Current Diagnosis & Treatment in Infectious Diseases

Section V - Bacterial Infections

61. Tuberculosis

Julie Brahmer MD

Merle A. Sande MD

Essentials of Diagnosis

  • The cardinal symptoms of tuberculosis (TB) are fatigue, weight loss, fever, and night sweats.
  • The most commonly infected populations include the homeless, institutionalized patients, and HIV-positive patients.
  • In most cases, a TB skin test (PPD) is positive.
  • To establish presence of infection, an acid-fast bacilli (AFB) smear demonstrates the acid-fast bacillus.
  • In primary pulmonary TB, an infiltrate in the lower lobes of the lung is usually seen on chest x-ray. In contrast, apical lung infiltrates are commonly seen in the reactivation of pulmonary TB.

General Considerations

Mycobacterium tuberculosis is still an important pathogen. Approximately one-third of the world's population is infected with M tuberculosis, according to World Health Organization estimates, resulting in 2.9 million annual deaths. In the United States, tuberculosis is on the rise, after several decades of steady decline.

The disease develops in a subset of those who are infected. In most patients, the reason disease develops is unclear unless they are immunosuppressed by either HIV infection or other immunocompromising diseases. HIV has played a major role in the resurgence of tuberculosis in the United States and in the emergence of multidrug-resistant disease. Prompt diagnosis and treatment of active disease is important in all patients to prevent severe disease and infection of the surrounding population. In those infected with the tuberculosis bacillus, the prevention of active tuberculosis disease is also important.

  1. Epidemiology.In the United States, tuberculosis had been on the decline until 1985, when the number of cases began to increase. This increase was undoubtedly a result of the HIV epidemic. Cases continued to increase until 1995, when the 22,813 new cases documented in the United States constituted a 6.4% drop from 1994. This drop resulted from a decreased incidence in the U.S.-born population. The overall incidence of tuberculosis in the United States is quite low, but case rates are high among specific groups such as HIV-infected patients, the homeless, recent immigrants from countries that have a high prevalence of tuberculosis, intravenous drug users, inner-city dwellers, and minorities.

In the late 1980s, tuberculosis caused by organisms resistant to antimicrobial agents increased sharply, especially in New York City, where, in 1991, one-third of all cases were resistant to at least one agent. The rates of resistance in the United States began to decrease in 1995. Of cases reported, the isoniazid (INH) resistance rate was 7.6%, and the INH-rifampin resistance rate was 1.4%. The decrease in resistance rates was most likely caused by the introduction of directly observed therapy and intensive case management.

One lesson learned from the resurgence of tuberculosis and multidrug-resistant tuberculosis is the importance of tuberculosis control strategies and the importance of making sure patients adhere to the medication regimens. The Centers for Disease Control recommends that all tuberculosis patients be observed taking their medications by health care providers (“directly observed therapy,” [DOT]). The decrease in U.S. case rates has been attributed to the institution of DOT. Other factors thought to have decreased the case and resistance rates are improved laboratory methods for identifying tuberculosis, broader use of drug-susceptibility testing, expanded use of preventive therapy in high-risk groups, decreased transmission of tuberculosis in congregative settings, improved follow-up of persons with TB, and increased federal resources for state and local TB control efforts.

M tuberculosis is transmitted in the air. The bacillus is packaged in a droplet nucleus and coughed out into the surrounding air by one person and inhaled by another. Patients with bronchopulmonary TB with a productive cough are particularly infectious. Other factors that increase the infectivity of a person are the extent of cavitary disease of the lung, presence of AFB on the sputum smear, unprotected coughing, and crowding in a household. Generally, patients with extrapulmonary TB are not infectious.

