eMedicine Specialties > Pediatrics: General Medicine > Infectious Disease

Tuberculosis

Vandana Batra, MD, Pediatrician, Department of Pediatrics, Division of General Pediatrics/Primary Care, Nemours Pediatrics
Jocelyn Y Ang, MD, Assistant Professor, Department of Pediatrics, Division of Infectious Diseases, Children's Hospital of Michigan and Wayne State University

Updated: Oct 30, 2008

Introduction

Background

Tuberculosis (TB) is the most common cause of infection-related death worldwide. In 1993, the World Health Organization (WHO) declared tuberculosis to be a global public health emergency. Mycobacterium tuberculosis is the most common cause of tuberculosis. Other rare causes include Mycobacterium bovis and Mycobacterium africanum. Tubercle bacilli belong to the family Mycobacteriaceae and order Actinomycetales. The acid-fast characteristic of the mycobacteria is their unique feature. M tuberculosis is an aerobic, non–spore-forming, nonmotile, slow-growing bacillus with a curved and beaded rod-shaped morphology. It is a very hardy bacillus that can survive under adverse environmental conditions. Humans are the only known reservoirs for M tuberculosis.

Pathophysiology

Tuberculosis occurs when individuals inhale bacteria aerosolized by infected persons. The organism is slow growing and tolerates the intracellular environment, where it may remain metabolically inert for years before reactivation and disease. The main determinant of the pathogenicity of tuberculosis is its ability to escape host defense mechanisms, including macrophages and delayed hypersensitivity responses.

Among the several virulence factors in the mycobacterial cell wall are the cord factor, lipoarabinomannan (LAM), and a highly immunogenic 65-kd M tuberculosis heat shock protein. Cord factor is a surface glycolipid present only in virulent strains that causes M tuberculosis to grow in serpentine cords in vitro. LAM is a heteropolysaccharide that inhibits macrophage activation by interferon-gamma and induces macrophages to secrete tumor necrosis factor-alpha, which causes fever, weight loss, and tissue damage.

The infective droplet nucleus is very small, measuring 5 micrometers or less, and may contain approximately 1-10 bacilli. Although a single organism may cause disease, 5-200 inhaled bacilli are usually necessary for infection. The small size of the droplets allows them to remain suspended in the air for a prolonged period of time. Primary infection of the respiratory tract occurs as a result of inhalation of these aerosols. The risk of infection is increased in small enclosed areas and in areas with poor ventilation. Upon inhalation, the bacilli are deposited (usually in the midlung zone) into the distal respiratory bronchiole or alveoli, which are subpleural in location. Subsequently, the alveolar macrophages phagocytose the inhaled bacilli. However, these naïve macrophages are unable to kill the mycobacteria, and the bacilli continue to multiply unimpeded.

Thereafter, transportation of the infected macrophages to the regional lymph nodes occurs. Lymphohematogenous dissemination of the mycobacteria to other lymph nodes, the kidney, epiphyses of long bones, vertebral bodies, juxtaependymal meninges adjacent to the subarachnoid space, and, occasionally, to the apical posterior areas of the lungs. In addition, chemotactic factors released by the macrophages attract circulating monocytes to the site of infection, leading to differentiation of the monocytes into macrophages and ingestion of free bacilli. Logarithmic multiplication of the mycobacteria occurs within the macrophage at the primary site of infection.

A cell-mediated immune (CMI) response terminates the unimpeded growth of the M tuberculosis 2-3 weeks after initial infection. CD4 helper T cells activate the macrophages to kill the intracellular bacteria with resultant epithelioid granuloma formation. CD8 suppressor T cells lyse the macrophages infected with the mycobacteria, resulting in the formation of caseating granulomas. Mycobacteria cannot continue to grow in the acidic extracellular environment, so most infections are controlled. The only evidence of infection is a positive tuberculin skin test (TST) result. However, the initial pulmonary site of infection and its adjacent lymph nodes (ie, primary complex or Ghon focus) sometimes reach sufficient size to develop necrosis and subsequent radiographic calcification.

Most persons infected with M tuberculosis do not develop active disease. In healthy individuals, the lifetime risk of developing disease is 5-10%. In certain instances, such as extremes of age or defects in CMI (eg, human immunodeficiency virus [HIV] infection, malnutrition, administration of chemotherapy, prolonged steroid use), tuberculosis may develop. For patients with HIV infection, the risk of developing tuberculosis is 7-10% per year.

Progression of the primary complex may lead to enlargement of hilar and mediastinal nodes with resultant bronchial collapse. Progressive primary tuberculosis may develop when the primary focus cavitates and organisms spread through contiguous bronchi. Lymphohematogenous dissemination, especially in young patients, may lead to miliary tuberculosis when caseous material reaches the bloodstream from a primary focus or a caseating metastatic focus in the wall of a pulmonary vein (Weigert focus). Tubercular meningitis may also result from hematogenous dissemination. Bacilli may remain dormant in the apical posterior areas of the lung for several months or years, with later progression of disease resulting in the development of reactivation-type tuberculosis (ie, endogenous re-infection tuberculosis).

Frequency

United States

Approximately 15 million people are infected with M tuberculosis in the United States. The number of tuberculosis cases reported annually in the United States dropped 74% between 1953 and 1985 (84,304 to 22,201). Subsequently, resurgence in the number of tuberculosis cases was reported, with a peak of 26,673 cases in 1992. Although the incidence increased by approximately 13% in all ages from 1985-1994, the rate among children younger than 15 years increased by 33%. This resurgence was attributed to the HIV epidemic, which increased the risk of developing active tuberculosis among persons with HIV and latent tuberculosis infection. Other contributory factors included emigration from developing countries and transmission in settings such as endemic hospitals and prisons.

Development of multidrug-resistant (MDR) organisms and deterioration of the public health infrastructure for TB services further contributed to the rise in the number of cases.

The incidence of tuberculosis in the United States decreased 44% from 1993-2003, with the lowest number of cases reported in 2003 (14,874). The decline in case numbers since 1992 has been attributed to increased awareness of the disease, the institution of more aggressive preventive measures, improvement in health care strategies (eg, prompt identification and treatment of patients with tuberculosis), and highly active antiretroviral therapy for individuals with HIV. Although the case rate has declined since 1992, a huge reservoir of individuals who are infected with M tuberculosis remains.

International

According to the WHO, more than 8 million new cases of tuberculosis occur each year. Currently, 19-43.5% of the world's population is infected with M tuberculosis.³ Tuberculosis occurs disproportionately among disadvantaged populations, such as homeless individuals, malnourished individuals, and those living in crowded areas. According to the WHO, developing countries including India, China, Pakistan, Philippines, Thailand, Indonesia, Bangladesh, and the Democratic Republic of Congo account for nearly 75% of all cases of tuberculosis.

Mortality/Morbidity

The mortality rate from tuberculosis in the United States is currently 0.6 deaths per 100,000 individuals, which represents approximately 1,700 deaths per year and an annual mortality rate of approximately 7% per newly identified case. In 1953, the mortality rate was 12.5 deaths per 100,000 individuals. This decrease in mortality is attributed to improved health care and prompt initiation of therapy. MDR-tuberculosis cases have a reported fatality rate of greater than 70%. Worldwide, deaths due to tuberculosis are estimated to be 3 million per year.

Race

According to the CDC, rates of tuberculosis are 10 times higher among Asians and Pacific Islanders, 8 times higher among non-Hispanic blacks, and 5 times higher among Hispanics, Native Americans, and Native Alaskans compared to non-Hispanic whites. However, race may not be an independent risk factor, and risk is best defined on the basis of social, economic, and medical factors as well.

Sex

TB equally affects females and males.

Age

An increased risk of mortality from tuberculosis is noted at the extremes of age.

