Medicine Specialties > Infectious Diseases > Mycobacterial Infections

Tuberculosis
Thomas Herchline, MD, Professor of Medicine, Wright State University Boonshoft School of Medicine;
Medical Director, Public Health, Dayton and Montgomery County, Ohio
Judith K Amorosa, MD, FACR, Clinical Professor and Program Director, Department of Radiology,
University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School; Consulting Staff,
Department of Radiology, Robert Wood Johnson University Hospital
Updated: Apr 14, 2ARCHI010
Introduction
Background
Tuberculosis (TB) is the most common cause of infectious disease–related mortality
worldwide. The World Health Organization estimates that 2 billion people have latent TB,
while another 3 million people worldwide die of TB each year.[1 ]
Although TB rates are decreasing in the United States, the disease is becoming more
common in many parts of the world. In addition, the prevalence of drug-resistant TB is also
increasing worldwide. Co-infection with HIV has been an important factor in the
emergence and spread of resistance.[2 ]New TB treatments are being developed,[3 ]and new
TB vaccines are currently under investigation.[4 ]
Pathophysiology
Humans are the only known reservoir for Mycobacterium tuberculosis. TB is transmitted
by airborne droplet nuclei, which may contain fewer than 10 bacilli. TB exposure occurs by
sharing common airspace with an individual who is in the infectious stage of TB. When
inhaled, droplet nuclei are deposited within the terminal airspaces of the lung. Upon
encountering the bacilli, macrophages ingest and transport the bacteria to regional lymph
nodes.
The bacilli have 4 potential fates: (1) They may be killed by the immune system, (2) they
may multiply and cause primary TB, (3) they may become dormant and remain
asymptomatic, or (4) they may proliferate after a latency period (reactivation disease).
Reactivation TB may occur following either (2) or (3) above.
Frequency
United States
The US Centers for Disease Control and Prevention (CDC) has been recording detailed
epidemiologic information on TB since 1953. The incidence of TB has been declining since
the early 20th century because various factors, including basic infection-control practices
(isolation). Beginning in 1985, a resurgence of TB was noted. The increase was observed
primarily in ethnic minorities and especially in persons infected with HIV. TB control
programs were revamped and strengthened across the United States.
After peaking at 25,287 cases in 1993, the number of reported cases began to fall again. In
2007, 13,293 cases of TB were reported.[5 ]This corresponds to a rate of 4.4 cases per
100,000 population. The overall frequency of TB is 9.7 times higher in foreign-born
persons than in native-born persons, accounting for a steadily increasing proportion of all
reported TB cases. In 2007, 7,690 cases of TB (58.5% of all US cases) were reported
among foreign-born persons. More than half (52%) of TB cases involving foreign-born
individuals in 2007 were reported in persons from 4 countries: Mexico (24%), the
Philippines (12.4%), India (8%), and Vietnam (7.4%). An estimated 10-15 million people
in the United States have latent TB infection.
International
An estimated 20-33% of the world's population is infected with M tuberculosis. Countries
with the highest prevalence include Russia, India, Bangladesh, Pakistan, Indonesia,
Philippines, Vietnam, Korea, China, Tibet, Hong Kong, Egypt, most sub-Saharan African
countries, Brazil, Mexico, Bolivia, Peru, Colombia, Dominican Republic, Ecuador, Puerto
Rico, El Salvador, Nicaragua, Haiti, Honduras, and areas undergoing civil war (eg, Balkan
countries). The prevalence of TB in countries in Eastern Europe is intermediate. The
prevalence of TB is lowest in Costa Rica, western and northern Europe, the United States,
Canada, Israel, and most countries in the Caribbean. Multidrug-resistant tuberculosis
(MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) are becoming
increasingly significant.[6 ]Genotyping studies have shown that between 63% and 75% of
TB cases progress to XDR-TB through acquisition of resistance.[7 ]
Mortality/Morbidity
The case-fatality rate for TB was 50% for untreated patients before the advent of antibiotic
therapy. TB-related deaths worldwide are estimated at 3 million per year. In the United
States, the mortality rate of TB dropped from 12.4 deaths per 100,000 population in 1953 to
0.2 deaths per 100,000 population in 2004; this is approximately 4% per newly identified
case.
 MDR-TB cases are associated with a higher mortality rate. The mortality rate is also
higher in patients with underlying diseases that predispose to active TB.
 The mortality rate associated with untreated congenital TB is 50%. Congenital TB
can mimic congenital syphilis or cytomegalovirus (CMV) infection.
Race
Based on 2007 CDC data, the frequency of TB in Hispanics, blacks, and Asians were 7.6,
8.5, and 23.5 times higher than in whites, respectively.[1 ]However, race is not clearly an
independent risk factor, as foreign-born persons account for 77% of TB cases among
Hispanics and 96% of TB cases among Asians, but only 29% of TB cases among blacks.
Risk is best defined based on social, economic, and medical factors.
Sex
Despite the fact that TB rates have declined in both sexes in the United States, certain
differences exist. TB rates in women decline with age, but, in men, rates increase with age.
Men are more likely to have a positive tuberculin skin test result. The reason for these
differences may be social rather than biological in nature.
Age
 In the United States, more than 60% of TB cases occur in persons aged 25-64 years;
however, the age-specific risk is highest in persons older than 65 years.[1 ]
 TB infection in infants and young children (≤5 y) always indicates recent
transmission. Untreated TB in this age group may result in life-threatening
meningitis or disseminated disease.
 Elderly individuals with TB may not display typical signs and symptoms of TB
infection because they may not mount a good immune response. Active TB
infection in this age group may manifest as nonresolving pneumonitis. Obesity in
elderly patients has been associated with a lower risk for pulmonary TB.[8 ]
Clinical
History
 Pulmonary tuberculosis (TB): Typical symptoms of pulmonary TB include a
productive cough, fever, and weight loss. Patients with pulmonary TB occasionally
 present with hemoptysis or chest pain. Other systemic symptoms include anorexia,
fatigue, and night sweats.
 Tuberculous meningitis: Patients with tuberculous meningitis may present with a
headache that is either intermittent or persistent for 2-3 weeks. Subtle mental status
changes may progress to coma over a period of days to weeks. Fever may be low-
grade or absent.
 Skeletal TB: The most common site of skeletal TB involvement is the spine (Pott
disease). Symptoms include back pain or stiffness. Lower-extremity paralysis
occurs in up to half of patients with undiagnosed Pott disease. Tuberculous arthritis
usually involves only one joint. Although any joint may be involved, the hips and
knees are affected most commonly, followed by the ankle, elbow, wrist, and
shoulder. Pain may precede radiographic changes by weeks to months.
 Genitourinary TB: Reported symptoms of genitourinary TB include flank pain,
dysuria, and frequency. In men, genital TB may manifest as epididymitis or a
scrotal mass. In women, genital TB may mimic pelvic inflammatory disease. TB is
the cause of approximately 10% of sterility cases in women worldwide and
approximately 1% in industrialized countries.
 Gastrointestinal TB: Any site along the gastrointestinal tract may become infected.
Symptoms of gastrointestinal TB are referable to the site infected, including the
following: nonhealing ulcers of the mouth or anus; difficulty swallowing with
esophageal disease; abdominal pain mimicking peptic ulcer disease with stomach or
duodenal infection; malabsorption with infection of the small intestine; and pain,
diarrhea, or hematochezia with infection of the colon.
 Tuberculous lymphadenitis (scrofula): The most common site of tuberculous
lymphadenitis is in the neck along the sternocleidomastoid muscle. It is usually
unilateral and causes little or no pain. Advanced cases of tuberculous lymphadenitis
may suppurate and form a draining sinus.
 Cutaneous TB: Direct inoculation may result in an ulcer or wartlike lesion.
Contiguous spread from an infected lymph node typically results in a draining sinus.
Hematogenous spread may result in a reddish brown plaque on the face or
extremities (lupus vulgaris) or tender nodules or abscesses.
Physical
Physical examination findings associated with TB depend on the organs involved.
 Patients with pulmonary TB have abnormal breath sounds, especially over the upper
lobes or areas involved.
 Signs of extrapulmonary TB differ depending on the tissues involved. Signs may
include confusion, coma, neurologic deficit, chorioretinitis, lymphadenopathy, and
cutaneous lesions (see History).
 Postnatal TB is contracted via the airborne route. The most common findings of
postnatal TB include adenopathy and a lung infiltrate. However, the chest
radiographic findings may be normal in infants with disseminated disease. Many
experts increase the treatment duration to 9 or 12 months because of the possible
impaired immune system in children younger than 12 months. Bacille Calmette-
Guérin (BCG) vaccine is not recommended in infants in the United States but is
commonly used around the world.
Causes
M tuberculosis is a slow-growing organism, requiring 4-8 weeks for visible growth on solid
medium. The organism grows in parallel groups called cords (as seen in the image below).
It retains many stains after decoloration with acid-alcohol, which is the basis of acid-fast
stains.

