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Tuberculosis

2.00 Contact Hours
This course is applicable for the following professions:
Advanced Registered Nurse Practitioner (ARNP), Certified Registered Nurse Anesthetist (CRNA), Clinical Nurse Specialist (CNS), Licensed Practical Nurse (LPN), Licensed Vocational Nurses (LVN), Midwife (MW), Nursing Student, Registered Nurse (RN), Respiratory Therapist (RT)
This course will be updated or discontinued on or before Saturday, July 31, 2021
Course Description
The course covers how to diagnosis and treat of tuberculosis. Upon completion of this course, you will be able to discuss the criteria used to diagnose tuberculosis, and know how to differentiate groups susceptible to primary tuberculosis versus reactivation of latent tuberculosis. You will also learn about prevention and drug treatment for primary, latent and drug-resistant tuberculosis.
CEUFast Inc. did not endorse any product, or receive any commercial support or sponsorship for this course. The Planning Committee and Authors do not have any conflict of interest.

Last Updated:
To earn of certificate of completion you have one of two options:
  1. Take test and pass with a score of at least 80%
  2. Reflect on practice impact by completing self-reflection, self-assessment and course evaluation.
    (NOTE: Some approval agencies and organizations require you to take a test and self reflection is NOT an option.)
Author:    Dana Bartlett (RN, BSN, MA, MA, CSPI)

Outcomes

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

Objectives

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

  1. Identify patients at risk for Tuberculosis
  2. Identify what factors influence the progression of latent TB to active TB
  3. List the four criteria used to diagnose TB and their relative importance
  4. Identify the preferred medications used to treat TB
  5. Determine when treatment for active and latent tuberculosis should be initiated in the different patient populations.

Epidemiology

A total of 9,029 cases of tuberculosis (TB) were reported in the United States in 2018.1 This is the lowest reported number of cases on record in the United States, and the incidence of TB cases in the United States has been declining for many years. In 2017 there were 128 cases of multi-drug resistant tuberculosis (MDR-TB) in the United States and 3 cases of extensively drug-resistant TB.1

Unfortunately, the statistics from the rest of the world are not encouraging. Tuberculosis is the second leading cause of death from infectious disease worldwide. According to the World Health Organization (WHO), TB worldwide is one of the top 10 causes of death and the leading cause from a single infectious agent (Above HIV/AIDS).2 The worldwide incidence of new cases has been steadily declining by approximately 2% a year2, but the available numbers are a clear reminder of the breadth and severity of the disease. The 2018 WHO Global report estimated that 1.7 billion people have latent TB; in 2017 there were 1.3 million deaths from TB in people who were not infected with HIV and 300,000 deaths in people with TB who were HIV infected, and; 3.5% of new cases and 18% of newly diagnosed cases had MDR-TB.2 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 the 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.3 The 10% that are not expelled will eventually reach the alveoli.3

Once the TB bacteria reach the alveoli one of three situations occurs:

  1. The patient may 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.3,4

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 enough 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.3,4 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 disease4; 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,5 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. Children who are < 1 year of age have approximately a 50% chance of developing primary active TB,6 and because of their immature immune system, infants and children are quite susceptible to developing non-pulmonary TB.7

Tuberculosis can disseminate and cause non-pulmonary infections; this is especially likely in people who are infected with HIV. Non-pulmonary TB infections occur in 10%-40% of patients and in descending order, the frequency of non-pulmonary TB infections is3:

  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 uncommon3 and isolated non-pulmonary TB is not considered contagious.8 Inhalation of the infected droplets happens by being near 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, and household contacts of someone who has TB are very susceptible to developing the disease.9 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.10

Vertical, mother-to-child transmission of tuberculosis can occur in utero or perinatally.11

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 and/or developing the disease after infection with TB12:

Table 1: 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
  • People who live in areas where TB is endemic, e.g., Asia, Africa, Eastern Europe
  • People who are immunosuppressed
  • Anyone who lives in close, household contact with someone infected with TB
  • Smokers, people who drink alcohol
  • 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 a cough of > two-three weeks duration, lymphadenopathy, fever, night sweats, and weight loss.7 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 if the patient is elderly or immuno-compromised.

The diagnosis of TB is made using the following four criteria.3 Of these four, the isolation and identification of tuberculosis in sputum is 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 the patient:
    1. Is infected with HIV;
    2. Has a positive TB screening test;
    3. Has been exposed to someone who is known to have active disease;
    4. Has been treated for TB;
    5. Has traveled to an area where TB is endemic;
    6. Is homeless or incarcerated;
    7. Uses IV drugs;
    8. Is very young, or;
    9. 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 (CXR) is an important part of the diagnostic work-up for TB. However, a chest x-ray is highly sensitive but poorly specific, and a CXR cannot distinguish between active and inactive TB and the "classic" findings of upper lobe infiltrate and cavitation may be absent.3 A chest x-ray can be suggestive of TB but not always confirmatory.
  4. Laboratory testing: Laboratory testing to confirm the presence of TB can be done using an acid-fast bacillus (AFB) smear, mycobacterial culture, or testing for the presence of TB DNA.3,7 The AFB smear test is inexpensive and quick to do, but the sensitivity is only 40%-60%.3 A mycobacterial culture is the definitive test for TB7; it is highly sensitive for the presence of TB, and is also used to identify the species and to determine drug susceptibility but the culturing, however, takes several days to complete.7 Testing for TB DNA has the advantage of quick results, high sensitivity and specificity and also determining the DNA and RNA sequences of the particular TB organism, a feature that is very helpful for tracking TB mutations and determining drug resistance.3,7