Clinical

History

• Staging: Although the natural history of tuberculosis (TB) in children follows a continuum, the American Thoracic Society (ATS) definition of stages is useful:^4,5,6,7,8
  • Stage 1: Exposure has occurred, implying that the child has had recent contact with an adult who has contagious tuberculosis. The child has no physical signs or symptoms and has a negative tuberculin skin test (TST) result. The chest radiography does not reveal any changes at this stage. Not all patients who are exposed become infected, the TST result may not be positive for 3 months. Unfortunately, children younger than 5 years may develop disseminated tuberculosis in the form of miliary disease or tubercular meningitis before the TST result becomes positive. Thus, a very high index of suspicion is required when a young patient has a history of contact.
  • Stage 2: This stage is heralded by a positive TST result. No signs and symptoms occur, although an incidental chest radiography may reveal the primary complex.
  • Stage 3: Tuberculous disease occurs and is characterized by the appearance of signs and symptoms depending on the location of the disease. Radiographic abnormalities may also be seen.
  • Stage 4: This stage is defined as tuberculosis with no current disease. This implies that the patient has a history of previous episodes of tuberculosis or abnormal, stable radiographic findings with a significant reaction to the TST and negative bacteriologic studies. No clinical findings suggesting current disease are present.
  • Stage 5: Tuberculosis is suspected, and the diagnosis is pending.
• Asymptomatic infection: Patients with asymptomatic infection have a positive TST result but do not have any clinical or radiographic manifestations. Children with asymptomatic infection may be identified on a routine well-child physical examination, or they may be identified subsequent to tuberculosis diagnosis in household or other contacts (eg, children who recently have immigrated, adopted children).
• Disease evaluation: Any patient with pneumonia, pleural effusion, or a cavitary or mass lesion in the lung that does not improve with standard antibacterial therapy should be evaluated for tuberculosis. Also, patients with fever of unknown origin, failure to thrive, significant weight loss, or unexplained lymphadenopathy should be evaluated for tuberculosis.
  • Pulmonary tuberculosis may manifest itself in several forms, including endobronchial tuberculosis with focal lymphadenopathy, progressive pulmonary disease, pleural involvement, and reactivated pulmonary disease. Symptoms of primary pulmonary disease in the pediatric population are often meager. Fever, night sweats, anorexia, nonproductive cough, failure to thrive, and difficulty gaining weight may occur.
    • Endobronchial tuberculosis with enlargement of lymph nodes: This is the most common variety of pulmonary tuberculosis. Symptoms are the result of impingement on various structures by the enlarged lymph nodes. Persistent cough may be indicative of bronchial obstruction, whereas difficulty swallowing may result from esophageal compression. Vocal cord paralysis may be suggested by hoarseness or difficulty breathing.
    • Tubercular pleural effusion: Pleural effusions due to tuberculosis usually occur in older children and are rarely associated with miliary disease. Typical history reveals an acute onset of fever, chest pain that increases in intensity on deep inspiration, and shortness of breath. Fever usually persists for 14-21 days.
    • Progressive primary tuberculosis: Progression of the pulmonary parenchymal component leads to enlargement of the caseous area and may lead to pneumonia, atelectasis, and air trapping. This is more likely to occur in young children than in adolescents. The child usually appears ill with symptoms of fever, cough, malaise, and weight loss.
    • Reactivation tuberculosis: This condition usually has a subacute presentation with weight loss, fever, cough, and, rarely, hemoptysis. Reactivation tuberculosis typically occurs in older children and adolescents. The condition is more common in patients who acquire tuberculosis when aged 7 years and older.
  • Extrapulmonary tuberculosis includes peripheral lymphadenopathy, tubercular meningitis, miliary tuberculosis, skeletal tuberculosis, and other organ involvement.
    • Lymphadenopathy: Patients with lymphadenopathy (ie, scrofula) may have a history of enlarged nodes. Fever, weight loss, fatigue, and malaise are usually absent or minimal. Lymph node involvement typically occurs 6-9 months following initial infection by the tubercle bacilli. More superficial lymph nodes commonly are involved. Frequent sites of involvement include the anterior cervical, submandibular, and supraclavicular nodes. Tuberculosis of the skeletal system may lead to involvement of the inguinal, epitrochlear, or axillary lymph nodes.
    • Tubercular meningitis: One of the most severe complications of tuberculosis is tubercular meningitis. Tubercular meningitis develops in 5-10% of children younger than 2 years; thereafter, the frequency drops to less than 1%. A very high index of suspicion is required to make a timely diagnosis because of the insidious onset of the disease. A subacute presentation usually occurs within 3-6 months after the initial infection. Nonspecific symptoms such as anorexia, weight loss, and fever may be present. After 1-2 weeks, patients may experience vomiting and seizures or alteration in the sensorium. Deterioration of mental status, coma, and death may occur despite prompt diagnosis and early intervention.
    • Miliary tuberculosis: This is a complication of primary tuberculosis in young children. It may manifest subacutely with low-grade fever, malaise, weight loss, and fatigue. A rapid onset of fever and associated symptoms may also be observed. History of cough and respiratory distress may be obtained.
    • Bone or joint tuberculosis: This may present acutely or subacutely. Vertebral tuberculosis may go unrecognized for months to years because of its indolent nature.
    • Additional sites: Other unusual sites for tuberculosis include the middle ear, GI tract, skin, kidneys, and ocular structures.
  • Congenital tuberculosis is rare. Symptoms typically develop during the second or third week of life and include poor feeding, poor weight gain, cough, lethargy, and irritability. Other symptoms include fever, ear discharge, and skin lesions. To make a diagnosis of congenital tuberculosis, the infant should have proven tuberculosis lesions and at least one of the following:
    • Skin lesions during the first week of life, including papular lesions or petechiae
    • Documentation of tuberculosis infection of the placenta or the maternal genital tract
    • Presence of a primary complex in the liver
    • Exclusion of the possibility of postnatal transmission

Physical

• Primary tuberculosis is characterized by the absence of any signs on clinical evaluation. These patients are identified by a positive TST result. Tuberculin hypersensitivity may be associated with erythema nodosum and phlyctenular conjunctivitis.
• Signs of disease depend on the site involved (pulmonary or extrapulmonary).
• Pulmonary disease may manifest itself in several forms, including endobronchial tuberculosis with focal lymphadenopathy, progressive pulmonary disease, pleural involvement, and reactivated pulmonary disease.
  • Endobronchial disease: Enlargement of lymph nodes may result in signs suggestive of bronchial obstruction or hemidiaphragmatic paralysis. Vocal cord paralysis may occur as a result of local nerve compression. Dysphagia due to esophageal compression also may be observed.
  • Progressive primary pulmonary tuberculosis: This condition presents with classic signs of pneumonia, including tachypnea, nasal flaring, grunting, dullness to percussion, egophony, decreased breath sounds, and crackles.
  • Pleural effusion: Signs include tachypnea, respiratory distress, dullness to percussion, decreased breath sounds, and, occasionally, features of mediastinal shift.
  • Reactivation tuberculosis: Physical examination results may be normal or may reveal posttussive crackles.
• Manifestations of extrapulmonary tuberculosis include peripheral lymphadenopathy, tubercular meningitis, miliary tuberculosis, skeletal tuberculosis, and other organ involvement.
  • Lymphadenopathy: This usually involves the anterior or posterior cervical and supraclavicular nodes. Less-commonly involved lymph nodes include: submandibular, submental, axillary, and inguinal lymph nodes. Typically, infected lymph nodes are firm and nontender with nonerythematous overlying skin. The nodes are initially nonfluctuant. Suppuration and spontaneous drainage of the lymph nodes may occur with caseation and the development of necrosis.
  • Tubercular meningitis: Three stages of tubercular meningitis have been identified.
    • Stage 1: No focal or generalized neurologic signs are present. Possibly, only nonspecific behavioral abnormalities are found.
    • Stage 2: This stage is characterized by the presence of nuchal rigidity, altered deep tendon reflexes, lethargy, and/or cranial nerve palsies. Tubercular meningitis most often affects the sixth cranial nerve, resulting in lateral rectus palsy. This is due to the pressure of the thick basilar inflammatory exudates on the cranial nerves or to hydrocephalus. The third, fourth, and seventh cranial nerves may also be affected. Funduscopic changes may include papilledema and the presence of choroid tubercles, which should be carefully sought.
    • Stage 3: This final stage comprises major neurologic defects, including coma, seizures, and abnormal movements (eg, choreoathetosis, paresis, paralysis of one or more extremities). In the terminal phase, decerebrate or decorticate posturing, opisthotonus, and/or death may occur. Patients with tuberculomas or tubercular brain abscesses may present with focal neurologic signs. Spinal cord disease may result in the acute development of spinal block or a transverse myelitis–like syndrome. A slowly ascending paralysis may develop over several months to years.
  • Miliary tuberculosis: Physical examination includes lymphadenopathy, hepatosplenomegaly, and systemic signs including fever. Respiratory signs may evolve to include tachypnea, cyanosis, and respiratory distress. Other signs, which are subtle and should be carefully sought in the physical examination, include papular, necrotic, or purpuric lesions on the skin or choroidal tubercles in the retina.
  • Bone tuberculosis: Common sites involved include the large weightbearing bones or joints, including the vertebrae (50%), hip (15%), and knee (15%). Destruction of the bones with deformity is a late sign of tuberculosis. Manifestations may include angulation of the spine (gibbus deformity) and/or Pott disease (severe kyphosis with destruction of the vertebral bodies). Cervical spine involvement may result in atlantoaxial subluxation, which may lead to paraplegia or quadriplegia.
• Signs of congenital tuberculosis include failure to thrive, icterus, hepatosplenomegaly, tachypnea, and lymphadenopathy.