Tuberculosis. Acid-fast bacillus smear showing characteristic cording in

Mycobacterium tuberculosis.

Differential Diagnoses
Actinomycosis Mycobacterium Gordonae
Aspergillosis Mycobacterium Kansasii
Bronchiectasis Mycobacterium Marinum
Crohn Disease Mycobacterium Xenopi
Epididymal Tuberculosis Nocardiosis
Fever of Unknown Origin Paracoccidioidomycosis
Histoplasmosis Pericarditis, Constrictive
Lung Abscess Pneumonia, Fungal
Lung Cancer, Non-Small Cell Pott Disease (Tuberculous Spondylitis)
Miliary Tuberculosis Prostatitis, Tuberculous
Mycobacterium Avium-Intracellulare Sarcoidosis
Mycobacterium Chelonae Tuberculosis of the Genitourinary System
Mycobacterium Fortuitum
Other Problems to Be Considered
Blastomycosis
Catscratch disease
Workup
Laboratory Studies
 Patients suspected of having tuberculosis (TB) should submit sputum for smear and
culture. Sputum should be collected in the early morning on 3 consecutive days. In
hospitalized patients, sputum may be collected every 8 hours. In patients without
spontaneous sputum production, sputum induction with hypertonic saline should be
attempted.[9 ]Early-morning gastric aspirate may also produce a good specimen,
especially in children. Another option is fiberoptic bronchoscopy with
transbronchial biopsy and bronchial washings. Biopsy of bone marrow, liver, or
blood cultures is occasionally necessary and may be helpful.
 Traditional mycobacterial cultures require weeks for growth and identification.
Newer technologies, including ribosomal RNA probes or DNA polymerase chain
reaction, allow identification within 24 hours. The DNA probes are approved for
direct testing on smear-positive or smear-negative sputa. However, smear-positive
specimens yielded higher sensitivity.
 Obtain the following laboratory tests:
o CBC count
o Chemistries, including alanine aminotransferase (ALT) or aspartate
aminotransferase (AST)
o Alkaline phosphatase
o Total bilirubin
o Uric acid
o Creatinine
 Obtain HIV serology in all patients with TB.
 For congenital TB, the best diagnostic test is the examination of the placenta for
pathology, histology, and culture. Mycobacterial blood cultures of the newborn may
also be helpful. Treatment may be necessary until placental culture results are
negative.
Imaging Studies
Chest radiographs may show a patchy or nodular infiltrate (as seen in the image below). TB
may be found in any part of the lung, but upper-lobe involvement is most common. The
lordotic view may better demonstrate apical abnormalities.