  1. Microbiology.M tuberculosisis an AFB that is curved or straight and nonmotile. It is slow growing, taking ≤ 18 h for one replication. Typically, it may take 2–6 weeks to grow a significant colony. The bacillus is non-pigment producing, which can be used to differentiate it from some other atypical mycobacteria.
  2. Pathogenesis.A person is infected with M tuberculosisby inhaling bacilli in droplet nuclei. The particles must be retained in the lung. Thus the inhaled particles, which are < 5 µm in size, travel to the alveolus during inspiration and are retained in the lung. Larger particles are filtered out before they reach the alveoli. In the alveolus, the bacillus activates the immune system. The first line of defense is the alveolar macrophage. These macrophages engulf the bacilli. Some macrophages are capable of killing the bacillus, whereas others cannot. The bacilli multiply within the cells. The factors controlling the macrophages' ability to kill M tuberculosis are not all known and may be genetic. At any rate, T cells are then attracted to these macrophages and recognize the M tuberculosis protein presented by the macrophage. The T cell lyses the infected macrophage. Memory T cells then develop which are thought to contribute to the delayed hypersensitivity reaction relied on by the purified protein derivative (PPD) skin test. These memory T cells also enable patients previously infected with TB to resist reinfection. Other factors that influence the progression of infection to disease include the intensity of exposure, interval since infection, age, and other coexisting or comorbid diseases. Extrapulmonary disease develops when the bacillus is not contained in the lungs and travels to other organs by way of the bloodstream.

Infection by M tuberculosis is reflected by a positive skin test reaction, although, in some immunocompromised patients, a PPD test result may be negative even though these patients are infected. Those who are immunosuppressed have an increased chance of developing illness, which may be caused by an ineffective cell-mediated response (Box 61-1). Cell-mediated immunity is thought to be the mechanism by which a contained TB infection is kept quiescent. Patients who are HIV positive (who have ineffective cell-mediated immunity) and are infected with TB have a 7% chance per year of developing active tuberculosis.

Active tuberculosis disease is defined as tissue involvement by the M tuberculosis bacillus that progresses to produce clinical symptoms and signs. On average, illness develops in 3–5% of infected patients. Of the other 95–97% of infected patients, 5% develop active tuberculosis in their lifetime. M tuberculosis infection can cause several clinical syndromes.

BOX 61-1 Mycobacterium tuberculosis

 

Children

Adults

More Common

· Lymphatic

· Other extrapulmonary sites

· Pulmonary

Less Common

· Pulmonary

· Extrapulmonary

CLINICAL SYNDROMES

PULMONARY TUBERCULOSIS

The most common syndrome in adults is pulmonary TB, which accounts for ~ 80% of cases of active disease.

Clinical Findings

  1. Signs and Symptoms.Symptoms of infection consist of fatigue, weight loss, fever, night sweats, and a productive cough. Most children who are infected with TB usually have no symptoms. Early symptoms can also include hemoptysis, which also occurs later in the disease when there is significant necrosis of lung parenchyma or if previous cavitations erode into arterioles. Patients with subpleural parenchymal inflammation with pleural membrane involvement or with TB pleuritis without parenchymal disease can experience pleuritic chest pain. Severe shortness of breath is not common. However, extensive pulmonary tuberculosis can cause respiratory failure.
  2. Laboratory Findings.Routine laboratory test abnormalities are not common. Hyponatremia due to the syndrome of inappropriate secretion of antidiuretic hormone can be seen in some patients with pulmonary TB. However, adrenal involvement with TB can cause adrenal insufficiency, which may also be present with hyponatremia. Anemia secondary to this chronic disease is common.
  3. Imaging.Pulmonary TB usually produces infiltrates observable on chest x-rays, but occasionally, chest x-rays are normal. Primary TB is the disease that develops before the development of an immune response to the bacillus. Primary TB has different characteristics than secondary reactivation of a pulmonary TB disease. Primary TB usually involves the lower lobes. Five percent of cases show a lobar or segmental infiltrate associated with ipsilateral hilar adenopathy. Fifteen percent of cases may have bilateral hilar adenopathy, but this is more commonly unilateral. A pleural effusion may also be present.