Causes

Risk factors for the acquisition of tuberculosis are usually exogenous to the patient. Thus, likelihood of being infected depends on the environment and the features of the index case. However, the development of tuberculosis disease depends on inherent immunologic status of the host.

• Infection
  • The number of bacilli in the inoculum and the relative virulence of the organism are the major factors determining transmission of the disease. Tuberculosis is transmitted by inhaling the tubercle bacilli.
  • The infectiousness of the source case is of vital importance in determining likelihood of transmission. Bacillary population of tuberculosis lesions varies and depends on the morphology of the lesion. Nodular lesions have 100-10,000 organisms, whereas cavitary lesions have 10 million to 1 billion bacilli. Thus, persons with cavitary lesions are highly infectious. Also, contacts of persons with sputum-positive smears have an increased prevalence of infection as opposed to contacts of those with sputum-negative smears.
  • Persons who have received antituberculosis drugs are much less infectious than those who have not received any treatment. This decline in infectiousness is due primarily to reduction in the bacillary population in the lungs.
  • Environmental factors also contribute to the likelihood of acquiring the infection. The concentration of bacilli depends on the ventilation of the surroundings and exposure to ultraviolet light. Thus, overcrowding, congregation in prison settings, poor housing, and inadequate ventilation predispose individuals to the development of tuberculosis.
• Disease
  • Defects in cell-mediated immunity and level of immunocompetence are major determinants for development of disease.
  • HIV infection is one of the most significant risk factors for tuberculosis infection. Case rates for persons who are dually infected with HIV and M tuberculosis exceed the lifetime risk of persons with tuberculosis infection who are not infected with HIV.
  • Steroid therapy, cancer chemotherapy, and hematologic malignancies increase the risk of tuberculosis.
  • Malnutrition interferes with the cell-mediated immune (CMI) response and therefore accounts for much of the increased frequency of tuberculosis in impoverished patients.
  • Nontuberculosis infections, such as measles, varicella, and pertussis, may activate quiescent tuberculosis.
  • Individuals with certain human leukocyte antigen (HLA) types have a predisposition to tuberculosis. Hereditary factors, including the presence of a Bcg gene, have been implicated in susceptibility to acquisition of tuberculosis.

Differential Diagnoses

Workup

Laboratory Studies

• Making the diagnosis of tuberculosis (TB) in children is extremely challenging because of the difficulty in isolating M tuberculosis. Definitive diagnosis of tuberculosis depends on isolation of the organism from secretions or biopsy specimens.
• Despite innovations in rapid diagnosis, many of the classic diagnostic tools remain useful and continue to be used in the evaluation of patients with tuberculosis.
• Detection and isolation of the mycobacterium are accomplished as follows:
  • The initial step is to obtain appropriate specimens for bacteriologic examination. Examination of sputum, gastric lavage, bronchoalveolar lavage, lung tissue, lymph node tissue, bone marrow, blood, liver, cerebrospinal fluid (CSF), urine, and stool may be useful, depending on the location of the disease.
  • Gastric aspirates are used in lieu of sputum in very young children (<6 y) who usually do not have a cough deep enough to produce sputum for analysis.
    • Using the correct technique for obtaining the gastric lavage is important because of the scarcity of the organisms in children compared to adults. An early morning sample should be obtained before the child has had a chance to eat or ambulate because these activities dilute the bronchial secretions accumulated during the night.
    • Initially, the stomach contents should be aspirated, and then a small amount of sterile water injected through the orogastric tube. This aspirate should also be added to the specimen.
    • Because gastric acidity is poorly tolerated by the tubercle bacilli, neutralization of the specimen should be performed immediately with 10% sodium carbonate or 40% anhydrous sodium phosphate. Even with careful attention to detail and meticulous technique, the tubercle bacilli can be detected in only 70% of infants and in 30-40% of children with disease.
  • Sputum specimens may be used in older children. Nasopharyngeal secretions and saliva are not acceptable. In older children, bronchial secretions may be obtained by the stimulation of cough by an aerosol solution of propylene glycol in 10% sodium chloride.
  • Bronchoalveolar lavage may also be used to provide bronchial secretions for detection of tubercle bacilli.
  • Decontamination of other microorganisms in the specimens obtained may be performed by the addition of sodium hydroxide, usually in combination with N -acetyl-L -cysteine. Other body fluids (eg, CSF, pleural fluid, peritoneal fluid) can also be centrifuged; the sediment can be stained and evaluated for presence of acid-fast bacilli (AFB). CSF smear results are positive in fewer than 10% of patients in some series. Enhancement of the yield may be possible by staining any clot that may have formed in standing CSF specimens, as well as using the sediment of a centrifuged specimen. Increased yield may also be obtained from cisternal or ventricular fluid.
  • Obtain overnight urine specimens in the early morning. Send immediately for analysis because the tubercle bacilli poorly tolerate the acidic pH of urine.
• Staining of the specimen is as follows:
  • Because M tuberculosis is an AFB, staining of AFB provides preliminary confirmation of the diagnosis.
  • Staining can also give a quantitative assessment of the number of bacilli being excreted (eg, 1+, 2+, 3+). This can be of clinical and epidemiologic importance in estimating the infectiousness of the patient and in determining the discontinuation of respiratory isolation. However, for reliably producing a positive result, smears require approximately 10,000 organisms/mL. Therefore, in early stages of the disease or in children in whom the bacilli in the respiratory secretions are sparse, the results may be negative. A single organism on a slide is highly suggestive and warrants further investigation.
  • A significant drawback of AFB smears is that they cannot be used to differentiate M tuberculosis from other acid-fast organisms such as other mycobacterial organisms or Nocardia species.
  • Conventional methods include the Ziehl-Neelsen staining method. The Kinyoun stain is modified to make heating unnecessary. Fluorochrome stains, such as auramine and rhodamine, are variations of the traditional stains. The major advantage of these is that slides can be screened faster because the acid-fast material stands out against the dark, nonfluorescent background. However, fluorochrome-positive smears must be confirmed by Ziehl-Neelsen staining.
• Conventional growth techniques are as follows:
  • Culture of mycobacterium is the definitive method to detect bacilli. It is also more sensitive than examination of the smear. Approximately 10 AFB/mm of a digested concentrated specimen are sufficient to detect the organisms by culture.
  • Another advantage of culture is that it allows specific species identification and testing for recognition of drug susceptibility patterns. However, because M tuberculosis is a slow-growing organism, a period of 6-8 weeks is required for colonies to appear on conventional culture media.
  • Conventional solid media include the Löwenstein-Jensen medium, which is an egg-based medium, and the Middlebrook 7H10 and the 7H11 media, which are agar-based media. Liquid media (eg, Dubos oleic-albumin media) are also available, and they require incubation in 5-10% carbon dioxide for 3-8 weeks. These media usually have antibacterial antibiotics, which are slightly inhibitory for tubercle bacilli.
• Modern approaches in diagnosis are as follows:
  • Because mycobacteria require 6-8 weeks for isolation from conventional media, automated radiometric culture methods (eg, BACTEC) are increasingly used for the rapid growth of mycobacteria. The methodology uses a liquid Middlebrook 7H12 medium that contains radiometric palmitic acid labeled with radioactive carbon 14 (¹⁴ C). Several antimicrobial agents are added to this medium to prevent the growth of nonmycobacterial contaminants. Production of¹⁴ CO₂ by the metabolizing organisms provides a growth index for the mycobacteria. Growth is generally detected within 9-16 days.
  • Another rapid method for isolation of mycobacteria is SEPTICHEK. This nonradiometric approach has a biphasic broth-based system that decreases the mean recovery time versus conventional methods.
  • Mycobacterial growth indicator tubes (MGITs), which presently are used as a research tool, have round-bottom tubes with oxygen-sensitive sensors at the bottom. MGITs indicate microbial growth and provide a quantitative index of M tuberculosis growth.
• Identification of species is as follows:
  • M tuberculosis can be reliably differentiated from other species on the basis of culture characteristics, growth parameters, and other empiric tests. M tuberculosis produces heat-sensitive catalase, reduces nitrates, produces niacin, and grows slowly. Serpentine cording is demonstrated on smears prepared from the BACTEC system.
  • Addition of p -nitro-acetyl-amino-hydroxy-propiophenone (NAP) inhibits the growth of M tuberculosis complex (including M bovis and M africanum) but does not inhibit growth of other mycobacteria. This provides the basis for the NAP differentiation test.
  • Chromatographic analysis of mycobacterial cell wall lipids can provide further speciation. The most useful approaches include gas-liquid chromatography and high-performance liquid chromatography (HPLC). The unique mycolic acid pattern associated with the species can be detected by the chromatographic separation of the ester. A significant drawback of these methods is the requirement of bacterial colonies grown in conventional solid media, a process that takes at least 3 weeks. However, the recent combination of HPLC with fluorescence detection has made the method more sensitive, thus BACTEC broth culture can be used instead of conventional solid media. This may make the method comparable to the NAP and AccuProbe tests. The expense of the initial equipment limits the availability of HPLC.
• Nucleic acid probes are used as follows:
  • Because biochemical methods are time-consuming and laborious, nucleic acid hybridization using molecular probes has become widely accepted. Commercially available probes, including the AccuProbe technology, help advance identification of the M tuberculosis complex. Sensitivity and specificity approach 100% when at least 100,000 organisms are present.
  • The basic principle is the use of a chemiluminescent, ester-labeled, single-strand DNA probe. A luminometer is used to assess the chemiluminescence.
  • Positive test results should be reported as M tuberculosis complex because the probe does not reliably differentiate between M tuberculosis and other members of the complex (eg, M bovis). Final identification to species level is required because pyrazinamide should not be included in the treatment regimen if the isolate is M bovis.
  • Niacin production, nitrate reduction, pyrazinamidase, and susceptibility to thiophene-2-carboxylic acid hydrazide can help differentiate between M bovis and M tuberculosis.
• Polymerase chain reaction (PCR) and other amplification tests are used as follows:
  • Nucleic acid amplification allows the direct identification of M tuberculosis in clinical specimens, unlike the nucleic acid probes, which require substantial time for bacterial accumulation in broth culture.
  • The US Food and Drug Administration (FDA) has approved 2 tests, the amplified M tuberculosis direct test and the AMPLICOR M tuberculosis test. The AMPLICLOR test targets the DNA. The most commonly used target sequence for the detection of M tuberculosis has been the insertion sequence IS6110. The amplified M tuberculosis direct test is an isothermal transcription-mediated amplification that targets RNA.
  • Although amplification techniques are promising tools for the rapid diagnosis of tuberculosis, several caveats remain. Contamination of samples by products of previous amplification and the presence of inhibitors in the sample may lead to false-positive or false-negative results.
  • Although the sensitivity and specificity of the nucleic acid techniques in smear-positive cases exceed 95%, the sensitivity of smear-negative cases varies from 40-70%. Thus, discordance between the acid-fast smear result and the nucleic acid amplification techniques requires careful clinical appraisal and judgment.
• T-SPOT Tb and QuantiFERON-TB Gold, interferon-gamma release assays (IGRAs), are 2 blood tests recently available to aid in the diagnosis of tuberculosis.⁹
  • The QuantiFERON-TB Gold has recently been approved by the FDA as an in vitro diagnostic test and the CDC has published a guideline for its use. The test is an enzyme-linked immunoassay (ELISA) that basically detects the presence of interferon gamma release protein (IFN-g) from the blood of sensitized patients when incubated with the early secretory antigenic target-6 (ESAT6) and culture filtrate protein 10 (CFP10) peptides. The test is as sensitive as, and more specific than, the tuberculin skin test (TST) and has been recommended as a screening tool in all situations in which the tuberculin skin test has been used (ie, for diagnosing disease as well as infection).
  • Other advantages include the fact that no return visits are needed to read the skin tests and no boosting occurs due to the tests.
  • Initial studies are underway to determine if these tests can be used to monitor response to therapy.
• M tuberculosis drug susceptibility is determined as follows:
  • Because of the emergence of multidrug-resistant (MDR) organisms, determination of the drug susceptibility panel of an isolate is important so that appropriate treatment can be ensured.
  • Numerous chromosomal mutations are associated with drug resistance. Genotypic methods now being evaluated to identify these mutations include DNA sequencing, solid phase hybridization, and PCR–single-strand combination polymorphism analysis.
  • Mutations of the catalase peroxidase gene katG, the inhA gene involved in fatty acid biosynthesis, the ahpc gene, and the oxyR gene have been identified as major determinants for isoniazid (INH) resistance.
  • Resistance to rifampin is determined by mutations in the rpoB gene encoding the beta subunit of the RNA polymerase.
  • Phenotypic susceptibility assays, which remain experimental, use mycobacteriophages to type the mycobacteria grown in the presence of antituberculous agents.
• Serology is as follows:
  • M tuberculosis increases the levels of antibody titers in the serum.
  • No available serodiagnostic test for tuberculosis has adequate sensitivity and specificity for routine use in diagnosing tuberculosis in children.