Tuberculosis. This radiograph shows a patient with typical radiographic findings of

tuberculosis.

Primary TB is more likely to mimic the appearance of routine community-acquired

pneumonia on chest radiography, in contrast to reactivation TB. Studies have shown that
either may be associated with pleural effusion or cavitation.
Various patterns may be seen, as follows:
 Cavity formation indicates advanced infection and is associated with a high
bacterial load.
 Noncalcified round infiltrates may be confused with lung carcinoma.
  Homogeneously calcified nodules (usually 5-20 mm) are tuberculomas and
represent old infection rather than active disease.
 Miliary TB is characterized by the appearance of numerous small nodular lesions
that resemble millet seeds on chest radiography.
CT scanning of the chest may help to better define abnormalities in patients with vague
findings on chest radiography.
Technetium-99m methoxy isobutyl isonitrile single-photon emission CT scanning for
solitary pulmonary nodules yields a high predictive value for distinguishing TB from
malignancy. Therefore, it has the potential to serve as a low-cost alternative when positron
emission tomography is not available, especially in endemic areas.[10 ]
Other Tests
Tuberculin skin testing (Mantoux test) is the most widely available test for diagnosing
tuberculous infection in the absence of active disease (latent infection). The tuberculin skin
test involves an intradermal injection of 5 tuberculin units of purified protein derivative.
The response is measured as the amount of induration at 48-72 hours. The size of
induration, rather than erythema, is diagnostic. Interpretation of skin testing depends on the
size of induration, age, and patient risk factors. The tuberculin skin test is not a sensitive
test for active TB. Three cutoff points of clinical significance exist; the criteria for each
cutoff point are listed below.
 Larger than or equal to 5 mm
o Close contacts to persons with newly diagnosed TB
o Persons with HIV infection
o Patients with organ transplant or patients who are taking the equivalent of
more than 15 mg/d of prednisone for one month or more
o Patients with fibrotic lesions on chest radiography (not granulomas)
 Larger than or equal to 10 mm
o Patients with medical conditions that increase the risk of TB (eg, diabetes
mellitus, hematologic malignancies, carcinoma of the head and neck,
intravenous drug use [known to be HIV-negative], end-stage renal disease,
silicosis, malnutrition, jejunoileal bypass, gastrectomy)
o Recent converter - At least 10-mm increase in skin test in past 2 years
(regardless of age)
o Recent immigrants (within 5 y) from a high-prevalence country
o Children younger than 4 years exposed to adults at high risk for TB
o Residents and employees of facilities for long-term care, including
correctional institutions, nursing homes, homeless shelters, and mental
institutions
 Larger than or equal to 15 mm - Persons with none of the above
Whole-blood assay based on interferon-gamma release (IGRA) with ESAT-6 and CFP-10
antigens (QuantiFERON-TB Gold, T-SPOT.TB) can also be used to screen for latent TB
infection and offers certain advantages over tuberculin skin testing.[11 ]Overall, sensitivity
and specificity are comparable to those of tuberculin skin testing; however, a second
encounter for reading is unnecessary, unlike with tuberculin skin testing. Results are
reported as positive, negative, or indeterminate. Patients with an indeterminate result are
likely to have evidence of immunosuppression and to be nonreactive on skin testing.[12 ]
Neither tuberculin skin testing nor IGRA testing is sufficiently sensitive to rule out TB
infection.[13 ]
Jafari et al found that an M tuberculosis –specific enzyme-linked immunospot (ELISpot)
assay can be used to differentiate TB cases with sputum smear negative for acid-fast
bacteria (AFB) from latent TB infection. In a prospective study of 347 patients suspected of
having active TB who were unable to produce sputum or who had AFB-negative sputum
smears, ELISpot testing of bronchoalveolar lavage fluid displayed a sensitivity and
specificity of 91% and 80%, respectively, for the diagnosis of active pulmonary TB.
ELISpot of bronchoalveolar lavage fluid (diagnostic odds ratio [OR], 40.4) was superior to
ELISpot of peripheral blood mononuclear cells (OR, 10.0), tuberculin skin testing (OR,
7.8), and M tuberculosis –specific nucleic acid amplification testing (OR, 12.4) for
diagnosing sputum AFB smear–negative TB.[14 ]
Treatment
Medical Care
 For initial empiric treatment of tuberculosis (TB), start patients on a 4-drug
regimen: isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin.
Once the TB isolate is known to be fully susceptible, ethambutol (or streptomycin if
used as a fourth drug) can be discontinued.
o After 2 months of therapy (for a fully susceptible isolate), pyrazinamide can
be stopped. Isoniazid plus rifampin are continued as daily or intermittent
therapy for 4 more months.
o If isolated isoniazid resistance is documented, discontinue isoniazid and
continue treatment with rifampin, pyrazinamide, and ethambutol for the
entire 6 months.
o Therapy must be extended if the patient has cavitary disease or remains
culture-positive after 2 months of treatment.
 Directly observed therapy (DOT) is recommended for all patients. Patients on the
above regimens as DOT can be switched to 2- to 3-times per week dosing after an
initial 2 weeks of daily dosing. Patients on twice-weekly dosing must not miss any
doses. Prescribe daily therapy for patients on self-administered medication.
 The diagnosis of MDR-TB is established with an isolate that is resistant to both
isoniazid and rifampin. Resistance may be initial (no known history of prior
treatment) or secondary (acquired during therapy or because of previous inadequate
therapy).
 Risk factors for initial resistance include exposure to a patient who has MDR-TB or
being from a country or region with a high prevalence of resistance. Symptoms and
radiographic findings do not differentiate MDR-TB from fully susceptible TB.
Suspect MDR-TB if the patient is on DOT with the 4 first-line drugs (no diarrhea)
and symptoms do not improve within 1-2 weeks.
 Continue treatment for MDR-TB for 18-24 months after sputum culture conversion.
The drugs should be prescribed daily (no intermittent therapy), and the patient
should always be on DOT. Weekend DOT may not be possible; therefore, giving
self-administered oral drugs on Saturdays and Sundays may be reasonable. Consult
an expert on MDR-TB. Costs are many times higher for treatment of MDR-TB.
Treatment should include an injectable drug together with at least 3 more drugs to
which the isolate is susceptible.
 In a phase 2, randomized, controlled trial, Diacon et al studied patients with newly
diagnosed multidrug-resistant pulmonary TB. Forty-seven patients were assigned
either TMC207 (400 mg PO qd for 2 wk, then 200 mg tid for 6 wk) or placebo in
 combination with a standard 5-drug, second-line antituberculosis regimen. TMC207
added to standard therapy for MDR-TB reduced the time to conversion to a negative
sputum culture compared with placebo (P = 0.003) and increased the proportion of
patients with conversion of sputum culture (48% vs 9%). These data provide
important results to continue investigation of TMC207 in a larger population for
multidrug-resistant pulmonary TB.[15 ]
 The diagnosis of extended drug-resistant TB (XDR-TB) is established with an
isolate that is resistant to isoniazid, rifampin, at least one of the quinolones, and at
least one injectable drug. Treatment options for XDR-TB are very limited, and
XDR-TB carries a very high mortality rate.
 Abdool Karim et al (2010) conducted an open-label, randomized trial in 642
patients coinfected with TB and HIV to determine the optimal initiation of
antiretroviral agents. The simultaneous initiation of antiretroviral therapy with TB
therapy (429 patients) decreased the death rate over a sequential approach (213
patients), with a mortality rate of 5.4 deaths per 100 person-years (25 deaths)
compared with 12.1 deaths per 100 person-years (27 deaths), respectively. The
relative reduction was 56% (P = 0.003). The authors concluded that the initiation of
antiretroviral therapy during TB therapy significantly improved survival. These
results provide further impetus for the integration of TB and HIV services.[16 ]
Surgical Care
 Surgical resection of an infected lung may be considered to reduce the bacillary
burden in patients with MDR-TB. Procedures include segmentectomy (rarely used),
lobectomy, and pneumonectomy. Pleurectomies for thick pleural peel are rarely
indicated. However, intraoperative infection of uninvolved lung tissue has been
observed.
 Complications include the usual perioperative complications, recurrent disease, and
bronchopleural fistulas.
Consultations
 Infectious disease specialist
 Pulmonologist
 General or thoracic surgeon
Activity
Smoking has been shown to be a risk factor for TB; smokers who develop TB should be
encouraged to stop smoking to decrease the risk of relapse.[17 ]
Medication
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Antimycobacterials
The goals of tuberculosis (TB) treatment are to shorten the clinical course, to prevent
complications, to prevent the development of latency and/or subsequent recurrences, and to
decrease the likelihood of TB transmission. In patients with latent TB, the goal of therapy is
to prevent progression of disease.