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.7 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. The induction will usually initiate coughing and hopefully, production of a sputum sample. There does not appear to be a significant advantage of self-produced versus induced sputum samples for diagnosing TB.7 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 a high sensitivity,13 but it is costly, invasive, 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.7

There is a classification system for patient history of TB.14

ClassTypeDescription
0No exposure to TB
Not infected

No history of exposure, negative reaction to tuberculin skin test

1Exposure to TB
No Evidence of infection

History of exposure, negative reaction to tuberculin skin test (given at least 10 weeks after exposure

2TB 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
3Current TB disease

Meets current laboratory criteria (for example, a positive culture) or criteria for current clinical case definition

4Previous 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

5TB 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 are15,16:

  • 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 fluoroquinolone and any second-line injectable, i.e., amikacin, capreomycin, and kanamycin.

There have been reports of a strain of TB called totally drug-resistant TB, aka TDR-TB,17,18,19 a type of TB that is resistant to INH and to the second-line drugs that are used to treat XDR-TB. Heysell and Friedland18 point out that these TB strains were not tested to a complete panel of second-line drugs, but the authors also note that the “. . . emergence of TDR-TB also highlights the limited availability of susceptibility testing for the less commonly used anti-tuberculosis drugs, the concern for amplified drug resistance in the face of weakly potent drug combinations, the relative inability to predict synergy or drug activity at the site of infection, and the need for optimized pharmacokinetic strategies and entirely new anti-tuberculosis drug regimens.” Currently, there are no accepted diagnostic criteria for these clinical situations.20

Diagnosis of Latent Tuberculosis

Over 1.7 billion people worldwide are estimated to have latent TB. Latent TB has the potential to develop into the active disease at any time, and the majority of cases of active TB are re-activated latent infections.5 Fortunately, only 4-6% of people with latent TB develop an active infection21, but given the numbers of latent TB infections, this represents a serious public health issue. Risk factors for reactivation of latent TB include22:

Table II: Risk Factors for Latent TB Reactivation

  • Use of systemic glucocorticoids, ≥ 15 mg/day for ≥ 1 month
  • Cancer of the head and neck
  • Casual or close contact with someone who has active, untreated TB
  • 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 jejunal bypass surgery
  • Living in areas where TB is endemic
  • 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
  • Age < 5 years
  • Silicosis
  • Use of tumor necrosis factor-alpha (TNF-a) antagonists: adalimumab, etanercept, golimumab, and infliximab

There is no method by which latent TB can be directly identified.22 The diagnostic tools available provide indirect evidence of the presence of M tuberculosis by detecting an immune response to the bacteria, and an initial suspicion of the presence of TB that is suggested by a positive test must be confirmed by a clinical examination and consideration of the epidemiological circumstances.3 The two laboratory tests methods that are used to help diagnose latent TB are the tuberculin skin test (TST) and interferon-gamma release assays (IGRAs).3,22 The Tine test and the Heaf test were methods previously used to detect TB, but they have fallen out of favor and are no longer recommended.

The TST 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 are23:

  • ≥ 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 ≥ 15 mm this is considered a positive reaction, regardless of the patient’s medical conditions or risk factors.

The tuberculin skin test is a useful screening tool, but it has limits; 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.23 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.

The causes of false-negative TST include22,23:

  • Administration or interpretation errors
  • A Weakened immune system, the patient cannot form a reaction
  • Viral infections, measles, mumps, varicella
  • Long-standing, old TB infection
  • Recent (within 8-10 weeks) TB infection
  • Recent measles and or MMR vaccination
  • Bacterial infections (Brucellosis, leprosy, pertussis, typhus, typhoid fever)
  • HIV infection, particularly with a very low (<200) CD4 cell count
  • Chronic renal failure
  • Severe malnutrition
  • Stress associated with burns or surgery
  • Active, advanced tuberculosis
  • Fungal infection (South American blastomycosis)
  • The use of immunosuppressive drugs
  • Infants < 6 months
  • Older adults
  • Lymphoid organ disease, chronic lymphocytic leukemia, lymphoma, sarcoidosis

False-positives are caused by the presence of another type of mycobacteria, if the patient who was vaccinated with the Bacillus Calmette-Guérin (BCG) vaccine, or by administration errors.23,24 A false-positive skin test caused by BCG vaccination is most likely within the first 10 years after the patient was vaccinated.24 The TB skin test cannot determine if a positive reaction was caused by BCG vaccination or latent TB, but an IRGA can make the distinction.24 Another potential issue with the TST is the boosting phenomenon.3 A TST that is repeated one to five weeks after the first can cause the reaction to be large enough so that it may be mistaken for a conversion.3