Imaging Studies

• Chest radiography
  • Chest radiography is a classic diagnostic tool when evaluating patients for pulmonary tuberculosis.
  • Initial studies include posteroanterior and lateral views. Apical-lordotic and oblique views may be helpful if further evaluation of the extent of lung involvement is indicated (eg, patients with apical lesions or extensive hilar adenopathy).
  • If pleural effusion is present, lateral decubitus views aid in the determination of the nature of effusion (ie, free moving, loculated).
• CT scanning and MRI
  • CT scanning and MRI are not routinely indicated when chest radiography findings are unremarkable.
  • However, in patients with pulmonary tuberculosis, these imaging studies can help demonstrate hilar lymphadenopathy, endobronchial tuberculosis, pericardial invasion, and early cavitations or bronchiectasis.

Other Tests

• The TST is a widely used diagnostic test for evaluation of patients who have symptoms of tuberculosis or in whom infection with M tuberculosis is suspected. Although the sensitivity and the specificity of the TST are less than 100%, no better diagnostic test is widely available.
• The American Academy of Pediatrics (AAP) has issued the following guidelines for pediatric testing:¹⁰
  • Immediate skin testing is indicated for the following children:
    • Those who have been in contact with persons with active or suspected tuberculosis
    • Immigrants from countries in which tuberculosis is endemic (eg, Asia, Middle East, Africa, Latin America) or children with travel histories to these countries
    • Those who have radiographic or clinical findings suggestive of tuberculosis
  • An annual TST is indicated for the following children:
    • Children who are infected with HIV or those living in a household with persons infected with HIV
    • Incarcerated adolescents
  • Testing at 2-year to 3-year intervals is indicated if the child has been exposed to high-risk individuals including those who are homeless, institutionalized adults who are infected with HIV, users of illicit drugs, residents of nursing homes, and incarcerated adolescents or adults.
  • Testing when children are aged 4-6 years and 11-16 years is indicated for the following children:
    • Children without risk factors residing in high-prevalence areas
    • Children whose parents emigrated from regions of the world with a high prevalence of tuberculosis or who have continued potential exposure by travel to the endemic areas and/or household contact
  • Performing an initial TST before the initiation of immunosuppressive therapy is recommended in any patient.
• Administration of TST is as follows:
  • The recommended TST is the Mantoux test. The dosage of 0.1 mL or 5 TU purified protein derivative (PPD) should be injected intradermally into the volar aspect of the forearm using a 27-gauge needle. A detergent called Tween 80 to prevent loss of efficacy on contact and adsorption by glass stabilizes the PPD. A wheal should be raised and should measure approximately 6-10 mm in diameter.
  • Skilled personnel always should read the test 48-72 hours after administration. Measure the amount of induration and not erythema. This should be measured transverse to the long axis of the forearm.
  • Multiple puncture tests (eg, tine test, Heaf test) lack sensitivity and specificity and hence are not recommended.
• The CDC and the AAP have provided recommendations on the size of the induration created by the TST that is considered a positive result and indicative of disease. The TST is interpreted on the basis of rule of 5 mm, 10 mm, and 15 mm.
  • Induration of 5 mm or more is considered a positive TST result in the following children:
    • Children having close contact with known or suspected contagious cases of the disease, including those with household contacts with active tuberculosis whose treatment cannot be verified before exposure
    • Children with immunosuppressive conditions (eg, HIV) or children who are on immunosuppressive medications
    • Children who have an abnormal chest radiography finding consistent with active tuberculosis, previously active tuberculosis, or clinical evidence of the disease
  • Induration of 10 mm or more is considered a positive TST result in the following children:
    • Children who are at a higher risk of dissemination of tuberculous disease, including those younger than 5 years or those who are immunosuppressed because of conditions such as lymphoma, Hodgkin disease, diabetes mellitus, and malnutrition
    • Children with increased exposure to the disease, including those who are exposed to adults in high-risk categories (eg, homeless, HIV infected, users of illicit drugs, residents of nursing homes, incarcerated or institutionalized persons); those who were born in or whose parents were born in high-prevalence areas of the world; and those with travel histories to high-prevalence areas of the world
  • Induration of 15 mm or more is considered a positive TST result in children aged 5 years or older without any risk factors for the disease.
• False-positive reactions and false-negative results can have various causes.
  • False-positive reactions often are attributed to asymptomatic infection by environmental nontuberculous mycobacteria (due to cross-reactivity).
  • False-negative results may be due to vaccination with live-attenuated virus, anergy, immunosuppression, immune deficiency, or malnutrition. Other factors that may cause a false-negative result include improper administration (eg, subcutaneous injection, injection of too little antigen), improper storage, and contamination. PPD has been recognized to have an initial false-negative rate of 29%.
• The following are important when administering the TST to prior recipients of bacille Calmette-Guérin (BCG) vaccine:
  • Immunization with BCG is not a contraindication to the TST. BCG vaccination is used in many parts of the world, especially in developing countries.
  • Differentiating tuberculin reactions caused by vaccination with BCG versus reactions caused by infection with M tuberculosis is difficult. History of contact with a person with contagious tuberculosis or emigration from a country with a high prevalence of tuberculosis suggests that the positive results are due to infection with M tuberculosis. However, multiple BCG vaccinations may increase the likelihood that the positive TST result is due to BCG vaccination. The positive reactivity caused by BCG vaccination generally wanes with the passage of time. With the administration of TST, this positive tuberculin reactivity may be boosted.
  • A prior BCG vaccination does not affect interpretation of a TST result for a person who is symptomatic or in whom tuberculosis is strongly suspected.