Isoniazid (Laniazid)
DOC for preventive therapy and primary drug in combination therapy for active TB. In
patients receiving treatment for active TB, pyridoxine 25-50 mg PO qd should be
coadministered to prevent peripheral neuropathy.
Dosing
Adult
300 mg PO qd
Pediatric
10 mg/kg/d PO qd; not to exceed 300 mg/d
Interactions
Higher incidence of isoniazid-related hepatitis can occur with daily alcohol ingestion;
aluminum salts may decrease isoniazid serum levels (administer 1-2 h before taking
aluminum salts); may increase effects of anticoagulants with coadministration; may inhibit
metabolic clearance of benzodiazepines
Carbamazepine toxicity or isoniazid hepatotoxicity may result from concurrent use
(monitor carbamazepine concentrations and liver function); coadministration with
cycloserine may increase adverse CNS effects (eg, dizziness); acute behavioral and
coordination changes may occur with coadministration of disulfiram
Coadministration with rifampin after halothane anesthesia may result in hepatotoxicity and
hepatic encephalopathy; may inhibit hepatic microsomal enzymes and increase toxicity of
hydantoin
Contraindications
Documented hypersensitivity; previous isoniazid-associated hepatic injury; other severe
adverse reactions
Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans;
may use if benefits outweigh risk to fetus
Precautions
Monitor patients with active chronic liver disease or severe renal dysfunction; periodic
ophthalmologic examinations during isoniazid therapy are recommended even when visual
symptoms do not occur

Rifampin (Rifadin, Rimactane)