Children with primary pulmonary TB often have hilar adenopathy and occasionally a lower-lobe infiltrate that can be seen on chest x-ray. Secondary or reactivation TB, which is by far the most common presentation, characteristically involves the lung apices (posterior apical segments) or, rarely, the superior segments of the lower lobes. This is seen in 95% of patients with localized pulmonary TB. The typical parenchymal pattern is cavitary lesions with associated air space consolidation of a patchy or confluent nature.

Old, healed pulmonary TB lesions can produce fibrosis or calcific lesions on chest x-ray. These lesions can cause volume loss or contraction of the involved lobe. Cavities also may persist. New infiltrates or masses in areas of old tuberculosis infections may represent carcinoma, bacterial infection, hemorrhage, mycetoma, or recurrence of TB.

  1. Differential Diagnosis.Differential diagnosis of pulmonary TB includes other atypical mycobacterium infections (Mycobacterium aviumcomplex or M kansasii) and viral infections (see Chapter 62).
  2. Complications.Complications of pulmonary TB include lung bulla formation, poor lung function, overwhelming infection, and death.

EXTRAPULMONARY TUBERCULOSIS

Extrapulmonary TB accounts for ~ 20% of cases of active tuberculosis. Extrapulmonary TB is more common in immunocompromised patients and in infants and young children. Of these extrapulmonary sites, meningeal and lymphatic locations for disease are more common in infants and young children. In adolescents, the extrapulmonary sites tend to be the pleura, genitourinary tract, or peritoneum. Overall, the most common extrapulmonary site of TB in children is in the lymphatic system.

Other sites of infection in adults can include pleura, genitourinary tract, gastrointestinal tract, bone, meninges, peritoneum, and adrenals. When the M tuberculosis bacillus infects the lung, it often disseminates and involves multiple organs, including the bone marrow. This is called disseminated or miliary tuberculosis, but it may be asymptomatic. Extrapulmonary TB develops when the bacillus overwhelms the immune system and disseminates by way of the lymphatics, the bloodstream, or both. In these cases, disease is documented by biopsy, positive blood cultures, or both.

Signs and symptoms of extrapulmonary TB depend on the organ system involved. Weight loss, night sweats, and fever are the classic but nonspecific signs of tuberculosis. Clinicians should do blood cultures as well as biopsy and culture of the suspected tissue.

TUBERCULOSIS IN PATIENTS WITH HIV INFECTION

HIV patients can have a wide variety of organ system involvement. In early HIV infection, pulmonary TB can be a presenting infection and an AIDS-defining illness. In advanced HIV infection, dissemination is common. A variety of unusual sites of infection have been documented, including brain, pericardium, and other more common extrapulmonary sites such as those for peritoneal and gastric TB. Overall, the most common site of TB disease in an HIV-positive patient is pulmonary; however, these patients are at increased risk for developing disseminated disease (Box 61-2).

Diagnosis

Diagnoses of extrapulmonary and pulmonary TB are the same. A skin test (PPD) is used to prove infection: 0.1 mL of PPD is placed intradermally on the volar surface of the forearm by means of a 26-gauge needle. At 48–72 h after injection, the diameter of induration, not erythema, is measured. A positive skin test reaction is caused by a delayed-type hypersensitivity response, which is directed at the TB protein antigens. Other tests include demonstration of the bacillus by means of culture or AFB smear of affected organs or blood culture in disseminated disease.

