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Current Medical Diagnosis & Treatment 2021
913: Pulmonary Tuberculosis
TREATMENT
A. General Measures
The goals of therapy are to cure the individual patient, minimize risk of morbidity and mortality related to treatment, reduce transmission of M
tuberculosis to other persons, and prevent the emergence of clinically significant drug resistance in tubercle bacilli. The basic principles of
antituberculous treatment are (1) to administer multiple medications to which the organisms are susceptible; (2) to provide the safest, most effective
therapy in the shortest period of time; (3) to ensure adherence to therapy; and (4) to add at least two new antituberculous agents to a regimen when
treatment failure is suspected.
All suspected and confirmed cases of tuberculosis should be reported promptly to local and state public health authorities. Public health departments
will perform case investigations on sources and patient contacts to determine if other individuals with untreated, infectious tuberculosis are present in
the community. They can identify infected contacts eligible for treatment of latent tuberculous infection and ensure that a plan for monitoring
adherence to therapy is established for each patient with tuberculosis. Patients with tuberculosis should be treated by clinicians who are skilled in the
management of this infection. Clinical expertise is especially important in cases of drugresistant tuberculosis.
Nonadherence to antituberculous treatment is a major cause of treatment failure, continued transmission of tuberculosis, and the development of
medication resistance. Adherence to treatment can be improved by providing detailed patient education about tuberculosis and its treatment in
addition to a case manager who oversees all aspects of an individual patient’s care. Directly observed therapy (DOT), which requires that a health
care worker physically observe the patient ingest antituberculous medications in the home, clinic, hospital, or elsewhere, also improves adherence to
treatment. The importance of direct observation of therapy cannot be overemphasized. The CDC recommends DOT for all patients with drugresistant
tuberculosis and for those receiving intermittent (twice or thriceweekly) therapy.
Hospitalization for initial therapy of tuberculosis is not necessary for most patients. It should be considered if a patient is incapable of selfcare or is
likely to expose new, susceptible individuals to tuberculosis. Hospitalized patients with active disease require a private room with negativepressure
ventilation until tubercle bacilli are no longer found in their sputum (“smearnegative”) on three consecutive smears taken on separate days.
Characteristics of antituberculous drugs are provided in Table 9–14. Additional treatment considerations can be found in Chapter 33 and e1, Anti
infective Chemotherapeutic & Antibiotic Agents. More complete information can be obtained from the CDC’s Division of Tuberculosis Elimination Web
site at https://www.cdc.gov/tb/.
Table 9–14.
Characteristics of antituberculous medications.
Most Common Tests for
Medication Drug Interactions Remarks
Side Effects Side Effects
Table 9–14.
Characteristics of antituberculous medications.
Most Common Tests for
Medication Drug Interactions Remarks
Side Effects Side Effects
ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CBC, complete blood count; LTBI, latent tuberculosis infection.
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B. Treatment of Tuberculosis in HIVNegative Persons
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Most patients with previously untreated pulmonary tuberculosis can be effectively treated with either a 6month or a 9month regimen, though the 6
month regimen is preferred. The initial phase of a 6month regimen consists of 2 months of daily isoniazid, rifampin, pyrazinamide, and ethambutol.
BUN and
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ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CBC, complete blood count; LTBI, latent tuberculosis infection.
B. Treatment of Tuberculosis in HIVNegative Persons
Most patients with previously untreated pulmonary tuberculosis can be effectively treated with either a 6month or a 9month regimen, though the 6
month regimen is preferred. The initial phase of a 6month regimen consists of 2 months of daily isoniazid, rifampin, pyrazinamide, and ethambutol.
Once the isolate is determined to be isoniazidsensitive, ethambutol may be discontinued. If the M tuberculosis isolate is susceptible to isoniazid and
rifampin, the second phase of therapy consists of isoniazid and rifampin for a minimum of 4 additional months, with treatment to extend at least 3
months beyond documentation of conversion of sputum cultures to negative for M tuberculosis. If DOT is used, medications may be given
intermittently using one of three regimens: (1) Daily isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months, followed by isoniazid and
rifampin two or three times each week for 4 months if susceptibility to isoniazid and rifampin is demonstrated. (2) Daily isoniazid, rifampin,
pyrazinamide, and ethambutol for 2 weeks, then administration of the same agents twice a week for 6 weeks followed by administration of isoniazid
and rifampin twice each week for 4 months if susceptibility to isoniazid and rifampin is demonstrated. (3) Isoniazid, rifampin, pyrazinamide, and
ethambutol three times a week for 6 months.