For use in combination with at least one other antituberculous drug. Inhibits DNA-
dependent bacterial but not mammalian RNA polymerase. Cross-resistance may occur.
Treat for 6 mo for most susceptible cases; 9 mo if sputum culture result is still positive after
2 mo of treatment.
Dosing
Adult
600 mg PO qd
Pediatric
10-20 mg/kg/d PO qd; not to exceed 600 mg/d
Interactions
Induces microsomal enzymes, which may decrease effects of acetaminophen, PO
anticoagulants, barbiturates, benzodiazepines, beta-blockers, chloramphenicol, PO
contraceptives, corticosteroids, mexiletine, cyclosporine, digitoxin, disopyramide,
estrogens, hydantoins, methadone, clofibrate, quinidine, dapsone, tazobactam,
sulfonylureas, theophyllines, tocainide, and digoxin; blood pressure may increase with
coadministration of enalapril; coadministration with isoniazid may result in higher rate of
hepatotoxicity than with either agent alone (discontinue one or both agents if alterations in
LFTs occur)
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in
animals
Precautions
Obtain CBCs and baseline clinical chemistries before and throughout therapy; in liver
disease, weigh benefits against risk of further liver damage; interruption of therapy and
high-dose intermittent therapy are associated with thrombocytopenia that is reversible if
therapy is discontinued as soon as purpura occurs; if treatment is continued or resumed
after appearance of purpura, cerebral hemorrhage or death may occur

Pyrazinamide (PZA)
Pyrazine analog of nicotinamide that may be bacteriostatic or bactericidal against M
tuberculosis depending on concentration of drug attained at site of infection; mechanism of
action is unknown.
Administer for initial 2 mo of a 6-mo or longer treatment regimen for drug-susceptible TB.
Treat drug-resistant TB with individualized regimens.
Dosing
Adult
<50 kg: 1.5 g PO qd
50-75 kg: 2 g PO qd
>75 kg: 2.5 g PO qd
Pediatric
15-30 mg/kg/d PO qd; not to exceed 2 g/d
Interactions
None reported
Contraindications
Documented hypersensitivity; severe hepatic damage; acute gout
Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans;
may use if benefits outweigh risk to fetus
Precautions
Use only in combination with other effective antituberculous agents; inhibits renal
excretion of urates; may result in hyperuricemia (usually asymptomatic); perform baseline
serum uric acid determinations; discontinue drug if signs of hyperuricemia with acute gouty
arthritis occur; perform baseline LFTs (closely monitor in liver disease); discontinue
pyrazinamide if signs of hepatocellular damage appear; caution in history of diabetes
mellitus

Ethambutol (Myambutol)
Diffuses into actively growing mycobacterial cells (eg, tubercle bacilli). Impairs cell
metabolism by inhibiting synthesis of one or more metabolites, which in turn, causes cell
death. No cross-resistance demonstrated.
Mycobacterial resistance is frequent with previous therapy. Use in these patients in
combination with second-line drugs that have not been previously administered. Administer
q24h until permanent bacteriological conversion and maximal clinical improvement are
observed. Absorption is not significantly altered by food.
Dosing
Adult
15-25 mg/kg PO qd
Pediatric
Administer as in adults
Interactions
Aluminum salts may delay and reduce absorption (administered several hours before or
after ethambutol dose)
Contraindications
Documented hypersensitivity; optic neuritis (unless clinically indicated)
Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in
animals
Precautions
Reduce dose in impaired renal function; may have reversible adverse visual effects if
promptly discontinued

Streptomycin sulfate
For treatment of susceptible mycobacterial infections. Use in combination with other
antituberculous drugs (eg, isoniazid, ethambutol, rifampin). Total period of treatment for
TB is a minimum of 6 mo; however, streptomycin therapy is not commonly used for the
duration of therapy. Recommended when less potentially hazardous therapeutic agents are
ineffective or contraindicated.
Dosing
Adult
15 mg/kg IM qd; can be administered 3-5 d/wk
Pediatric
20-30 mg/kg IM qd
Interactions
Nephrotoxicity may be increased with aminoglycosides, cephalosporins, penicillins,
amphotericin B, and loop diuretics
Contraindications
Documented hypersensitivity; non–dialysis-dependent renal insufficiency
Precautions
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Narrow therapeutic index; not intended for long-term therapy; caution in renal failure,
patient not taking dialysis; caution with myasthenia gravis, hypocalcemia, and conditions
that depress neuromuscular transmission

Levofloxacin (Levaquin)
Second-line drug. Useful in the treatment of TB in combination with rifampin and other
antituberculous agents. Useful in treating most cases of MDR-TB.
Dosing
Adult
500-1000 mg PO qd
Pediatric
<18 years: Not recommended unless no alternates available
Interactions
Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h
before or after taking fluoroquinolones; cimetidine may interfere with metabolism of
fluoroquinolones; reduces therapeutic effects of phenytoin; probenecid may increase serum
concentrations; may increase toxicity of theophylline, caffeine, cyclosporine, and digoxin
(monitor digoxin levels); may increase effects of anticoagulants (monitor PT)
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans;
may use if benefits outweigh risk to fetus
Precautions
In prolonged therapy, perform periodic evaluations of organ system functions (eg, renal,
hepatic, hematopoietic); adjust dose in renal function impairment; superinfections may
occur with prolonged or repeated antibiotic therapy