The IRGA test is like the tuberculin skin test in that they do not detect the presence of bacteria: they detect a specific immune response to TB. The IGRA test uses a blood sample that measures T-cell release of interferon-gamma in response to M tuberculosis antigens.25 The IRGA tests offer some advantages when compared to skin testing. The results are available in 24-48 hours; there is no boosting phenomenon as there is with the TST; the IRGA test is more sensitive and at least as specific as the TST; the patient only needs one visit to a healthcare provider; the IRGA is not affected by vaccination with BCG; it is a more suitable test if, for some reason, the patient would not return for a reading of a TST; the result of an IRGA test is a laboratory value and does not, like the TST, rely on an examiner’s visual inspection; and IRGA test results do not appear to be affected by infection with some (but not all) non-tuberculosis mycobacteria.23

As with essentially any diagnostic test, the IRGAs have limitations. The IRGAs cannot distinguish between latent infection and active TB.23 The test is expensive, which is a consideration in resource-poor areas, and; there is limited data on its use in children < 5 years of age, people who were recently exposed to TB, and people who are immunocompromised.23

If the patient has a positive IRGA test result, he/she should be considered for treatment of latent TB based on the likelihood that the disease will reactivate and active TB will occur,25 e.g., the patient has an HIV infection, he/she has other medical conditions like diabetes, head or neck malignancy, or renal failure.

If the patient has a negative HRGA test result, treatment for latent TB may be needed if the patient has a high-risk for reactivation, e.g., she/he has an HIV infection and false-positive tests can occur if the patient is immunosuppressed.25

If the result is indeterminate, that means the test could not be interpreted, and it should be repeated.25 If the repeat IRGA is negative, the patient should be treated in the same way as if the initial test was negative. If the repeat test is positive, the patient should be treated in the same way as if the initial test was positive.25 If the repeat test is indeterminate, treatment will depend on the TST result; if the TST is negative, treat the patient as in the initial IRGA had been negative, and if the TST is positive, treat the patient as if the initial IRGA had been positive.25

Screening

Screening for Latent Tuberculosis

The goal of screening for latent TB is to identify people who have the disease so that they can be treated prophylactically, and treatment of those in need can reduce the risk of developing active TB by approximately 90%.22 However, the screening tests can identify people who have latent TB, but they cannot accurately predict if a latent infection will reactivate. Between 4-6% of all those who have latent TB will reactivate, but this risk is not spread evenly through the population, and it also depends on how long the infection has been present and the medical co-morbidities of the patient.22 Infants < 1 year of age have a 50% chance of reactivating; healthy individuals without risk factors, > 10 years of age and an infection that has been present < two years have a risk of 1%-2%, and; people who have an HIV infection and latent TB have a 10% annual risk of developing the active disease 26,27 compared to the annual risk of 0.1% of healthy people who have latent TB but who are healthy.22

Screening must be targeted to identify people who need treatment, those who do not, and to avoid unnecessary treatment. The following screening guidelines are recommended by the CDC, the American Thoracic Society, and the Infectious Diseases Society of America, and they are based on:

  1. The likelihood that a patient has a latent TB infection, and;
  2. The risk that a latent TB infection will progress to the active disease.21

People who are likely to have an infection are those who have close or casual contact with people who have active, untreated TB; people who use illicit drugs; residents of a correctional facility or a homeless shelter, or; health care workers in certain circumstances.22 People who have a high risk for reactivation are those who have any of the following22: HIV infection; transplant patients; head and neck cancer, leukemia, or lymphoma; silicosis ESRD requiring dialysis; treatment with TNF-alpha inhibitors; an abnormal CXR that shows findings typical of healed TB.

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 following screening guidelines are recommended by the CDC, the American Thoracic Society, and the Infectious Diseases Society of America.21 The choice between using the TST or the IRGA depends on how likely it is the patient who has suspected latent TB will progress to the active disease; if progression is unlikely, use the IRGA, but if progression is likely, the TST or the IRGA can be used.22

The patient is likely to be infected, has a high risk of progression to active TB, and the TST result is ≥ 5 mm. If these criteria are met: Adults can be tested with either an IRGA or a TST, or with dual testing, if either test is positive. Children ≤ 5 years can be tested with an IRGA or a TST, but a TST is preferred.

The patient is likely to be infected, has a low to moderate risk of progression to active TB, and the TST result is ≥ 10 mm. If these criteria are met: The IRGA is preferred, but the IRGA or TST can be used.

The patient is unlikely to be infected and the TST is ≥ 15 mm: Testing for latent TB is not recommended.

Routine testing of healthcare workers is a separate issue. Healthcare workers have traditionally been considered to have a higher potential for exposure to TB than the general public, but this may not be the case, and as with reactivation rates in the general population, this risk is not spread evenly.28

The current recommendations from the CDC for screening healthcare personnel for the presence of TB are listed below.29

  1. A risk assessment and an evaluation for symptoms should be done at baseline, before hiring.
  2. If the person does not have documented TB or latent TB, an IGRA or a skin test can be used for screening.
  3. If there is a known exposure, perform a symptom evaluation. If the patient has a prior TB test that was negative, does not have latent TB and has not had TB in the past, perform a skin test or an IRGA and repeat the test 8-10 weeks later.
  4. Routine serial testing for TB after the baseline assessment and testing does not need to be done if there is no known exposure or ongoing transmission.
  5. Encourage treatment for all health care personnel with untreated latent TB, unless treatment is contraindicated;
  6. Healthcare personnel who have untreated latent TB should have an annual screening for symptoms of TB.
  7. Healthcare personnel are to receive annual TB education.