Patients who cannot or should not (eg, pregnant women) take pyrazinamide should receive daily isoniazid and rifampin along with ethambutol for 4–8
weeks. If susceptibility to isoniazid and rifampin is demonstrated or drug resistance is unlikely, ethambutol can be discontinued, and isoniazid and
rifampin may be given twice a week for a total of 9 months of therapy. If drug resistance is a concern, patients should receive isoniazid, rifampin, and
ethambutol for 9 months. Patients with smear and culturenegative disease (eg, pulmonary tuberculosis diagnosed on clinical grounds) and patients
for whom drug susceptibility testing is not available can be treated with 6 months of isoniazid and rifampin combined with pyrazinamide for the first 2
months. This regimen assumes low prevalence of drug resistance. Previous guidelines have used streptomycin interchangeably with ethambutol.
Increasing worldwide streptomycin resistance has made this medication less useful as empiric therapy.
When a twiceweekly or thriceweekly regimen is used instead of a daily regimen, the dosages of isoniazid, pyrazinamide, and ethambutol or
streptomycin must be increased. Recommended dosages for the initial treatment of tuberculosis are listed in Table 9–15. Fixeddose combinations of
isoniazid and rifampin (Rifamate) and of isoniazid, rifampin, and pyrazinamide (Rifater) are available to simplify treatment. Single tablets improve
compliance but are more expensive than the individual medications purchased separately.
Table 9–15.
Recommended dosages for the initial treatment of tuberculosis.1
1Data from Nahid P et al. Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice
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Guidelines: Treatment of drugsusceptible tuberculosis. Clin Infect Dis. 2016 Oct 1;63(7):e147–95.
TREATMENT, Asha N. Chesnutt; Mark S. Chesnutt; Niall T. Prendergast; Thomas J. Prendergast Page 3 / 7
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2All dosing regimens should be used with directly observed therapy.
3Average wholesale price (AWP, for ABrated generic when available) for quantity listed. Source: IBM Micromedex. Red Book (electronic version). IBM Watson Health,
When a twiceweekly or thriceweekly regimen is used instead of a daily regimen, the dosages of isoniazid, pyrazinamide, and ethambutol or
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streptomycin must be increased. Recommended dosages for the initial treatment of tuberculosis are listed in Table 9–15. Fixeddose combinations of
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isoniazid and rifampin (Rifamate) and of isoniazid, rifampin, and pyrazinamide (Rifater) are available to simplify treatment. Single tablets improve
compliance but are more expensive than the individual medications purchased separately.
Table 9–15.
Recommended dosages for the initial treatment of tuberculosis.1
1Data from Nahid P et al. Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice
Guidelines: Treatment of drugsusceptible tuberculosis. Clin Infect Dis. 2016 Oct 1;63(7):e147–95.
2All dosing regimens should be used with directly observed therapy.
3Average wholesale price (AWP, for ABrated generic when available) for quantity listed. Source: IBM Micromedex. Red Book (electronic version). IBM Watson Health,
Greenwood Village, CO, USA. Available at https://www.micromedexsolutions.com/ (cited March 25, 2020). AWP may not accurately represent the actual pharmacy
cost because wide contractual variations exist among institutions.
Also available at www.cdc.gov/tb/topic/treatment/guidelinehighlights.htm.
C. Treatment of Tuberculosis in HIVPositive Persons
Management of tuberculosis is complex in patients with concomitant HIV disease. Experts in the management of both tuberculosis and HIV disease
should be involved in the care of such patients. The CDC has published detailed recommendations for the treatment of tuberculosis in HIVpositive
patients (www.cdc.gov/tb/topic/basics/tbhivcoinfection.htm).