Rifapentine (Priftin)
Used in once-weekly regimens along with isoniazid. Should not be used in individuals with
HIV or with positive cultures after 2 mo of treatment.
Dosing
Adult
600 mg PO qwk during the continuation phase of treatment for TB; given in combination
with isoniazid for susceptible organism
Pediatric
Not established
Interactions
Induces cytochrome P 4503 A 4 and P 4502 C 8/9, thereby decreasing levels of other drugs
that are metabolized by these enzymes; may decrease plasma concentration of calcium
channel blockers (verapamil, nifedipine, diltiazem), methadone, oral anticoagulants, oral
contraceptives, benzodiazepines, acetaminophen, dapsone, clofibrate, doxycycline,
levothyroxine, nortriptyline, tacrolimus, zidovudine, protease inhibitors, hydantoins, sulfa
drugs, or enalapril; toxicity may increase when taken concurrently with halothane or
isoniazid
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans;
may use if benefits outweigh risk to fetus
Precautions
Adverse effects include serious hepatic events, including hepatitis and liver failure;
Clostridium difficile -associated colitis; hyperbilirubinemia; urticaria; thrombocytopenia;
hyperkalemia; fatigue; gout; may cause red-orange discoloration of body fluids (eg, tears,
urine, sweat, CSF)

Para-aminosalicylic acid (Sodium PAS)

Second-line drug. Bacteriostatic agent useful against M tuberculosis. Inhibits the onset of
bacterial resistance to streptomycin and isoniazid. Administer aminosalicylate sodium with
other antituberculous drugs.
Dosing
Adult
4-6 g PO bid
Pediatric
75 mg/kg PO bid
Interactions
PO absorption of digoxin may be reduced, causing a reduction in serum levels when
administered concurrently with PAS; increase in digoxin dosing may be necessary; a
deficiency in vitamin B-12 (PO) may be induced because of PAS interference of its GI
absorption; parenteral vitamin B-12 supplementation may be required
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in
animals
Precautions
Caution in gastric ulcer and history of congestive heart failure; avoid situations in which
excess sodium is potentially harmful

Ethionamide (Trecator-SC)
Second-line drug. Bacteriostatic against M tuberculosis. Recommended if treatment with
first-line drugs (isoniazid, rifampin) is unsuccessful. Treats any form of active TB.
However, should only be used with other effective antituberculous agents.
Dosing
Adult
250-500 mg PO bid
Pediatric
15-20 mg/kg PO bid
Interactions
Hepatotoxicity increases when used concurrently with rifampin
Contraindications
Documented hypersensitivity; severe hepatic damage
Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans;
may use if benefits outweigh risk to fetus
Precautions
Make determinations of serum transaminase (AST, ALT) prior to therapy and q2-4wk
thereafter; perform in vitro susceptibility tests of recent cultures of M tuberculosis from
patient, with ethionamide and usual first-line antituberculous drugs; management of
diabetes mellitus may be more difficult, and hepatitis may occur more frequently

Amikacin (Amikin)
Second-line drug. Irreversibly binds to 30S subunit of bacterial ribosomes; blocks
recognition step in protein synthesis; causes growth inhibition. Use patient's IBW for
dosage calculation.
Dosing
Adult
15 mg/kg IM qd; can administer 3-5 d/wk
Pediatric
15-30 mg/kg IM qd
Interactions
Coadministration with other aminoglycosides, penicillins, cephalosporins, and
amphotericin B (increases nephrotoxicity); enhances effects of neuromuscular-blocking
agents; causes respiratory depression; irreversible hearing loss may occur with
coadministration of loop diuretics
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Not intended for long-term therapy; caution in patients with renal failure (patient not taking
dialysis), hypocalcemia, myasthenia gravis, and conditions that depress neuromuscular
transmission

Cycloserine (Seromycin)
Second-line drug. Inhibits cell wall synthesis in susceptible strains of gram-positive and
gram-negative bacteria and in M tuberculosis. Structural analogue of D -alanine, which
antagonizes role of D -alanine in bacterial cell wall synthesis, inhibiting growth.
Dosing
Adult
250-500 mg PO bid
Pediatric
10-20 mg/kg PO bid
Interactions
Incompatible with alcohol consumption because may increase possibility and risk of
epileptic episodes; isoniazid in combination with cycloserine may result in increased
adverse cycloserine CNS effects (eg, dizziness)
Contraindications
Documented hypersensitivity; severe anxiety or psychosis; epilepsy; depression; severe
renal insufficiency; alcoholism; severe neurologic impairments
Precautions
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Discontinue drug or reduce dosage if allergic dermatitis or symptoms of CNS toxicity (eg,
convulsions, headache, tremor, depression, confusion, psychosis, somnolence,
hyperreflexia, vertigo, paresis, or dysarthria) develop; risk of convulsions is increased in
long-term alcoholism; administration has been associated with vitamin B-12 and folic acid
deficiency, megaloblastic anemia, and sideroblastic anemia; monitor blood levels weekly in
reduced renal function, patients receiving >500 mg/d, and patients with symptoms of
toxicity

Capreomycin (Capastat)
A second-line drug. Obtained from Streptomyces capreolus for coadministration with other
antituberculous agents in pulmonary infections caused by capreomycin-susceptible strains
of M tuberculosis. For use only when first-line agents (eg, isoniazid, rifampin) have been
ineffective or cannot be used because of toxicity or presence of resistant tubercle bacilli.
Dosing
Adult
15 mg/kg IM qd; also administered as IV infusion
Pediatric
15-30 mg/kg IM qd
Interactions
Coadministration with aminoglycosides may increase risk of respiratory paralysis and renal
dysfunction; with nondepolarizing neuromuscular-blocking agents, has synergistic effects
on myoneural function
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans;
may use if benefits outweigh risk to fetus
Precautions
Assess vestibular auditory function prior to therapy and regularly while treating; monitor
renal function throughout treatment (reduce dose in renal impairment); monitor serum
potassium levels