  1. Interpreting Tuberculin Skin Tests.The criteria vary for interpreting a PPD test as positive. An induration ≥ 5 mm is considered positive in patients who are at high risk of infection and developing disease; these include patients with known or suspected HIV infection, which includes all injection drug users. This group also includes close contacts of patients with active disease and patients with a chest x-ray suggestive of previously inactive tuberculosis. An induration of ≥ 10 mm is considered positive in patients who are at intermediate risk of infection and developing TB. This group includes known HIV-negative injection drug users, immigrants from high-prevalence countries (such as Asia and Mexico), residents of long-term care or correctional facilities, locally identified high-prevalence groups (migrant workers, the homeless, and high-risk racial or ethnic groups), and children ≤ 4 years old. Patients also at intermediate risk of TB include those with an immunosuppressive illness other than HIV or those receiving immunosuppressive therapy. These include patients with diabetes, renal failure, or hematologic malignancies or those receiving steroids on a long-term basis (> 15 mg of prednisone/d). Finally, an induration of ≥ 15 mm is considered positive in patients with no known risk of developing TB or being infected with TB.
  1. False-positive PPDs.False-positive results can occur in two situations. Patients who are infected with atypical mycobacteria such as M aviumor M kansasii may have false-positive PPD results. Bacillus Calmette-Guérin (BCG) vaccination can also cause a positive result. However, a history of prior BCG vaccination should be ignored when one is interpreting skin test results in individuals with a high likelihood of being infected with M tuberculosis.
  2. False-negative PPDs.False-negative results are much more common. In patients with distant infection, reactivity to a PPD test can decrease over time. These patients may require a “boost” PPD given 2 weeks after the first injection. There are multiple other factors to consider that cause a false-negative reaction (Table 61-1). Patients with coexisting diseases can also have false-negative reactions. In these patients, administration of other antigens such as those for Candidainfection and mumps may be used to rule out anergy. However, some patients can have selective PPD nonreactivity.
  3. Bacteriologic Evaluation.Smears and cultures of sputum are the most reliable ways to diagnose active pulmonary tuberculosis. Three separate early-morning sputum samples should be collected for AFB staining. Cultures should be performed on all specimens of patients suspected of having tuberculosis. Because M tuberculosisgrows so slowly, it may take ≤ 6 weeks to identify the organism by culture. Drug susceptibility testing should be done on all positive cultures. In extrapulmonary TB, AFB stains and cultures are done on the infected tissue.

Table 61-1. Factors causing a false-negative PPD test.1

Technical errors

o   Improper administration

o   Inaccurate reading

o   Loss of potency of antigen

Patient-related factors

o   Age

o   Nutritional status

o   Medications—corticosteroids, immunosuppressives, anti-neoplastic agents

o   Severe tuberculosis

o   Coexisting diseases such as renal failure

o   HIV infection

o   Viral illness or vaccination

o   Lymphoreticular malignancies

o   Sarcoidosis

o   Solid tumors

o   Lepromatous leprosy

o   Sjögren's syndrome

o   Ataxia telangiectasia

o   Uremia

o   Primary biliary cirrhosis

o   Systemic lupus erythematosus

o   Severe systemic disease of any etiology

1Adapted from Brahmer, JR, Small PM: Tuberculosis and nontuberculous mycobacterial infections. In Stein JH (ed): Textbook of Internal Medicine, 5th ed. Mosby Yearbook, 1998.

  1. Polymerase Chain Reaction (PCR) Technique.Rapid diagnosis by the PCR technique is another option for the diagnosis of TB. It is commercially available and recently received approval by the U.S. Food and Drug Administration. PCR is approved only for testing AFB-positive sputum smears. In a research setting, PCR's specificity and sensitivity are > 95%. It does not take the place of acid-fast smears or mycobacterial cultures. Many more studies must be performed to better define the utility of PCR in the clinical setting.

BOX 61-2 Mycobacterium TB in AIDS Patients (CD4 <100)

 

Children

Adults

More Common

· Disseminated

· Pulmonary

· Pulmonary

· Disseminated

Less Common

· Other extrapulmonary sites

· Other extrapulmonary sites

Treatment

Treatments of active extrapulmonary and pulmonary TB are the same. Treatment should be started presumptively before diagnosis in patients with severe disease thought to be TB. Treatment usually does not reduce the isolation rate of AFB in the first several days. In patients with less severe disease or those who present diagnostic dilemmas, therapy can be withheld until a diagnosis is made or until several specimens have been collected.

Patients should be started initially on a four-drug regimen until drug susceptibility tests are finalized, unless the patient is from an area where drug resistance is very low. Most communities in the United States have a > 4% incidence of cases resistant to at least one drug. However, if a community has a < 4% resistance rate, an initial three-drug regimen is acceptable.

