http://evolve.elsevier.com/Edmunds/NP/
| Class | Generic Name | Trade Name |
| Antituberculars | isoniazid (INH) | Generic |
| rifampicin (RIF) | Rifampin, Rifadin | |
| rifabutin | Mycobutin | |
| rifapentine | Priftin | |
| pyrazinamide (PZA) | Generic | |
| ethambutol HCl (EMB) | Myambutol | |
| streptomycin (SM) | Generic | |
| cycloserine | Seromycin | |
| ethionamide | Trecator | |
| p-aminosalicylic acid (PAS) | Paser | |
| Aminoglycosides | amikacin/kanamycin | Generic |
| capreomycin | Capastat | |
| Fluoroquinolones | levofloxacin | Levaquin |
| moxifloxacin | Avelox | |
| gatifloxacin | Tequin |
This chapter discusses antibiotics commonly used in the prevention and treatment of tuberculosis. Their mechanisms of action differ and are discussed in the specific drug sections. No key drug is indicated for this chapter because all antibiotics differ from one other in many ways. The focus here is on the drugs used to treat patients with latent tuberculosis infection because this is an important component of primary care.
TB is a highly contagious, reportable disease whose treatment should be initiated by an infectious disease specialist. The primary care provider should be attentive to the possibility that patients may have TB, especially if they come from a high-risk population such as those with HIV/AIDS. These patients should be referred for initial workup and treatment. The primary care provider frequently follows the patient throughout the course of therapy.
Therapeutic Overview
TB is caused by Mycobacterium tuberculosis, a thick-walled bacterium. The primary route of infection is inhalation of infectious particles. The bacilli are also spread to the lymphatic system and may lodge in bone or other organ systems such as the bone, bladder, or central nervous system. A cell-mediated immune response results in tubercle formation.
Disease Process
TB is an infection that has been known for centuries.
The Centers for Disease Control and Prevention (CDC) has reported that the number of tuberculosis cases in the United States has continued to drop; in 2011 there were 10,521 cases, or 3.4 cases per 100,000 people. The current incidence is linked to the increased prevalence of HIV infection and the increase in foreign-born immigrants in the United States. The CDC found that TB rates were 12 times higher among foreign-born people. More than half of those cases originated in Mexico, the Philippines, India, China, and Vietnam.
A nonimmunocompromised adult exposed to the disease (who reacts positively to a tuberculin skin test) has a 10% risk of developing clinical illness or active TB. Patients infected with HIV, however, are significantly more likely to develop active disease and account for 30% to 50% of new cases. In 2006, the TB rate among foreign-born persons in the United States was 9.5 times that of those born in the United States.
Clusters of patients with TB are considered recently transmitted cases that occur within geographic localities, in demographic groups, or among individuals who share certain behaviors and lifestyles. Neighborhoods associated with clustered cases and recent transmissions tend to be characterized by low socioeconomic status, inadequate housing, and high rates of drug abuse, poverty, and crime. Unclustered cases are those most likely associated with reactivation of old infection; these usually are found in middle-class neighborhoods.
The most common site of TB infection is the pulmonary system. TB can also infect the bone, causing bone pain, and the urinary tract, causing UTI symptoms. It then can become disseminated, causing systemic symptoms. Pulmonary TB is seen predominantly in urban areas, whereas rural areas have an increased incidence of urinary and bone TB.
Reactivation disease occurs in a patient who was infected in the past. When the patient becomes old or immunocompromised, the disease may reactivate. This can occur in a patient with COPD who is taking prednisone (see Box 66-1 for risk factors for TB).
Latent TB infection occurs when a person is infected with TB bacteria but does not yet have symptoms and so cannot transmit the bacteria to others. However, if the bacteria become active, the person will develop the disease and can also spread it to others. Certain people, including those with weakened immune systems, are more likely to progress from latent to active TB. Many high-risk people with latent TB feel fine and do not begin the 9-month course of treatment, and many of those who do begin the therapy do not see it through to the end. However, a new regimen streamlines the treatment to 12 once-per-week doses of isoniazid, along with rifapentine.
There is a huge problem globally with drug-resistant tuberculosis. Many countries such as India and China now have all-but-incurable TB because there has not been widespread testing and treatment procedures. Thus, worldwide, TB has been allowed to mutate into a killer that rivals the historic TB.