Screening to Latent Tuberculosis in Patients infected with HIV

Every patient should have testing for TB at the time of diagnosis of HIV infection using a skin test or an IRGA.22 It is not known which test, a skin test or an IRGA test, is best for diagnosing latent TB in this patient population,21 although there is some research that indicates the IRGA is more sensitive, more specific, and was more accurate in identifying patients at risk for progression to TB,30 consideration that clinicians should keep in mind.

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 and/or when the CD4 cell count is > 200 cell/mm 3,22,31 because of the possibility of a false-negative result. If a patient is infected with HIV, a skin test is considered reactive if the transverse width of the induration is ≥ 5 mm.

Screening for Latent Tuberculosis in Pregnant Women

Routine screening of pregnant women for latent TB is not recommended32,33; screening is only recommended if the pregnant woman is at risk for progression to active TB. Pregnancy does not increase the risk for reactivation of latent TB, and the factors that increase the risk for reactivation in other populations apply to pregnant women, as well.32,33 The tuberculin skin test is safe to administer to a pregnant woman, pregnancy does not affect the results of the TB skin test, and either the skin test or the IRGA can be used to diagnose latent TB during pregnancy.32,33

Tuberculosis can be transmitted in utero, by direct contact with genital lesions, or perinatally by aspiration or ingestion of infected amniotic fluid.11

Congenital TB is a rare disease even in parts of the world where TB is endemic34 and fortunately so, as the outcome for these children is often poor. If congenital TB is undiagnosed, the mortality rate is 100%, if it is diagnosed late, the mortality can be 40%-50%, and if it is diagnosed and treated early the mortality can be 20%.11

Treatment

Treatment of Primary Active Tuberculosis

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 initiation 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, and 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.

There are four treatment regimens that can be used and four drugs that are the backbone of therapy: isoniazid, rifampin, pyrazinamide, and ethambutol.35,36 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 initial 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.35,36

All 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.35,36

Regimen 1

INH, rifampin, pyrazinamide, and ethambutol. In some situations, rifapentine is used. This is the preferred regimen for most patients who are newly diagnosed and found to have drug-susceptible TB.

Initial Phase: INH, rifampin or pyrazinamide, and ethambutol. INH, ethambutol, and are taken daily; pyrazinamide is taken five days a week, and the duration of this phase is eight weeks. Pyrazinamide may be removed from the regimen if the patient is at risk for hepatotoxicity. Ethambutol can be discontinued if susceptibility testing shows that the TB strain is susceptible to INH. Peripheral neuropathy caused by depletion of vitamin B6 (pyridoxine) stores is a well-known complication of INH, and vitamin B6 supplementation, 25 mg to 50 mg a day should be given to any patient who is at risk for developing peripheral neuropathy: breastfeeding infants, people who abuse alcohol, anyone who is malnourished, patients who have diabetes, an HIV infection, or chronic renal failure, pregnant women, and patients of advanced age.36

Continuation phase: INH seven days a week for four months or rifampin five days a week for four months.

Regimen 2

INH, rifampin, pyrazinamide, and ethambutol. In some situations, rifapentine is used. This regimen is preferred if more frequent DOT cannot be done.

Initial phase: INH, rifampin or pyrazinamide, and ethambutol. INH, ethambutol, and are taken daily for eight weeks; pyrazinamide is taken five days a week for eight weeks.

Continuation phase: INH and rifampin, three times a week for 18 weeks

Regimen 3

INH, rifampin, pyrazinamide, and ethambutol. This regimen should be used cautiously if the patient has an HIV infection and/or cavitary lung disease as missed doses can cause relapse, treatment failure, and drug resistance.

Initial phase. INH and rifampin are taken three times a week for 8 weeks. Pyrazinamide is taken five days a week for eight weeks, and ethambutol is taken daily for eight weeks.

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

Regimen 4

INH, rifampin, pyrazinamide, and ethambutol. This regimen should not be used if the patient has an HIV infection, cavitary disease, or smear-positive disease.

Initial phase: INH is taken once a day for two weeks then twice a week for six weeks. Rifampin is taken daily for two weeks, the twice a week for 12 doses. Pyrazinamide is taken five days a week for eight weeks, and ethambutol is taken daily for eight weeks.

Continuation phase: INH and rifampin are taken twice a week for 18 weeks.

Anti-Tuberculars: Brief Review of Mechanisms of Action

The basic mechanisms of actions 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 they are divided into five groups.

Group 1 is the first-line drugs. These drugs are safer and more effective against most TB infections.

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

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 first-line drugs. The second-line drugs are:

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

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

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

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

The first-line 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.

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

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.

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 are known to be sensitive to INH, ethambutol can be discontinued.

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

Directly Observed Therapy (DOT)

Tuberculosis can be cured in almost every case,3 but treatment failures and relapses do occur. Treatment failure is defined as a positive sputum culture after four months of treatment, and relapse is defined as TB that recurs any time after therapy has been completed.35 Factors that cause failure or relapse include drug resistance, malabsorption, malnourishment, non-compliance with the treatment regimen, a severe case of TB, or an alternative cause of the illness.35

Many treatment failures are caused by non-compliance, and non-compliance has serious consequences: transmission of TB to uninfected people, significantly increasing the risk of developing drug-resistant TB and decreasing the rate of cure.36,32,37,38 Completing the six month TB drug regimen is difficult due to the length of therapy and toxicity of the drugs, and in response to this, DOT was developed.

