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Tuberculosis

2.00 Contact Hours:
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A score of 80% correct answers on a test is required to successfully complete any course and attain a certificate of completion.
Authors:    Dana Bartlett (BS, MS, MA) , Julia Tortorice (RN, MBA, MSN, NEA-BC, CPHQ)

Purpose/Goals

The purpose of this course is to update the healthcare professional on current diagnosis and treatment of tuberculosis.

Objectives

After completing the course, the learner will be able to:

  1. Discuss the four criteria used to diagnose TB.
  2. Identify groups susceptible to primary TB and reactivation of latent TB
  3. Discuss methods of screening for latent TB
  4. Discuss basic principles of drug therapy for the treatment of primary TB, latent TB and drug-resistant TB.
  5. Apply methods of TB prevention and control.

Epidemiology

A total of 9,945 cases of tuberculosis (TB) were reported in the United States in 2012 (CDC, 2014). This is the lowest reported number of cases since 1953, and the incidence of TB cases in the United States has been declining every year since 1992. The reported number of cases of multi-drug resistant tuberculosis (MDR-TB) in the United States has also been declining in the past two decades and only 72 cases were reported in 2012 (CDC, 2014).

Unfortunately the statistics from the rest of the world are not encouraging. Tuberculosis is the second leading cause of death from infectious disease world-wide. According to the World Health Organization (WHO) TB is "a major health problem" (WHO, 2013). The world-wide incidence of new cases has been steadily declining for the past decade and the mortality rate has decreased 45% since 1990, but world-wide in 2012 there were 8.6 million new cases of TB and 1.2 million people died from the disease (WHO, 2013) There were 450,000 reported cases of MDR-TB, and TB is also a significant contributor to the mortality rate of people who are infected with the human immunodeficiency virus (HIV). The burden of the TB epidemic is predominantly in poor and developing countries. If it is treated promptly and properly TB is curable in almost every case. But control and cure rates are seriously affected by lack of resources in many parts of the world, and in some countries the fatality rate of untreated TB is 50-65% within five years of infection.

Pathophysiology of Tuberculosis

The disease of TB is caused by the Mycobacterium tuberculosis bacteria. The primary organs that are infected and harmed by TB are the lungs. The TB bacteria primarily gains access to the body by inhalation of infected droplets which are spread by an infected host through coughing, sneezing, or talking. Some of the infected droplets can remain suspended in the air for several hours. Approximately 90% of TB-infected droplets that are inhaled are trapped in the upper airways and expelled (Raviglione, O'Brien, 2012). The 10 % that are not expelled will eventually reach the alveoli.

Once the TB bacteria reach the alveoli one of three situations occurs: 1) The patient may clear completely clear the bacteria and no infection develops; 2) The patient may develop an active infection soon after transmission, a condition called primary TB, or; 3) The body's immune response to the infection may contain the TB bacteria, causing a chronic, asymptomatic sub-clinical infection that is called latent TB (Herchline, 2014; Raviglione, O'Brien, 2012). Tuberculosis infections, latent or primary, can be easily treated but they can develop to be multidrug-resistant tuberculosis (MDR-TB) or extensively drug-resistant tuberculosis (XDR-TB). The body's immune system can often produce a response that is sufficient to clear a TB infection or contain it. However, the immune system does not produce long-lasting immunity against TB. Another infection and active disease can occur even if the bacteria from a previous infection were cleared.

Latent TB is the most common of these three possibilities. If the host has a normal immune system the TB bacteria reach the alveoli and they are contained by macrophages. Macrophages are specialized cells of the immune system that perform many functions. In the situation of a TB infection, the macrophages surround and contain TB bacteria by a process called phagocytosis. Phagocytosis of TB bacteria produces a barrier around them, a shell called a granuloma. Typically when macrophages engulf bacteria or other xenobiotics, the foreign particles are eventually destroyed by enzymes inside the macrophage. However, because of the physical nature of the granuloma and characteristics of the TB bacteria that protect it from macrophagic enzymes, TB can live inside these granulomas for many, many years.

Approximately 5-10% of the people who have latent TB will eventually develop the active disease (Parekh, Schluger 2013); this is called reactivation and will be discussed in a separate section. Approximately 90% of all cases of TB are considered to be caused by reactivation (Chestnutt, Prendergast, Tavan, 2014), but in areas where TB is endemic and healthcare resources are lacking, primary TB is much more common.

Primary TB happens in about 5% of all cases of infection. It typically happens to children or people with a compromised immune system (Chestnut, Prendergast, Tavan, 2014; Raviglione, O'Brien, 2012). Children who are = 1 year have approximately a 50% chance of developing primary active TB (Marais, Gie, Schaaf, et al, 2004).

Tuberculosis can disseminate and cause non-pulmonary infections; this is especially likely in people who are infected with HIV. In descending order the frequency of non-pulmonary TB infections is: (Raviglione, O'Brien, 2012)

  1. Lymph nodes
  2. Pleura
  3. Genito-urinary tract
  4. Bones and joints
  5. Meninges
  6. Peritoneum
  7. Pericardium

With the correct medical care, primary tuberculosis and latent TB that has been reactivated can be easily cured. However, TB infections may develop into what is called drug-resistant tuberculosis (DRT), either MDR-TB or XDR-TB. The risk factors for, and diagnosis and treatment of these two forms of DRT will be discussed in separate sections.

Transmission of Tuberculosis

Transmission of pulmonary TB occurs by inhalation of infected droplets. The bacteria can be transmitted cutaneously and by other routes, but this is quite uncommon (Raviglione, O'Brien, 2012) and isolated non-pulmonary TB is not considered contagious (Zachary, 2013). Inhalation of the infected droplets happens by being in close proximity to someone who has an active infection - the host is coughing, sneezing, talking and the infected droplets are spread into the air The closer and more prolonged the contact the greater the risk of transmission. Approximately 20% of all close household contacts of someone with active disease will become infected themselves (Raviglione, O'Brien, 2012), although some estimates of this transmission are lower. There are host, environmental, and bacterial factors that influence the chances of transmitting TB, and the process of transmission is not completely understood. Patients with active disease and a positive AFB smear (AFB smears will be discussed later) may not produce infected droplets when they cough, sneeze, etc., but the higher the concentration of bacteria in the exhaled aerosols of an infected patient the greater the risk of transmitting TB to close contacts (Jones-López, Namugoa, Mumbowa, 2013).

Tuberculosis can also be transmitted during medical procedures such as bronchoscopy, elective intubation, nebulizer treatments, and sputum induction. Latent tuberculosis is not contagious.

The following groups are considered susceptible to the transmission of TB. (CDC, 2012):

Table I: Groups Susceptible to TB

People with HIV infection

People who have been recently infected with TB (in the last two years)

People who inject illegal drugs;

Babies and young children;

The elderly

People who were not treated correctly for TB in the past; and people with certain medical conditions such as diabetes, certain types of cancer and being underweight.

Other at-risk groups include African Americans, immigrants, and persons living in poverty with limited access to medical care, inadequate housing, and inadequate nutrition.

Diagnosis of Tuberculosis

This section will discuss the diagnosis of someone with a primary pulmonary TB infection. Diagnosing latent TB, MDR-TB, and XDR-TB will be discussed in separate sections.

The signs and symptoms that are considered typical of TB are chest pain, cough, fatigue, fever, hemoptysis, night sweats, and weight loss (Herchline, 2014). These are non-specific and can be caused by many infections or medical conditions, and it is possible they may be absent or relatively minor in severity of the patient is elderly or immuno-compromised.

The diagnosis of TB is made using the following four criteria (Herchline 2014; Raviglione, O'Brien 2011). Of these four, the growth of M tuberculosis in sputum is considered to be the definitive, gold-standard test for diagnosing TB.

  1. High index of suspicion: Consider someone at high risk and have a high index of suspicion of the presence of TB if the patient has characteristic signs and symptoms of TB and: is infected with HIV; has a positive TB screening test; has been exposed to someone who is known to have active disease; has been treated for TB; has traveled to an area where TB is endemic; is homeless or incarcerated; uses IV drugs; is very young, or; has other medical conditions that increase the susceptibility to development of TB. Because the signs and symptoms of TB are non-specific and laboratory confirmation of TB takes time, it is the index of suspicion that is the most important part of a provisional diagnosis of TB.
  2. Signs and symptoms: Discussed earlier.
  3. X-ray findings: A chest x-ray is an important part of the diagnostic work-up for TB. However, a chest x-ray cannot distinguish between active and inactive TB and the "classic" findings of upper lobe infiltrates and cavitation may be absent (Bernardo, 2014; Raviglione, O'Brien, 2012). A chest x-ray can be suggestive of TB but not always confirmatory.
  4. Acid-fast bacillus smear and sputum culture: An acid-fast bacillus (AFB) smear and a sputum culture are the definitive test used to determine the presence of TB bacteria and the sensitivity of the bacteria to particular drugs. The presence of AFB indicates that TB may be present. But there are bacteria that have AFB that are not TB, so the results must be confirmed by the culture. Procurement of a sputum sample that can be used for detecting AFB and drug sensitivity is a very important topic and will be discussed separately.

