TUBERCULOSIS

Introduction
Background

Tuberculosis (TB) is the most common cause of infectious disease–related mortality worldwide. The World Health Organization estimates that 2 billion people have latent TB, while another 3 million people worldwide die of TB each year.1

Although TB rates are decreasing in the United States, the disease is becoming more common in many parts of the world. In addition, the prevalence of drug-resistant TB is also increasing worldwide. Co-infection with HIV has been an important factor in the emergence and spread of resistance.2 New TB treatments are being developed,3 and new TB vaccines are currently under investigation.4
Pathophysiology

Humans are the only known reservoir for Mycobacterium tuberculosis. TB is transmitted by airborne droplet nuclei, which may contain fewer than 10 bacilli. TB exposure occurs by sharing common airspace with an individual who is in the infectious stage of TB. When inhaled, droplet nuclei are deposited within the terminal airspaces of the lung. Upon encountering the bacilli, macrophages ingest and transport the bacteria to regional lymph nodes.

The bacilli have 4 potential fates: (1) They may be killed by the immune system, (2) they may multiply and cause primary TB, (3) they may become dormant and remain asymptomatic, or (4) they may proliferate after a latency period (reactivation disease). Reactivation TB may occur following either (2) or (3) above.
Frequency
United States

The US Centers for Disease Control and Prevention (CDC) has been recording detailed epidemiologic information on TB since 1953. The incidence of TB has been declining since the early 20th century because various factors, including basic infection-control practices (isolation). Beginning in 1985, a resurgence of TB was noted. The increase was observed primarily in ethnic minorities and especially in persons infected with HIV. TB control programs were revamped and strengthened across the United States.

After peaking at 25,287 cases in 1993, the number of reported cases began to fall again. In 2007, 13,293 cases of TB were reported.5 This corresponds to a rate of 4.4 cases per 100,000 population. The overall frequency of TB is 9.7 times higher in foreign-born persons than in native-born persons, accounting for a steadily increasing proportion of all reported TB cases. In 2007, 7,690 cases of TB (58.5% of all US cases) were reported among foreign-born persons. More than half (52%) of TB cases involving foreign-born individuals in 2007 were reported in persons from 4 countries: Mexico (24%), the Philippines (12.4%), India (8%), and Vietnam (7.4%). An estimated 10-15 million people in the United States have latent TB infection.
International

An estimated 20-33% of the world's population is infected with M tuberculosis. Countries with the highest prevalence include Russia, India, Bangladesh, Pakistan, Indonesia, Philippines, Vietnam, Korea, China, Tibet, Hong Kong, Egypt, most sub-Saharan African countries, Brazil, Mexico, Bolivia, Peru, Colombia, Dominican Republic, Ecuador, Puerto Rico, El Salvador, Nicaragua, Haiti, Honduras, and areas undergoing civil war (eg, Balkan countries). The prevalence of TB in countries in Eastern Europe is intermediate. The prevalence of TB is lowest in Costa Rica, western and northern Europe, the United States, Canada, Israel, and most countries in the Caribbean. Multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) are becoming increasingly significant.6 Genotyping studies have shown that between 63% and 75% of TB cases progress to XDR-TB through acquisition of resistance.7
Mortality/Morbidity

The case-fatality rate for TB was 50% for untreated patients before the advent of antibiotic therapy. TB-related deaths worldwide are estimated at 3 million per year. In the United States, the mortality rate of TB dropped from 12.4 deaths per 100,000 population in 1953 to 0.2 deaths per 100,000 population in 2004; this is approximately 4% per newly identified case.

MDR-TB cases are associated with a higher mortality rate. The mortality rate is also higher in patients with underlying diseases that predispose to active TB.

The mortality rate associated with untreated congenital TB is 50%. Congenital TB can mimic congenital syphilis or cytomegalovirus (CMV) infection.
Race

Based on 2007 CDC data, the frequency of TB in Hispanics, blacks, and Asians were 7.6, 8.5, and 23.5 times higher than in whites, respectively.1 However, race is not clearly an independent risk factor, as foreign-born persons account for 77% of TB cases among Hispanics and 96% of TB cases among Asians, but only 29% of TB cases among blacks. Risk is best defined based on social, economic, and medical factors.
Sex

Despite the fact that TB rates have declined in both sexes in the United States, certain differences exist. TB rates in women decline with age, but, in men, rates increase with age. Men are more likely to have a positive tuberculin skin test result. The reason for these differences may be social rather than biological in nature.
Age

In the United States, more than 60% of TB cases occur in persons aged 25-64 years; however, the age-specific risk is highest in persons older than 65 years.1

TB infection in infants and young children (≤5 y) always indicates recent transmission. Untreated TB in this age group may result in life-threatening meningitis or disseminated disease.

Elderly individuals with TB may not display typical signs and symptoms of TB infection because they may not mount a good immune response. Active TB infection in this age group may manifest as nonresolving pneumonitis. Obesity in elderly patients has been associated with a lower risk for pulmonary TB.8
Clinical
History

Pulmonary tuberculosis (TB)

Typical symptoms of pulmonary TB include a productive cough, fever, and weight loss. Patients with pulmonary TB occasionally present with hemoptysis or chest pain. Other systemic symptoms include anorexia, fatigue, and night sweats.

Tuberculous meningitis

Patients with tuberculous meningitis may present with a headache that is either intermittent or persistent for 2-3 weeks. Subtle mental status changes may progress to coma over a period of days to weeks. Fever may be low-grade or absent.