Directly observed therapy is witnessed ingestion by a healthcare professional of the patient taking the anti-tubercular drugs. Directly observed therapy has been in use for many years, and it is the recommended approach for TB drug therapy.35,36 Directly observed therapy can be an effective way of increasing patient compliance with TB drug therapy, and it has other benefits such as early identification of adverse drug effects and complications of therapy.36 Although DOT is the standard of care in the United States, there is no significant difference between DOT and self-administered therapy in terms of adherence to the TB drug regimen,35,36,39,40 but DOT has been associated with more cures, patients completing TB drug therapy, and with a higher number of sputum smear conversion than self-administered therapy.36 Directly observed therapy is the standard of care, but clinicians should understand that while DOT can be a part of the approach to helping patients comply with TB drug therapy, there are many other tools, e.g., combination drugs that have INH and rifampin, education, psychological counseling, incentives, and reminders that can be used with DOT.3,36,38

Adverse Effects of Tuberculosis Drug Therapy and Monitoring Drug Therapy

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

Hepatotoxicity can be caused by INH, rifampin, pyrazinamide, and ethambutol,35,36,41,42,43 and hepatoxicity it is the most frequent, serious adverse effect caused by these drugs during TB therapy. Hepatoxicity during TB drug therapy is defined as a serum ALT level ≥ 3 times the upper limit of normal in patients who have signs/symptoms of hepatitis or an ALT level ≥ 5 times the upper limit of normal in patients who do not have signs and symptoms.36 Mild and transient elevations of serum transaminases with no symptoms of liver damage are a common adverse effect of INH and rifampin, occurring in 10%-20% of all patients taking these drugs the incidence of serum transaminase elevation caused by ethambutol and pyrazinamide is unclear as these drugs are primarily used with INH and rifampin.35,41,42,43 Alcohol, male gender, advanced age, African American ethnicity, and concurrent use of other hepatotoxic drugs appear to increase the risk of liver injury when taking INH, and pre-existing liver disease (especially hepatitis C) and immunosuppressive treatment for an HIV infection also increase the risk for hepatic damage during TB drug therapy.44,45 Serious liver damage caused by these drugs during TB therapy is unusual and death quite rare.44,46,47 Bright et al. reviewed 2,070 cases of TB drug therapy and found a 3.0% incidence of drug-related hepatitis.46

If the patient is asymptomatic and the transaminase levels are low, continue with the drug regimen and increase the level of monitoring; in most patients, these laboratory abnormalities will resolve.36 If the patient is asymptomatic, and her/his serum transaminase levels are ≥ 5 times the upper limit of normal or the serum bilirubin is ≥3 mg/dL, or the serum ALT level ≥ 3 times the upper limit of normal in symptomatic patients, the use of the anti-tubercular drugs should stopped45 and a complete evaluation for the cause of the laboratory abnormalities and signs and symptoms should be done. The optimal approach to treating this clinical situation, i.e., when to restart therapy with the first-line drugs or whether to use different drugs, is not known.35,36 The CDC, the Infectious Diseases Society of America, and the American Thoracic Society recommend that once the ALT level is < 2 times the upper limit of normal, the TB drugs can be restarted sequentially, rifampin first, then INH, then pyrazinamide; this is the ascending order of their likelihood of causing liver injury.36

Treatment failure is defined as a positive sputum culture after four months of treatment.35,36 For the vast majority of patients, the sputum culture will be negative after three months of treatment,3,36 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. Treating a patient who is considered to have TB drug therapy failure is a complex issue, and an infectious disease specialist should be consulted.

Relapse of TB is defined as a recurrent TB infection after the therapy has been completed and the patient has been considered cured, and a relapse can occur by re-growth of the TB strain that caused the initial infection or by re-infection with a different strain of TB. Factors that increase the risk of relapse or re-infection include35,36,48:

  • Drug resistance
  • HIV infection
  • Malabsorption
  • Malnourishment
  • Misdiagnosis
  • Poor compliance with the treatment regimen
  • Residence in an area where TB is very common
  • A severe case of TB
  • Social factors like homelessness, incarceration, alcohol or drug misuse

Gastrointestinal distress and rashes are common adverse effects of anti-tubercular drugs. Patients who are taking rifampin and develop a rash should be evaluated for thrombocytopenia, a well-reported adverse effect of this drug.36

Other adverse effects that may be caused by the TB drug regimens include ocular toxicity from ethambutol 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,49 and the risk of optic neuropathy may be reduced by lowering the dose.50 Pyrazinamide can inhibit the excretion of uric acid and cause an acute gout attack; the drug should be used cautiously in patients who have a history of gout, and its use is contraindicated in patients who are having an acute gout attack.51

Monitoring the patient during drug therapy is not complicated, but there are specific protocols that should be followed, certain laboratory testing that should be done, and complications to be aware of.