The basic approach to HIVpositive patients with tuberculosis is similar to that detailed above for patients without HIV disease. Additional
considerations in HIVpositive patients include (1) longer duration of therapy and (2) drug interactions between rifamycin derivatives such as rifampin
and rifabutin used to treat tuberculosis and some of the protease inhibitors and nonnucleoside reverse transcriptase inhibitors (NNRTIs) used to treat
HIV (see www.cdc.gov/tb/topic/basics/tbhivcoinfection.htm). DOT should be used for all HIVpositive tuberculosis patients. Pyridoxine (vitamin B6), 25–
50 mg orally each day, should be administered to all HIVpositive patients being treated with isoniazid to reduce central and peripheral nervous system
side effects.
D. Treatment of DrugResistant Tuberculosis
Patients with drugresistant M tuberculosis infection require careful supervision and management. Clinicians who are unfamiliar with the treatment of
drugresistant tuberculosis should seek expert advice. Tuberculosis resistant only to isoniazid can be successfully treated with a 6month regimen of
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rifampin, pyrazinamide, and ethambutol or streptomycin or a 12month regimen of rifampin and ethambutol. When isoniazid resistance is
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documented during a 9month regimen without pyrazinamide, isoniazid should be discontinued. If ethambutol was part of the initial regimen,
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rifampin and ethambutol should be continued for a minimum of 12 months. If ethambutol was not part of the initial regimen, susceptibility tests
should be repeated and two other medications to which the organism is susceptible should be added. Treatment of M tuberculosis isolates resistant to
side effects.
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D. Treatment of DrugResistant Tuberculosis
Patients with drugresistant M tuberculosis infection require careful supervision and management. Clinicians who are unfamiliar with the treatment of
drugresistant tuberculosis should seek expert advice. Tuberculosis resistant only to isoniazid can be successfully treated with a 6month regimen of
rifampin, pyrazinamide, and ethambutol or streptomycin or a 12month regimen of rifampin and ethambutol. When isoniazid resistance is
documented during a 9month regimen without pyrazinamide, isoniazid should be discontinued. If ethambutol was part of the initial regimen,
rifampin and ethambutol should be continued for a minimum of 12 months. If ethambutol was not part of the initial regimen, susceptibility tests
should be repeated and two other medications to which the organism is susceptible should be added. Treatment of M tuberculosis isolates resistant to
agents other than isoniazid and treatment of drug resistance in HIVinfected patients require expert consultation.
Multidrugresistant tuberculosis and extensively drugresistant tuberculosis call for an individualized daily DOT plan under the supervision of an
experienced clinician. Treatment regimens are based on the patient’s overall status and the results of susceptibility studies. Most drugresistant
isolates are resistant to at least isoniazid and rifampin and require a minimum of three drugs to which the organism is susceptible. These regimens are
continued until culture conversion is documented, and then a twodrug regimen is continued for at least another 12 months. Some experts
recommend at least 18–24 months of a threedrug regimen.
E. Treatment of Extrapulmonary Tuberculosis
In most cases, regimens that are effective for treating pulmonary tuberculosis are also effective for treating extrapulmonary disease. However, many
experts recommend 9–12 months of therapy when miliary, meningeal, or bone and joint disease is present. Treatment of skeletal tuberculosis is
enhanced by early surgical drainage and debridement of necrotic bone. Corticosteroid therapy has been shown to help prevent constrictive
pericarditis from tuberculous pericarditis and to reduce neurologic complications from tuberculous meningitis (Chapter 33).
F. Treatment of Pregnant or Lactating Women
Tuberculosis in pregnancy is usually treated with isoniazid, rifampin, and ethambutol for 2 months, followed by isoniazid and rifampin for an
additional 7 months. Ethambutol can be stopped after the first month if isoniazid and rifampin susceptibility is confirmed. Since the risk of
teratogenicity with pyrazinamide has not been clearly defined, pyrazinamide should be used only if resistance to other drugs is documented and
susceptibility to pyrazinamide is likely. Streptomycin is contraindicated in pregnancy because it may cause congenital deafness. Pregnant women
taking isoniazid should receive pyridoxine (vitamin B6), 10–25 mg orally once a day, to prevent peripheral neuropathy.