Skeletal TB

The most common site of skeletal TB involvement is the spine (Pott disease). Symptoms include back pain or stiffness. Lower-extremity paralysis occurs in up to half of patients with undiagnosed Pott disease. Tuberculous arthritis usually involves only one joint. Although any joint may be involved, the hips and knees are affected most commonly, followed by the ankle, elbow, wrist, and shoulder. Pain may precede radiographic changes by weeks to months.

Genitourinary TB

Reported symptoms of genitourinary TB include flank pain, dysuria, and frequency. In men, genital TB may manifest as epididymitis or a scrotal mass. In women, genital TB may mimic pelvic inflammatory disease. TB is the cause of approximately 10% of sterility cases in women worldwide and approximately 1% in industrialized countries.

Gastrointestinal TB

Any site along the gastrointestinal tract may become infected. Symptoms of gastrointestinal TB are referable to the site infected, including the following: nonhealing ulcers of the mouth or anus; difficulty swallowing with esophageal disease; abdominal pain mimicking peptic ulcer disease with stomach or duodenal infection; malabsorption with infection of the small intestine; and pain, diarrhea, or hematochezia with infection of the colon.

Tuberculous lymphadenitis ( scrofula)

The most common site of tuberculous lymphadenitis is in the neck along the sternocleidomastoid muscle. It is usually unilateral and causes little or no pain. Advanced cases of tuberculous lymphadenitis may suppurate and form a draining sinus.

Cutaneous TB

Direct inoculation may result in an ulcer or wartlike lesion. Contiguous spread from an infected lymph node typically results in a draining sinus. Hematogenous spread may result in a reddish brown plaque on the face or extremities (lupus vulgaris) or tender nodules or abscesses.
Physical

Physical examination findings associated with TB depend on the organs involved.

Patients with pulmonary TB have abnormal breath sounds, especially over the upper lobes or areas involved.

Signs of extrapulmonary TB differ depending on the tissues involved. Signs may include confusion, coma, neurologic deficit, chorioretinitis, lymphadenopathy, and cutaneous lesions (see History).

Postnatal TB is contracted via the airborne route. The most common findings of postnatal TB include adenopathy and a lung infiltrate. However, the chest radiographic findings may be normal in infants with disseminated disease. Many experts increase the treatment duration to 9 or 12 months because of the possible impaired immune system in children younger than 12 months. Bacille Calmette-Guérin (BCG) vaccine is not recommended in infants in the United States but is commonly used around the world.
Causes

M tuberculosis is a slow-growing organism, requiring 4-8 weeks for visible growth on solid medium. The organism grows in parallel groups called cords (as seen in the image below). It retains many stains after decoloration with acid-alcohol, which is the basis of acid-fast stains.

Tuberculosis. Acid-fast bacillus smear showing ch...
Tuberculosis. Acid-fast bacillus smear showing characteristic cording in Mycobacterium tuberculosis.Differential Diagnoses
Actinomycosis
Mycobacterium Gordonae
Aspergillosis
Mycobacterium Kansasii
Bronchiectasis
Mycobacterium Marinum
Crohn Disease
Mycobacterium Xenopi
Epididymal Tuberculosis
Nocardiosis
Fever of Unknown Origin
Paracoccidioidomycosis
Histoplasmosis
Pericarditis, Constrictive
Lung Abscess
Pneumonia, Fungal
Lung Cancer, Non-Small Cell
Pott Disease (Tuberculous Spondylitis)
Miliary Tuberculosis
Prostatitis, Tuberculous
Mycobacterium Avium-Intracellulare
Sarcoidosis
Mycobacterium Chelonae
Tuberculosis of the Genitourinary System
Mycobacterium Fortuitum

Other Problems to Be Considered

Blastomycosis
Catscratch disease

Workup
Laboratory Studies

Patients suspected of having tuberculosis (TB) should submit sputum for smear and culture. Sputum should be collected in the early morning on 3 consecutive days. In hospitalized patients, sputum may be collected every 8 hours. In patients without spontaneous sputum production, sputum induction with hypertonic saline should be attempted.9 Early-morning gastric aspirate may also produce a good specimen, especially in children. Another option is fiberoptic bronchoscopy with transbronchial biopsy and bronchial washings. Biopsy of bone marrow, liver, or blood cultures is occasionally necessary and may be helpful.

Traditional mycobacterial cultures require weeks for growth and identification. Newer technologies, including ribosomal RNA probes or DNA polymerase chain reaction, allow identification within 24 hours. The DNA probes are approved for direct testing on smear-positive or smear-negative sputa. However, smear-positive specimens yielded higher sensitivity.

Because conventional drug susceptibility tests for drug-resistant M tuberculosis take at least 3-8 weeks, Choi et al (2010) recommend direct DNA sequencing analysis as a rapid and useful method for detecting drug-resistant TB. In their clinical study of the use of direct DNA sequencing analysis for detecting drug-resistant TB, turnaround time of the direct DNA sequencing analysis was 3.8 +/- 1.8 days. A total of 113 sputum specimens from 111 patients were tested for genes conferring resistance to isoniazid, rifampin, ethambutol, and pyrazinamide and the results compared with drug susceptibility tests. The sensitivity and specificity of the assay were 63.6% and 94.6% for isoniazid, 96.2 and 93.9% for rifampin, 69.2% and 97.5% for ethambutol, and 100% and 92.6% for pyrazinamide, respectively.10

Obtain the following laboratory tests:

* CBC count
* Chemistries, including alanine aminotransferase (ALT) or aspartate aminotransferase (AST)
* Alkaline phosphatase
* Total bilirubin
* Uric acid
* Creatinine

Obtain HIV serology in all patients with TB.