Rifabutin (Mycobutin)
Ansamycin antibiotic derived from rifamycin S. Inhibits DNA-dependent RNA
polymerase, preventing chain initiation. Used in treatment for TB in individuals on specific
HIV medications, when rifampin is contraindicated (most protease inhibitors).
Dosing
Adult
300 mg PO qd; as part of an intermittent regimen, 300 mg PO 3 times/wk
Pediatric
Not established; suggested dose is 5 mg/kg/d PO
Interactions
Decreases plasma concentration of methadone, verapamil, cyclosporine, digoxin,
corticosteroids, oral anticoagulants, barbiturates, theophylline, quinidine, halothane,
protease inhibitors, non-nucleoside reverse transcriptase inhibitors, oral contraceptives,
ketoconazole, and chloramphenicol; toxicity of rifabutin increases when administered
concurrently with indinavir, ketoconazole, itraconazole, ritonavir, erythromycin, or
protease inhibitors
Contraindications
Documented hypersensitivity; WBC count <1000/μL or platelet count <50,000/μL
Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans;
may use if benefits outweigh risk to fetus
Precautions
Perform hematologic studies periodically due to association with neutropenia, and more
rarely thrombocytopenia
Follow-up
Further Inpatient Care
 Hospitalized patients with suspected or documented tuberculosis (TB) must be
placed in appropriate isolation. This includes a private room with negative pressure
and adequate air exchanges. Persons entering the room must wear masks or
respirators capable of filtering droplet nuclei.
 Worldwide, TB rates are consistently higher among health care workers than in the
general population; infection-control measures yield a significant impact in high-
income countries but less impact in low- and middle-income countries.[18 ]
 Patients with TB should remain in isolation until sputum becomes smear-negative;
however, patients should not ordinarily be kept in the hospital for the sole purpose
of providing isolation. Special arrangements are necessary for patients with TB who
live with children, individuals infected with HIV, or patients returning to a closed-
group setting (eg, nursing home, correctional facilities, residential facility, homeless
shelter).
Further Outpatient Care
  Patients diagnosed with active TB should undergo sputum analysis for M
tuberculosis weekly until sputum conversion is documented. Monitoring for toxicity
includes baseline and periodic liver enzymes, CBC count, and serum creatinine.
 In addition, patients with TB who are receiving pyrazinamide should undergo
baseline or periodic serum uric acid assessments, and patients with TB who are
receiving long-term ethambutol therapy should undergo baseline or periodic visual
acuity and red-green color perception testing. The latter can be performed with a
standard test such as the Ishihara test for color blindness.
Deterrence/Prevention
 Patients with a clinically significant result on tuberculin skin testing or positive
IGRA result (see Other Tests) should receive a course of therapy once active
infection and disease is ruled out. Guidelines published by the CDC in 2000 now
refer to this as treatment of latent TB. The recommended regimens are listed below:
o Isoniazid daily for 9 months
o Isoniazid twice weekly for 9 months (administered as DOT)
o Isoniazid daily for 6 months (should not be used in patients with fibrotic
lesions on chest radiography, patients with HIV, or children)
o Isoniazid twice weekly for 6 months (administered as DOT; should not be
used in patients with fibrotic lesions on chest radiography, patients with
HIV, or children)
o Rifampin daily for 4 months
o Rifampin plus pyrazinamide daily for 2 months (This regimen is no longer
recommended because of an increased risk for liver toxicity.)
 Children should receive isoniazid for 9 months. In addition, children younger than 5
years who have close contact with a person who has active TB should be started on
isoniazid, even if results on skin testing are negative; preventive therapy can be
stopped if results on repeat skin testing are negative 2-3 months after last contact
with a culture-positive source case.
 Patients exposed to MDR-TB may be administered ethambutol plus pyrazinamide
for 6-12 months or pyrazinamide plus levofloxacin for 6-12 months; the index
isolate should be susceptible to all drugs used.
 Recommended regimens in patients with HIV infection include rifampin alone daily
for 4 months or isoniazid, daily or twice weekly, for 9 months. Patients on
antiretroviral therapy may need rifabutin instead of rifampin because of potential
drug interactions. The 2-month combination of pyrazinamide plus rifampin is no
longer recommended.
 The BCG vaccine continues to be used throughout much of the world and provides
protection mostly until early childhood. Immunity begins to wane as early as 3
months after administration.[19 ]
Complications
 Late complications of pulmonary TB include relapse, aspergilloma, bronchiectasis,
broncholithiasis, fibrothorax, and possibly carcinoma. A copy of the chest
radiograph at the time of completion of therapy should be provided to the patient to
facilitate the diagnosis of late complications.
o The relapse rate following appropriate completed therapy is only 0-4% and
occurs within the first 2 years after completion. Therefore, re-treatment is
usually unnecessary, especially after DOT.
 o Aspergilloma is a fungus ball that develops in a residual lung abnormality
(eg, pneumatocele, bulla, bleb, cyst). It may appear as a crescent sign on
chest radiographs. Other superinfections may manifest with an air-fluid level
and often contain mixed bacteria, including anaerobes.
o Hemoptysis is the most common late complication. Broncholithiasis is the
result of spontaneous lymph node migration into the bronchial tree and may
be associated with postobstructive pneumonia or esophageal perforation.
Bronchiectasis may progress to chronic bronchitis; bleeding from
submucosal bronchial veins is usually self-limited.
o Fibrothorax is the development of trapped lung due to pleural fibrosis and
scarring.
o The risk of carcinoma is controversial but should be considered with newly
developing clubbing.
Prognosis
Among published studies involving DOTS treatment, the rate of recurrence ranges from 0-
14%.[20 ]In countries with low TB rates, recurrences usually occur within 12 months of
