Tuberculosis: An Overview
Wanda Cruz-Knight, MD, MBA*, Lyla Blake-Gumbs, MD, MPH
Department of Family Medicine and Community Health, University Hospitals Case Medical
Center, Case Western Reserve University School of Medicine, 11100 Euclid Avenue, Cleveland,
OH 44118, USA
* Corresponding author.
E-mail address: Wanda.Cruz-Knight@UHhospitals.org
KEYWORDS
Latent tuberculosis infection Clinical presentations tuberculosis
Treatment of tuberculosis Genital tuberculosis Transmission of tuberculosis
KEY POINTS
Tuberculosis (TB) is still a public health issue. TB continues to reign as one of the world’s
deadliest diseases. One-third of the world’s population has been infected with TB. Identified cases of mycobacterium must be notified in an attempt to reduce the public health
impact of TB on the population.
The principal cause of tissue destruction from Mycobacterium tuberculosis (MTB) infection is related to an organism’s ability to incite intense host immune reactions to antigenic
cell wall proteins.
TB transmission occurs via inhalation of droplet nuclei. Person-to-person transmission
continues to present significant public health issues as work continues toward decreasing
the spread of TB.
The Centers for Disease Control and Prevention (CDC) recommends that high-risk populations in the United States be screened for latent infection, including HIV patients, intravenous (IV) drug users, health care workers who serve high-risk populations, and contacts
of individuals with pulmonary TB.
The most common site for the development of TB is the lungs; 85% of patients with TB
present with pulmonary complaints. Extrapulmonary TB may present with primary infection or can be accompanied by reactivation.
Tuberculin skin test (TST) and interferon-g release assay (IGRA) are the standard methods
for identifying persons infected with the mycobacterium.
TB may clinically manifest as primary TB, reactivation TB, laryngeal TB, endobronchial TB,
lower lung field TB infection, and tuberculoma. Clinical manifestations of TB vary according to site of mycobacterial proliferation.
Primary pulmonary TB is often accompanied by a normal chest radiograph. Hilar adenopathy is the most common chest abnormality.
Treatment of TB depends on whether latent TB infection (LTBI) or active TB is treated.
Initial empiric treatment of MTB consists of a 4-drug regimen: isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin. Once the MTB isolate is known to be fully
susceptible, ethambutol (or streptomycin, if it is used as a fourth drug) can be discontinued. Patients diagnosed with active MTB should undergo sputum analysis for MTB weekly
until sputum conversion is documented. Treatment duration is typically 6 to 9 months.
Prim Care Clin Office Pract 40 (2013) 743–756
http://dx.doi.org/10.1016/j.pop.2013.06.003 primarycare.theclinics.com
0095-4543/13/$ – see front matter 2013 Elsevier Inc. All rights reserved.
INTRODUCTION
TB is an infectious disease caused by MTB. Mycobacterium commonly affects the
lungs but may affect almost any organ system, including the lymph nodes, central nervous system, liver, bones, genitourinary tract, and gastrointestinal tract. TB is highly
transmissible through respiratory droplets. Identified cases of mycobacterium must
be notified in an attempt to reduce the public health impact of TB on the population.
MYCOBACTERIUM TUBERCULOSIS
MBT is large nonmotile rod-shaped obligate aerobic bacterium requiring oxygen for
survival. Commonly introduced to the body through inhalation of droplet nuclei,
MTB is usually found in well-aerated upper lobes of the longs.1 As a facultative intracellular parasite, the bacterium inhabits macrophages, multiplying within the macrophages. As the bacterium proliferates, they are released from dying macrophages
into the alveolar environment. The fate of the mycobacterium is dependent on the
host’s immune system. A healthy immune system may clear the bacterium whereas
exposure may also lead to LTBI or progress to primary TB.
The cellular immune system leads to successful containment of TB. This response is
mediated by helper T cells. The ability of T cells and macrophages to block the proliferating bacterium, by forming a granuloma consisting of a caseous center (necrotic
cells) surrounded by macrophages and lymphocytes, prevents the growth and spread
of mycobacterium. This is the basis for LTBI, where a person infected with MTB does
not currently have active TB disease.2 Unfortunately, 5% to 10% of persons with LTBI
are at risk of progressing to active TB; therefore, the authors most actively identify individuals with LTBI and treat to prevent progression to active TB. Individuals with LTBI
are noninfectious. Immunocompromised individuals, such as those with HIV infection,
cancer, or patients on immunosuppressing medications, are at higher risk of progression to active TB from primary infection or reactivation.