Treatment

Medical Care

The ATS and CDC have provided standard guidelines for the treatment of tuberculosis. The ultimate goal of treatment is to achieve sterilization of the tuberculosis lesion in the shortest possible time. The general rule is strict adherence to tuberculosis treatment regimens for a sufficient period of time. To prevent the emergence of resistance, the regimens for the treatment of tuberculosis always should consist of multiple drugs.

Pulmonary tuberculosis

Current recommendations for the treatment of pulmonary tuberculosis include a 6-month course of isoniazid (INH) and rifampin, supplemented during the first 2 months with pyrazinamide. Ethambutol (or streptomycin in children too young to be monitored for visual acuity) may need to be included in the initial regimen until the results of drug susceptibility studies are available. Drug susceptibility studies may not be required if the risk of drug resistance is not significant. Significant risk factors include residence in a community with greater than 4% primary resistance to INH, history of previous treatment with antituberculosis drugs, history of exposure to a drug-resistant case, and origin in a country with a high prevalence of drug resistance. The purpose of this recommendation is to decrease the development of multidrug-resistant (MDR) tuberculosis in areas in which primary INH resistance is increased.

Another treatment option is a 2-month regimen of INH, rifampin, and pyrazinamide daily, followed by 4 months of INH and rifampin twice a week. Effective treatment of hilar adenopathy when the organisms are fully susceptible is a 9-month regimen of INH and rifampin daily or a 1-month regimen of INH and rifampin once a day followed by 8 months of INH and rifampin twice a week.

Because poor adherence to these regimens is a common cause of treatment failure, directly observed therapy (DOT) is recommended for treatment of tuberculosis. DOT means a health care provider or other responsible person must watch the patient ingest the medications. Intermittent regimens should be monitored by DOT for the duration of therapy because poor compliance may result in inadequate drug delivery.

Another initiative recently launched by the WHO is the DOTS-plus strategy, which is based on finding appropriate treatment strategies for MDR tuberculosis and drug susceptibility testing, as well as judicious usage of second-line drugs.^11,12  It also focuses on community involvement and a good recording and reporting system.

Extrapulmonary tuberculosis

Most cases of extrapulmonary tuberculosis, including cervical lymphadenopathy, can be treated with the same regimens used to treat pulmonary tuberculosis. Exceptions include bone and joint disease, miliary disease, and meningitis. For these severe forms of drug-susceptible disease, the recommendation is a regimen of 2 months of INH, rifampin, pyrazinamide, and streptomycin once a day, followed by 7-10 months of INH and rifampin once a day. The other recommended regimen is 2 months of INH, rifampin, pyrazinamide, and streptomycin, followed by 7-10 months of INH and rifampin twice a week. Streptomycin may be administered with initial therapy until drug susceptibility is known. Consider administering capreomycin or kanamycin instead of streptomycin in patients who may have acquired tuberculosis in areas in which resistance to streptomycin is common.

Tuberculosis in patients with HIV

Optimal therapy for tuberculosis in children with HIV infection has not been established. According to the current guidelines provided by the CDC, effective treatment of tuberculosis for patients infected with HIV should include DOT and consultation with a specialist. 

A regimen that uses rifabutin instead of rifampin has been advised when simultaneously treating HIV disease and tuberculosis. This situation may occur (1) when antiretroviral treatment is recommended for a newly diagnosed HIV infection in a patient with active tuberculosis or (2) when a patient with active tuberculosis has established HIV infection and continuation of antiretroviral therapy is recommended. This recommendation is based on the fact that the use of rifampin with protease inhibitors or nonnucleoside reverse transcriptase inhibitors is contraindicated.

The treatment regimen for tuberculosis should initially include at least 3 drugs and should be continued for at least 9 months. INH, rifampin, and pyrazinamide with or without ethambutol or streptomycin should be administered for the first 2 months. Treatment of disseminated disease or drug-resistant tuberculosis may require the addition of a fourth drug.

Multidrug resistant tuberculosis

Infection caused by MDR organisms, defined as organisms resistant to at least INH and rifampin, has reached critical levels worldwide. The median prevalence of resistance to any of the 4 antituberculosis drugs in a recent update by the WHO and the International Union Against Tuberculosis and Lung Disease (IUATLD) has been shown to be 10.2% (range 0-57.1%).^13,12

Two categories of drug resistance are recognized: primary and secondary. Primary resistance is defined as the occurrence of resistance to antituberculosis treatment in an individual who has no history of prior treatment. Secondary resistance involves the emergence of resistance during the course of ineffectual antituberculosis therapy.

In 2006, the WHO Global Task Force defined another category of MDR tuberculosis termed extensively drug-resistant (XDR) tuberculosis.³ This is defined as resistance to first-line drugs, including resistance to at least rifampicin and INH, in addition to resistance to any fluoroquinolone and at least one of following second-line antituberculosis drugs: capreomycin, kanamicin, and amikacin. This usually occurs as a result of mismanagement of MDR tuberculosis.

Risk factors for the development of primary drug resistance include patient contact with drug-resistant contagious tuberculosis, residence in areas with a high prevalence of drug-resistant M tuberculosis, birth outside the United States, ethnicity other than non-Hispanic white, young age, HIV infection, and the use of intravenous drugs. Secondary drug resistance reflects patient nonadherence to the regimen, inappropriate drug regimens, and/or interference with absorption of the drug.

The current guidelines endorsed by the CDC state that if a child is at risk of or has disease resistant to INH, at least 2 drugs to which the isolate is susceptible should be administered. Another important management principle is to never add a single drug to an already failing regimen. The resistance pattern, toxicities of the drugs, and patients' responses to treatment determine duration and the regimen selected. The initial treatment regimen for patients with MDR tuberculosis should include 4 drugs. At least 2 bactericidal drugs (eg, INH, rifampin), pyrazinamide, and either streptomycin or another aminoglycoside (also bactericidal) or high-dose ethambutol (25 mg/kg/d) should also be incorporated into the regimen.

Six-month treatment regimens are not advocated for patients with strains resistant to INH or rifampin. Intermittent therapy with twice-a-week regimens is also not recommended. In isolated INH resistance, the 4-drug, 6-month regimen should be initially started for the treatment of pulmonary tuberculosis. INH should be discontinued when resistance is documented. Continue pyrazinamide for the entire 6-month course of treatment. In the 9-month regimen, INH should be discontinued upon the documentation of isolated INH resistance. If ethambutol was included in the initial regimen, continue treatment with rifampin and ethambutol for a minimum of 12 months. If ethambutol was not included, then repeating susceptibility tests is advocated, as are discontinuation of INH and the addition of 2 new drugs (eg, ethambutol and pyrazinamide).

Resistance to both INH and rifampin presents a complex problem that often necessitates consultation with a specialist. Continuing the initial drug regimen (with 2 drugs to which the organism is susceptible) until bacteriologic sputum conversion is documented is preferable; then administer at least 12 months of 2-drug therapy. The role of new agents such as quinolone derivatives and amikacin in MDR cases remains unclear.