An acid-fast bacillus is a microorganism that will retain dye when it is in an acid milieu. M tuberculosis is such a microorganism. The AFB smear is a simple and inexpensive way to detect the presence of TB in sputum. It is considered to have a sensitivity rate of 45-80% and a positive predictive value of 50-80% (Bernardo, 2104). The smear is not as sensitive as the culture for detecting TB bacteria. After the AFB smear is performed, the sputum will be cultured so that bacteria can grow and the TB bacteria can be definitely identified. Testing for drug susceptibility will also be done. The sensitivity and specificity of the culture for TB identification are 80 and 98%, respectively.

Three sputum samples should be obtained. There should be an 8-24 hour interval between the collections of specimens. A minimum of 5 mL is required, and at least one specimen should be obtained in the early morning (Bernardo, 2014; Sengooba, Kateete, Waija, et al, 2012). If the patient is not able to produce an adequate specimen by coughing, production of a cough and sputum collection can be done by induction. A hypertonic saline solution (Usually 3-7%) is administered via nebulization; depending on the strength of the saline the patient will inhale the solution for 20-60 minutes. Induction will usually initiate coughing and hopefully, production of a sputum sample. The diagnostic sensitivity of this method is superior to self-production of sputum and equal to bronchoscopy with lavage (Seong, Lee, Kim, et al, 2014; Peter, Theron, Pooran, et al, 2013). Care should be taken to label specimens as induced because they are often thin and watery and could mistakenly be discarded.

Bronchoscopy with lavage can be used to obtain a sputum sample. This method of obtaining sputum samples for diagnosis of TB has sensitivity, specificity, positive predictive value, and negative predictive value that are relatively quite high, especially when combined with a CT scan of the chest (Yu, Song, Koh, et al, 2013). Bronchoscopy is complicated and time-consuming, and it should only be used if the patient cannot produce sputum by coughing or induction, if the smear is negative but there is a high index of suspicion for the presence of TB, or if there is an immediate need for a diagnosis (Bernardo, 2014; Yu, Song, Koh, et al, 2013).

There is a classification system for patient history of TB (CDC, 2012).

Class Type Description
0 No exposure to TB
Not infected
No history of exposure, negative reaction to the tuberculin skin test
1 Exposure to TB
No evidence of infection
History of exposure, negative reaction to a tuberculin skin test (given at least 10 weeks after exposure)
2 TB infection
No TB disease
Positive reaction to the tuberculin skin test, negative bacteriologic examinations (if done), no clinical or x-ray evidence of TB disease
3 Current TB disease Meets current laboratory criteria (for example, a positive culture) or criteria for current clinical case definition
4 Previous TB disease (not current) Medical history of TB disease, or Abnormal but stable x-ray findings for a person who has a positive reaction to the tuberculin skin test, negative bacteriologic examinations (if done), and no clinical or x-ray evidence of current TB disease
5 TB suspected Signs and symptoms of TB disease, but evaluation not complete (diagnosis pending)

Diagnosis of MDR-TB and XDR-TB

The clinical signs and symptoms of a patient who has MDR-TB and XDR-TB are identical to those of someone who has drug-susceptible TB. The diagnostic procedure for MDR-TB and XDR-TB is the same as it is for a suspected drug-susceptible TB infection. After the results of the culture and drug susceptibility testing are known, the diagnostic criteria for these two infections are (Calligaro, Moodley, Symons, et al, 2014):

MDR-TB: Tuberculosis bacteria that is resistant to at least isoniazid and rifampin, the two most commonly used first-line drugs

XDR-TB: The MDR-TB criteria plus resistance to any fluroquinilone and any second-line injectable, i.e., amikacin, capreomycin, and kanamycin.

Infections with TB bacteria that are considered to be "beyond" XDR-TB and that have resistance to other drugs have been reported. These have been called extremely drug-resistant TB or totally drug-resistant TB. At this time there are no accepted diagnostic criteria for these clinical situations (Calligaro, Moodley, Symons, et al, 2014).

Diagnosis of Latent Tuberculosis

Over 2 billion people worldwide are estimated to have latent TB (Parekh, Schluger, 2013). Latent TB has the potential to develop into active disease at any time, and the majority of cases of active TB are re-activated latent infections (Chestnutt, Prendergast, Tavan, 2014). Fortunately, only 5-10% of people with latent TB develop an active infection, but given the numbers of latent TB infections this represents a serious public health issue. Risk factors for reactivation of latent TB include (Herchline, 2014; Parekh, Schluger, 2013; Raviglione, O'Brien, 2012):

Table II: Risk Factors for Latent TB Reactivation
Alcohol abuse, chronic
Cancer of the head and neck
Children < 5 years of age
Chronic malabsorption syndromes
Cigarette smoking
Conversion of a screening test to positive within a two year span
Diabetes mellitus (3-fold risk increase)
End-stage renal disease
Gastrectomy or jejeunal bypass surgery
Head and neck malignancy
Hematologic malignancies
HIV infection
Immunosuppressive therapy
IV drug abuse
Low body weight
Organ transplantation
Radiographic evidence of healed, untreated TB
TB infection within the past year
Silicosis
Use of tumor necrosis factor–alpha (TNF-a) antagonists: adalimumab, entanercept, golimumab, and inflixamib.

There is no method by which latent TB can be directly identified. The diagnostic tools available provide indirect evidence of the presence of M tuberculosis by detecting an immune response to the bacteria. The two methods that are used to diagnose latent TB are the tuberculin skin test and interferon-? release assays (IGRAs). The Tine test and the Heaf test were methods previously used but have fallen out of favor and are no longer recommended.

The tuberculin skin test has been in use for many years. An injection of 0.1 mL of tuberculin material that contains 5 tuberculin units, purified protein derivative (PPD), is injected intradermally into the volar surface of the patient's forearm. This is called the Mantoux technique. The PPD acts as an antigen and produces a specific immune response that is seen as a skin reaction at the injection site. The injection site is examined 48-72 hours after the injection and the transverse width of the reaction is used to determine the possibility of latent infection with TB. The criteria for interpreting the skin reaction are (Chestnutt, Prendergast, Tavan, 2104):

≥ 5 mm - If the transverse width of the induration is ≥ 5 mm this is considered a positive reaction if the patient: is HIV-positive; has had recent contact with someone who has active TB; x-ray findings are suggestive of TB; has had an organ transplant, is immunosuppressed, or; has been receiving the equivalent of > 15 mg of prednisone for 1 month or longer.

≥ 10 mm – If the transverse width of the induration is ≥ 10 mm this is considered a positive reaction if the patient: is a recent immigrant from an area where TB is endemic; is an HIV- negative IV drug user; works in a laboratory that processes mycobacterium specimens; is incarcerated, lives in a homeless shelter, is hospitalized, or lives in a long-term care facility; is at risk for reactivation of latent TB, or; is < 4 years of age or is an infant, child or adolescent who has been exposed to a high-risk adult.

≥ 15 mm – If the transverse width of the induration is = this is considered a positive reaction.

The tuberculin skin test is a useful screening tool, but it has limits. The sensitivity and specificity are approximately 77%, false negative and false positive results are possible, and it cannot predict who will or will not develop reactivation of latent TB. False negatives are possible if improper technique is used or if the test interpretation is done improperly. The test must be read no later than 72 hours after it was done as longer intervals between testing and interpretation increase the incidence of false negatives.

False negatives can also occur if the patient: is elderly or < 6 months of age; has recently been vaccinated for a viral infection; has active tuberculosis; has another active infection; is malnourished; is HIV-positive; has chronic kidney disease or a malignancy, or; has been on corticosteroid therapy or therapy with tumor necrosis factor inhibitors (Pai, Menzies, 2014; Raviglione, O'Brien, 2012). A false negative tuberculin skin test is also possible if the patient has had latent TB for many years.

False positives are caused by either the presence of another type of myobacteria or in patients who were vaccinated with the Bacillus Calmette-Guérin (BCG) vaccine. A false positive skin test caused by BCG vaccination is most likely within the first 10 years after the patient was vaccinated. The TB skin test cannot determine if a positive reaction was caused by BCG vaccination or latent TB: an IRGA can make the distinction.