For congenital TB, the best diagnostic test is the examination of the placenta for pathology, histology, and culture. Mycobacterial blood cultures of the newborn may also be helpful. Treatment may be necessary until placental culture results are negative.
Imaging Studies

Chest radiographs may show a patchy or nodular infiltrate (as seen in the image below). TB may be found in any part of the lung, but upper-lobe involvement is most common. The lordotic view may better demonstrate apical abnormalities.

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

[ CLOSE WINDOW ]

Tuberculosis. This radiograph shows a patient wit...

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

Primary TB is more likely to mimic the appearance of routine community-acquired pneumonia on chest radiography, in contrast to reactivation TB. Studies have shown that either may be associated with pleural effusion or cavitation.

Various patterns may be seen, as follows:

* Cavity formation indicates advanced infection and is associated with a high bacterial load.
* Noncalcified round infiltrates may be confused with lung carcinoma.
* Homogeneously calcified nodules (usually 5-20 mm) are tuberculomas and represent old infection rather than active disease.
* Miliary TB is characterized by the appearance of numerous small nodular lesions that resemble millet seeds on chest radiography.

CT scanning of the chest may help to better define abnormalities in patients with vague findings on chest radiography.

Technetium-99m methoxy isobutyl isonitrile single-photon emission CT scanning for solitary pulmonary nodules yields a high predictive value for distinguishing TB from malignancy. Therefore, it has the potential to serve as a low-cost alternative when positron emission tomography is not available, especially in endemic areas.11
Other Tests

Tuberculin skin testing (Mantoux test) is the most widely available test for diagnosing tuberculous infection in the absence of active disease (latent infection). The tuberculin skin test involves an intradermal injection of 5 tuberculin units of purified protein derivative. The response is measured as the amount of induration at 48-72 hours. The size of induration, rather than erythema, is diagnostic. Interpretation of skin testing depends on the size of induration, age, and patient risk factors. The tuberculin skin test is not a sensitive test for active TB. Three cutoff points of clinical significance exist; the criteria for each cutoff point are listed below.

* Larger than or equal to 5 mm
o Close contacts to persons with newly diagnosed TB
o Persons with HIV infection
o Patients with organ transplant or patients who are taking the equivalent of more than 15 mg/d of prednisone for one month or more
o Patients with fibrotic lesions on chest radiography (not granulomas)
* Larger than or equal to 10 mm
o Patients with medical conditions that increase the risk of TB (eg, diabetes mellitus, hematologic malignancies, carcinoma of the head and neck, intravenous drug use [known to be HIV-negative], end-stage renal disease, silicosis, malnutrition, jejunoileal bypass, gastrectomy)
o Recent converter - At least 10-mm increase in skin test in past 2 years (regardless of age)
o Recent immigrants (within 5 y) from a high-prevalence country
o Children younger than 4 years exposed to adults at high risk for TB
o Residents and employees of facilities for long-term care, including correctional institutions, nursing homes, homeless shelters, and mental institutions
* Larger than or equal to 15 mm - Persons with none of the above

Whole-blood assay based on interferon-gamma release (IGRA) with early secretory antigenic target 6 (ESAT-6) and culture filtrate protein (CFP-10) antigens (QuantiFERON-TB Gold, T-SPOT.TB) can also be used to screen for latent TB infection and offers certain advantages over tuberculin skin testing.12 Overall, sensitivity and specificity are comparable to those of tuberculin skin testing; however, unlike tuberculin skin testing, a second encounter for reading is unnecessary. Results are reported as positive, negative, or indeterminate. Patients with an indeterminate result may have evidence of immunosuppression and may be nonreactive on skin testing.13

Neither tuberculin skin testing nor IGRA testing is sufficiently sensitive to rule out TB infection.14

A systematic review of QuantiFERON-TB Gold (QFT-G)/Gold in-Tube (QFT-G-IT) and T-SPOT.TB by Chang and Leung concluded that QFT-G had the highest positive likelihood ratio (48.1) for latent TB infection and T-SPOT.TB had the best negative likelihood ratio (0.10). A negative T-SPOT.TB result in middle-aged and older patients makes active TB very unlikely.15

Leung et al followed 308 males with increased risk of TB due to a diagnosis of silicosis.16 Tuberculin skin testing was not predictive of the subsequent development of active TB. A positive T-SPOT.TB finding was associated with a relative risk of 4.5 for subsequent TB in the group overall and a relative risk of 8.5 among the men who did not receive preventive treatment for latent TB. CFP-10 spot count was more predictive than the ESAT-6 spot count.

A systematic review of QuantiFERON-TB Gold (QFT-G)/Gold in-Tube (QFT-G-IT) and T-SPOT.TB by Chang and Leung (2010) concluded that, at a 90% certainty threshold, latent TB infection is best diagnosed with QFT-G/QFT-G-IT and best excluded with T-SPOT.TB. Neither test can diagnose TB disease, but T-SPOT.TB can exclude it in middle-aged and older patients.15

Jafari et al found that an M tuberculosis –specific enzyme-linked immunospot (ELISpot) assay can be used to differentiate TB cases with sputum smear negative for acid-fast bacteria (AFB) from latent TB infection. In a prospective study of 347 patients suspected of having active TB who were unable to produce sputum or who had AFB-negative sputum smears, ELISpot testing of bronchoalveolar lavage fluid displayed a sensitivity and specificity of 91% and 80%, respectively, for the diagnosis of active pulmonary TB. ELISpot of bronchoalveolar lavage fluid (diagnostic odds ratio [OR], 40.4) was superior to ELISpot of peripheral blood mononuclear cells (OR, 10.0), tuberculin skin testing (OR, 7.8), and M tuberculosis –specific nucleic acid amplification testing (OR, 12.4) for diagnosing sputum AFB smear–negative TB.Treatment
Medical Care

For initial empiric treatment of tuberculosis (TB), start patients on a 4-drug regimen: isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin. Once the TB isolate is known to be fully susceptible, ethambutol (or streptomycin if used as a fourth drug) can be discontinued.