Management of a neonate whose mother or other household contact has tuberculosis 

The AAP and CDC guidelines advocate avoidance of separation of the mother and infant if possible. Authorities have endorsed the following recommendations:

• The mother has a positive TST result and no evidence of current disease: Because the positive TST result may be evidence of an unrecognized case of contagious tuberculosis within the household, careful screening and evaluation of the other members of the household should be performed. Perform a Mantoux test when the infant is aged 4-6 weeks and 3-4 months. Consider administration of INH (10 mg/kg/d) to the infant if the family cannot be promptly tested.
• The mother is having current disease but is noncontagious at delivery: In this situation, separation of the mother and infant is not necessary, and the mother can breastfeed the infant. Evaluation of the infant includes chest radiography and Mantoux test at age 4-6 weeks; if negative, a repeat test is warranted at age 3-4 months and at age 6 months. INH should be administered even if the TST result and chest radiography do not suggest tuberculosis because sufficient cell-mediated immunity (CMI) to prevent progressive disease may not develop until age 6 months.
• The mother has current disease and is contagious at delivery: In this situation, separation of the mother and infant is recommended until the mother is noncontagious. The rest of the management is the same as for category 2.
• The mother has hematogenous spread: Congenital tuberculosis is possible in this scenario. Promptly perform a Mantoux test and chest radiography and immediately begin treatment for the infant. INH should be administered until the infant is aged 6 months, at which time evaluation of the infant with a TST should be repeated. If the TST result is positive, the infant should be treated with INH for a total of 9 months.

Monitoring for adverse effects

Adverse effects of INH (eg, hepatitis) are rare in children; therefore, routine determination of serum aminotransferase levels is not necessary. Consider monthly monitoring of hepatic function tests in the following patients: (1) those with severe or disseminated tuberculosis; (2) those with concurrent or recent hepatic disease; (3) those receiving high daily doses of INH (10 mg/kg/d) in combination with rifampin, pyrazinamide, or both; (4) women who are pregnant or within the first 6 weeks postpartum; (5) those with clinical evidence of hepatotoxic effects; and (6) those with hepatobiliary tract disease from other causes.

Surgical Care

Pulmonary resection in patients with tuberculosis may be required in drug-resistant cases because of the high likelihood of failure of the medication regimen. Surgical resection may also be required in patients with advanced disease with extensive caseation necrosis. Hemoptysis, although rare in children, may necessitate surgical intervention. Tubercular abscesses and bronchopleural fistulae also should be surgically removed.

Consultations

Infectious diseases consultation may be helpful.

Diet

Diet is as tolerated.

Activity

The advisability of bed rest varies with the type and severity of the disease. No limitation of activity is required in patients with tuberculosis infection or asymptomatic primary pulmonary tuberculosis. Severely ill patients with miliary tuberculosis and tubercular meningitis may require complete bed rest.

Medication

Antituberculous medications kill mycobacteria, thereby preventing further complications of early primary disease and progression of disease. However, disappearance of caseous or granulomatous lesions does not occur even with therapy.

Antitubercular drugs are classified as first-line and second-line drugs. First-line drugs have less toxicity with greater efficacy than second-line drugs. All first-line agents are bactericidal with the exception of ethambutol.

First-line agents include rifampin, isoniazid (INH), pyrazinamide, ethambutol, and streptomycin. Second-line agents are capreomycin, ciprofloxacin, cycloserine, ethionamide, kanamycin, ofloxacin, levofloxacin, and para-aminosalicylic acid.

INH and rifampin are effective against bacilli in necrotic foci and intracellular populations of mycobacteria. Streptomycin, aminoglycosides, and capreomycin have poor intracellular penetration. Multidrug-resistant (MDR) tuberculosis (TB) is defined as resistance to at least INH and rifampin. The emergence of drug-resistant strains has necessitated use of second-line agents.

Naturally drug-resistant organisms occur with a frequency of approximately 10^-6; however, individual resistances may vary. The resistance to streptomycin is 10^-5, to INH is 10^-6, and to rifampin is 10^-8. The chance that an organism is naturally resistant to both INH and rifampin is on the order of 10^-14. Because populations of this size do not occur in patients, organisms naturally resistant to 2 drugs are essentially nonexistent. If only a single medication is administered to a patient with tuberculosis, the subpopulations susceptible to that medication are destroyed, but the other categories continue to multiply. Thus, the use of multiple agents in the treatment of tuberculosis is essential.

Antitubercular drugs

Antimycobacterial agents are a miscellaneous group of antibiotics whose spectrum of activity includes Mycobacterium species. They are used to treat tuberculosis, leprosy, and other mycobacterial infections.

Rifampin (Rifadin)

Bactericidal for M tuberculosis. Penetrates well into all body fluids including CSF. For use in combination with at least one other antituberculous drug. Inhibits RNA synthesis in bacteria by binding to beta subunit of DNA-dependent RNA polymerase, which, in turn, blocks RNA transcription. Cross-resistance may occur.

Dosing

Adult

600 mg PO/IV qd

Pediatric

10-20 mg/kg PO/IV 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 or pyrazinamide may result in higher rate of hepatotoxicity than with either agent alone (discontinue one or both agents if alterations in serum transaminases occur)

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 adults and those at risk, obtain CBC counts and baseline clinical chemistries prior to 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 occur; if treatment is continued or resumed after appearance of purpura, cerebral hemorrhage or death may occur; orange discoloration of secretions or urine may occur; staining of contact lenses may occur

Isoniazid (Laniazid, Nydrazid)

Commonly referred to as INH. Best combination of effectiveness, low cost, and minor adverse effects. First-line drug unless known resistance or another contraindication is present. Therapeutic regimens of <6 mo demonstrate unacceptably high relapse rates. Coadministration of pyridoxine is recommended if peripheral neuropathies secondary to INH therapy develop. Prophylactic doses of 6-50 mg of pyridoxine daily are recommended in some populations.

Dosing

Adult

5 mg/kg PO qd (usually 300 mg/d) and 10 mg/kg qd or divided bid in patients with disseminated disease; not to exceed 300 mg/d
DOT: 15 mg/kg twice PO weekly; not to exceed 900 mg/d

Pediatric

10-20 mg/kg PO qd; not to exceed 300 mg/d

Interactions

Higher incidence of INH-related hepatitis can occur with alcohol ingestion on daily basis; aluminum salts may decrease INH serum levels (administer 1-2 h before taking aluminum salts); may increase anticoagulant effects with coadministration; may inhibit metabolic clearance of benzodiazepines; carbamazepine toxicity or INH hepatotoxicity may result from concurrent use (monitor carbamazepine concentrations and liver functions); coadministration with cycloserine may increase CNS adverse 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 INH-associated hepatic injury or 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 INH therapy are recommended even when visual symptoms do not occur

Streptomycin

For treatment of susceptible mycobacterial infections. Use in combination with other antituberculous drugs (eg, INH, ethambutol, rifampin).

Dosing

Adult

1 g IM qd
2 times/wk dosing: 15 mg/kg/d IM; not to exceed 1 g/d
3 times/wk dosing: 25-30 mg/kg/d IM; not to exceed 1.5 g/d

Pediatric

2 times/wk dosing: 20-40 mg/kg/d IM; not to exceed 1 g/d
3 times/wk dosing: 25-30 mg/kg/d IM; not to exceed 1.5 g/d

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 patients with renal failure who are not on dialysis; caution with myasthenia gravis, hypocalcemia, and conditions that depress neuromuscular transmission

Pyrazinamide

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 patients who are drug-susceptible. Treat patients with drug-resistant cases with individualized regimens.

Dosing

Adult

15-30 mg/kg PO qd; not to exceed 2 g/d
DOT: 50-70 mg/kg PO 2 times/wk, not to exceed 4 g/d; or 50-70 mg/kg 3 times/wk, not to exceed 3 g/d

Pediatric

Administer as in adults

Interactions

Coadministration with rifampin may result in higher rate of hepatotoxicity (liver failure and death have occurred) than with either agent alone (discontinue if alterations in LFT results occur)

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 if signs of hyperuricemia with acute gouty arthritis; perform baseline serum transaminases (closely monitor in liver disease); discontinue if signs of hepatocellular damage appear; caution in history of diabetes mellitus

Ethambutol (Myambutol)

Diffuses into actively growing mycobacterial cells, such as 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 bacteriologic conversion and maximal clinical improvement are observed. Absorption is not significantly altered by food.

Dosing

Adult

No previous antituberculous therapy: 15 mg/kg (7 mg/lb) PO qd
Previous antituberculous therapy: 25 mg/kg (11 mg/lb) PO qd

Pediatric

<13 years: Not recommended
>13 years: Administer as in adults

Interactions

Aluminum salts may delay and reduce absorption (give 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 visual adverse effects if promptly discontinued; monitor for visual acuity and color vision; avoid administration in children if unable to test vision

Cycloserine (Seromycin)

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 and inhibits growth.