PATHOPHYSIOLOGY
Transmission occurs when inhaled droplet nuclei are deposited within the terminal airspaces of the lung. A cellular immune response that can be detected by a reaction to
the TST occurs when tuberculi numbers reach 1000 to 10,000. This usually occurs
within 2 to 12 weeks after infection.3
MTB have multiple cell wall constituents consisting of glycoproteins, phopholipids,
and wax D.1 These constituents activate Langerhans cells, lymphocytes, and polymorphonuclear leukocytes. Their antigenicity promotes a vigorous, nonspecific immune response. Infection MTB does not always lead to actual TB. The infection
may be cleared by the host immune system or suppressed into an inactive form,
LTBI, with resistant hosts controlling mycobacterial growth at distant foci before the
development of disease. Patients with LTBI cannot spread TB.
The most common site for the development of TB is the lungs; 85% of patients with
TB present with pulmonary complaints. Extrapulmonary TB may present with primary
infection or can be accompanied by reactivation.
Common extrapulmonary sites are as follows:
Mediastinal, retroperitoneal, and cervical (scrofula) lymph nodes—the most common site of tuberculous lymphadenitis (scrofula) 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
744 Cruz-Knight & Blake-Gumbs
Vertebral bodies
Adrenals
Meninges
Gastrointestinal tract
The principal cause of tissue destruction from MTB infection is related to an organism’s ability to incite intense host immune reactions to antigenic cell wall proteins.
Mycoplasm forms spherical tubercles consisting of up to 3-mm nodules with approximately 4 cellular zones. The lesions are epithelioid granulomas with central caseation
necrosis. The primary lesion is usually found within alveolar macrophages in subpleural regions of the lung; local proliferation of bacilli occurs and spread through the lymphatics to a hilar node, forming the Ghon complex.
Tuberculi nodules consist of
A central caseation necrosis
An inner cellular zone of epithelioid macrophages and Langerhans giant cells admixed with lymphocytes
An outer cellular zone of lymphocytes, plasma cells, and immature macrophages
A rim of fibrosis (in healing lesions)
Healing of tuberculin lesions may take various forms and stages. Initial lesions may
heal and the infection become latent before symptomatic disease occurs. Smaller tubercles may resolve completely. Fibrosis occurs when hydrolytic enzymes dissolve tubercles and larger lesions are surrounded by a fibrous capsule. Such fibrocaseous
nodules usually contain viable mycobacteria and are potential lifelong foci for reactivation or cavitation. Some nodules calcify or ossify and are seen easily on chest
radiographs.
Tissues within areas of caseation necrosis have high levels of fatty acids, low pH,
and low oxygen tension, all of which inhibit growth of the tubercle bacillus.1 The body’s
immune responses ability to manage this initial infection and the proliferation of mycoplasm prevent development of primary TB. Otherwise, purulent exudates with large
numbers of acid-fast bacilli (AFB) become present in sputum and tissue. Subserosal
granulomas may rupture into the pleural or pericardial spaces and create serous
inflammation and effusions. The immune systems response to the mycobacteria
may lead to either proliferative or exudative lesions. Both types of lesions can develop
in the same host, because infective dose and local immunity vary from site to site.
Proliferative lesions occur when there is a small bacillary load and the host cellular
immune responses dominate. Tubercles are compact, with admixed activated macrophages admixed surrounded by proliferating lymphocytes, plasma cells, and an outer
rim of fibrosis. Intracellular killing of mycobacteria is effective, and the bacillary load
remains low. When large numbers of bacilli are present and host defenses are
weak, then exudative lesions predominate. These loose aggregates of immature macrophages, neutrophils, fibrin, and caseation necrosis are sites of mycobacterial
growth. Untreated, these lesions progress and infection spreads.