After 2 months of therapy (for a fully susceptible isolate), pyrazinamide can be stopped. Isoniazid plus rifampin are continued as daily or intermittent therapy for 4 more months. If isolated isoniazid resistance is documented, discontinue isoniazid and continue treatment with rifampin, pyrazinamide, and ethambutol for the entire 6 months. Therapy must be extended if the patient has cavitary disease or remains culture-positive after 2 months of treatment.

Directly observed therapy (DOT) is recommended for all patients. Patients on the above regimens as DOT can be switched to 2- to 3-times per week dosing after an initial 2 weeks of daily dosing. Patients on twice-weekly dosing must not miss any doses. Prescribe daily therapy for patients on self-administered medication.

The diagnosis of MDR-TB is established with an isolate that is resistant to both isoniazid and rifampin. Resistance may be initial (no known history of prior treatment) or secondary (acquired during therapy or because of previous inadequate therapy).

Risk factors for initial resistance include exposure to a patient who has MDR-TB or being from a country or region with a high prevalence of resistance. Symptoms and radiographic findings do not differentiate MDR-TB from fully susceptible TB. Suspect MDR-TB if the patient is on DOT with the 4 first-line drugs (no diarrhea) and symptoms do not improve within 1-2 weeks.

Continue treatment for MDR-TB for 18-24 months after sputum culture conversion. The drugs should be prescribed daily (no intermittent therapy), and the patient should always be on DOT. Weekend DOT may not be possible; therefore, giving self-administered oral drugs on Saturdays and Sundays may be reasonable. Consult an expert on MDR-TB. Costs are many times higher for treatment of MDR-TB. Treatment should include an injectable drug together with at least 3 more drugs to which the isolate is susceptible.

In a phase 2, randomized, controlled trial, Diacon et al studied patients with newly diagnosed multidrug-resistant pulmonary TB. Forty-seven patients were assigned either TMC207 (400 mg PO qd for 2 wk, then 200 mg tid for 6 wk) or placebo in combination with a standard 5-drug, second-line antituberculosis regimen. TMC207 added to standard therapy for MDR-TB reduced the time to conversion to a negative sputum culture compared with placebo (P = 0.003) and increased the proportion of patients with conversion of sputum culture (48% vs 9%). These data provide important results to continue investigation of TMC207 in a larger population for multidrug-resistant pulmonary TB.18

The diagnosis of extended drug-resistant TB (XDR-TB) is established with an isolate that is resistant to isoniazid, rifampin, at least one of the quinolones, and at least one injectable drug. Treatment options for XDR-TB are very limited, and XDR-TB carries a very high mortality rate.

Abdool Karim et al (2010) conducted an open-label, randomized trial in 642 patients coinfected with TB and HIV to determine the optimal initiation of antiretroviral agents. The simultaneous initiation of antiretroviral therapy with TB therapy (429 patients) decreased the death rate over a sequential approach (213 patients), with a mortality rate of 5.4 deaths per 100 person-years (25 deaths) compared with 12.1 deaths per 100 person-years (27 deaths), respectively. The relative reduction was 56% (P = 0.003). The authors concluded that the initiation of antiretroviral therapy during TB therapy significantly improved survival. These results provide further impetus for the integration of TB and HIV services.19

Swaminathan et al (2010) compared intermittent (3 times/wk) antitubular treatment regimens in patients with HIV infection and newly diagnosed TB. Patient received either a 6-month 4-drug regimen or a 9-month 4-drug regimen. Significantly lower bacteriological recurrence rate was observed in the 9-month group. Acquired rifampin resistance (ARR) was high, and neither mortality nor ARR was altered by lengthening TB treatment.20
Surgical Care

Surgical resection of an infected lung may be considered to reduce the bacillary burden in patients with MDR-TB. Procedures include segmentectomy (rarely used), lobectomy, and pneumonectomy. Pleurectomies for thick pleural peel are rarely indicated. However, intraoperative infection of uninvolved lung tissue has been observed.

Complications include the usual perioperative complications, recurrent disease, and bronchopleural fistulas.
Consultations

* Infectious disease specialist
* Pulmonologist
* General or thoracic surgeon

Activity

Smoking has been shown to be a risk factor for TB; smokers who develop TB should be encouraged to stop smoking to decrease the risk of relapse.21
Medication

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Antimycobacterials

The goals of tuberculosis (TB) treatment are to shorten the clinical course, to prevent complications, to prevent the development of latency and/or subsequent recurrences, and to decrease the likelihood of TB transmission. In patients with latent TB, the goal of therapy is to prevent progression of disease.