treatment completion and are due to relapse.[21 ]In countries with higher TB rates, most
recurrences after appropriate treatment are probably due to reinfection rather than
relapse.[22 ]
Patient Education
For excellent patient education resources, visit eMedicine's Bacterial and Viral Infections
Center. Also, see eMedicine's patient education article Tuberculosis.
Miscellaneous
Medicolegal Pitfalls
 Laws vary from state to state, but communicable-disease laws typically empower
public health officials to investigate suspected cases of tuberculosis (TB), including
potential contacts. In addition, patients may be incarcerated for noncompliance with
therapy. For example, in the Denver Metro Tuberculosis Clinic from 1984-1994,
5% of patients were incarcerated for noncompliance and an additional 5% who were
lost to follow-up before completing therapy would have been candidates for
incarceration.
Special Concerns
 Pregnancy
o Pregnancy provides an opportunity to screen for TB; all pregnant women
can undergo tuberculin skin testing. If skin-testing results are positive, chest
radiography can be performed with lead shielding (the amount of radiation
exposure of a single chest radiograph has been compared to that incurred on
a regular flight from New York to Los Angeles). Chest radiography should
not be delayed during the first 3 months of pregnancy in patients with
suggestive symptoms.
o Active TB should be treated, even in women in the first stage of pregnancy.
Isoniazid, rifampin, and ethambutol may be used. In the United States,
pyrazinamide is reserved for women with suspected MDR-TB. Elsewhere in
the world, pyrazinamide is commonly used in pregnant women with TB.
o Preventive treatment is recommended during pregnancy, especially in the
following situations:
  Pregnant women with a positive tuberculin skin test result who are
HIV seropositive or who have behavioral risk factors for HIV
infection but decline HIV testing
 Pregnant women with a positive tuberculin skin test result who have
been in close contact with a patient who is smear-positive for
pulmonary TB
 Pregnant women who have had a documented tuberculin skin test
conversion in the past 2 years
o Pregnant women are at an increased risk for isoniazid-induced
hepatotoxicity and should undergo monthly ALT monitoring while on
treatment. This risk continues 2-3 months into the postpartum period.
Pyridoxine should also be administered to pregnant women receiving
isoniazid. Breastfeeding can be continued during preventive therapy. Many
experts recommend supplemental pyridoxine to the breastfed infant.
 Tuberculosis in children
o TB in a child is a sentinel event indicating recent transmission, and contacts
should be evaluated to find the source case as soon as possible. Children do
not commonly infect other children because they rarely develop cough and
sputum production is scant. However, cases of child-child and child-adult
TB transmission are well-documented.
o Chest radiographs in children with TB may show only hilar
lymphadenopathy or a patchy infiltrate. Most children with TB can be
treated with isoniazid and rifampin for 6 months, along with pyrazinamide
for the first 2 months if the culture from the source case is fully susceptible.
Gastric aspirates or biopsies are not necessary if positive cultures have been
obtained from the source case.
o In children younger than 5 years, the potential for development of fatal
miliary TB or meningeal TB is a significant concern. TB disease is
uncommon in children aged 5-15 years (the golden age of childhood).
o Isoniazid tablets may be crushed and added to food. Isoniazid liquid without
sorbitol should be used to avoid osmotic diarrhea, causing decreased
absorption. Rifampin capsules may be opened and the powder added to
food. If rifampin is not tolerated, it may be taken in divided doses 20
minutes after light meals.
o Ethambutol is often avoided in young children because of difficulties
monitoring visual acuity and color perception. However, studies show that
ethambutol (15 mg/kg) is well tolerated and can prevent further resistance if
the child is infected with a resistant strain.
 Human immunodeficiency virus
o Individuals infected with HIV are at an increased risk for TB, beginning
within the first year of HIV infection.[23 ]Based on historical data, the
initiation of antiretroviral therapy decreases the risk of developing TB in
these patients.[24 ]
o Patients with TB must be tested for HIV, and patients with HIV need
periodic evaluation for TB with tuberculin skin testing and/or chest
radiography. Patients with HIV and a positive tuberculin skin test result
develop active TB at a rate of 3-16% per year.
 o Patients with TB and HIV are more likely to have disseminated disease and
less likely to have upper-lobe infiltrates or classic cavitary pulmonary
disease. Patients with a CD4 count of less than 200/μL may have
mediastinal adenopathy with infiltrates.
o Treatment regimens for active or latent TB in patients with HIV infection
are similar to the treatment of individuals who are HIV negative, but dose
adjustments may be necessary.[25 ]The most significant differences involve
the avoidance of rifampin in patients who are on protease inhibitors.
Rifabutin may be used in place of rifampin in such patients.
o Patients with HIV and TB may develop a paradoxical response when
starting antiretroviral therapy. This response has been attributed to a stronger
immune response to M tuberculosis. Clinical findings include fever,
worsening pulmonary infiltrates, and lymphadenopathy.
 Tumor necrosis factor-alpha (TNF-a) antagonists have been associated with a
significantly increased risk for TB.[26 ]Reports have included atypical presentations,
extrapulmonary and disseminated disease, and deaths. Patients scheduled to begin
therapy with a TNF-α antagonist should be screened for latent TB and counseled
regarding the risk of TB.
Multimedia
Media file 1: Tuberculosis. Acid-fast bacillus smear showing characteristic cording in
Mycobacterium tuberculosis.
Media file 2: Tuberculosis. This radiograph shows a patient with typical radiographic
findings of tuberculosis.
Media file 3: Tuberculosis. This is a chest radiograph taken after therapy of a patient
with tuberculosis.
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