EPIDEMIOLOGY
TB continues to reign as one of the world’s deadliest diseases. One-third of the
world’s population has been infected with TB.3,4 In the United States, there are an estimated 9 million people with LTBI.5,6 Worldwide in 2011, there were approximately 1.4
million TB-related deaths. Among HIV-infected individuals, TB is the leading cause of
death. Foreign-born individuals are 10 times more likely to be infected with TB than
those born in the United States. In the United States, the rate of TB is declining.4
Tuberculosis 745
TRANSMISSION
TB transmission occurs via inhalation of droplet nuclei. Person-to-person transmission continues to present significant public health issues as work continues toward
decreasing the spread of TB. Individuals with undiagnosed active untreated pulmonary or laryngeal disease are contagious, particularly when cavitary disease is present
or when the sputum is AFB smear positive.7 Likewise, patients with sputum smearnegative, culture-positive pulmonary TB can also transmit infection. In immonocompetent individuals, TB can remain in an inactive (dormant) state for years without
causing symptoms or spreading to other people.8 Only individuals with active TB
can spread the disease. Isolated extrapulmonary TB is not contagious, although
such patients require careful evaluation for pulmonary or laryngeal TB.9 Immunocompromised patients with extrapulmonary TB should be presumed to have pulmonary TB
until proved otherwise with negative sputum samples, even if chest radiography is
normal.10
SCREENING/DIAGNOSES
The CDC recommends that high-risk populations in the United States are screened for
latent infection, including HIV patients, IV drug users, health care workers who serve
high-risk populations, and contacts of individuals with pulmonary TB.11 The US Preventive Services Task Force recommends routine screening for TB in high-risk populations.12 The goal of this recommendation is to identify persons at significant risk for
progressing to active disease. A validated risk-assessment questionnaire may be
used to identify children who are likely to benefit from screening. Screening persons
other than high-risk populations places a burden on resources and is, therefore, not
recommended.13
TST and IGRA are the standard methods for identifying persons infected with the
mycobacterium.14 All individuals with positive screens and suspicious for active infection should have a chest radiograph, 3 sputum samples obtained for AFB, nucleic acid
amplification test (NAAT), complete blood cell count, and electrolytes (eg, sodium). If a
patient is unable to spontaneously produce sputum, it should be induced (with appropriate precautions to prevent transmission) or obtained via a gastric aspirate. Stained
smears should be made from sputum specimens to identify AFB, because this is the
first bacteriologic evidence of infection and gives an estimate of how infectious a patient is.15 If AFBs are seen on smear, therapy should be started and patients maintained in isolation.
Sputum culture may also be used for diagnosis of TB. It is more sensitive than smear
staining, facilitates identification of the mycobacterium species by nucleic acid hybridization or amplification, and evaluates drug sensitivity. Limitations of sputum culture
are dependent on the medium used to culture mycobacterium. Cultures may take 4
to 8 weeks to get results.
NAAT performed on at least one respiratory specimen may also be used as a diagnostic tool.14 NAAT may speed the diagnosis in smear-negative cases or in patients
with other strains of mycobacterium. Genotyping is expensive and best used when
there are TB outbreaks. Finally, patients with positive TB tests should also be tested
for HIV within 2 months of diagnosis.
One of the diagnostic challenges is secondary to accurate testing; 40% to 50% of
TB cases are AFB smear negative and 15% to 20% have negative cultures. If there is a
strong clinical suspicion of active TB, especially when accompanied by a positive skin
test, empiric TB therapy may be tried before laboratory confirmation of infection. In
746 Cruz-Knight & Blake-Gumbs
patients with low suspicion for active TB and smears negative for AFB, it is acceptable
to wait for the results of AFB culture or repeat chest radiograph before starting
treatment.
The TST or IGRA helps diagnose LTBI in a person exposed to MTB but without signs
of active TB.16 The TST and IGRA measure the response of T cells to TB antigens.
Because false-negative results occur in 20% to 25% of patients with active pulmonary
TB, these tests should not be used alone to exclude a diagnosis of active TB.17 Immunocompetenceand vaccination status may affect interpretation of the TST. Induration of
greater thanor equalto 15 mm in diameter is a positive test in an immunocompetent person.18 Immunocompromised individuals may require a 2-step testing approach at least
2 weeks apart to prime the immune system. In this subset of patients, induration of
greater than or equal to 10 mm is considered a positive test. In individuals with a history
of bacille Calmette-Gue ´ rin, vaccination and IGRA are preferred due to superior specificity. IGRA is also used for patient subsets at high risk of TB but low adherence with
TB testing, requiring a 48- to 72-hour confirmatory reading, as in the case of the TST.13
The CDC and American Thoracic Society recommend targeted testing for LTBI in
high-risk groups, such as people with HIV, IV drug users, health care workers who
serve high-risk populations, and contacts of individuals with pulmonary TB. Patients
receiving tumor necrosis factor a antagonist should be tested before initiation of
therapy.