Isoniazid (Laniazid)

DOC for preventive therapy and primary drug in combination therapy for active TB. In patients receiving treatment for active TB, pyridoxine 25-50 mg PO qd should be coadministered to prevent peripheral neuropathy.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

300 mg PO qd
Pediatric

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

* Dosing
* Interactions
* Contraindications
* Precautions

Higher incidence of isoniazid-related hepatitis can occur with daily alcohol ingestion; aluminum salts may decrease isoniazid serum levels (administer 1-2 h before taking aluminum salts); may increase effects of anticoagulants with coadministration; may inhibit metabolic clearance of benzodiazepines
Carbamazepine toxicity or isoniazid hepatotoxicity may result from concurrent use (monitor carbamazepine concentrations and liver function); coadministration with cycloserine may increase adverse CNS effects (eg, dizziness); acute behavioral and coordination changes may occur with coadministration of disulfiram
Coadministration with rifampin after halothane anesthesia may result in hepatotoxicity and hepatic encephalopathy; may inhibit hepatic microsomal enzymes and increase toxicity of hydantoin

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; previous isoniazid-associated hepatic injury; other severe adverse reactions

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions

Monitor patients with active chronic liver disease or severe renal dysfunction; periodic ophthalmologic examinations during isoniazid therapy are recommended even when visual symptoms do not occur

Rifampin (Rifadin, Rimactane)

For use in combination with at least one other antituberculous drug. Inhibits DNA-dependent bacterial but not mammalian RNA polymerase. Cross-resistance may occur.
Treat for 6 mo for most susceptible cases; 9 mo if sputum culture result is still positive after 2 mo of treatment.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

600 mg PO qd
Pediatric

10-20 mg/kg/d PO qd; not to exceed 600 mg/d

* Dosing
* Interactions
* Contraindications
* Precautions

Induces microsomal enzymes, which may decrease effects of acetaminophen, PO anticoagulants, barbiturates, benzodiazepines, beta-blockers, chloramphenicol, PO contraceptives, corticosteroids, mexiletine, cyclosporine, digitoxin, disopyramide, estrogens, hydantoins, methadone, clofibrate, quinidine, dapsone, tazobactam, sulfonylureas, theophyllines, tocainide, and digoxin; blood pressure may increase with coadministration of enalapril; coadministration with isoniazid may result in higher rate of hepatotoxicity than with either agent alone (discontinue one or both agents if alterations in LFTs occur)

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions

Obtain CBCs and baseline clinical chemistries before and throughout therapy; in liver disease, weigh benefits against risk of further liver damage; interruption of therapy and high-dose intermittent therapy are associated with thrombocytopenia that is reversible if therapy is discontinued as soon as purpura occurs; if treatment is continued or resumed after appearance of purpura, cerebral hemorrhage or death may occur

Pyrazinamide (PZA)

Pyrazine analog of nicotinamide that may be bacteriostatic or bactericidal against M tuberculosis depending on concentration of drug attained at site of infection; mechanism of action is unknown.
Administer for initial 2 mo of a 6-mo or longer treatment regimen for drug-susceptible TB. Treat drug-resistant TB with individualized regimens.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

<50 kg: 1.5 g PO qd 50-75 kg: 2 g PO qd >75 kg: 2.5 g PO qd
Pediatric

15-30 mg/kg/d PO qd; not to exceed 2 g/d

* Dosing
* Interactions
* Contraindications
* Precautions

None reported

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; severe hepatic damage; acute gout

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions

Use only in combination with other effective antituberculous agents; inhibits renal excretion of urates; may result in hyperuricemia (usually asymptomatic); perform baseline serum uric acid determinations; discontinue drug if signs of hyperuricemia with acute gouty arthritis occur; perform baseline LFTs (closely monitor in liver disease); discontinue pyrazinamide if signs of hepatocellular damage appear; caution in history of diabetes mellitus

Ethambutol (Myambutol)

Diffuses into actively growing mycobacterial cells (eg, tubercle bacilli). Impairs cell metabolism by inhibiting synthesis of one or more metabolites, which in turn, causes cell death. No cross-resistance demonstrated.
Mycobacterial resistance is frequent with previous therapy. Use in these patients in combination with second-line drugs that have not been previously administered. Administer q24h until permanent bacteriological conversion and maximal clinical improvement are observed. Absorption is not significantly altered by food.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

15-25 mg/kg PO qd
Pediatric

Administer as in adults

* Dosing
* Interactions
* Contraindications
* Precautions

Aluminum salts may delay and reduce absorption (administered several hours before or after ethambutol dose)

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; optic neuritis (unless clinically indicated)

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions

Reduce dose in impaired renal function; may have reversible adverse visual effects if promptly discontinued

Streptomycin sulfate

For treatment of susceptible mycobacterial infections. Use in combination with other antituberculous drugs (eg, isoniazid, ethambutol, rifampin). Total period of treatment for TB is a minimum of 6 mo; however, streptomycin therapy is not commonly used for the duration of therapy. Recommended when less potentially hazardous therapeutic agents are ineffective or contraindicated.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

15 mg/kg IM qd; can be administered 3-5 d/wk
Pediatric

20-30 mg/kg IM qd

* Dosing
* Interactions
* Contraindications
* Precautions

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

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; non–dialysis-dependent renal insufficiency

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

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

Narrow therapeutic index; not intended for long-term therapy; caution in renal failure, patient not taking dialysis; caution with myasthenia gravis, hypocalcemia, and conditions that depress neuromuscular transmission

Levofloxacin (Levaquin)

Second-line drug. Useful in the treatment of TB in combination with rifampin and other antituberculous agents. Useful in treating most cases of MDR-TB.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