The IRGA tests are similar to the tuberculin skin test in that they do not detect the presence of bacteria: they detect a specific immune response to TB. The IGRAs use a blood sample that measures T-cell release of interferon-gamma in response to M tuberculosis antigens (Pai, Menzies May 2014).There are several IRGA tests available: the QuantiFERON TB Gold ® (QFT-G) is one that is commonly used. The IRGA tests offer some advantages when compared to skin testing. The results are available in 24-48 hours; the sensitivity is > 90% and the specificity is > 95%; the patient only needs one visit to a healthcare provider; they are not be affected by vaccination with BCG; and IRGA test results do not appear to be affected by non-tuberculosis myobacteria (Pai, Menzies, 2014; Parekh, Schluger, 2013).

As with essentially any diagnostic test the IRGAs have limitations. The IRGAs cannot distinguish between latent infection and active TB. If the result is positive, then it is likely that the patient has M tuberculosis infection. There is no reason to follow a positive QFT-G result with a skin test. However, TB disease should be ruled out by medical evaluation before latent TB is diagnosed.

If the result of the HRGA is negative then the patient is unlikely to have M tuberculosis infection and may not require further evaluation unless they have signs and symptoms of TB disease. Moreover, as with the skin test, persons who have a negative test result can still have latent TB.

If the result is indeterminate, that means the test could not be interpreted. The options then are to retest the patient with the QFT-G again, perform a skin test or do no further testing. The QFT-G can be used in all circumstances in which the skin test is used, including contact investigations, evaluation of recent immigrants who have had BCG vaccination, and TB testing of health care workers and others undergoing serial evaluation for M tuberculosis.

Screening for Latent TB

The goal of screening for latent TB is to identify people who have the disease so that they can be treated prophylactically. However, the screening tests can identify people who have latent TB, but they cannot accurately predict if a latent infection will reactivate. Between 5-10% of all those who have latent TB will reactivate, but this risk is not spread evenly through the population. Healthy individuals without risk factors have an annual risk of reactivation of 0.1%, but for someone with an HIV infection the risk is estimated to be > 10% (Pai, Menzies, 2014).Treatment is not without risks so identifying which patients who have a positive screening test and who need treatment is imperative.

Screening of low-risk populations is discouraged because it diverts resources from activities of higher priority, and programs that screen low-risk groups should be replaced by targeted testing (CDC, 2013). Tuberculosis screening is discouraged unless there is a plan to complete a course of treatment in persons found to have latent TB. The plan should include arrangements for medical evaluation (e.g., chest x-ray, sputum samples) of people with positive skin tests and for the medical supervision of the course of treatment.

The IGRAs are preferred for screening people who may not return for reading of a skin test and a skin test is preferred for children < 5 years of age (CDC, 2013).

Table III: Risk Categories Used for Latent TB Screening

High risk: This group should be screened for latent TB. It includes anyone who has any the risk factors from Table II. These people have a reactivation risk that is > six times that of healthy individuals (Pai, Menzies, 2014).

Moderate risk: These people have a reactivation risk estimated to be 3-6 times that of healthy individuals. This group includes people who have diabetes mellitus or are on corticosteroid therapy. Anyone who is diabetic or is taking corticosteroids and is = 65 years should be screened (Pai, Menzies, 2014).

Slight risk: people who have a slight risk of reactivation are those who are underweight, smoke cigarettes, or have small granulomas that are seen on a chest x-ray. If someone has any of those three conditions and he/she is = 50 years of age then screening is needed (Pai, Menzies, 2014).


People who have emigrated from areas of the world with high rates of TB have latent TB incidence rates similar to those of their countries of origin for the first several years after arrival in the United States. Areas of the world with high TB rates include countries in Latin America, the Caribbean, Africa, Asia, Eastern Europe, and Russia. These people would also be considered high-risk if an IGRA test is positive.

In most circumstances if the tuberculin skin test is positive it will not need to be repeated. A repeat test is indicated if the patient has had very recent close contact with someone who active pulmonary TB as it can take 3-7 weeks for a skin test to be positive after a new exposure (Menzies, 1999).

Routine testing of healthcare workers is a separate issue. Healthcare workers as a group have a higher potential for exposure to TB than the general public. But as with reactivation rates in the general population, this risk is not spread evenly and widespread screening of all healthcare workers may not be an optimal allocation of resources (Pai, Banaei, 2013. Regardless, healthcare workers who have patient contact are routinely screened, and the process is: 1) A baseline two-step test, and; 2) Annual screening. (Pai, Menzies, 2014).

For the two-step test a skin test is applied and if the result is negative the test is repeated one to three weeks later. If the repeat test is positive this is due to what is called the booster phenomenon. Someone who was infected with TB many, many years prior may not have the immune capability of producing a reaction to the initial test. But the initial test stimulates the "memory" of the immune system, a repeat test will be positive, and this could be incorrectly interpreted as recent exposure and a conversion. If this occurs it is evidence of latent TB (CDC, 2013). The two-step test is recommended as a baseline procedure for healthcare workers who will be annually screened (CDC, 2013). The second skin test should be considered positive if the induration is ≥ 10 mm or the induration increased by = 6 mm from a previous test (Menzies, 1999).

The level of risk for healthcare workers can be classified as low, medium, or as a potential ongoing risk. The low risk classification should be used for settings in which persons with TB disease are not expected to be encountered. Exposure to TB this setting is unlikely. The medium risk classification should be used for settings in which the risk assessment has determined that health care workers will possibly be exposed to persons with TB disease. Medium risk classification can also be used for settings in which health care workers will be exposed to clinical specimens that may contain M tuberculosis. The potential ongoing transmission classification should be temporarily assigned to any setting where there is evidence of person-to-person transmission of M. tuberculosis in the past year.

TB Risk Classification and TB Testing Frequency for Health Care Settings TB Risk Classification Frequency for TB Testing
Low Risk Conduct baseline test when health care worker is hired
No further testing needed unless exposure occurs
Medium Risk Conduct baseline test when health care worker is hired
Repeat test annually
Potential Ongoing Transmission Conduct baseline test when health care worker is hired
Repeat test every 8-10 weeks until there is no evidence of ongoing M. tuberculosis transmission in the setting

Screening for Latent TB in Patients Infected with HIV

Every patient should have testing for TB at the time of diagnosis of HIV infection. If the patient has a negative screening test but she/he is very immunocompromised (e.g., a CD4 cell count of < 200 cell/mm3) then retesting should be done when anti-retroviral therapy (ART) has begun (CDC, 2013). Diagnosing/screening for latent TB in a patient who is infected with HIV is done by using either a skin test or an IGRA test. There is no evidence that suggests either method is superior in this situation (Cattamanchi, Smith, Steingart, et al, 2011), and using both is not recommended (CDC, 2013). However, there are some issues with using the skin test in a patient infected with HIV that should be kept in mind. If a patient is infected with HIV a skin test is considered reactive if the transverse width of the induration is ≥ 5 mm: in people not infected with HIV a 10 mm width is considered reactive. False negative tests are possible if the patient is very immunosuppressed (Pai, Menzies, 2014).

Screening for Latent TB in Pregnant Women

Routine screening of pregnant women for latent TB is not recommended. Pregnancy does not increase the risk for reactivation, and the factors that increase the risk for reactivation in other populations apply to pregnant women (Friedman, Tanoue, 2014). The risk of vertical transmission of TB is considered to be extremely small (Friedman, Tanoue, 2014): newborns are more at risk from respiratory transmission than the fetus is from transmission in utero (Asuquo, Vellore, Walters, et al, 2012). If a woman is at a high risk for reactivation it is preferable that she be tested before becoming pregnant.

Either the skin test or an IGRA can be used. Both are safe to use during pregnancy, and pregnancy does not affect the results (Friedman, Tanoue, 2014).

Treatment of Primary Active TB

Treatment of active TB is a relatively long process, but if the drug regimens are adhered to faithfully the cure rate is very good.

The treatment is a two-step process. The first phase lasts two months and is the bacterial phase: the goal is to dramatically decrease the number of bacteria so that the patient is not infectious. The second phase is the sterilization phase, also called the continuation phase: the goal is to eradicate the remaining bacteria. The duration of the therapy is prolonged because the TB bacteria live and replicate in areas where drug penetration is problematic (Raviglione, O'Brien, 2012).

There are four treatment regimens that can be used and four drugs that are the backbone of therapy: isoniazid, rifampin, pyrazinamide, and ethambutol (Sterling 2013; American Thoracic Society, et al, 2003). In some situations rifapentine or streptomycin may be used. The four primary drugs are given for two months in the first phase. For most patients the therapy is then continued for four more months. In some situations the continuation phase should be seven months. The seven month continuation is recommended if the patient: 1) has cavitary pulmonary tuberculosis caused by drug susceptible organisms and a sputum culture that is positive after two months of treatment; 2) did not take pyrazinamide during the intial phase, or; 3) was being treated once a week with INH and rifapentine and had a positive sputum culture at the end of the initial phase (Sterling, 2013; American Thoracic Society, et al, 2003).