  1. Choice of Treatment Regimen.There are several available regimens for treatment (Box 61-3). Several considerations should be made when deciding on a particular regimen. These include the probability of primary resistance, previous treatment for tuberculosis, patient compliance, other coexisting illnesses, drug susceptibility of the organism, and history of hypersensitivity to or side effects of antituberculosis drugs. The risk factors for drug resistance include > 4% of INH resistance in the community, prior treatment with INH, exposure to a known drug-resistant case, immigration from countries with a high incidence of drug resistance (countries in Asia, Africa, or Central or South America), HIV coinfection, and intravenous drug use. These patients should be placed on an initial four-drug regimen (Table 61-2).

Tuberculosis treatment is based on three basic principles. Regimens for treatment of the disease must contain multiple drugs to which the organism is susceptible. The medications must be taken regularly. Finally, drug therapy must continue for an extended period because of the slow growing nature of the M tuberculosis bacillus.

If patients do not take their medications regularly, many adverse consequences can result. M tuberculosis can develop resistance. It can take a long time for the patient to become noninfective or for the disease to be contained. These factors are why DOT was introduced. Some experts advocate that DOT should be used in all patients. However, this would be an expensive burden on the public health system. Most physicians use DOT for patients who have a history of noncompliance, risk factors for noncompliance such as substance abuse, and multidrug-resistant TB.

Table 61-2. Treatment options per risk of antimicrobial resistance.12

Risk Group

First Option

Second Option

Third Option

U.S. born & not living in an area of increased resistance (<4%) & no risk factors for MDR TB

o   1st 2 mo, INH + RIF + PZA

o   Followed by 16 weeks of INH + RIF daily or 2×per week

o   INH + RIF + PZA + SM or ETB daily for 2 weeks

o   Then 2×/week for 6 weeks by DOT

o   Then INH + RIF 2×/week for 16 weeks by DOT

o   INH + RIF + PZA + ETB or SM for 6 mo 3×/week by DOT

Recent immigrant from Latin America or Asia or living in an area of increased resistance or previous treatment without RIF

o   INH + RIF + PZA + ETB or SM for 2 mo

o   If INH + RIF sensitive, then DC PZA + ETB or SM after 2 mo of four-drug treatment

o   Then INH + RIF daily or 2×/ week for 4 mo

o   DOT preferred unless compliance is quite certain

 

Proven, high-risk, or known exposure to MDR TB

Injectable drug (amikacin or capreomycin or kanamycin) + fluoroquinolone (cipro or oflox) + ETB + PZA + INH + RIF + cycloserine or ethionamide or aminosalicylic acid

Daily treatment recommended, not intermittent

HIV + or AIDS, pulmonary or extrapulmonary

Same as row 2 above: stop protease inhibitor

If INH or RIF can't be used, treatment should be for 18 and 12 mo after cultures are negative

Maintenance treatment is not required

1Adapted with permission from The Sanford Guide to Antimicrobial Therapy, Antimicrobial Therapy, Inc., 1997.

2Abbreviations: MDR, multidrug resistant; INH, isoniazid; RIF, rifampin; PZA, pyrazinamide; SM, streptomycin; ETB, ethambutol; DC, discontinue.

  1. Monitoring During Treatment.While treating patients for tuberculosis, clinicians should monitor for clearing of the organism and for side effects of the medication. Before treatment is begun, laboratory tests of liver and renal functions should be performed and a baseline blood count obtained. If a patient is starting on pyrazinamide, a baseline uric acid level should be established. If a patient is to be treated with ethambutol, visual acuity and red-green color perception should be checked because this drug is known to produce optic neuritis. Ethambutol should not be used in children who are too young to report vision changes (Table 61-3).
  2. Follow-up.Monthly follow-up should be done to check for symptoms of toxicity or disease progression. The patient with TB (pulmonary or extrapulmonary) should have a follow-up sputum monthly until the M tuberculosisculture is negative. Successful drug therapy using a combination regimen should eradicate the TB bacillus from the sputum of ~ 85% of patients in 2 months and ~ 100% of patients within 6 months. It is therefore important to obtain a sputum TB culture after the first 2–3 months of treatment and again after 6 months of treatment to document the negative cultures. If organisms are still present in the sputum after 3 months of treatment, patients should be evaluated for noncompliance, poor absorption of medications, or resistance of organisms. These patients should be referred to a tuberculosis specialist, as should patients for whom therapy has failed, patients with known drug-resistant organisms, and patients with complicated drug toxicities secondary to the treatment regimen.