500-1000 mg PO qd
Pediatric

<18 years: Not recommended unless no alternates available * Dosing * Interactions * Contraindications * Precautions Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h before or after taking fluoroquinolones; cimetidine may interfere with metabolism of fluoroquinolones; reduces therapeutic effects of phenytoin; probenecid may increase serum concentrations; may increase toxicity of theophylline, caffeine, cyclosporine, and digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT) * Dosing * Interactions * Contraindications * Precautions Documented hypersensitivity * Dosing * Interactions * Contraindications * Precautions Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus Precautions In prolonged therapy, perform periodic evaluations of organ system functions (eg, renal, hepatic, hematopoietic); adjust dose in renal function impairment; superinfections may occur with prolonged or repeated antibiotic therapy Rifapentine (Priftin) Used in once-weekly regimens along with isoniazid. Should not be used in individuals with HIV or with positive cultures after 2 mo of treatment. * Dosing * Interactions * Contraindications * Precautions Adult 600 mg PO qwk during the continuation phase of treatment for TB; given in combination with isoniazid for susceptible organism Pediatric Not established * Dosing * Interactions * Contraindications * Precautions Induces cytochrome P 4503 A 4 and P 4502 C 8/9, thereby decreasing levels of other drugs that are metabolized by these enzymes; may decrease plasma concentration of calcium channel blockers (verapamil, nifedipine, diltiazem), methadone, oral anticoagulants, oral contraceptives, benzodiazepines, acetaminophen, dapsone, clofibrate, doxycycline, levothyroxine, nortriptyline, tacrolimus, zidovudine, protease inhibitors, hydantoins, sulfa drugs, or enalapril; toxicity may increase when taken concurrently with halothane or isoniazid * Dosing * Interactions * Contraindications * Precautions Documented hypersensitivity * Dosing * Interactions * Contraindications * Precautions Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus Precautions Adverse effects include serious hepatic events, including hepatitis and liver failure; Clostridium difficile -associated colitis; hyperbilirubinemia; urticaria; thrombocytopenia; hyperkalemia; fatigue; gout; may cause red-orange discoloration of body fluids (eg, tears, urine, sweat, CSF) Para-aminosalicylic acid (Sodium PAS) Second-line drug. Bacteriostatic agent useful against M tuberculosis. Inhibits the onset of bacterial resistance to streptomycin and isoniazid. Administer aminosalicylate sodium with other antituberculous drugs. * Dosing * Interactions * Contraindications * Precautions Adult 4-6 g PO bid Pediatric 75 mg/kg PO bid * Dosing * Interactions * Contraindications * Precautions PO absorption of digoxin may be reduced, causing a reduction in serum levels when administered concurrently with PAS; increase in digoxin dosing may be necessary; a deficiency in vitamin B-12 (PO) may be induced because of PAS interference of its GI absorption; parenteral vitamin B-12 supplementation may be required * Dosing * Interactions * Contraindications * Precautions Documented hypersensitivity * Dosing * Interactions * Contraindications * Precautions Pregnancy B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals Precautions Caution in gastric ulcer and history of congestive heart failure; avoid situations in which excess sodium is potentially harmful Ethionamide (Trecator-SC) Second-line drug. Bacteriostatic against M tuberculosis. Recommended if treatment with first-line drugs (isoniazid, rifampin) is unsuccessful. Treats any form of active TB. However, should only be used with other effective antituberculous agents. * Dosing * Interactions * Contraindications * Precautions Adult 250-500 mg PO bid Pediatric 15-20 mg/kg PO bid * Dosing * Interactions * Contraindications * Precautions Hepatotoxicity increases when used concurrently with rifampin * Dosing * Interactions * Contraindications * Precautions Documented hypersensitivity; severe hepatic damage * Dosing * Interactions * Contraindications * Precautions Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus Precautions Make determinations of serum transaminase (AST, ALT) prior to therapy and q2-4wk thereafter; perform in vitro susceptibility tests of recent cultures of M tuberculosis from patient, with ethionamide and usual first-line antituberculous drugs; management of diabetes mellitus may be more difficult, and hepatitis may occur more frequently Amikacin (Amikin) Second-line drug. Irreversibly binds to 30S subunit of bacterial ribosomes; blocks recognition step in protein synthesis; causes growth inhibition. Use patient's IBW for dosage calculation. * Dosing * Interactions * Contraindications * Precautions Adult 15 mg/kg IM qd; can administer 3-5 d/wk Pediatric 15-30 mg/kg IM qd * Dosing * Interactions * Contraindications * Precautions Coadministration with other aminoglycosides, penicillins, cephalosporins, and amphotericin B (increases nephrotoxicity); enhances effects of neuromuscular-blocking agents; causes respiratory depression; irreversible hearing loss may occur with coadministration of loop diuretics * Dosing * Interactions * Contraindications * Precautions Documented hypersensitivity * Dosing * Interactions * Contraindications * Precautions Pregnancy D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus Precautions Not intended for long-term therapy; caution in patients with renal failure (patient not taking dialysis), hypocalcemia, myasthenia gravis, and conditions that depress neuromuscular transmission Cycloserine (Seromycin) Second-line drug. Inhibits cell wall synthesis in susceptible strains of gram-positive and gram-negative bacteria and in M tuberculosis. Structural analogue of D -alanine, which antagonizes role of D -alanine in bacterial cell wall synthesis, inhibiting growth. * Dosing * Interactions * Contraindications * Precautions Adult 250-500 mg PO bid Pediatric 10-20 mg/kg PO bid * Dosing * Interactions * Contraindications * Precautions Incompatible with alcohol consumption because may increase possibility and risk of epileptic episodes; isoniazid in combination with cycloserine may result in increased adverse cycloserine CNS effects (eg, dizziness) * Dosing * Interactions * Contraindications * Precautions Documented hypersensitivity; severe anxiety or psychosis; epilepsy; depression; severe renal insufficiency; alcoholism; severe neurologic impairments * Dosing * Interactions * Contraindications * Precautions Pregnancy D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus Precautions Discontinue drug or reduce dosage if allergic dermatitis or symptoms of CNS toxicity (eg, convulsions, headache, tremor, depression, confusion, psychosis, somnolence, hyperreflexia, vertigo, paresis, or dysarthria) develop; risk of convulsions is increased in long-term alcoholism; administration has been associated with vitamin B-12 and folic acid deficiency, megaloblastic anemia, and sideroblastic anemia; monitor blood levels weekly in reduced renal function, patients receiving >500 mg/d, and patients with symptoms of toxicity