All of these treatment regimens have been approved by the American Thoracic Society, the Centers for Disease Control and Prevention (CDC), and the Infectious Diseases Society of America: Regimens 1 and 2 are preferred.

Regimen 1

INH, rifampin, pyrazinamide, and ethambutol. In some situations rifapentine is used.

Initial Phase: The drugs are taken seven days a week for 56 doses/8 weeks or five days a week for 40 doses/8 weeks by directly observed therapy (DOT). Directly observed therapy will be discussed later in the module.

Continuation phase: 1a. INH and rifampin seven days a week for 126 doses/18 weeks, or five days a week for 90 doses/18 weeks by DOT. 1b. INH and rifampin twice a week for 36 doses/18 weeks. 1c. INH and rifapentine once a week for 18 doses/18 weeks. This option is used for HIV-negative patients who have a negative smear at the end of two months of therapy and who do not have cavitation.

Regimen 2

INH, rifampin, pyrazinamide, and ethambutol. In some situations rifapentine is used.

Initial phase: The drugs are taken seven days a week for 14 doses/two weeks then twice a week for 12 doses/6 weeks. The DOT regimen is five days a week for 10 doses/12 weeks the twice a week for 12 doses/6 weeks.

Continuation phase: INH and rifampin, twice a week for 36 doses/18 weeks. If the patient is HIV-negative, has a negative smear at the end of two months of therapy and does not have cavitation on x-ray, INH and rifapentine are given once a week for 18 doses/18 weeks.

Regimen 3

INH, rifampin, pyrazinamide, and ethambutol

Initial phase. The drugs are taken three times a week for 24 doses/8 weeks.

Continuation phase: INH and rifampin, three times a week for 54 doses/18 weeks.

Regimen 4

INH, rifampin, and ethambutol

Initial phase: The drugs are taken seven days a week for 56 doses/8 weeks. DOT is five days a week for 40 doses/8 weeks.

Continuation phase: 1a. INH and rifampin, seven days a week for 217 doses/31 weeks. DOT is five days a week for 155 doses/31 weeks. 2a. INH and rifampin twice a week for 61 doses/31 weeks.

Note: If the susceptibility testing shows that the bacteria are sensitive to INH, rifampin, and pyrazinamide, ethambutol can be stopped (Sterling, 2013).

 

Drugs and Dosages

The basic mechanisms of actions and adult and pediatric dosing of the first-line drugs will be discussed here. Adverse effects and monitoring of therapy will be covered in a separate section. Some older references recommend the use of streptomycin as an anti-tubercular drug. Streptomycin may be used in certain circumstances, but it is no longer considered to be a first-line drug for treating TB.

Drugs used to treat TB are referred to as first-line or second-line and are divided into five groups.

Group 1 is the first-line drugs. These drugs are considered to be the most effective against most TB infections.
Groups 2-5 are considered second-line. They are more toxic and less effective against TB, but they are needed if the patient is infected with M tuberculosis that is resistant to the first line drugs. The second-line drugs are:

Group 1: INH, ethambutol, pyrazinamide, rifampin, and rifepentine.

Group 2: Amikacin, capreomycin, kamamycin, streptomycin (All are injectables).

Group 3: The fluoroqunilones, gatifloxacin, levofloxacin, moxifloxacin, ofloxacin.

Group 4: Cycloserine, ethionamide, para-aminosalicylic acid, prothionamide, terizidone (All are oral bacteriostatics).

Group 5: Amoxicillin/calvulanate, bedaquiline, clarithromycin, clofazimine, high-dose INH, imipenem/cilastatin, linezolid, and thiacetazone. The efficacy of these drugs for treating TB is not clear.

The drug doses listed below were obtained from Lexicomp®, a widely accepted and used on-line pharmacology resource.

Isoniazid is classified as an antitubercular. Its mechanism of action is not known, but most likely it acts by disruption if the integrity of the TB cell wall.

Adult dose, HIV-negative: Oral or IM, 5 mg/kg day. The dose or DOT is 15 mg/kg; maximum dose is 900 mg, two to three times a week. Once weekly dosing may be used but only after the first two months of therapy and only with concurrent use of rifampin.

Pediatric dose: 10-15 mg/kg a day, maximum dose is 300 mg. The dose for DOT is 20-30 mg/kg, two-three times a week, maximum dose is 900 mg.

Rifampin is classified as an antibiotic and an antitubercular. Its mechanism of action is inhibition of bacterial RNA synthesis.

Adult dose, HIV-negative: Oral or IV, 10 mg/kg a day, maximum dose 600 mg. The dose for DOT is 10 mg/kg two-three times a week, maximum dose of 600 mg.

Pediatric dose: 10-20 mg/kg a day, maximum dose of 600 mg. The dose for DOT is the same, but given two-three times a week.

Pyrazinamide is classified as an anti-tubercular drug. Its mechanism of action is not known, but its therapeutic effect may be due to lowering pH to a level that is disadvantageous to the bacteria. The drug is given orally.

Adult dose, HIV-negative: The dosing is based on lean weight. Daily dosing is 40-55 kg, 1000 mg a day; 56-75 kg, 1500 mg a day; 76-90 kg, 2000 mg. 2000 mg is the maximum dose regardless of weight. The twice a week DOT dose is: 40-55 kg, 2000 mg; 56-75 kg, 3000 mg; 76-90 kg, 4000 mg. 4000 mg is the maximum dose regardless of weight. The three times a week DOT dose is: 40-55 kg, 1500 mg; 56-75 kg, 2500 mg; 76-90 kg, 3000 mg. 3000 mg is the maximum dose regardless of weight.

Pediatric dose: HIV-negative, daily therapy: 15-30 mg/kg, the maximum daily dose is 2 grams. The twice a week DOT dose is 50 mg/kg, maximum dose is 2 grams. HIV exposed or infected daily therapy: 20-40 mg/kg, the maximum dose is 2 grams.

Ethambutol is classified as an antitubercular drug. Its mechanism of action is disruption of bacterial cell wall synthesis. The drug is given orally. Once the bacteria is known to be sensitive to INH, ethambutol can be discontinued (Chestnutt, Prendergast, Tavan, 2014).

Adult dose, HIV-negative: The dosing can be body weight-based or based on lean body weight. Body weight dosing is: 15 mg/kg a day, maximum dose is 1.5 grams. The lean body weight dosing is: daily therapy 15-2=5 mg/kg, maximum dose is 1.5 grams. 40-55 kg, 80 mg; 46-75 kg, 1200 mg; 76-90 kg, 1600 mg. Twice a week DOT therapy dose is 50 mg/kg, maximum dose 4 grams. 40-55 kg, 2000 mg; 46-75 kg, 2800 mg; 76-90 kg, 4000 mg. Three times a week DOT therapy dose is 25-30 mg/kg, maximum dose is 2.4 grams. 40-55 kg, 1200 mg; 46-75 kg, 2000 mg; 76-90 kg, 2400 mg.

Pediatric dose, ≥ 13 years: HIV-negative, daily therapy: 15-20 mg/kg a day, maximum dose is 1 gram a day. The twice a week DOT dose is 50 mg/kg, the maximum dose is 2.5 grams a dose. HIV exposed or infected daily therapy: 15-25 mg/kg a day, the maximum dose is 2.5 grams a day.

Rifapentine is classified as an anti-tubercular drug. Its mechanism of action is as a bacteriacidal and by disruption of M tuberculosis RNA synthesis. The drug is given orally.

Adult dose: 600 mg twice a week (72 hours between doses) during the first two months of therapy and 600 mg once a week for the next six months. Pediatric dose: This drug has been use to treat latent TB in pediatric patients, but this is an unlabeled use.

Directly Observed Therapy

Tuberculosis can be cured in almost every case. Treatment failures are reported, and the majority of these are caused by poor patient compliance (Chestnutt, Prendegast, Tavan, 2014; Reichmann, Lardizabal, 2013). Poor adherence to the drug regimens used to treat tuberculosis has many causes. The length of therapy and the toxicity of the drugs can be major obstacles that prevent completion of therapy, and there are many other factors that can decrease patient compliance. In response to this, DOT was developed as a method of increasing patient compliance. In many cases of TB infection it is considered to be the standard approach.