Assessment
Clinical symptoms of primary pulmonary TB include fever (70%), cough, pain in the chest when breathing or coughing, and cough productive of sputum or blood. General symptoms of TB, either pulmonary or disseminated, include weight loss, fatigue, malaise, fever, and night sweats. A child is likely to be asymptomatic or to present with a systemic infection rather than with pulmonary symptoms. In patients who have a history of TB, the clinician should always suspect reactivation; this accounts for approximately 90% of TB cases among non-HIV patients with TB.
Testing for Exposure to TB
A patient with a positive test is considered to have a latent tuberculosis infection. The Mantoux tuberculin skin test is the preferred test for TB because it is the most accurate. The tine test should no longer be used. With the Mantoux tuberculin skin test, 0.1 ml of purified protein derivative (PPD) tuberculin containing 5 tuberculin units (TU) is injected intradermally to produce a discrete, pale elevation of skin 6 to 10 mm in diameter.
Criteria used for interpretation of the PPD are listed in Box 66-2. The test should be read 48 to 72 hours after the injection is given. Positive reactions may still be measurable up to 1 week after testing. If the patient returns after more than 3 days and the results appear negative, the test must be repeated. The test site is measured crosswise to the axis of the forearm. Only the induration (hardness) is measured. Erythema is not measured. The result is recorded in millimeters, not as positive or negative.
Candidates for testing include all high-risk patients (as indicated in Box 66-1) plus employees or residents in congregate settings, such as hospitals, prisons and jails, homeless shelters, and nursing homes, or people from areas of the world with a high prevalence of TB. Close contacts of someone with infectious TB who has a negative PPD should be retested 10 weeks after the contact. Previously, it was taught that the clinician should never give a PPD to a patient who had received a bacille Calmette-Guérin (BCG) vaccination. However, previous vaccination with BCG usually should not influence the need for tuberculin skin testing. Most patients who have received BCG have been told that they must never have a PPD because of the risk for a serious adverse reaction, thus they will refuse the PPD. Previous vaccination with BCG does not change the need for treatment or testing.
Patients who are immunocompromised should be evaluated for anergy prior to receiving the PPD. When a clinician elects to use anergy testing as part of a multifactorial assessment of a person’s risk for TB, FDA-approved methods include the Mantoux-method tests (e.g., mumps and Candida), which are used together and have cutoff diameters of 5 mm of induration (see http://www.cdc.gov/mmwr/preview/mmwrhtml/00049386.htm). Other protocols suggest that the mumps skin test antigen (MSTA) and tetanus toxoid (fluid) may be used. Give 0.1 ml of the antigen intradermally. Read at 48 to 72 hours. Any induration greater than 2 mm is considered positive (reactive), so PPD testing can proceed. Causes of a false-negative skin test include HIV, lymphoma, and recent live vaccinations.
The two-step method should be used in patients who may have diminished skin test reactivity, such as geriatric patients. The procedure is to give a PPD, which is followed by a second PPD in 1 to 3 weeks if the first is negative. Yearly administration of the PPD obviates the need for further two-step testing. If the first test is negative but the second is positive, the patient is considered to have a positive PPD. This reaction is commonly called “boosted.” Evaluate elderly patients and high-risk employees with the two-step procedure. It is important to know whether a patient has truly converted from negative to positive, or if he or she was boosted by a two-step PPD to avoid the false impression of a conversion.
Diagnosis of Tuberculosis
The chest radiograph is no longer a good screening tool for TB disease among low-risk persons, such as the Caucasian population born in the United States. However, in high-risk environments, such as a homeless shelter with a recent history of infectious TB among its residents, the radiograph may be a useful tool for screening contacts and symptomatic persons. A chest x-ray (CXR) examination should be obtained on all patients who have a positive PPD. Posteroanterior and lateral views should be obtained. An apical lordotic view should be obtained if the history is suggestive of TB and initial films are normal. A person with a normal x-ray is unlikely to have pulmonary TB, making the chest x-ray a very sensitive test. The diagnosis of tuberculosis in a child, especially a young child, presents many challenges.
X-ray examination is performed to detect lung abnormalities that indicate active disease. However, the films do not confirm that TB causes any detected abnormalities. A biopsy showing caseation granulomas would confirm the diagnosis. Previously, an annual chest x-ray was required for all persons with a positive PPD. Although state policies may vary, most people are considered cleared of TB indefinitely if their chest x-ray is clear, and another chest x-ray is required only if they again develop signs or symptoms of TB.