A sputum sample for an AFB smear and culture should be obtained every month until two consecutive cultures are negative. It is recommended to obtain a chest x-ray after the end of the initiation phase.36

Liver function tests (Alkaline phosphatase, ALT, AST, and bilirubin) do not need to be measured before starting TB drug therapy unless the patient has a risk factor like chronic alcohol misuse that makes him/her likely to have pre-existing elevated LFTs. After TB drug therapy has been started, the LFTs should be measured once a month until therapy has been completed.36

Screening for diabetes, hepatitis B, hepatitis C, and HIV, should be done before beginning TB drug therapy, and serum creatinine should be measured, as well.36

Patients who are taking ethambutol should have baseline visual acuity testing (Snellen test) and assessment for color discrimination and clinicians should ask the patient once a month about any changes in visual acuity or color discrimination.36

The HIV infected Patient and Tuberculosis Treatment

Co-infection with TB and HIV can be quite harmful. An HIV infection is one of the leading causes of death in patients who have TB; patients who have latent TB and HIV are far more likely to develop active TB and to have extra-pulmonary forms of TB, and to develop MDR TB, and; the diagnosis of TB in patients who have HIV is challenging as these patients may have an atypical presentation and smears are often negative.3,53,54,55

The treatment of TB for a patient who has an HIV infection is essentially the same as the treatment for patients who are HIV-negative, but there are four considerations clinicians must keep in mind. same

Initiation of drug therapy: If the patient has a previously established diagnosis of TB and is subsequently diagnosed as having HIV, anti-retroviral therapy (ART) should be started immediately, whatever the CD4 cell count may be and TB drug therapy with INH, rifampin, pyrazinamide, and ethambutol and should be started immediately, as well a daily dose of pyridoxine should be part of the regimen. The duration of the initiation and continuation phases of TB drug therapy should be the standard two and four months if there is a risk for relapse the continuation phase can be lengthened but extending the continuation phase has not been shown to be necessary for most situations.35,36,56 During the continuation phase, the patient should take INH and rifampin.

If the patient has a previously established diagnosis of HIV infection, TB treatment with INH, rifampin, pyrazinamide, and ethambutol (and a daily dose of pyridoxine) should be started immediately, and the timing of the initiation of ART will depend on the CD4 cell count. If the CD4 cell count is < 50 cells/µL, begin ART within two weeks after TB drug therapy has been started; if the CD4 cell count is > 50 cells/µL ART should be started within 8-12 weeks after TB drug therapy has been started. If the patient has TB involving the nervous system, ART should not be started in the first eight weeks after the start of TB drug therapy, regardless of the CD4 cell count.35,36

DOT and dosing schedule: Patients who have an HIV infection and are being treated for TB must use DOT.35,56 Daily dosing is recommended; two or three times a week dosing is not recommended.36,56

Drug interactions: There are many drug-drug interactions between the first-line anti-tubercular medications, particularly rifampin, and the medications that are used for ART. For example, rifampin induces (increases the activity of) the cytochrome p450 enzyme CYP3A4. This enzyme metabolizes non-nucleoside transcriptase inhibitors (NNTRIs) like etravirine and nevirapine and the protease inhibitors if rifampin and an NNRTI or a protease inhibitor are taken together, the effectiveness of ART can be compromised .

Information from the CDC about the use of ATR and rifampin together is listed in Table IV. A good source for information about drug interactions involving ART is the University of Liverpool: HIV Drug Interactions. Other useful sources are the AIDSinfo site and the subscription site LexiComp.®

Table IV: Recommendations for Dosage Adjustments When Administering Anti-Retroviral Drugs and Rifampin57

Non-nucleoside reverse transcriptase inhibitors

  • Nevirapine and rifampin: Start nevirapine at a dose of 200 mg twice a day instead of once a day.
  • Etravirine and rifampin: This combination should be avoided.

 

Ritonavir-boosted protease inhibitors

  • Lopinavir-ritonavir and rifampin: The lopinavir-ritonavir dose should be 800 mg and 200 twice a day.
  • Atazanavir-ritonavir and rifampin: This combination should be avoided.
  • Darunavir-ritonavir and rifampin: This combination should be avoided.
  • Fosamprenavir-ritonavir and rifampin: This combination should be avoided.
  • Saquinavir-ritonavir and rifampin: This combination should be avoided.

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 antagonist Maraviroc and rifampin: Increase maraviroc dose to 600 mg twice a day.

 

Immune reconstitution inflammatory syndrome (IRIS): IRIS is a constellation of symptoms including (but not limited to) fever, lymphadenopathy, worsening of respiratory symptoms, and weight loss.3,35 IRIS has been reported to occur in 10%-50% of patients who have TB and have been started on ART and although the pathologic mechanism that initiates and drives IRIS is not completely understood, it is thought to be caused by an improvement of immune system function that occurs after ART has been started.36 IRIS usually begins within one to three months after ART has been started and it is a clinical diagnosis.58 People who have an advanced HIV infection appear to have a higher risk for developing IRIS,59 and although deaths from IRIS are uncommon, patients can develop serious neurologic complications, abscesses, ARDS, and other morbidities.35,36,60 The treatment of IRIS is symptomatic and supportive. Prednisone is recommended as a prophylactic against IRIS61 and as a treatment for IRIS.36