Directly observed therapy is witnessed ingestion by a healthcare professional of the patient taking the anti-tubercular drugs and antibiotics. Directly observed therapy has been in use for many years, and there is a considerable amount of evidence supporting its effectiveness. When patients use the DOT approach, cure rates can be higher and the incidence of adverse effects lower than if the patient self-administers the drugs (Sivaraj, Umarani, Parasuraman, et al, 2014). Directly observed therapy may help decrease the resistance to second line drugs and the prevalence of XDR-TB (Chien, Tsou, Chien, et al 2014), and it has been associated with a decreased mortality rate from tuberculosis (Yen, Yen, Lip, et al, 2013).

Directly observed therapy is the approach recommended by the American Thoracic Society, the WHO, the CDC, and the Infectious Diseases Society of America, especially if the patient is receiving intermittent (two or three times a week) therapy or has drug-resistant TB (Chestnutt, Prendergast, Tavan 2014; American Thoracic Society, et al, 2003). As with any therapeutic approach there are failures, and reviews of the literature that have examined the effectiveness of DOT have not always found that DOT is a better approach to TB therapy than self-administration (Sagbakken, Frich, Bjune, et al 2013). Sagbakken, Frich, Bjune, et al (2013) noted that while DOT can be a part of the approach to TB care, patient characteristics need to be considered when prescribing therapy and a rigid protocol such as DOT may not always work.

Adverse Effects and Monitoring During Therapy

Hepatotoxicity, treatment failure, and relapse are the most serious adverse effects/outcomes of TB drug therapy.

Hepatotoxicity can be caused by INH, rifampin, or pyrazinamide. Minor and asymptomatic evidence of hepatotoxicity - a slight rise in the serum transaminases - can be expected in approximately 20% of all patients (Sterling, 2013; Raviglione, O'Brien, 2012), but fortunately clinical hepatitis is seen in only 1% of patients receiving first-line drug therapy (Gradam, Hota, 2012; Saukonnen, Cohn, Jasmer, 2006). Patients who are > 35 years of age, pediatric patients, patients who abuse alcohol or are malnourished may be at an increased risk for developing hepatitis during the drug therapy (Saukonnen, Cohn, Jasmer, 2006). Patients who are at high-risk for vitamin B6 deficiency should be given 10-25 mg of pyridoxine (vitamin B6) a day to help prevent INH-related neuropathy. This group would include patients who: abuse alcohol; are malnourished; are pregnant or lactating, or; have chronic kidney disease, diabetes, or an HIV infection (Raviglione, O'Brien, 2012).

Treatment failure is defined as positive sputum cultures during therapy, continuous or recurrent. After three months of the standard regimen, 90-95% of all patients will have a negative sputum culture, and if the cultures are continually or recurrently positive then re-testing for drug susceptibility is needed and other causes of drug failure should be considered. If the patient is clinically stable then the same drug regimen can be continued until the results of susceptibility testing have returned. If the patient is not stable, at least two and preferably three drugs that the patient has not been given before should be added to the regimen (Raviglione, O'Brien, 2012).

Relapse of TB is defined as a recurrent TB infection after the therapy has been completed and the patient has been considered cured (Sterling, 2013). Relapses are usually not due to drug-resistant bacteria (Ravigilione, O'Brien 2012), they are more likely caused by with a new strain of bacteria or a relapsed infection from the same strain that was originally treated (Sterling, 2013).

Other adverse effects that may be caused by the TB drug regimens include ocular toxicity from ethambutol, skin rashes, and gouty arthritis from pyrazinamide. The incidence of ethambutol-related visual disturbances has been reported to be 22.5 cases out of 1000 patients receiving nine months of therapy and permanent impairment was reported in 2.3 out of 1000 patients (Ezer, Benedetti, Darvish-Zargar, et al, 2013).

Baseline measurements of liver function should be obtained in all patients who are being treated for TB. Continued monitoring of liver function tests (LFTs) in patients who do not have risk factors (Discussed in the next paragraph) is not required unless the patient has some clinical signs and symptoms of liver damage.

Monitoring of LFTs is recommended if the patient: has had INH-induced hepatitis; is elderly; abuses alcohol; has viral hepatitis; is taking other drugs that can be hepatotoxic; has abnormal baseline tests; pregnant or within three months post-partum, or; is infected with HIV (Raviglione, O'Brien, 2012; Saukonnen, Cohn, Jasmer, 2006).

If the LFT results are > three times the upper limit of normal and the patient is symptomatic treatment should be stopped (Sterling, 2013). If the LFTs results are > five times the upper limit of normal treatment should be stopped, whether the patient is symptomatic or not (Sterling, 2013). Restarting therapy is a complicated issue, and there is no standardized protocol for how to restart the drugs if the patient has evidence of liver damage. If it is imperative that therapy not be stopped, other drugs can be given until the LFTs normalize and then the standard regimen can be resumed (Sterling, 2013). If an interruption in therapy is allowable then once the LFTs have returned to normal then the drugs can be re-introduced one at a time (Raviglione, O'Brien, 2012).

Patients who are taking doses of ethambutol that are higher than the standard dose should have visual acuity and color discrimination checked every month (Sterling, 2013). Patients who are taking pyrazinamide should have a baseline level of uric acid measured and the level should be periodically re-checked. Sputum samples should be evaluated monthly while the patient is being treated (Raviglione, O'Brien, 2012). By the end of the second month the majority of patient will have a negative sputum culture and by the end of the third month virtually every patient will have a negative sputum culture. If the sputum culture is still positive after three months of treatment, poor patient compliance with therapy, treatment failure, or drug resistance are likely and these possibilities should be investigated; this will be discussed in the next paragraph. Routine chest x-rays during therapy are not recommended (Raviglione, O'Brien, 2012).

A relapse is defined as TB that recurs at any time after treatment is completed (Blumberg, Burman, Chaisson, et al 2003). Relapses are caused by either the original M tuberculosis strain or re-infection with a new strain: if the patient lives in an area where the incidence of TB is very high the relapse is probably due to a re-infection with a new strain. Risk factors for re-infection include cavitation of the initial chest x-ray, concurrent HIV infection, positive AFB culture at the end of the two-month phase of treatment, previous infection or infections with TB, and living in an area with a high incidence of TB (Joo, Yoo, Hong, et al, 2014; Millet, Shaw, Orcau, et al, 2013). . Most relapses happen within 6-12 month after completion of therapy (Raviglione, O'Brien, 2012). The WHO estimated that in 2011, 5% of all cases of TB world-wide were recurrences (Bryant, Harris, Parkhill, et al, 2013).

A failure is defined as sputum cultures that are continuously or recurrently positive during therapy (Blumberg, Burman, Chaisson, et al, 2003).

If a relapse or a failure occurs, DOT should be started and drug susceptibility testing for first and second line agents should be done again. Whether or not to change the regimen from the standard four drug protocol depends on the clinical situation. If the patient is clinically unstable new drugs should be added before the susceptibility testing results are known and at least three new drugs should be started (Sterling, 2013; Raviglione, O'Brien, 2012). There are many considerations for choosing which new drugs are needed: in these situations an infectious disease specialist should be consulted.

Treatment of TB and the HIV Infected Patient

Tuberculosis and HIV have an influence on each other that is quite harmful. An infection with HIV increases the risk of latent TB reactivation, the risk of developing active TB, and increases the risk of mortality from TB (Gray, Cohn, 2013). Conversely, a TB infection can increase the morbidity associated with HIV by increasing the risk of developing opportunistic infections. Someone who is infected with HIV and has latent TB is much more likely to develop active TB than someone who is HIV-negative and the risk of reactivation increases markedly if the patient's immune system is seriously compromised (Markowitz, Hansen, Hopewell, et al, 1997).

The basic treatment of TB for a patient who is infected with HIV is the same as for an HIV-negative patient and if the regimen is carried out correctly, the cure rate is very good (Sterling, 2014). The same four drugs are used, the duration of therapy is usually six months, and patients should be given 10-25 mg of pyroxidine daily. Two important differences between treatment of HIV positive and HIV-negative patients are the dosing schedule and the risk of drug interactions.

Intermittent TB drug therapy, especially once or twice a week therapy, is not recommended for HIV-positive patients: daily therapy is recommended (WHO 2010). Intermittent therapy during the initial phase and the continuation phase has been shown to increase the rate of relapse and drug resistance (Gray, Cohn 2013).

Potentially serious interactions between the drugs used to treat TB and anti-retroviral therapy (ART) are a major concern. Significantly delaying ART is not recommended, but ART will need to be adjusted and closely monitored while the patient is being treated for TB. It is not practical in this module to thoroughly discuss all of the complex, potential drug interactions of ART and TB therapy, but rifampin deserves special mention. Rifampin induces (increases the activity of) a cytochrome p450 enzyme called CYP3A4 that metabolizes protease inhibitors and non-nucleoside reverse transcriptase inhibitors (Gray, Cohn, 2103).