Culturing of the TB organism takes 6 weeks. Thus, for diagnosing TB and determining the severity of a patient’s illness, TB control programs worldwide rely on the acid-fast bacilli (AFB) smear. In this test, a sample of sputum is inspected under a light microscope for the presence of tuberculosis bacteria. It is a fast, inexpensive, and simple method of diagnosing TB. Gastric aspiration also can be used to obtain specimens of swallowed sputum. Although this procedure is uncomfortable, it is more cost-effective and less invasive then bronchoscopy. It is the best way to obtain specimens from infants and from some young children who cannot produce sputum even with aerosol inhalation. When gastric aspiration is used to obtain specimens from children, the procedure should be done in the morning, before the patient gets out of bed or eats.
Positive results mean that a patient should immediately be placed in isolation in a hospital, because every cough could launch enough bacteria to infect many other people. Negative results must be interpreted in view of other findings or test results. Both theoretical and experimental results have cast doubt on the ability of the AFB smear to detect infected patients. Although as few as five TB bacteria in the lungs can start a new infection, a sample must contain 5000 to 10,000 bacteria per milliliter to reach the test’s threshold of detection. Epidemiologic investigations confirm an elevated rate of TB among those exposed to patients who tested negative. Thus, awareness is growing worldwide that persons with negative smears but positive cultures of sputum cause a significant number of infections.
Direct examination of sputum samples reveals the presence of acid-fast bacilli. Patients with a positive smear are considered contagious. Culturing sputum, which takes 6 weeks, yields the classic definitive diagnosis. A sputum test, the Mycobacterium tuberculosis Direct Test, can give results in 4 to 5 hours. However, this test misses TB in about 5% of cases, so a culture is still required.
In conclusion, the presumptive diagnosis of active TB is made when the patient has any of the following:
The confirmed diagnosis of active TB is made by a positive culture from any body fluid or biopsy specimen.
Mechanism of Action
All drugs used in the treatment of TB are antibiotics. Each drug is quite different. See section on a specific drug for its specific mechanism of action.
Treatment Principles
Evidence-Based Recommendations
To prevent TB in high-risk people without HIV infection, isoniazid is given for 6 to 12 months (6 months was as effective as 12 months). Isoniazid increases the risk of hepatotoxicity compared with placebo.
The first-line anti-TB agents that form the core of FDA- approved drug treatment regimens include: isoniazid (INH); rifampin (RIF); ethambutol (EMB); and pyrazinamide (PZA).
For patients with newly diagnosed pulmonary tuberculosis, a 6-month course of chemotherapy with at least two drugs is recommended. Several regimens are available. Each regimen has an initial phase, which includes three or four drugs given for 6 to 8 weeks, followed by a continuation phase, with two drugs given for 18 weeks. See Table 66-1.
TABLE 66-1
CDC-Approved Basic TB Disease Treatment Regimens
| Preferred Regimen | Alternative Regimen | Alternative Regimen |
| Initial Phase | ||
| Daily INH, RIF, PZA, and EMB∗ for 56 doses (8 weeks) | Daily INH, RIF, PZA, and EMB∗ for 14 doses (2 weeks), then twice weekly for 12 doses (6 weeks) | Thrice-weekly INH, RIF, PZA, and EMB∗ for 24 doses (8 weeks) |
| Continuation Phase | ||
| Daily INH and RIF for 126 doses (18 weeks) or Twice-weekly INH and RIF for 36 doses (18 weeks) | Twice-weekly INH and RIF for 36 doses (18 weeks) | Thrice-weekly INH and RIF for 54 doses (18 weeks) |
Note: A continuation phase of once-weekly INH/rifapentine can be used for HIV-negative patients who do not have cavities on the chest film and who have negative acid-fast bacilli (AFB) smears at the completion of the initial phase of treatment.
∗EMB can be discontinued if drug susceptibility studies demonstrate susceptibility to first-line drugs.
From Centers for Disease Control and Prevention: Treatment of latent TB infection and TB disease. www.cdc.gov/tb. Accessed 9-12-2012.
Cardinal Points of Treatment
Treatment of Active Infection