Table 61-3. Side effects of anti-TB drugs.1

Anti-TB Drug

Major Side Effects

Major Drug Interactions

Ethambutol

o   Optic neuritis

None noted in the PDR

Isoniazid

o   Hepatitis

o   Peripheral neuropathy (prevent by co-administering pyridoxime)

o   Inhibits some cytochrome P-450 enzymes

o   Warfarin (potentiation)

o   Benzodiazepines (potentiation)

o   Theophylline (potentiation)

Pyrazinamide

o   Arthralgia

o   Hyperuricemia

None noted by the PDR

Rifampin

o   Elevated liver function tests

o   Flulike syndrome

o   Discoloration of secretions which stain

o   Induces cytochrome P-450 system

o   Inhibits effects of oral contraceptives, quinidine, corticosteroids, warfarin, methadone, digoxin, and oral hypoglycemics

Streptomycin

o   Ototoxicity

o   Potentiates the action of neuromuscular blocking agents

1Adapted with permission from Physicians Desk Reference, Medical Economics Co., Inc., 1997, and The Sanford Guide to Antimicrobial Therapy, Antimicrobial Therapy, Inc., 1997.

Table 61-4. Preventive therapy for tuberculosis infection. 1

Tuberculin Reaction Classification

Persons Recommended for Preventive Therapy

≥ 5 mm is positive if high risk

All persons regardless of age

   

o   Known or suspected HIV infection including injection drug users

o   Close contacts of active cases

o   Chest radiograph suggests previous inactive tuberculosis

 

≥10 mm is positive if intermediate risk

   

o   HIV-negative injection drug users

All persons regardless of age

o   Immunosuppressive illness or therapy (diabetic, renal failure, hematologic malignancy, rapid weight loss illness, prolonged prednisone use >15 mg/d)

All persons regardless of age

o   Immigrants from high-prevalence countries

Only if <35 years old

o   Residents of long-term care or correctional facilities

Only if <35 years old

o   Locally identified high-prevalence groups (migrant workers, homeless, high-risk racial or ethnic groups)

Only if <35 years old

o   Children ≤4 years old

≥15 mm is positive if no known risk
New converters on serial testing

Only if <35 years old

o   ≥10 mm increase if <35 years old

All persons

o   ≥15 mm increase if ≥35 years old

All persons

PPD negative but high risk

o   Anergic HIV-infected persons

All persons

o   High-risk contacts of active cases

Treat until repeat PPD is negative 12 weeks later

1Adapted with permission from Medical Knowledge Self Assessment Plan 11, American College of Physicians, 1997.

BOX 61-3 Treatment of Mycobacterium TB

 

Children

Adults

First-Line Drugs

· Isoniazid

o   Daily dose 10–15 mg/kg/d (300 mg/d max)

o   2×weekly dose 20–40 mg/kg/ dose (900 mg/dose max)

· Rifampin

o   Daily dose and 2×weekly 10–20 mg/kg/d (600 mg/d per dose max)