CLINICAL MANIFESTATION
TB may clinically manifest as primary TB, reactivation TB, laryngeal TB, endobronchial
TB, lower lung field TB infection, and tuberculoma. Clinical manifestations of TB vary
according to site of mycobacterial proliferation.13 The most common route of entry of
MTB is through the bronchial system. Patients with pleural TB may present with a
chronic cough, night sweat, pleurisy, blood-tinged sputum, and weight loss.19,20 TB
initial presentation may mimic other medical conditions. The table below highlights
the common clinical presentations of TB.
Clinical Presentations of Tuberculosis
Site of Organism Proliferation Clinical Symptoms
Pleural TB Blood-tinged sputum producing chronic cough, pleurisy,
chest pain
TB lymphadenitis Enlarged cervical or supraclavicular lymphnodes
Tuberculous meningits Persistent or intermittent headach for 2–3 weeks. Mental
status changes, coma
Skeletal TB Spine is most common site (Pott disease). Back pain,
stiffness, lower extremity paralysis (50%) occurrence
Tuberculous arthritis Involves on joint. Hips and knees more commonly affected.
Pain precedes radiographic changes
Genitourinary TB Flank pain, dysuria, and frequent urination. Men may
present with painful scrotal mass, prostatitis, orchitis, or
epididymitis. In women, condition may mimic pelvic
inflammatory disease. 10% of sterility in women
worldwide and 1% of women in industrialized countries
Gastrointestinal TB TB may infect any site along the gastrointestinal tract. TB
can manifest as nonhealing ulcers of the mouth or anus,
difficulty swallowing, abdominal pain (peptic ulcer like),
malabsorption, pain diarrhea, or hematochezia
Tuberculosis 747
Patients with TB lymphadenitis most commonly present with enlarged lymph nodes
in the cervical and supraclavicular areas.21 There can be unilateral or bilateral involvement. In patients suspected of having TB with superficial lymphadenitis, the first diagnostic test should be fine-needle aspiration. For questionable diagnosis, lymph node
excisional biopsy should be obtained. In patients with skeletal TB, approximately 70%
have a positive tuberculin skin test.22 In skeletal TB, pain of the involved area is the
most common complaint with absent constitutional symptoms. Because onset of
symptoms is gradual, diagnosis is frequently delayed. Patients may present with lower
extremity paralysis or limited movement with local swelling. Patients may also present
with a nontender abscess. When a diagnosis of TB arthritis/skeletal TB is in question,
then synovial biopsy or tissue biopsy is the diagnostic modality. Although fluid/tissue
cultures may be positive in up to 80% of cases, AFB smear is a poor diagnostic
modality.23
Patients with central nervous system TB and meningitis or intracranial tuberculomas
(rounded mass lesions can develop during primary infection or when a focus of reactivation TB becomes encapsulated) may present with headache, neck stiffness,
altered mental status, and cranial nerve abnormalities.24 Cerebrospinal fluid examination is essential for diagnosis of TB meningitis. Rapid diagnosis leads to improved outcomes but depends on a high level of suspicion, especially in industrialized
medicine.25 AFB culture of cerebrospinal fluid is definitive modality for diagnosis,
whereas cerebrospinal fluid analysis is usually normal. Because awaiting cultures
may present a delay in cure, treatment is initiated presumptively based on clinical suspicion, risk factors, and cerebrospinal fluid results. Approximately 50% of patients
with central nervous system TB have chest radiograph abnormalities consistent
with pulmonary TB; head CT or MRI may show tuberculomas or signs of intracranial
pressure.26
In abdominal TB, the TST is positive 70% of the time with radiographic evidence of
LTBI.27 Patients may present with abdominal swelling (ascites), abdominal pain, fever,
and/or change in bowel habits. Diagnosis is based on culture growth from ascetic fluid
or biopsy. TB enteritis presents most commonly with ileocecum involvement, followed
by ileum, cecum, and ascending colon. Patients most commonly present with chronic
abdominal pain. Changes in bowel habits are usually present along with heme-positive
stool. Emergency clinical presentations may be due to small bowel obstruction or a
right lower quadrant mass. Peritoneal fluid culture is 92% sensitive but results may
take up to 8 weeks. Peritoneal biopsy may reveal military nodules over the peritoneum
and lead to presumptive diagnosis in 80% to 95% of patients. TB enteritis is best diagnosed by colonoscopy and biopsy, which may reveal ulcers, pseudopolyps, or
nodules.