Small concentrations of antituberculous drugs are present in breast milk. Firstline therapy is not known to be harmful to nursing newborns at these
concentrations. Therefore, breastfeeding is not contraindicated while receiving firstline antituberculous therapy. Lactating women receiving other
agents should consult a tuberculosis expert.
G. Treatment Monitoring
Adults should have measurements of a complete blood count (including platelets) and serum bilirubin, hepatic enzymes, urea nitrogen, and creatinine
before starting therapy for tuberculosis. Visual acuity and redgreen color vision tests are recommended before initiation of ethambutol, and serum
uric acid is recommended before starting pyrazinamide. Audiometry should be performed if streptomycin therapy is initiated.
Routine monitoring of laboratory tests for evidence of medication toxicity during therapy is not recommended, unless baseline results are abnormal or
liver disease is suspected. Monthly questioning for symptoms of medication toxicity is advised. Patients should be educated about common side
effects of antituberculous medications and instructed to seek medical attention should these symptoms occur. Monthly followup of outpatients is
recommended, including sputum smear and culture for M tuberculosis, until cultures convert to negative. Patients with negative sputum cultures after
2 months of treatment should have at least one additional sputum smear and culture performed at the end of therapy. Patients with drugresistant
isolates should have sputum cultures performed monthly during the entire course of treatment. A chest radiograph at the end of therapy provides a
useful baseline for any future films.
Patients whose cultures do not become negative or whose symptoms do not resolve despite 3 months of therapy should be evaluated for
nonadherence to the regimen and for drugresistant organisms. DOT is required for the remainder of the treatment regimen, and the addition of at
least two drugs not previously given should be considered pending repeat drug susceptibility testing. The clinician should seek expert assistance if
drug resistance is newly found, if the patient remains symptomatic, or if smears or cultures remain positive.
Patients with only a clinical diagnosis of pulmonary tuberculosis (smears and cultures negative for M tuberculosis) whose symptoms and radiographic
abnormalities are unchanged after 3 months of treatment usually either have another process or have had tuberculosis in the past.
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H. Treatment of Latent Tuberculosis
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Treatment of latent tuberculous infection is essential to controlling and eliminating tuberculosis. Treatment of latent tuberculous infection
nonadherence to the regimen and for drugresistant organisms. DOT is required for the remainder of the treatment regimen, and the addition of at
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least two drugs not previously given should be considered pending repeat drug susceptibility testing. The clinician should seek expert assistance if
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drug resistance is newly found, if the patient remains symptomatic, or if smears or cultures remain positive.
Patients with only a clinical diagnosis of pulmonary tuberculosis (smears and cultures negative for M tuberculosis) whose symptoms and radiographic
abnormalities are unchanged after 3 months of treatment usually either have another process or have had tuberculosis in the past.
H. Treatment of Latent Tuberculosis
Treatment of latent tuberculous infection is essential to controlling and eliminating tuberculosis. Treatment of latent tuberculous infection
substantially reduces the risk that infection will progress to active disease. Targeted testing with the tuberculin skin test or interferon gamma release
assays is used to identify persons who are at high risk for tuberculosis and who stand to benefit from treatment of latent infection. Table 9–13 gives the
tuberculin skin test criteria for treatment of latent tuberculous infection. In general, patients with a positive tuberculin skin test or interferon gamma
release assay who are at increased risk for exposure or disease are treated. It is essential that each person who meets the criteria for treatment of
latent tuberculous infection undergo a careful assessment to exclude active disease. A history of past treatment for tuberculosis and contraindications
to treatment should be sought. All patients at risk for HIV infection should have an HIV test. Patients suspected of having tuberculosis should receive
one of the recommended multidrug regimens for active disease until the diagnosis is confirmed or excluded.
Some close contacts of persons with active tuberculosis should be evaluated for treatment of latent tuberculous infection despite a negative
tuberculin skin test reaction (less than 5 mm induration). These include immunosuppressed persons and those who may develop disease quickly after
tuberculous infection. Close contacts who have a negative tuberculin skin test reaction on initial testing should be retested 10–12 weeks later.