Table IV: Recommendations for Dosage Adjustments
When Administering Anti-Retroviral Drugs and Rifampin

Non-nucleoside reverse transcriptase inhibitors

Nevirapine and rifampin: Start nevirapine at a dose of 200 mg twice a day instead of once a day.

Etravine and rifampin: This combination should be avoided.

Ritonavir-boosted protease inhibitors

Lopinavir-ritonavir and rifampin: The lopinavir-ritronavir dose should be 800 mg and 200 twice a day (Double dose) or lopinavir 400 mg and ritinovar 400 mg twice a day.

Atazanavir-ritonavir and rifampin: Avid the standard dose of ritonavir-boosted atazanvir, 300 mg twice daily with 100 mg of ritonavir.

Darunavir-ritonavir and rifampin: This combination should be avoided.

Fosaprenavir-ritonavir and rifampin: This combination should be avoided.

Saquinavir-ritonavir and rifampin: Saquinavir-ritonavir, 400 mg and 400 mg twice daily.

Integrase inhibitors

Raltegravir and rifampin: Increase the dose of raltegravir to 800 mg twice a day.

Elvitegravir-ritonavir and rifampin: This combination should be avoided.

CCRS receptor antagonistMaraviroc and rifampin: Increase maraviroc dose to 600 mg twice a day

Note: This list is adapted from: CDC. Managing drug interactions in the treatment of HIV-related tuberculosis, June, 2013.

As mentioned previously, it is beyond the scope of this module to thoroughly discuss all of the drug interactions that are possible when patients are receiving ART and being treated for TB. The reference cited below is from the CDC, National Institutes of Health and the HIV Medicine Association of the Infectious Diseases Society of America and it provides a comprehensive review of ART and TB drug interactions (CDC, et al, 2013):

Guidelines for the prevention and treatment of opportunistic infections in HIV infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medical Association of the Infectious Diseases Society of America. Myobacterial disease; June 17, 2103.

Finally, patients who are infected with HIV and are receiving ART are at risk for developing immune reconstitution inflammatory syndrome (IRIS). This syndrome represents a response to M tuberculosis antigens, alive or dead, that occurs within several months after ART is started. Patients who had been previously treated with TB develop new or worsening signs and symptoms of TB after starting ART or a TB infection that is undetected in unmasked by ART (Lai, Nakiwala, Meintjes, et al, 2013).

Treatment of Latent TB

Treatment of latent TB begins with an examination for the presence of active disease. If there is no active disease and the patient is determined to have latent TB, treatment should be started with one of the following regimens. Regimens 1, 2 and 3 that are outlined below are recommended by the American Thoracic Society, the CDC, and the Infectious Diseases Society of America (Parekh, Schluger, 2013; CDC/MMWR, 2011; American Thoracic Society, et al, 2000).

Regimen 1
Isonazid: 300 mg daily or 900 mg twice a week. The duration of therapy is nine months. A six month duration can be used. The intermittent regimens should be administered by DOT.

Regimen 2
Rifampin: 600 mg, daily dosing, the duration of therapy is four months.

Regimen 3
Rifampin plus INH: 600 mg of rifampin and 300 mg of INH given daily. The duration of therapy is three months.

Regimen 4
Rifapentine plus INH: 900 mg of rifapentine and 900 mg of INH given weekly. The duration of therapy is 3 months.

The treatment regimen preferred by the CDC is Regimen 1 for nine months (American Thoracic Society, et al, 2000). If the patient is ≥ 12 years and is in one of the following four risk categories, Regimen 4 should be used (CDC/MMWR, 2011): 1) Close contact with persons with culture-confirmed contagious TB and a positive tuberculin test; 2) Conversion of skin test from negative to positive; 3) Patients who are HIV-positive, not on anti-retrorviral medications, and have a positive skin test or HIV-positive patients who have had close contact with someone who has confirmed TB regardless of the skin test result, and; 4) A positive skin test and fibrotic changes on CXR that are consistent with previously untreated TB.

The INH-rifapentine regimen ( #4) is not recommended for use in the following situations: children aged <2 years as the safety and pharmacokinetics of this regimen have not been established for this group; HIV-infected patients receiving antiretroviral treatment as the drug interactions have not been studied; pregnant women or women expecting to become pregnant during treatment as safety in pregnancy is unknown, and; patients who have latent TB that is presumed to be INH or rifampin-resistant (CDC/MMWR, 2011).

Treatment of latent TB with rifampin and pyrazinamide is not recommended as there have been reports of serious liver injury and death associated with this regimen (Iiaz, Jereb, Lambert, et al, 2006; CDC/MMWR, 2003; Jasmer, Saukonnen, Blumberg, et al, 2002).

The decision to treat should be based on the risk of re-activation. People who should be treated are (CDC, 2012)

People who have a positive IGRA test result or skin test reaction ≥ 5 mm and

  1. Are infected with HIV,
  2. Have had recent contact with someone confirmed to have TB,
  3. Have fibrotic changes on CXR consistent with a previous exposure to TB,
  4. Have had an organ transplant, or
  5. Are immunosuppressed or have the potential to be or are taking prednisone or TNF antagonists.

People who have a positive IRGA test result or a skin reaction ≥ 10 mm and

  1. Are recent immigrants from a country with a high prevalence of TB,
  2. Are IV drug users
  3. Are residents or employees of high-risk environments, e.g., correctional facilities, nursing homes, homeless shelters, hospitals,
  4. Work in a laboratory that processes myobacteria samples, or
  5. Are < 4 years of age or are children or adolescents that have been exposed to a high-risks adult.

Someone who does not have any risk factors but has a positive IGRA test result or a skin reaction = 15 mm can be considered for treatment.

Treatment of Latent TB during Pregnancy

The decision to treat pregnant women who have latent TB is controversial. Some authors have found that reactivation of latent TB during pregnancy confers a high risk of death, prenatal complications, and poor fetal outcome (Mathad, Bhosale, Sankar, et al, 2014), and that women who have latent TB and are in the early post-partum period are twice as likely as non-pregnant women to reactivate (Mathad, Bhosale, Sankar, et al, 2014). Others authors note that pregnancy does not affect the pathogenesis of TB (Friedman, Tanoue, 2014). These differences could be explained by differing populations in terms of healthcare resources, baseline pre-natal health, and respective incidences of risk factors. There are no guidelines for when during pregnancy to treat latent TB, but it may be prudent to do so if the mother has reactivation risk factors, e.g., a recent TB infection, infection with HIV, or she is immunocompromised (Friedman, Tanoue, 2014).INH, ethambutol, pyrazinamide, and rifampin are considered to be pregnancy risk category C. Category C means that there are no adequate animal or human studies that clearly outline the potential risks or adverse fetal effects have been reported in animal but there is no human data.

INH and rifampin cross the human placenta. Post-natal hemorrhages have been reported in the mother and infant when INH and rifampin were used during the last weeks of pregnancy. Ophthalmic abnormalities have been reported in infants of mothers who were taking ethambutol (Lexicomp ®).

Suggested treatment regimens for pregnant women who have latent TB:

Regimen 1
This is recommended in areas where the burden of TB is considered low. Isoniazid, 300 mg daily, the duration of therapy is six to nine months. The patient should also receive pyridoxine 25 mg daily for the duration of the therapy. Isoniazid at 900 mg twice a week can also be used.

Regimen 2
This is recommended in areas where the burden of TB is considered high (WHO 2011). Isoniazid 300 mg daily for six months or for 36 months if the patient's living conditions pose a high level of risk for transmission or prevalence, e.g., correctional facilities, nursing homes, homeless shelters. The patient should also receive pyridoxine 25 mg daily for the duration of the therapy

If the patient cannot tolerate INH, 600 mg of rifampin daily can be used (Friedman, Tanoue, 2014).

It does not appear that pregnancy increases the risk of developing drug-induced hepatitis (Taylor, Mosimaneotsile, 2013).

Breast feeding is not contraindicated if the mother is being treated for latent TB because of the very small amounts of the drugs that are excreted in breast milk. However, although no toxicity has been reported in breastfeeding infants whose mothers are receiving drug therapy for TB, if the infant is also being treated then dosage adjustments should be considered (Loto, Awowole, 2012).Infants that are receiving ING directly or in breast milk should be given supplemental pyridoxine.

Treating Latent TB in the HIV-Infected Patient

People who are infected with HIV and have latent TB are more likely to reactivate than people who are HIV-negative (Menzies, 2014). The risk factors for reactivation that apply to people who are not HIV-positive apply to HIV infected individuals (e.g., alcohol abuse, diabetes, IV drug use, etc.). Someone who is infected with HIV is also more likely to reactivate is she/he is has a high HIV-RNA count or is very immunosuppressed, e.g., a low CD4 cell count < 200 cell/mm3 (Sterling, Lau, Zhang, et al, 2011).