The Pregnant Patient and Turberculosis Treatment

Active TB can cause adverse fetal and maternal outcomes, and if there is a moderate to high level of suspicion that the patient has active disease, treatment should be started.32 The recommended treatment regimen (assuming the TB is drug-susceptible) is two months of INH, ethambutol, and rifampin, and then seven months of INH and rifampin.32,36 The CDC advises against using pyrazinamide because of concerns about its effect on the fetus,62 but the WHO and other experts recommend including pyrazinamide. Supplemental pyridoxine should be given to pregnant women taking INH, and to nursing infants whose mothers are taking INH.32,62 Breastfeeding while taking first-line anti-tuberculars is considered safe.62

Treatment of Latent Tuberculosis

There is no way to detect latent TB definitively, and there is no way to know with 100% accuracy which patients who are presumed to have latent TB will develop the active disease.3 The consensus is that patients who are presumed to have latent TB, based on history, examination, and skin test results and have a high risk of developing the active disease and should be treated. This would include3,63:

  • Children < 5 years of age: TST ≥ 10 mm
  • Children/adolescents exposed to high-risk adults: TST ≥ 10 mm
  • HIV positive patients: TST ≥ 5 mm
  • Injection drug users: TST ≥ 10 mm
  • Laboratory personnel who work with mycobacterium: TST ≥ 10 mm
  • Organ transplant recipients: TST ≥ 5 mm
  • Patients who have a high-risk medical condition like ESRD or silicosis: TST ≥ 5 mm
  • Patients who have fibrotic lesions on CXR that are consistent with TB: TST ≥ 5 mm
  • Patients who are immunosuppressed: TST ≥ 5 mm
  • Patients who have recently had contact with someone who has TB: TST ≥ 5 mm

There are four standard recommended regimens for treating latent TB in adult patients who are not pregnant and are HIV-negative.3,63 None has been proven to be superior to the others, and patient preference, the local incidence of TB, the potential adverse effects, and the likelihood of patient adherence to the regimen should be the deciding factors when choosing which one to use.63 There are other treatment regimens that can be used, but as mentioned; these are the standard protocols.

Regimen 1

Isoniazid: Adults should take 5 mg/kg once a day (24-hour maximum 300 mg). The duration of therapy is six or nine months; nine months is preferred.

Regimen 2

Rifampin: Adults should take 10 mg/kg a day, 24-maximum of 600 mg, and the duration of therapy should be four months.

Regimen 3

Rifampin plus INH: Adults should take INH 5 mg/kg a day, the 24-hour maximum should be 600 mg. The rifampin dose is 10 mg/kg a day, a 24-hour maximum dose of 300 mg. The duration of therapy should be four months.

Regimen 4

Rifapentine plus INH: INH, 15 mg/kg, once a week. The dose should be rounded up to the nearest 50 mg or 100 mg, the 24-hour maximum dose is 900 mg, and the duration of the therapy should be three months. The rifapentine should be taken once a week for three months, and the dose should be:

  • 10 to 14 kg: 300 mg
  • 14.1 to 25.0 kg: 450 mg
  • 25.1 to 32.0 kg: 600 mg
  • 32.1 to 49.9 kg: 750 mg
  • ≥50 kg: 900 mg maximum

Treatment of Latent Tuberculosis during Pregnancy

Pregnant women who have latent TB should be treated if there has been recent contact with someone who is actively infected or if the patient is HIV positive or is immunocompromised. If the patient is diagnosed as having latent TB during pregnancy, but there is no immediate need for treatment, treatment should be delayed until three months after delivery.32 INH is considered safe to use during pregnancy; rifampin is a pregnancy risk category C drug, but there is no definitive evidence that rifampin causes birth defects.33

A pregnant woman who has latent TB should be treated if she is HIV-positive, immunocompromised, or had recent contact with someone who has active TB.32,33 The preferred treatment regimens are32,33,64:

Regimen 1

INH: 5 mg/kg once a day, 24-hours maximum dose of 900 mg. The treatment duration should be nine months. Patients should take 25mg-50 mg of pyridoxine every day. The CDC also recommends that INH can be taken twice a week.

Regimen 2

Rifampin: 600 mg once a day for four months.

The use of these first-line drugs is not a contraindication to breastfeeding.32,64

Drugs that are contraindicated during pregnancy are amikacin, capreomycin, fluoroquinolones, kanamycin, and streptomycin.64

Treating Latent Tuberculosis 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.54 All patients who are infected with HIV and have latent TB should receive anti-tubercular therapy. Treatment of latent TB infection in this population significantly reduces the risk of progression to active TB, it reduces mortality, and it lowers the rate of TB transmission.54,65

In areas in which the incidence of TB is low, the recommended regimen is INH, 300 mg every day, for a duration of six to nine months.54,65 Six months is better in terms of treatment adherence and completion; nine months appears to be better in terms of efficacy.54 Other regimens can be used; they can be viewed at the World Health Organization (WHO) website in their 2018 publication, Latent TB Infection: Updated and consolidated guidelines for programmatic management.

In areas in which the incidence and transmission of TB are high, INH 300 mg a day for 36 months is recommended65; this approach is also recommended for patients on ART, pregnant patients, patients who are immunocompromised, and those who have previously been treated for TB.54

Treatment of latent TB in patients who are HIV-positive and on ART can be complicated by drug interactions, but in areas in which the incidence of TB is low, the standard regimen of INH 300 mg a day for six to nine months should be used.54 ART regimens that contain a rifampin type drug must be used cautiously because of interactions between rifampin and NNRTIs and protease inhibitors.