Capreomycin (Capastat)

A second-line drug. Obtained from Streptomyces capreolus for coadministration with other antituberculous agents in pulmonary infections caused by capreomycin-susceptible strains of M tuberculosis. For use only when first-line agents (eg, isoniazid, rifampin) have been ineffective or cannot be used because of toxicity or presence of resistant tubercle bacilli.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

15 mg/kg IM qd; also administered as IV infusion
Pediatric

15-30 mg/kg IM qd

* Dosing
* Interactions
* Contraindications
* Precautions

Coadministration with aminoglycosides may increase risk of respiratory paralysis and renal dysfunction; with nondepolarizing neuromuscular-blocking agents, has synergistic effects on myoneural function

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions

Assess vestibular auditory function prior to therapy and regularly while treating; monitor renal function throughout treatment (reduce dose in renal impairment); monitor serum potassium levels

Rifabutin (Mycobutin)

Ansamycin antibiotic derived from rifamycin S. Inhibits DNA-dependent RNA polymerase, preventing chain initiation. Used in treatment for TB in individuals on specific HIV medications, when rifampin is contraindicated (most protease inhibitors).

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

300 mg PO qd; as part of an intermittent regimen, 300 mg PO 3 times/wk
Pediatric

Not established; suggested dose is 5 mg/kg/d PO.Follow-up
Further Inpatient Care

Hospitalized patients with suspected or documented tuberculosis (TB) must be placed in appropriate isolation. This includes a private room with negative pressure and adequate air exchanges. Persons entering the room must wear masks or respirators capable of filtering droplet nuclei.

Worldwide, TB rates are consistently higher among health care workers than in the general population; infection-control measures yield a significant impact in high-income countries but less impact in low- and middle-income countries.22

Patients with TB should remain in isolation until sputum becomes smear-negative; however, patients should not ordinarily be kept in the hospital for the sole purpose of providing isolation. Special arrangements are necessary for patients with TB who live with children, individuals infected with HIV, or patients returning to a closed-group setting (eg, nursing home, correctional facilities, residential facility, homeless shelter).
Further Outpatient Care

Patients diagnosed with active TB should undergo sputum analysis for M tuberculosis weekly until sputum conversion is documented. Monitoring for toxicity includes baseline and periodic liver enzymes, CBC count, and serum creatinine.

In addition, patients with TB who are receiving pyrazinamide should undergo baseline or periodic serum uric acid assessments, and patients with TB who are receiving long-term ethambutol therapy should undergo baseline or periodic visual acuity and red-green color perception testing. The latter can be performed with a standard test such as the Ishihara test for color blindness.
Deterrence/Prevention

Patients with a clinically significant result on tuberculin skin testing or positive IGRA result (see Other Tests) should receive a course of therapy once active infection and disease is ruled out. Guidelines published by the CDC in 2000 now refer to this as treatment of latent TB. The recommended regimens are listed below:

* Isoniazid daily for 9 months
* Isoniazid twice weekly for 9 months (administered as DOT)
* Isoniazid daily for 6 months (should not be used in patients with fibrotic lesions on chest radiography, patients with HIV, or children)
* Isoniazid twice weekly for 6 months (administered as DOT; should not be used in patients with fibrotic lesions on chest radiography, patients with HIV, or children)
* Rifampin daily for 4 months
* Rifampin plus pyrazinamide daily for 2 months (This regimen is no longer recommended because of an increased risk for liver toxicity.)

Children should receive isoniazid for 9 months. In addition, children younger than 5 years who have close contact with a person who has active TB should be started on isoniazid, even if results on skin testing are negative; preventive therapy can be stopped if results on repeat skin testing are negative 2-3 months after last contact with a culture-positive source case.

Patients exposed to MDR-TB may be administered ethambutol plus pyrazinamide for 6-12 months or pyrazinamide plus levofloxacin for 6-12 months; the index isolate should be susceptible to all drugs used.

Recommended regimens in patients with HIV infection include rifampin alone daily for 4 months or isoniazid, daily or twice weekly, for 9 months. Patients on antiretroviral therapy may need rifabutin instead of rifampin because of potential drug interactions. The 2-month combination of pyrazinamide plus rifampin is no longer recommended.

The BCG vaccine continues to be used throughout much of the world and provides protection mostly until early childhood. Immunity begins to wane as early as 3 months after administration.23
Complications

Late complications of pulmonary TB include relapse, aspergilloma, bronchiectasis, broncholithiasis, fibrothorax, and possibly carcinoma. A copy of the chest radiograph at the time of completion of therapy should be provided to the patient to facilitate the diagnosis of late complications.

The relapse rate following appropriate completed therapy is only 0-4% and occurs within the first 2 years after completion. Therefore, re-treatment is usually unnecessary, especially after DOT.

Aspergilloma is a fungus ball that develops in a residual lung abnormality (eg, pneumatocele, bulla, bleb, cyst). It may appear as a crescent sign on chest radiographs. Other superinfections may manifest with an air-fluid level and often contain mixed bacteria, including anaerobes.

Hemoptysis is the most common late complication. Broncholithiasis is the result of spontaneous lymph node migration into the bronchial tree and may be associated with postobstructive pneumonia or esophageal perforation. Bronchiectasis may progress to chronic bronchitis; bleeding from submucosal bronchial veins is usually self-limited.

Fibrothorax is the development of trapped lung due to pleural fibrosis and scarring.