All patients who are infected with HIV and have latent TB should receive anti-tubercular therapy. Treatment for latent TB infection in this population reduces the incidence of TB and reduces mortality rate (Martinson Barnes, Moulton, et al, 2011; Akolo, Adetifa, Shepperd, et al, 2010). The reduction of the risk of developing TB in HIV-infected patients who receive treatment has been reported to be between 32-64% (Dierberg, Chaisson, 2013).

The regimens for treating latent TB in an HIV-infected individual depend on availability of resources. Nine months of INH or INH plus rifampin for three months can be used (Dierberg, Chaisson, 2013).

Treatment of MDR-TB and XDR-TB

Resistance to the first-line drugs used to treat TB is caused by mutation of M tuberculosis. This can happen naturally, as a result of drug therapy for TB, or as result of improper drug therapy for TB. (Lemos, Matos, 2013). Drug-resistant strains of M tuberculosis are often present in small numbers, and if drug therapy for TB is not optimal these drug-resistant strains can become the dominant organism of the infection. Poor compliance with drug therapy is the biggest risk factor for developing MDR-TB and XDR-TB.

Multidrug-resistant TB is difficult to treat successfully. The duration of therapy is much longer than what is required for drug-susceptible TB, and the drugs that are used are less effective and have a greater number of side effects than the first-line drugs.

The ideal treatment for MDR-TB has not been determined, but it is generally agreed on that at least four drugs should be used, and at least three of them should be drugs that the patient was not previously treated with (Calligaro, Moodley, Symons, et al, 2014; Lemos, Matos, 2013). Empiric treatment that is based on the local patterns of drug susceptibility can be used. Treatment of MDR-TB includes: any first-line drug that the bacteria are susceptible to; a later generation fluroquinilone, i.e., gatifloxacin, levofloxacin, or moxifloxacin; amikacin or kanamycin, and; one of the Group 4 drugs (Calligaro, Moodley, Symons, et al, 2014). The first phase will include the injectable drugs and the duration is eight months; the second phase should be 12-18 months. The duration of therapy is determined by the results of sputum cultures, and it will often be extended for many months past the point of negative sputum cultures. The success rate has been estimated to be < 50%. Success rates are dependent in part on patient factors and the availability of resources.

Extensively drug-resistant TB is very difficult to treat successfully. Treatment requires a very long duration of therapy and the use of drugs that are less effective than first-line drugs and more toxic. Reliable drug susceptibility testing of some of the medications that are used to treat XDR-TB is not available (Heysell, Friedland, 2014), and there is little clinical data on the effectiveness of some of the second-line drugs. The success rate is low, between 20-44% (Calligaro, Moodley, Symons, et al, 2014). The mortality rate has been reported to be > 20% and if the patient is infected with HIV the mortality rate can be as high as 98% (Heysell, Friedland, 2014). However, higher treatment success rates - 65% - have been reported (Sotigou, Ferra, Mattelli, et al, 2009). Patients who have XDR-TB have a relatively high risk of developing extra-pulmonary tuberculosis. Success rates are in part dependent on patient factors and the availability of resources.

The optimum treatment regimen for XDR-TB has not been established by the use of large, controlled clinical trials.

Treatment of XDR-TB should include at least five drugs, including any of the first-line medications to which the bacteria are susceptible (Heysell, Friedland, 2014). Empiric treatment that is based on the drug susceptibility patterns of the local area can be used.

Surgery is an option for treating MDR-TB and XDR-TB (Calligaro, Moodley, Symons, et al, 2013). Pulmonary resection can remove well localized, cavitated lesions that contain a considerable number of bacteria (Xie, Yang, He, et al, 2013). Patients who have DR-TB are considered to be candidates for surgery if: there is a persistently positive smear despite optimal drug therapy; the drug resistance is extensive and relapse and/or failure are highly probable; the disease is localized and the affected area/areas can be resected; cardiac and pulmonary reserved post-operatively are expected to be adequate, and; there is sufficient drug susceptibility for the bronchial stump to heal (Calligaro, Moodley, Symons, et al, 2014).

Hospital Infection Control

Healthcare facilities should have administrative controls and environmental controls in place to prevent the transmission of TB. The administrative controls involve issues such as staff education, reporting requirements, and risk assessments. Environmental controls are controlling the source of the infection and controlling the environment in order to prevent the spread of TB. A detailed discussion of these administrative and environmental controls is available from the CDC website (CDC, 2005).

Patients who are initially suspected of having active TB should be placed in an airborne infection isolation room. If this is not immediately possible, the patient should be place in an enclosed area away from patients who are immunocompromised, and the patient should wear a surgical mask. The patient should be instructed about respiratory and cough etiquette. All staff members who are providing patient care should wear an N95 respirator.

Once the patient is in an airborne infection isolation room, the patient no longer needs to wear a surgical mask, but respiratory and cough etiquette should be maintained. Staff entering the room should wear an N95 respirator. If the patient needs to leave the room for a procedure or testing, he/she should wear a surgical mask, not an N95 respirator. The former are designed to trap exhaled infected droplets in the mask: the latter are designed to filter air before it is inhaled.

The N95 must be individually fitted and properly used. It is disposable and cannot be cleaned and a seal test should be done each time an N95 is put on (Benson, Novak, Ogg, 2013). Standard and airborne precautions should be observed.

Isolation can be discontinued when: 1) Three sputum samples from three consecutive days are AFB negative; 2) The patient is on the appropriate therapy, and; 3) The patient is clinically improving (Zachary, 2013).
 

Prevention

Someone who has AFB smear positive TB is considered to have been contagious for three months prior to the first positive smear or the onset of symptoms, whichever is earlier (Zachary, 2013). If the AFB smear is positive, the patient has signs/symptoms consistent with TB, or a chest x-ray shows cavitation then a contact investigation should be initiated (National Tuberculosis Controllers Association, CDC, 2005). Healthcare workers who have had contact with an infected patient should be screened for TB.

Tuberculosis is a reportable disease. Notifying the local health department about a confirmed case of TB is mandatory and should be done as soon as possible via telephone. Physicians are primarily responsible for reporting TB cases, but other healthcare personnel and professionals (e.g., laboratory personnel, school nurses) can notify the health department. Once the notification has been made, the patient will be interviewed and patient contacts will be located and interviewed. Household contacts with someone who has active TB or patient care contact with someone who has drug-resistant TB confers a risk of developing TB of 3.1% and 3.4%, respectively (Fox, Barry, Britton, et al, 2013), but rates up to 20 % have been reported.

Patient Education

The following recommendations are from the CDC: Self Study Modules on Tuberculosis (CDC, 2008).

Patients who are suspected or confirmed for having TB disease are frequently sent home after starting treatment, even though they may still be infectious. Patients with TB disease can be sent home even if they do not have three negative sputum smears, if the following criteria are met:

  • A follow-up plan has been made with the local TB program;
  • The patient is on standard TB treatment and directly observed therapy (DOT) has been arranged;
  • No infants or children less than 4 years of age or persons who are immunocompromised are present in the household;
  • All household members, who are not immunocompromised, have been previously exposed to the person with TB; and
  • The patient is willing to not travel outside his/her home until he/she has negative sputum smear results.

If all of the above criteria are met, patients with TB disease are allowed to go home. Additionally they are more likely to have already transmitted TB to members of their household before their TB was diagnosed and treatment was started. However, TB patients and members of their household should still take steps to prevent the spread of TB in their home. For example, patients with TB should be instructed to cover their mouth and nose with a tissue when coughing or sneezing. Infectious TB patients should sleep alone, not in a room with other household members. Furthermore, TB patients should be advised to not have visitors until they are non-infectious.

Patients with infectious TB should not be allowed to return home where they may expose a person who is at high risk for progressing to TB disease if infected (for example, persons who are infected with HIV, or infants and children younger than age 4). Healthcare workers in home-based health care or outreach settings should be trained on detecting the signs and symptoms of TB disease. Training should include the role of the health care worker in educating patients about the importance of reporting symptoms or signs. Health care workers should also educate patients and other household members about the importance of taking medications as prescribed.

Health care workers should not perform cough-inducing or aerosol-generating procedures on patients with suspected or confirmed infectious TB disease inside a patient's home. Sputum collection should be performed outdoors, away from other persons, windows, or ventilation intakes.