Genitourinary TB may present as dysuria, hematuria, and urinary frequency.28
Although symptoms may be absent in up to 30% of patients, men may present with
a scrotal mass and women may present with pelvic inflammatory disease–like symptoms.29,30 Constitutional symptoms are rare. Diagnosis is often delayed, leading to
kidney involvement. Chest radiograph is abnormal in 40% to 75% of patients, with
positive skin test in up to 90% of patients.31 Diagnosis depends on culturing TB
from morning urine samples (3 are recommended) or biopsy of a lesion seen on cystoscope or other imaging modalities. Urine culture for TB may be positive in 80% of patients; 3 samples for culture improve sensitivity; this requires a high level of suspicion.
The classic finding of sterile pyuria is neither sensitive nor specific. Definitive diagnosis
of genital TB is based on tissue biopsy.32
Pericardial TB is rare but may present with chest or pleurisy and cardiac effusion on
imaging. Chest radiograph shows cardiomegaly (up to 95% of cases) and pleural
748 Cruz-Knight & Blake-Gumbs
effusion (approximately 50%) with low-voltage ECG occurring 25% of the time.
T-wave inversion is common in approximately 90% of patients. Diagnosis requires
pericardial fluid or biopsy. AFB smear is commonly negative; cultures are positive
only 50% of the time; biopsy leads to a higher diagnostic yield.
Patients presenting with full-blown constitutional symptoms and a diagnosis of TB
should be evaluated for disseminated TB.33 The diagnosis is based on the number of
organs involved. The most common organs are lungs, liver, spleen, kidneys, and bone
marrow. Chest radiograph (if nondiagnostic, consider a chest CT), sputum for AFB
smear and culture, blood culture for mycobacteria, and first morning void urine for
AFB should be obtained.34 Lumber puncture and biopsy of superficial lymph nodes
may be done based on clinical presentation. Sputum smear is positive in one-third
of patients, with culture positive in approximately 60%. TST is positive in only 45%
of patients with disseminated disease. Prompt diagnosis of disseminated TB is necessary to improve clinical outcome.
Elderly individuals with TB may not display typical signs and symptoms of TB infection due to poor immunogenicity. Active TB infection in this age group may manifest as
nonresolving pneumonitis. Likewise, signs and symptoms of extrapulmonary TB may
be nonspecific and include leukocytosis, anemia, and hyponatremia due to the release
of antidiuretic hormone–like hormone from affected lung tissue.
RADIOGRAPHIC MANIFESTATION
Primary pulmonary TB is often accompanied by a normal chest radiograph. Hilar
adenopathy is the most common chest abnormality. There are studies showing a
65% occurrence of cases.35 Hilar changes can occur within a week after skin test conversion or in the span of 2 months. In most cases, these findings often resolve within
the first year of detecting a positive skin test for primary TB.
Another study showed one-third of the 517 converters developed pleural effusions,
within the first 3 to 4 months after infection but occasionally as late as 1 year.36 Pulmonary infiltrates were documented in 27% of patients.37 Perihilar and right-sided infiltrates were the most common, and ipsilateral hilar enlargement was the rule.
Although contralateral hilar changes sometimes were present, only 2% of patients
had bilateral infiltrates. Lower and upper lobe infiltrates were observed in 33% and
13% of adults, respectively; 43% of adults with infiltrates also had effusions. Most infiltrates resolved over months to years. In 20 patients (15% of cases), however, the infiltrates progressed within the first year after skin test conversion, so-called
progressive primary TB. The majority of these patients had progression of disease
at the original site, and 4 developed cavitation.38
In studies looking at culture positive, the most common radiologic finding was hilar
lymphadenopathy, present in 67% of cases.39 Right middle lobe collapse may complicate the adenopathy but usually resolves with therapy.