Dosing

Adult

0.5-1 g PO qd in divided doses; monitor by blood levels
Alternatively, 250-500 mg PO bid for first 2 weeks; not to exceed 1 g/d
Reducing dose to 200-300 mg/d may prevent neurotoxic effects

Pediatric

10-20 mg/kg/d; not to exceed 0.75-1 g/d

Interactions

Incompatible with alcohol consumption (may increase possibility and risk of epileptic episodes); INH in combination with cycloserine may result in increased cycloserine CNS adverse effects such as dizziness

Contraindications

Documented hypersensitivity; severe anxiety or psychosis; epilepsy; depression; severe renal insufficiency; alcoholism; patients with severe neurologic impairments should not receive this drug

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

Discontinue or reduce dosage if allergic dermatitis or symptoms of CNS toxicity (eg, convulsions, headache, tremor, depression, confusion, psychosis, somnolence, hyperreflexia, vertigo, paresis, dysarthria) develop; risk of convulsions is increased in chronic 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, in patients receiving more than 500 mg/d, and in those with symptoms of toxicity

Ethionamide (Trecator)

Bacteriostatic against M tuberculosis. Recommended when treatment with first-line drugs (INH, rifampin) has failed. Treats any form of active TB. However, should only be used with other effective antituberculous agents.

Dosing

Adult

0.5-1 g/d PO divided qid; concomitant administration of 25 mg pyridoxine recommended

Pediatric

15-20 mg/kg/d PO divided tid/qid; not to exceed 1 g/d; concomitant administration of pyridoxine recommended

Interactions

None reported

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 transaminases 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

Para-aminosalicylic acid (Sodium P.A.S.)

Bacteriostatic agent useful against M tuberculosis. Inhibits onset of bacterial resistance to streptomycin and INH. Administer aminosalicylate sodium with other antituberculous drugs.

Dosing

Adult

12 g/d PO divided bid/tid

Pediatric

150 mg/kg/d PO divided tid/qid; not to exceed 12 g/d

Interactions

Oral absorption of digoxin may be reduced, causing reduction in serum levels when administered concurrently; increase in digoxin dosing may be necessary; deficiency in vitamin B-12 (oral) may be induced due to PAS interference of its GI absorption; parenteral vitamin B-12 supplementation may be required

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

Caution in gastric ulcer and history of CHF; avoid situations in which excess sodium is potentially harmful

Capreomycin (Capastat)

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, INH, rifampin) have been ineffective or cannot be used because of toxicity or presence of resistant tubercle bacilli.

Dosing

Adult

1 g IM qd for 60-120 d, followed by 1 g IM bid/tid; not to exceed 20 mg/kg/d

Pediatric

Not established; limited data suggest 15 mg/kg/d IM; not to exceed 1 g/d

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

Levofloxacin (Levaquin)

For treatment of TB in combination with rifampin and other anti-TB agents.

Dosing

Adult

0.5-1 g PO qd or divided bid

Pediatric

<18 years: Not recommended
>18 years: Administer as in adults

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 levofloxacin 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

Ciprofloxacin (Cipro)

For treatment of TB in combination with rifampin and other anti-TB agents. Fluoroquinolones have not been approved for use in patients <18 y. Use in pediatric population necessitates assessment of risk versus benefit.

Dosing

Adult

750 mg PO bid

Pediatric

<18 years: Not recommended
>18 years: Administer as in adults

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 ciprofloxacin 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

Ofloxacin (Floxin)

For treatment of TB in combination with rifampin and other anti-TB agents. Fluoroquinolones have not been approved for use in patients <18 y. Use in pediatric population necessitates assessment of risk versus benefit.

Dosing

Adult

400-800 mg/d PO divided bid

Pediatric

<18 years: Not recommended
>18 years: Administer as in adults

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 ofloxacin 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

Kanamycin (Kantrex)

Aminoglycoside antibiotic produced by Streptomyces kanamyceticus. May be used as second-line agent in treatment of TB.

Dosing

Adult

15-30 mg/kg/d IM

Pediatric

Administer as in adults

Interactions

Nephrotoxicity may be increased with aminoglycosides, cephalosporins, penicillins, amphotericin B, and loop diuretics

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

May lead to auditory and vestibular toxicity, renal toxicity, and neuromuscular blockade; increased risk exists for patients with present or past history of renal impairment, for those receiving concomitant or sequential treatment with other ototoxic or nephrotoxic drugs or rapid-acting diuretic agents given IV (eg, ethacrynic acid, furosemide, mannitol), and for patients treated for longer periods and/or with higher doses than recommended; monitor renal function by measuring serum creatinine concentration or calculating endogenous CrCl rate; measure peak and trough serum concentrations intermittently during treatment to monitor toxicity

Rifabutin (Mycobutin)

Ansamycin antibiotic derived from rifamycin S. Inhibits DNA-dependent RNA polymerase, preventing chain initiation, in susceptible strains of Escherichia coli and Bacillus subtilis but not in mammalian cells. If GI upset occurs, administer dose bid with food.

Dosing

Adult

300-600 mg PO qd

Pediatric

10-20 mg/kg/d PO; not to exceed adult dose

Interactions

Steady-state zidovudine plasma levels may decrease after repeated rifabutin dosing; this does not affect inhibition of HIV by zidovudine; ritonavir or delavirdine significantly increases serum levels (do not use in combination); induces CYP3A4 (to a lesser degree than rifampin); use cautiously with substrates of CYP3A4; drugs inhibiting CYP3A4 (eg, erythromycin, itraconazole) may increase rifabutin levels

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

Do not administer to patients with active TB; no evidence of effectiveness in prophylaxis against M tuberculosis; may give INH and rifabutin concurrently in patients requiring prophylaxis against both M tuberculosis and M avium complex; perform hematologic studies periodically in patients receiving prophylaxis because of association with neutropenia and, more rarely, thrombocytopenia

Follow-up

Further Outpatient Care

• Public health authorities should be notified of all cases of tuberculosis (TB).
• Directly observed therapy (DOT) is mandatory for the treatment of patients with coexistent HIV disease, those with multidrug-resistant (MDR) tuberculosis, and those who may be noncompliant.
• The WHO launched the Stop TB strategy in 2006 (modelled after the DOT strategy) and the core components include pursuing high-quality DOT expansion and enhancement; addressing tuberculosis and HIV, MDR tuberculosis, and other challenges; contributing to health system strengthening; engaging all care providers; empowering people with tuberculosis; and enabling and promoting research.³
• A regular follow-up appointment every 4-8 weeks should be scheduled to ensure compliance and to monitor the adverse effects of and response to the medications administered. Adherence to the regimen is of vital importance to its success. Therefore, every measure should be taken to provide language-specific and culturally appropriate material to ensure compliance. Clear and written instructions regarding the timing of medication and the quantity to be administered should be provided.
• Monitoring of liver function test results is not indicated routinely. However, it may be required in the treatment of patients with miliary tuberculosis, tubercular meningitis, and coexistence of other hepatic disorders or with concomitant hepatotoxic drug therapy. In the rare event the patient has symptoms of hepatitis, discontinue the regimen and evaluate liver function. If the tests are normal or return to normal, then a decision to restart the medications may be made. Re-introduce the drugs one by one.
• Follow-up chest radiography may be performed after 2-3 months of therapy to observe the response to treatment in patients with pulmonary tuberculosis. However, hilar lymphadenopathy may take several years to resolve. Thus, a normal chest radiography finding is not required for termination of therapy.

Transfer

• Patients with miliary tuberculosis, tubercular meningitis, or disseminated tuberculosis may need transfer to the ICU until their condition is stabilized.