· Pyrazinamide

o   Daily dose 15–30 mg/kg/d

o   2×weekly 50–70 mg/kg/dose

o   Max dose 2 g

· Streptomycin

o   Daily dose 20–40 mg/kg/d IM (max dose 1 g)

o   2×weekly dose 25–30 mg/kg/ dose IM

· Ethambutol

o   Daily dose 15–25 mg/kg/d

o   2×weekly dose 50 mg/kg/ dose

o   Max dose 2.5 g

· Ethambutol (bacteriostatic)

o   Daily dose 25 mg/kg/d for 2 mo, then 15 mg/kg/d

o   2×weekly dose 50 mg/kg/dose

· Isoniazid (bactericidal)

o   Daily dose 5–10 mg/kg/d (300 mg/d max)

o   2×weekly dose 15 mg/kg (900 mg max)

· Pyrazinamide (bactericidal)

o   Daily dose 25 mg/kg/d (2.5 g/d max)

o   2×weekly dose 50–70 mg/kg/dose

· Rifampin (bactericidal)

o   Daily and 2×weekly dose 10 mg/kg/d (600 mg/d max)

· Streptomycin

o   15 mg/kg IM daily for initial 2 mo

o   Rest of Rx if needed 1.0 g IM 2–3×/week (25–30 mg/kg/dose)

Second-Line Drugs

· Ethionamide

o   10–20 mg/kg/d (max dose 1 g)

· Kanamycin

o   Daily dose 15 mg/kg/d IM

o   2×weekly dose 15–25 mg/kg/ dose IM or IV

o   Max dose 1 g

· Cycloserine

o   Daily dose 10–20 mg/kg/d (max dose 1 g)

· Amikacin (bactericidal)

o   7.5–10 mg/kg IVor IM daily

· Capreomycin sulfate

o   1 g/d (15 mg/kg/d) IM

· Ciprofloxacin

o   750 mg orallyor IV twice a day

· Clofazimine

o   50 mg/d + 300 mg 1×/mo supervised or 100 mg/d orally

· Cycloserine (bacteriostatic)

o   750–1000 mg/d (15 mg/kg/d) in 2–4 doses/d orally

· Ethionamide (bacteriostatic)

o   500–1000 mg/d (10–15 mg/kg/d) orallyin 1–3 doses/d

· Ofloxacin

o   400 mg orally or IV twice a day

· Para-aminosalicylic acid (bacteriostatic)

o   4–6 g orally twice a day (200 mg/kg/d)

· Rifabutin

o   300 mg/d orally

Special Considerations

· Other drugs used in children but rarely are listed in second line under adults; optimal doses for children have not been established.

· Ethambutol is not recommended in children <13 years of age

· In patients older than 60 years, the daily dose of streptomycin should be only 10 mg/kg/d (max dose of 750 mg)

BOX 61-4 Control of Mycobacterium TB

Prophylactic Measures

· Preventative therapy for PPD-positive patients and known household contacts

· See Table 61-5 for preventative therapy

Isolation Precautions

· Negative pressure room for patient with pulmonary TB until AFB sputum smear quantifications are significantly decreased

· Masks for health care workers are of unproven efficacy

Prevention & Control

The key to prevention and control of TB centers on preventing exposure and, if infection occurs, preventing disease progression (Box 61-4). It is important to prevent exposure of the surrounding population to a patient with active tuberculosis. Thus isolation of patients with suspected TB is critical. Isolation can be achieved at home, if the patient lives alone, or in a special room in the hospital. Isolation rooms should have negative pressure and have six exchanges of air per hour with no recirculation of that air within the hospital. These rooms also should have ultraviolet lights to kill the bacilli in that room. Any patient with a cough and an infiltrate consistent with TB on a chest x-ray should always be isolated. Before a patient can be removed from isolation, three negative sputum AFB smears should be obtained. If the patient's disease is TB, the patient can be removed from isolation when the sputum AFB smear quantification decreases significantly (ie, 4+ to 1+). Masks have been a mainstay in preventing infection in health care workers, but efficacy remains unproven. The bacillus is spread from an infected patient by way of airborne droplets with active pulmonary disease only. Extrapulmonary TB is not contagious except when health care workers directly handle infected specimens (see below).