Several treatment regimens for both HIVnegative and HIVpositive persons are available for the treatment of latent tuberculous infection: (1)
Isoniazid: A 9month oral regimen (minimum of 270 doses administered within 12 months) is preferable to 6 months of therapy. Dosing options
include a daily dose of 300 mg or twiceweekly doses of 15 mg/kg. Persons at risk for developing isoniazidassociated peripheral neuropathy (those
with diabetes mellitus, uremia, malnutrition, alcoholism, HIV infection, pregnancy, or seizure disorder) may be given supplemental pyridoxine (vitamin
B6), 10–50 mg/day. (2) Isoniazid and rifampin: A 3month oral regimen of daily isoniazid (300 mg) and rifampin (600 mg). (3) Isoniazid and
rifapentine: A 3month oral regimen of once weekly isoniazid at 15 mg/kg and rifapentine at 15–30 mg/kg. (4) Rifampin: Patients who cannot
tolerate isoniazid can be considered for a 4month oral regimen of rifampin at 600 mg daily. HIVpositive patients receiving protease inhibitors or
NNRTIs who are given rifampin or rifapentine require management by experts in both tuberculosis and HIV disease (see Treatment of Tuberculosis in
HIVPositive Persons, above).
Contacts of persons with isoniazidresistant, rifampinsensitive tuberculosis should receive a 2month regimen of rifampin and pyrazinamide or a 4
month regimen of daily rifampin alone. Contacts of persons with drugresistant tuberculosis should receive two drugs to which the infecting organism
has demonstrated susceptibility. Contacts in whom the tuberculin skin test or interferon gamma release assay is negative and contacts who are HIV
seronegative may be observed without treatment or treated for 6 months. HIVpositive contacts should be treated for 12 months. All contacts of
persons with multidrugresistant tuberculosis or extensively drugresistant tuberculosis should have 2 years of followup regardless of type of
treatment.
Persons with a positive tuberculin skin test (5 mm or more of induration) and fibrotic lesions suggestive of old tuberculosis on chest radiographs who
have no evidence of active disease and no history of treatment for tuberculosis should receive 9 months of isoniazid or 4 months of rifampin (with or
without isoniazid). Pregnant or breastfeeding women with latent tuberculosis should receive either daily or twiceweekly isoniazid with pyridoxine
(vitamin B6).
Baseline laboratory testing is indicated for patients at risk for liver disease, patients with HIV infection, women who are pregnant or within 3 months of
delivery, and persons who use alcohol regularly. Patients receiving treatment for latent tuberculous infection should be evaluated once a month to
assess for symptoms and signs of active tuberculosis and hepatitis and for adherence to their treatment regimen. Routine laboratory testing during
treatment is indicated for those with abnormal baseline laboratory tests and for those at risk for developing liver disease.
BCG vaccine is an antimycobacterial vaccine developed from an attenuated strain of M bovis. Millions of individuals worldwide have been vaccinated
with BCG. However, it is not generally recommended in the United States because of the low prevalence of tuberculous infection, the vaccine’s
interference with the ability to determine latent tuberculous infection using tuberculin skin test reactivity, and its variable effectiveness in prophylaxis
of pulmonary tuberculosis. BCG vaccination in the United States should be undertaken only after consultation with local health officials and
tuberculosis experts. Vaccination of health care workers should be considered on an individual basis in settings in which a high percentage of
tuberculosis patients are infected with strains resistant to both isoniazid and rifampin, in which transmission of such drugresistant M tuberculosis
and subsequent infection are likely, and in which comprehensive tuberculous infectioncontrol precautions have been implemented but have not
been successful. The BCG vaccine is contraindicated in persons with impaired immune responses due to disease or medications.
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interference with the ability to determine latent tuberculous infection using tuberculin skin test reactivity, and its variable effectiveness in prophylaxis
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of pulmonary tuberculosis. BCG vaccination in the United States should be undertaken only after consultation with local health officials and
tuberculosis experts. Vaccination of health care workers should be considered on an individual basis in settings in which a high percentage of
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tuberculosis patients are infected with strains resistant to both isoniazid and rifampin, in which transmission of such drugresistant M tuberculosis
and subsequent infection are likely, and in which comprehensive tuberculous infectioncontrol precautions have been implemented but have not
been successful. The BCG vaccine is contraindicated in persons with impaired immune responses due to disease or medications.
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