Several factors probably favor involvement of the right middle lobe39:
Dense lymph nodes
Longer length and smaller internal caliber
Sharper branching angle
Pleural effusions are also common in active TB infection. A Canadian retrospective study demonstrated pulmonary infiltrates in 63% of patients, and 85% of infiltrates were in the midlung to lower lung fields.40 Two patients had cavitation and
2 others evidence of endobronchial spread. A majority of patients with reactivation
TB have abnormalities on chest radiography. Reactivation TB typically involves the
Tuberculosis 749
apical-posterior segments of the upper lobes (80%–90% of patients), followed in
frequency by the superior segment of the lower lobes and the anterior segment of
the upper lobes.41
Atypical radiographic patterns may occur in up to 30% adults with reactivation TB.
Findings may include hilar adenopathy, infiltrates or cavities in the middle or lower lung
zones, pleural effusions, and solitary nodules. Atypical findings are seen more often in
the setting of primary TB. Ironically, approximately 5% of patients with active TB present with upper lobe fibrocalcific changes thought to be indicative of healed primary
TB. In the setting of pulmonary symptoms, these patients should be evaluated for
active TB. A normal chest radiograph is also possible even in active pulmonary TB.
CT scanning of chest is more sensitive than plain chest films for diagnosis, with higher
sensitivity for smaller lesions located in the apex of the lung.42 CT scan may demonstrate a cavity or apicoposterior infiltrates, cavities, pleural effusions, fibrotic lesions
causing distortion of lung parenchyma, elevation of fissures and hila, pleural adhesions,
and formation of traction bronchiectasis. To detect early bronchogenic spread, highresolution CT is the imaging technique of choice. The most common findings consist
of centrilobular 2-mm to 4-mm nodules or branching linear lesions representing intrabronchiolar and peribronchiolar caseation necrosis. MRI detects intrathoracic lymphadenopathy, pericardial thickening, and pericardial and pleural effusions.
Currently, there is no role for routine use of positron emission tomography (PET) for
evaluation of TB. PET uptake of fludeoxyglucose F 18 (FDG) does not differentiate
infection from tumor, but the macrophages in active TB do not proliferate and do
not need choline C 11, resulting in low choline C 11 uptake; this in contrast to the macrophages in malignancy. Therefore, the combination of a high FDG and low choline C
11 uptake on PET may be useful but not diagnostic of TB.
Tuberculous infection of the tracheobronchial tree can develop from direct extension to the bronchi from a parencymal focus. This happens from infected sputum
that leads to spread of MTB. The lesions are seen in the main and upper bronchi.
Five percent of the time the lower trachea is involved. Endobronchial TB has been
described in 10% to 40% of patients with active pulmonary TB. Bronchial stenosis
is observed in 90% of cases not receiving early diagnosis to prevent development
of fibrosis.
TREATMENT
Treatment of TB depends on whether LTBI or active TB is treated. If a patient has had
recent close contact with a person with active TB but is still in the 12-week window
where TST may be negative, immediate LTBI treatment should be considered if the
patient is at high risk of progression to active TB or has increased susceptibility to disease.43 In patients with significant exposure with active TB repeat, TST should be performed 12 weeks after contact has ended, and treatment should be continued if the
TST result is positive or discontinued if the result is negative. The exception to this
recommendation is that persons who are immunocompromised, including those
with HIV infection, who had contact with individuals with active TB should continue
treatment of LTBI, even if repeat TST is negative.
Initial empiric treatment of MTB consists of a 4-drug regimen: isoniazid, rifampin,
pyrazinamide, and either ethambutol or streptomycin.44 Once the MTB isolate is
known to be fully susceptible, ethambutol (or streptomycin, if it is used as a fourth
drug) can be discontinued.45 Patients diagnosed with active MTB should undergo
sputum analysis for MTB weekly until sputum conversion is documented. Treatment
duration is typically 6 to 9 months.
750 Cruz-Knight & Blake-Gumbs
Pyrazinamide may be stopped after 2 months of treatment of a proved susceptible
isolate. Isoniazid plus rifampin must be continued for an additional 4 months. If isolated isoniazid resistance is proved, isoniazid should be stopped and rifampin, pyrazinamide, and ethambutol should be continued for the entire 6 months. It is
necessary to extend therapy if the patient has cavitary disease and/or remains
culture-positive after the first 2 months of treatment.