Prevention of disease in patients exposed to tuberculosis is important. It is accomplished by preventive therapy with INH. Patients who are at risk of infection have either a positive PPD, a history of exposure such as household contacts with a patient who has active TB, or both. A patient with a positive PPD test should have a screening chest x-ray. If signs of active disease are present, a screening sputum evaluation should be done. The risk of having infection is extremely high in children who are the household contacts. Known exposed children < 6 years of age should have a chest x-ray done even if the PPD is negative, since these children can have a severe course if active TB is left untreated. If a household contact's first PPD is negative, another PPD should be placed in 8–12 weeks (which, if the patient has been truly exposed, should be positive at this time). If the second PPD is negative, preventative therapy can be stopped if the patient is no longer in danger of being exposed.

Table 61-5. Prophylaxis for drug-resistant M tuberculosis 12

 

Prophylaxis Therapy

Resistance

First Option

Other Options

INH-Resistant Organisms

· RIF, 600 mg/d orally for 6–12 months

· Children (<4 years), RIF + INH for 9 mo

· ETB + RIF daily ×6–12 mo

· PZA + RIF daily ×2 mo; then INH + RIF daily until sensitivities are known (if index case is INH resistant, DC INH & continue RIF ×9 mo)

INH + RIF-Resistant Organisms

· PZA (25–30 mg/kg/d orally) + ETB (15–25 mg/kg/d orally) for 6 mo (if HIV positive, treat for 12 mo)

· PZA + ciprofloxacin (750 mg orally twice a day) or ofloxacin (400 mg orally twice a day) for 6–12 mo

1Adapted with permission from JP Sanford, ed., The Sanford Guide to Antimicrobial Therapy, Antimicrobial Therapy, Inc., 1997.

2Abbreviations: INH, isoniazid; RIF, rifampin; PZA, pyrazinamide; SM, streptomycin; ETB, ethambutol; DC, discontinue.

Prevention Among Health Care Workers

Health care workers should have regular PPD checks unless they have a history of PPD positivity. Most centers recommend yearly PPDs. PPDs should be placed on anyone who is a household contact of a patient with active TB or anyone who has had close contact with an active case of TB. Also, patients who are in extended-care facilities or correctional facilities should have a PPD at the time of initial placement because of the high risk of infecting a large group of people.

Patients who qualify for preventative therapy should receive INH, 300 mg by mouth daily for a minimum of 6 months (Table 61-4). If the patient has radiographic evidence of previous tuberculosis, he or she should be treated with INH for 12 months. Children should be given a dose of INH of 10 mg/kg/d to a maximal dose of ≤ 300 mg/d. People receiving INH for prevention should be monitored monthly for signs of INH toxicity. Patients with symptoms of hepatitis, such as gastrointestinal complaints, jaundice, anorexia, or some combination of these symptoms, should have liver function tests performed. If those tests are abnormal, INH should be stopped. Patients with an increased risk of INH hepatitis should have their liver function checked regularly. These patients include those > 35 years of age, alcohol users, and those with preexisting liver disease. INH therapy should not be given to patients with active liver disease or to pregnant women. It is important to remember that patients with radiographic evidence of tuberculosis must be first evaluated for active disease before beginning preventative treatment.

If a person has a high risk of exposure to INH- or rifampin-resistant organisms, the data for the efficacy of preventative therapy are limited. If the risk of infection with INH-resistant organisms is high and the patient would be unable to tolerate the disease, rifampin should be used. If the patient was exposed to INH- and rifampin-resistant organisms, a multidrug preventive therapy should be used. Each case must be assessed individually (Table 61-5).

BCG vaccination has been used in some countries to improve the ability of a person who is acutely infected with Mycobacterium TB to contain the infection. The reported effectiveness of BCG vaccination varies, and the indications for use are limited. In the United States, the only people who might benefit from a BCG vaccination could be people who are repeatedly exposed to TB. Because BCG will cause a PPD test to be positive, it can complicate the diagnosis of a TB infection. However, the history of a BCG vaccination should be ignored when a PPD is placed, and the patient should be treated based on the guidelines in Table 61-4 or the patient's symptoms of active disease.

REFERENCES

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