Health care workers who visit TB patients at their homes should take these precautions to protect themselves from exposure to M tuberculosis:

Instruct patients to cover their mouth and nose with a tissue when coughing or sneezing;

Wear a personal respirator when visiting the home of an infectious patient with TB or when transporting an infectious patient with TB in a vehicle;

When it is necessary to collect a sputum specimen in the home, collect the specimen in a well-ventilated area, away from other household members; if possible, the specimen should be collected outdoors; and

Participate in a TB testing and prevention program.

Patients should also be instructed about the signs and symptoms of adverse effects of the medications used to treat TB, particularly those that may indicate drug-induced hepatitis, ocular damage, or peripheral neuropathy.

  • INH: Abdominal pain, dark urine, fatigue, fever for more than three days, flu-like symptoms, nausea, vomiting, and yellow coloring of the eyes or skin (Drug-induced hepatitis). Numbness or tingling in the face or extremities (Peripheral neuropathy).
  • Ethambutol: blurred vision, any change in vision or color perception.
  • Pyrazinamide: Anorexia, fatigue, joint pain, nausea, vomiting.
  • Rifampin: Abdominal pain, dark urine, fatigue, fever for more than three days, flu-like symptoms, nausea, vomiting, and yellow coloring of the eyes or skin (Drug-induced hepatitis).

Patients should also be instructed on the importance of strict adherence to the medication regimen and the consequences of non-compliance.

Vaccination for TB

The only TB vaccine that is currently available is BCG. Bacillus Calmette-Guérin vaccine is not routinely used in the US, but many foreign-born persons have been BCG-vaccinated. BCG is primarily used in countries with a high prevalence of TB to prevent childhood tuberculous meningitis and miliary disease. Vaccination with BCG may be done in either of these two circumstances (Lexicomp ®).

Children: Children with a negative tuberculin skin test who are in a living situation in which the likelihood of exposure to TB is considered to be high and the child cannot be removed from that situation. Vaccination should also be done if the child is continually exposed and cannot be treated or if the child is exposed to TB that is resistant to INH and rifampin. The vaccine is considered to be > 80% effective for children (Advisory Council for the Elimination of Tuberculosis, Advisory Committee on Immunization Practices, 1996).

Healthcare workers: Healthcare workers who are exposed to a high percentage of patients of who have M tuberculosis that is resistant to INH and rifampin should be vaccinated with BCG. Healthcare workers should be vaccinated with BCG if there is ongoing transmission of drug-resistant M tuberculosis strains to health care workers and subsequent infection is likely or comprehensive TB infection-control precautions have been implemented but have not been successful.

BCG vaccination should not be given to persons who are immunosuppressed (e.g., persons who are HIV infected) or who are likely to become immunocompromised (e.g., persons who are candidates for organ transplant).

BCG vaccination should not be given during pregnancy. Even though no harmful effects of BCG vaccination on the fetus have been observed, further studies are needed to prove its safety.

Non-Pulmonary TB

The incidence of non-pulmonary TB is increasing. In 1995 one of every patient with TB had some form of non-pulmonary TB; in 2011, one of every 3 patients with TB had some form of non-pulmonary TB (Pusch, Pasipandoya, Hall, et al, 2014). Non-pulmonary TB infections are especially common in people infected with HIV (Gray, Cohn, 2013). Non-pulmonary infections, often at multiple sites, have been noted in up to 70% of HIV-infected patients who are severely immunosuppressed (Jones, Young, Antoniskis, et al, 1993).

Treatment of Children With TB

Tuberculosis is a significant burden on children. Approximately 11% of new cases of TB each year occur in children (Berti, Galli, Venturini, et al, 2014). There are well established pediatric treatment guidelines, but there are also areas of uncertainty and obvious research needs, e.g., the risk of INH-induced hepatotoxicity at doses > 10 mg/kg, and pharmacokinetic studies on the first-line drugs when used in the newly recommended doses (WHO, 2010). Co-infections with TB and HIV in children in areas where TB is endemic are relatively common, and as with adults, the prognosis for children who are infected with HIV and TB is grim.

Given the risk of drug-induced hepatotoxicity, WHO recommends these doses of antituberculosis medicines and treatment regimens for the treatment of tuberculosis in children (WHO, 2010):

Isoniazid (H) – 10 mg/kg (range 10–15 mg/kg); maximum dose 300 mg/day
Rifampicin (R) – 15 mg/kg (range 10–20 mg/kg); maximum dose 600 mg/day
Pyrazinamide (Z) – 35 mg/kg (30–40 mg/kg)
Ethambutol (E) – 20 mg/kg (15–25 mg/kg)

Children living in settings where the prevalence of HIV is high or where resistance to isoniazid is high, or both, with suspected or confirmed pulmonary tuberculosis or peripheral lymphadenitis; or children with extensive pulmonary disease living in settings of low HIV prevalence or low isoniazid resistance, should be treated with a four-drug regimen (HRZE) for 2 months followed by a two-drug regimen (HR) for 4 months at the following dosages:

Isoniazid (H) – 10 mg/kg (range 10–15 mg/kg); maximum dose 300 mg/day
Rifampicin (R) – 15 mg/kg (range 10–20 mg/kg); maximum dose: 600 mg/day
Pyrazinamide (Z) – 35 mg/kg (30–40 mg/kg)
Ethambutol (E) – 20 mg/kg (15-25 mg/kg)

Children with suspected or confirmed pulmonary tuberculosis or tuberculosis peripheral lymphadenitis who live in settings with low HIV prevalence or low resistance to isoniazid and children who are HIV-negative can be treated with a three-drug regimen (HRZ) for 2 months followed by a two-drug (HR) regimen for 4 months at the following dosages:

Isoniazid (H) – 10 mg/kg (range 10–15 mg/kg); maximum dose 300 mg/day
Rifampicin (R) – 15 mg/kg (range 10–20 mg/kg); maximum dose 600 mg/day
Pyrazinamide (Z) – 35 mg/kg (30–40 mg/kg)

Children with suspected or confirmed pulmonary tuberculosis or tuberculosis peripheral lymphadenitis living in settings with a high HIV prevalence (or with confirmed HIV infection) should not be treated with intermittent regimens (that is, twice-weekly or thrice-weekly doses).

During the continuation phase of treatment, thrice-weekly regimens can be considered for children known to be HIV-uninfected and living in settings with well-established directly-observed therapy (DOT).

Infants (aged 0–3 months) with suspected or confirmed pulmonary tuberculosis or tuberculous peripheral lymphadenitis should be promptly treated with the standard treatment regimens, as described above. Treatment may require dose adjustment to reconcile the affect of age and possible toxicity in young infants. The decision to adjust doses should be taken by a clinician experienced in managing pediatric tuberculosis.

Streptomycin should not be used as part of first-line treatment regimens for children with pulmonary tuberculosis or tuberculous peripheral lymphadenitis.

Children with suspected or confirmed tuberculous meningitis should be treated with a four-drug regimen (HRZE) for 2 months, followed by a two-drug regimen (HR) for 10 months; the total duration of treatment being 12 months. The doses recommended for the treatment of tuberculous meningitis are the same as those described for pulmonary tuberculosis.

Children with suspected or confirmed osteoarticular tuberculosis should be treated with a four-drug regimen (HRZE) for 2 months followed by a two-drug regimen (HR) for 10 months; the total duration of treatment being 12 months. The doses recommended for the treatment of osteoarticular tuberculosis are the same as those described for pulmonary tuberculosis.

Children with proven or suspected pulmonary tuberculosis or tuberculosis meningitis caused by multiple drug-resistant bacilli can be treated with a fluoroquinolone in the context of a well-functioning MDR-TB control program and within an appropriate MDR-TB regimen. The decision to treat should be taken by a clinician experienced in managing pediatric tuberculosis.

In the US children who have latent TB are treated with nine months of INH (Cruz, Stark, Lobato, 2014). Other regimens are available for specific clinical situations.

Conclusion

Tuberculosis is increasingly uncommon in the United States. However, recent immigrants, people infected with HIV, the elderly, and people with certain risk factors are susceptible to developing primary disease or reactivation of latent TB, and some of these populations (e.g., the elderly, people with medical risk factors) are increasing each year. Elimination of TB depends on targeted screening for latent TB, strict adherence to drug regimens, and the proper use of infection control techniques for hospitalized patients who have TB. If screening, treatment, and infection control are done properly, TB could be effectively eliminated.

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This course is applicable for the following professions:

Advanced Registered Nurse Practitioner (ARNP), Clinical Nurse Specialist (CNS), Licensed Practical Nurse (LPN), Licensed Vocational Nurses (LVN), Registered Nurse (RN), Respiratory Therapist (RT)

Topics:

Advance Practice Nurse Pharmacology Credit, CPD: Practice Effectively, Infection Control/Disease, Puerto Rico Requirements


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