Deterrence/Prevention

• Treatment of latent tuberculosis infection
  • Current recommendations for preventive therapy are based on a comparative analysis of the risk of administration of isoniazid (INH) versus the risk of acquiring the disease. Adults with a positive tuberculin skin test (TST) result and no clinical or radiographic manifestations who are receiving INH therapy have been demonstrated to have 54-88% protection against the development of the disease, whereas children have been shown to have 100% protection.
  • The risk of acquisition of tuberculosis is particularly high in very young children (<5 y) and in the adolescent population. Thus, patients in these age groups with a positive TST result and no other manifestations should receive INH therapy. Active tuberculosis should be carefully excluded prior to the initiation of preventive therapy.
  • For recent contacts of patients with contagious tuberculosis (ie, in the past 3 mo), INH therapy is indicated even if the TST result is negative. This is especially true for contacts who are infected with HIV or for household contacts younger than 5 years. Household contacts of any age should be considered for INH therapy if they are from a high-prevalence area, even if the TST result is negative.
  • The recommendations from the AAP are to administer 9 months of therapy. The drug of choice is INH. A period of treatment of 12 months is recommended for patients with HIV infection. For the management of contacts of INH-resistant cases, rifampin is recommended for 6 months in children.
  • In case of a high probability of infection with MDR-TB, observation is recommended since none of the other drugs have been evaluated for preventive therapy. Several drugs have been used in these circumstances, including pyrazinamide, fluoroquinolones, and ethambutol, depending on the susceptibility patterns.
• Vaccination
  • The bacille Calmette-Guérin (BCG) vaccine is available for the prevention of disseminated tuberculosis. BCG is a live vaccine prepared from attenuated strains of M bovis.
  • Although BCG vaccine has been in use since 1921 and approximately 3 billion doses have been administered, its efficacy continues to be debated. Several trials have been performed to assess the efficacy of the vaccine, and results vary. However, 2 meta-analyses of the various trials concluded that the vaccine is efficacious against miliary and meningeal tuberculosis.¹⁴ Controversy surrounds the efficacy of BCG vaccination against pulmonary tuberculosis.
  • The major role of BCG vaccination is the prevention of serious and life-threatening disease such as disseminated tuberculosis and tubercular meningitis in children. The BCG vaccine does not prevent infection with M tuberculosis.
  • The Expanded Program on Immunization of the WHO recommends the administration of BCG at birth. The vaccine is being used in more than 100 countries. In the United States, BCG vaccination is currently recommended only in certain situations, including the following:
    • Child has negative HIV and TST results, is exposed to persons with contagious MDR (resistant to INH and rifampin) pulmonary tuberculosis, and cannot be removed from the exposure
    • Child has negative HIV and TST results, is exposed to persons with untreated or ineffectively treated contagious pulmonary tuberculosis, and cannot be removed from the exposure or treated with antitubercular medication
  • From birth to age 2 months, administration of BCG does not require a prior TST. Thereafter, a TST is mandatory prior to vaccination.
  • Adverse reactions due to the vaccine include subcutaneous abscess formation and the development of lymphadenopathy. Rare complications, such as osteitis of the epiphyses of the long bones and disseminated tuberculosis, may necessitate administration of antitubercular therapy, except for pyrazinamide.
  • Contraindications to the administration of the vaccine include immunosuppressed conditions such as primary or secondary immunodeficiency, including steroid use and HIV infection. However, in areas of the world where the risk of tuberculosis is high, the WHO recommends using the BCG vaccine in children who have asymptomatic HIV infection.

Complications

• Miliary disease and tubercular meningitis are the earliest and most deadly complications of primary tuberculosis. A high index of suspicion is required for prompt diagnosis and management of these conditions. Pulmonary complications of tuberculosis include the development of pleural effusions and pneumothorax. Complete obstruction of a bronchus can result if caseous material extrudes into the lumen. This can lead to atelectasis of the involved lung. Bronchiectasis, stenosis of the airways, bronchoesophageal fistula, and endobronchial disease caused by penetration through an airway wall are other catastrophes that may occur with primary tuberculosis.
• Perforation of the small bowel, obstruction, enterocutaneous fistula, and the development of severe malabsorption may complicate tuberculosis of the small intestine.
• Pericardial effusion can be an acute complication or can resemble chronic constrictive pericarditis.
• Renal complications including hydronephrosis and autonephrectomy usually do not occur in children. Paraplegia may complicate Pott disease of the spine (ie, tubercular spondylitis).

Prognosis

• Prognosis of tuberculosis varies according to the clinical manifestation. Poor prognosis is associated with disseminated tuberculosis, miliary disease, and tubercular meningitis.
• The prognosis of tubercular meningitis varies according to the stage of the disease at the time treatment is started. Stage 1 has a good prognosis, whereas patients with stage 3 usually have sequelae such as deafness, blindness, paraplegia, mental retardation, movement disorders, and diabetes insipidus.
• Higher mortality rates occur in children younger than 5 years (20%) and in those with a illness lasting longer than 2 months (80%).

Patient Education

• Educate patients regarding compliance to therapy, adverse effects of medications, and follow-up care.
• For excellent patient education resources, visit eMedicine's Bacterial and Viral Infections Center. Also, see eMedicine's patient education article Tuberculosis.

Miscellaneous

Medicolegal Pitfalls

• Tuberculosis (TB) presents a potential health hazard to the public.
• Legal measures have been initiated in several states in the United States allowing for civil or criminal detention of patients with active tuberculosis with persistent noncompliance with directly observed therapy (DOT).

Special Concerns

• Tuberculosis can cause significant morbidity in the pregnant woman and the fetus; hence, pregnant women must be carefully evaluated and be placed on prophylaxis or treatment as indicated. Hematogenous spread of the bacilli through the umbilical vein and the placenta to the fetal liver or aspiration of tubercle bacilli from infected amniotic fluid may lead to the development of congenital tuberculosis.
• First-line agents recommended by the AAP include isoniazid (INH), rifampin, and ethambutol. No significant teratogenicity on the fetus has been observed. Streptomycin is contraindicated because it may lead to the development of deafness in the fetus. Data regarding the use of pyrazinamide, cycloserine, and ethionamide are not available; avoid these drugs if possible. Treatment should be started as soon as the diagnosis of tuberculosis is confirmed or after the first trimester in women younger than 35 years with recent tuberculin skin test (TST) conversion. Strict adherence to the treatment protocol is essential to prevent the development of congenital tuberculosis and maternal morbidity.
• Breastfeeding should not be discouraged because the amount of drug in breast milk is very small, and no adverse effects have been documented. All pregnant women on INH therapy should receive pyridoxine.

References

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Keywords

tuberculosis, TB, consumption, mycobacterial infection, Mycobacterium tuberculosis, M tuberculosis, primary tuberculosis, primary TB, miliary tuberculosis, miliary TB, tubercular meningitis, multidrug-resistant tuberculosis, MDR-TB, multidrug-resistant TB, pulmonary tuberculosis, pulmonary TB, endobronchial tuberculosis, endobronchial TB, reactivation tuberculosis, reactivation TB, extrapulmonary tuberculosis, extrapulmonary TB, lymphadenopathy, scrofula, vertebral tuberculosis, vertebral TB, bone tuberculosis, bone TB, joint tuberculosis, joint TB, congenital tuberculosis, congenital TB, skeletal tuberculosis, skeletal TB, Pott disease, tuberculous spondylitis, human immunodeficiency virus, HIV, pneumonia, pleural effusion, fever of unknown origin, failure to thrive, atelectasis, respiratory distress, measles, varicella, pertussis

Contributor Information and Disclosures

Author

Vandana Batra, MD, Pediatrician, Department of Pediatrics, Division of General Pediatrics/Primary Care, Nemours Pediatrics
Vandana Batra, MD is a member of the following medical societies: American Academy of Pediatrics
Disclosure: Nothing to disclose.

Coauthor(s)

Jocelyn Y Ang, MD, Assistant Professor, Department of Pediatrics, Division of Infectious Diseases, Children's Hospital of Michigan and Wayne State University
Jocelyn Y Ang, MD is a member of the following medical societies: American Academy of Pediatrics, Infectious Diseases Society of America, and Pediatric Infectious Diseases Society
Disclosure: Nothing to disclose.

Medical Editor

Robert W Tolan Jr, MD, Chief, Division of Allergy, Immunology and Infectious Diseases, The Children's Hospital at Saint Peter's University Hospital; Clinical Associate Professor of Pediatrics, Drexel University College of Medicine
Robert W Tolan Jr, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Society for Microbiology, American Society of Tropical Medicine and Hygiene, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, Phi Beta Kappa, and Physicians for Social Responsibility
Disclosure: GlaxoSmithKline Honoraria Speaking and teaching; MedImmune Honoraria Consulting; MedImmune Honoraria Speaking and teaching; Merck Honoraria Speaking and teaching; Novartis Honoraria Speaking and teaching; sanofi pasteur Grant/research funds Unrestricted research grant; sanofi pasteur  Consulting; sanofi pasteur Honoraria Speaking and teaching; Tap Honoraria Speaking and teaching

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

Managing Editor

Leslie L Barton, MD, Professor, Program Director, Department of Pediatrics, University of Arizona School of Medicine
Leslie L Barton, MD is a member of the following medical societies: American Academy of Pediatrics, Association of Pediatric Program Directors, Infectious Diseases Society of America, and Pediatric Infectious Diseases Society
Disclosure: Nothing to disclose.

CME Editor

Daniel Rauch, MD, FAAP, Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine
Daniel Rauch, MD, FAAP is a member of the following medical societies: Ambulatory Pediatric Association, American Academy of Pediatrics, and Society of Hospital Medicine
Disclosure: Baxter Honoraria Consulting; Pfizer Honoraria Consulting

Chief Editor

Russell W Steele, MD, Head, Division of Pediatric Infectious Diseases, Ochsner Children's Health Center; Clinical Professor, Department of Pediatrics, Tulane University School of Medicine
Russell W Steele, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Immunologists, American Pediatric Society, American Society for Microbiology, Infectious Diseases Society of America, Louisiana State Medical Society, Pediatric Infectious Diseases Society, Society for Pediatric Research, and Southern Medical Association
Disclosure: None None None

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