest that a 4-month treatment miliary tuberculosis and for
for patients with tuberculous meningitis
regimen is adequate for treatment of HIV- drug-susceptible tuberculous
(strong recommendation, moderate
negative adult patients with acid-fast bacillus lymphadenitis. n
certainty in the evidence).
smear– and culture-negative pulmonary
tuberculosis (conditional recommendation, Two metaanalyses of randomized Author disclosures are available with the text
very low certainty in the evidence). trials found a significant mortality of this article at www.atsjournals.org.

References 3 Luetkemeyer AF, Kendall MA, Nyirenda M, Wu X, Ive P, Benson CA,


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ATS CLINICAL PRACTICE GUIDELINE: SUMMARY FOR CLINICIANS

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ATS Clinical Practice Guideline: Summary for Clinicians 2063

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