Patients receiving pyrazinamide should undergo baseline and periodic serum uric
acid assessments, and those receiving long-term ethambutol therapy should undergo
baseline and periodic visual acuity and red-green color perception testing (ie, the Ishihara test for color blindness). Monitoring for toxicity includes baseline and periodic
liver enzymes, complete blood cell count, and serum creatinine.
The development of drug resistance to 1 or more drugs by MTB is a major concern
worldwide. Typically, drug resistance results from spontaneous mutations within the
MTB DNA. Strains of drug-resistant MTB (DR-MTB) were first demonstrated after
streptomycin was introduced as a treatment in 1944.46 Rates of drug resistance are
highest in cases where previous treatment has occurred, especially when treatment
has been incomplete due to either poor adherence or inadequate therapeutic regimen.
Currently, 17% of newly diagnosed MTB cases are resistant to 1 or more first-line
agents. Isoniazid is the drug most commonly associated with resistance (10%), but
MTB strains can develop resistance to any medication or combination of medications.47 Strains resistant to both isoniazid and rifampin, the 2 most effective currently
available drugs, and possibly resistant to other drugs are called multidrug resistant
(MDR) and were first reported on in the early 1980s. MDR cases are now found worldwide. In 2009, WHO estimated that there were 440,000 new MDR-TB cases or 3.3% of
new TB cases were MDR.49 Annual mortality from MDR-TB was estimated to be
Box 1
High-risk populations needing targeted tuberculin testing and treatment of latent infection
Persons at high risk of exposure to and infection with MBT
Persons in close contact with someone who has confirmed active TB
Foreign-born persons from endemic countries who have been living in the United States for
5 years or less (especially children younger than 4 years)
Residents and employees of congregate settings (eg, correctional facilities, long-term care
facilities, and homeless shelters)
Health care workers with high-risk patients
Medically underserved, low-income populations
Infants, children, and adolescents exposed to adults in high-risk categories
Persons at high risk of progression from LTBI to active disease
Persons with HIV infection
Persons recently (within the past 2 years) infected with MTB
Children younger than 4 years
Patients who are immunosuppressed (eg, those with diabetes, chronic or end-stage renal
disease, silicosis, cancer, malnutrition, prolonged steroid use, or organ transplants; those taking
tumor necrosis factor a inhibitors)
Data from Potter B, Rindfleisch K, Kraus CK. Management of active tuberculosis. Am Fam Physician 2005;72(11):2225–32.
Tuberculosis 751
150,000 worldwide.48 Inadequate treatment of MDR-TB leads to treatment failure,
increased mortality, and the creation of MTB strains with an even more complex resistance profile.
Directly observed therapy short-term (DOTS) programs increase the likelihood of
adherence and treatment completion and reduce the risk of the development of
DR-MTB and extensively drug-resistant TB (XDR-TB).49 DOTS is recommended for
all patients diagnosed with MTB, whether drug-resistant or susceptible. With DOTS, patients on the regimens (discussed previously) can be placed on 2- to 3-times per week
dosing after an initial 2 weeks of daily dosing. Patients on twice-weekly dosing may not
miss any doses. Prescribe daily therapy for patients on self-administered medication.
Treatment recommendations for MDR-TB consist of an intensive 8 months of treatment that includes pyrazinamide and a minimum of 4 additional effective second-line
drugs, including a fluoroquinolone (not to include ciprofloxacin), an injectable antibiotic
(either kanamycin, amikacin, capreomycin, or viomycin, but not streptomycin, which is
considered a first-line drug), a thioamide (either ethionamide or prothionamide), and
Table 1
Currently available antituberculosis drugs
Group 1: first-line oral anti-TB drugs Isoniazid (H)
Rifampin or rifampicin (R)
Ethambutol (E)
Group 2: injectables Pyrazinamide (Z) rifabutin (Rfb)
Kanamycin amikacin
Capreomycin streptomycina
Group 3: fluoroquinolones Levofloxacin moxifloxacin
Ofloxacin
Gatifloxacin
Group 4: oral bacteriostatic
second-line drugs
Ethionamide
Protionamide
Cycloserine terizidone
Group 5: anti-TB drugs with
unclear efficacy or role
p-Aminosalicylic acid clofazimine linezolid
Amoxicillin/clavulanate thioacetazone
Clarithromycin imipenem
a Considered a first-line drug.