The risk of carcinoma is controversial but should be considered with newly developing clubbing.
Prognosis

Among published studies involving DOTS treatment, the rate of recurrence ranges from 0-14%.24 In countries with low TB rates, recurrences usually occur within 12 months of treatment completion and are due to relapse.25 In countries with higher TB rates, most recurrences after appropriate treatment are probably due to reinfection rather than relapse.26
Patient Education

For excellent patient education resources, visit eMedicine's Bacterial and Viral Infections Center. Also, see eMedicine's patient education article Tuberculosis.
Miscellaneous
Medicolegal Pitfalls

Laws vary from state to state, but communicable-disease laws typically empower public health officials to investigate suspected cases of tuberculosis (TB), including potential contacts. In addition, patients may be incarcerated for noncompliance with therapy. For example, in the Denver Metro Tuberculosis Clinic from 1984-1994, 5% of patients were incarcerated for noncompliance and an additional 5% who were lost to follow-up before completing therapy would have been candidates for incarceration.
Special Concerns

Pregnancy

Pregnancy provides an opportunity to screen for TB; all pregnant women can undergo tuberculin skin testing. If skin-testing results are positive, chest radiography can be performed with lead shielding (the amount of radiation exposure of a single chest radiograph has been compared to that incurred on a regular flight from New York to Los Angeles). Chest radiography should not be delayed during the first 3 months of pregnancy in patients with suggestive symptoms.

Active TB should be treated, even in women in the first stage of pregnancy. Isoniazid, rifampin, and ethambutol may be used. In the United States, pyrazinamide is reserved for women with suspected MDR-TB. Elsewhere in the world, pyrazinamide is commonly used in pregnant women with TB.

Preventive treatment is recommended during pregnancy, especially in the following situations:

* Pregnant women with a positive tuberculin skin test result who are HIV seropositive or who have behavioral risk factors for HIV infection but decline HIV testing
* Pregnant women with a positive tuberculin skin test result who have been in close contact with a patient who is smear-positive for pulmonary TB
* Pregnant women who have had a documented tuberculin skin test conversion in the past 2 years

Pregnant women are at an increased risk for isoniazid-induced hepatotoxicity and should undergo monthly ALT monitoring while on treatment. This risk continues 2-3 months into the postpartum period. Pyridoxine should also be administered to pregnant women receiving isoniazid. Breastfeeding can be continued during preventive therapy. Many experts recommend supplemental pyridoxine to the breastfed infant.

Lin et al (2010) have reported that women diagnosed with TB during pregnancy are at an increased risk of having babies who are of low birthweight and small for gestational age. However, preterm birth was not more common in women with TB.27

Tuberculosis in children

TB in a child is a sentinel event indicating recent transmission, and contacts should be evaluated to find the source case as soon as possible. Children do not commonly infect other children because they rarely develop cough and sputum production is scant. However, cases of child-child and child-adult TB transmission are well-documented.

Chest radiographs in children with TB may show only hilar lymphadenopathy or a patchy infiltrate. Most children with TB can be treated with isoniazid and rifampin for 6 months, along with pyrazinamide for the first 2 months if the culture from the source case is fully susceptible. Gastric aspirates or biopsies are not necessary if positive cultures have been obtained from the source case.

In children younger than 5 years, the potential for development of fatal miliary TB or meningeal TB is a significant concern. TB disease is uncommon in children aged 5-15 years (the golden age of childhood).

Isoniazid tablets may be crushed and added to food. Isoniazid liquid without sorbitol should be used to avoid osmotic diarrhea, causing decreased absorption. Rifampin capsules may be opened and the powder added to food. If rifampin is not tolerated, it may be taken in divided doses 20 minutes after light meals.

Ethambutol is often avoided in young children because of difficulties monitoring visual acuity and color perception. However, studies show that ethambutol (15 mg/kg) is well tolerated and can prevent further resistance if the child is infected with a resistant strain.

Human immunodeficiency virus

Individuals infected with HIV are at an increased risk for TB, beginning within the first year of HIV infection.28 Based on historical data, the initiation of antiretroviral therapy (ART) decreases the risk of developing TB in these patients.29

In a study from Durban, South Africa, nearly 20% of patients starting ART had undiagnosed, culture-positive pulmonary TB. Neither cough nor acid-fast bacillus smear were sufficiently sensitive for screening. TB sputum cultures should be attempted before ART initiation in areas with a high prevalence of TB.30

Patients with TB must be tested for HIV, and patients with HIV need periodic evaluation for TB with tuberculin skin testing and/or chest radiography. Patients with HIV and a positive tuberculin skin test result develop active TB at a rate of 3-16% per year.

Patients with TB and HIV are more likely to have disseminated disease and less likely to have upper-lobe infiltrates or classic cavitary pulmonary disease. Patients with a CD4 count of less than 200/μL may have mediastinal adenopathy with infiltrates.

Treatment regimens for active or latent TB in patients with HIV infection are similar to the treatment of individuals who are HIV negative, but dose adjustments may be necessary.31 The most significant differences involve the avoidance of rifampin in patients who are on protease inhibitors. Rifabutin may be used in place of rifampin in such patients.

Patients with HIV and TB may develop a paradoxical response when starting antiretroviral therapy. This response has been attributed to a stronger immune response to M tuberculosis. Clinical findings include fever, worsening pulmonary infiltrates, and lymphadenopathy.

Tumor necrosis factor-alpha (TNF-a) antagonists have been associated with a significantly increased risk for TB.32 Reports have included atypical presentations, extrapulmonary and disseminated disease, and deaths. Patients scheduled to begin therapy with a TNF-α antagonist should be screened for latent TB and counseled regarding the risk of TB.