Table 2
Treatment options for latent tuberculosis infection
Drug
Daily Dosage
(Maximum)
Adult Intermittent
Dosage (Maximum) Duration
Isoniazid 5 mg per kg
(300 mg)
15 mg per kg
(900 mg per dose)
twice per week
Nine months in adults and children
(6 mo may be an alternative
treatment duration in adults)
Rifampin
(Rifadin)
10 mg per kg
(600 mg)
10 mg per kg
(600 mg per dose);
daily dosing required
when used alone
Four months in adults; 6 mo in
children
Note: Rifampin plus pyrazinamide is no longer recommended for the treatment of LTBI.
Rifampin plus isoniazid (same dosing) for 3 months may be an alternative treatment option in
select patients, but risk of hepatotoxicity may increase.
Data from World Health Organization. Treatment of tuberculosis: guidelines for national programmes. 4th edition. 2010. Available at: http://www.who.int. Accessed January 24, 2013.
752 Cruz-Knight & Blake-Gumbs
Table 3
Adverse effects of antituberculin drugs
Drug Main Adverse Effects Monitoring Parameters
Isoniazid Hepatotoxicity
Lupus-like syndrome
Peripheral neuropathy
Monitor LFTs and for flushing and decreased sensation in extremities LFTs should be
monitored monthly in patients who are at a higher risk of hepatotoxicity, have
preexisting liver disease, or develop abnormal LFTresults. LFTs should also be checked
in patients who develop clinical symptoms of hepatitis; isoniazid should be
discontinued if findings on LFTs increase by more than 5 times the upper limits of
normal in patients without symptoms of hepatotoxicity and by more than 3 times the
upper limits of normal in patients with symptoms.
Monoamine toxicity If flushing occurs, patients should be counseled to avoid foods with high
concentrations of monoamines (eg, aged cheeses, wine).
Rifampin (Rifadin) Drug interactions
Hepatotoxicity
Immunologic reactions
Orange discoloration of body fluids
Baseline laboratory tests (including complete blood cell count and serum creatinine
measurements) and monthly; every-other-month; or 1-, 3-, or 6-mo monitoring of
LFTs and clinical symptoms are acceptable for most patients but not required. LFTs
should be monitored monthly or twice monthly in patients who are at a higher risk of
hepatotoxicity, have preexisting liver disease, or develop abnormal LFT results.
Acute renal failure
Influenza-like symptoms
Hemolytic anemia, thrombocytopenia (with potential for acute renal failure)
Pruritus (with or without rash)
Patients should be counseled about the risk of contact lens discoloration.
Pyrazinamide Arthralgias
Gastrointestinal upset
Hepatotoxicity
Rash
Baseline LFTs; serum creatinine may be assessed at baseline for dosing adjustments. LFTs
should be monitored monthly or twice monthly in patients who are at a higher risk of
hepatotoxicity or who have underlying hepatic dysfunction.
Hyperuricemia Check uric acid levels if patient is symptomatic
Ethambutol (Myambutol) Optic neuritis Baseline and monthly testing of visual acuity and color discrimination; serum creatinine
may be assessed at baseline for dosing adjustments.
Abbreviation: LFT, liver function test.
Data from Potter B, Rindfleisch K, Kraus CK. Management of active tuberculosis. Am Fam Physician 2005;72(11):2225–32.
Tuberculosis 753
cycloserine or teridizone.50 Treatment should be continued for a minimum of 20 months
with 4 effective medications. The injectable antibiotic may be discontinued after
completion of 8 months of therapy.
XDR-TB is a rare type of MDR-TB that is resistant to isoniazid and rifampin, plus any
fluoroquinolone and at least 1 of 3 injectable second-line drugs (ie, amikacin, kanamycin, or capreomycin).43 Because XDR-TB is resistant to the most potent MTB
drugs, patients are left with treatment options that are much less effective. XDR-TB
is of special concern for persons with HIV infection or other conditions that can
weaken the immune system. These persons are more likely to develop TB disease
once they are infected and, moreover, have a higher risk of death once they develop
TB. See Box 1 and Tables 1–3 for outline of antituberculosis drugs.
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