Treatment of MDR-TB and XDR-TB

Multidrug-resistant TB is defined as TB that is not susceptible to INH, rifampin, and possibly other drugs.23 There are two treatment approaches, a shorter, standardized approach, and a long-term, individualized approach.58,66 The World Health Organization (WHO) recommends using the longer approach, noting that this method increases the likelihood of a cure and decreases the rate of mortality.66 The shorter approach may be used for “. . . patients who have not been previously treated for more than 1 month with second-line medicines used in the shorter MDR-TB regimen or in whom resistance to fluoroquinolones and second-line injectable agents has been excluded, a shorter MDR-TB regimen of 9–12 months may be used instead of the longer regimens.”66

The recommended duration of the long-term approach is 18 to 20 months (modifiable depending on the response to therapy), and patients are prescribed drugs from three groups.66 There are specific considerations for using these drugs, e.g., a long-term approach regimen that includes amikacin or streptomycin should include an intensive therapy stage of 6-7 months; ethionamide, prothionamide are not commercially available in the United States, and these drugs and p-aminosalicylic acid are only used when the use of other medications is not possible. For details about specific drugs and the long-term regimen, readers should refer to the WHO Consolidated Guidelines on Drug-Resistant Tuberculosis Treatment 2019. Also, clinicians must consider the adverse effect profile of the medications, their availability and cost, cross-resistance between drugs, and the results of drug susceptibility testing.58

The long-term approach should always be used if any of the following are present66:

  • The clinician and the patient prefer a longer MDR-TB regimen
  • Confirmed resistance to or suspected ineffectiveness of a medicine of the short-term regimen, except for isoniazid resistance
  • Exposure to one or more second-line medicines in the short-term regimen for >1 month (unless susceptibility to these second-line medicines is confirmed)
  • Intolerance to medicines in the short-term or risk of toxicity (e.g., drug-drug interactions)
  • Pregnancy
  • Disseminated, meningeal, or CNS TB
  • Any extrapulmonary disease in people living with HIV
  • One or more medicines of the short-term regimen not available

Long Term Approach for MDR-TB

Group A: Levofloxacin or moxifloxacin, plus bedaquiline and linezolid. The patient should take all three medications.

Group B: Use one or both - clofazimine and cycloserine or terizidone

Group C: Drugs from Group C are added to complete the regimen, and when Group A and Group B medications cannot be used. These drugs are listed in the descending order of preference.

  • Ethambutol
  • Delamanid
  • Pyrazinamide
  • Imipenem-cilastatin or meropenem
  • Amikacin or streptomycin
  • Ethionamide or prothionamide
  • p-aminosalicylic acid

As with other TB drug therapy regimens, the long-term treatment regimen for MDR-TB consists of an intensive phase and a continuation phase. The intensive phase uses at least four effective drugs given for at least six months after sputum culture conversion (this is done at two months) and a continuation phase, using at least three effective drugs that are given for 15-17 months after sputum culture conversion.58 Sputum culture conversion refers to the change in culture results, from growing M tuberculosis to being negative for the organism, and sputum culture conversion is a common way of predicting the efficacy of drug therapy for MDR-TB.13

The treatment for XDR-TB consists of an intensive phase using at least five drugs: a first-line drug to which the TB strain is susceptible, a fluoroquinolone, bedaquiline, linezolid, and other oral drugs (clofazimine, cycloserine, or terizidone) as needed.58 The intensive phase should be given for six months past the two- month sputum culture conversion, and it is followed by a continuation phase. The continuation phase uses the same drugs used during the intensive phase, except for bedaquiline or the injectable drug, and the duration should be for 24 months past the two-month sputum culture conversion.58

Pulmonary resection can remove well localized, cavitated lesions that contain TB bacteria,67,68 and surgery combined with drug therapy is an option for patients who:

  1. Do not have access to MDR-TB and XDR-TB drug regimens;
  2. Are unlikely to respond to MDR-TB or XDR-TB drug regimens;
  3. Have complications like significant hemoptysis or a bronchopleural fistula, or;
  4. After several months of drug therapy still have positive sputum cultures.58,66,68

Some clinicians have reported a good success rate using this approach while others have not67,68,69; the differences are likely due to the selection process used for choosing operative candidates.67,69

Hospital Infection Control and Screening and Testing of Healthcare Personnel

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.70

Patients who are initially suspected of having active TB should be placed in an airborne infection isolation room.8,70 If this is not immediately possible, the patient should be placed 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 respiratory protection, and the N95 respirator is an appropriate and common choice.8,70 Visitors should wear an N95, as well.

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 is designed to trap exhaled infected droplets in the mask: the latter is 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.71 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.8

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.8 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. Healthcare workers who have had contact with an infected patient and who do not have documented evidence of latent TB or prior TB should be screened for TB.29

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 contact with someone who has TB, particularly MDR-TB, is at significant risk for developing latent TB.72,73 Martinez et al. found that children exposed to a household contact who had TB were 3.79 times more likely to have TB than unexposed children.73 In the United States (A country with a low incidence of TB) healthcare workers have a very low risk of contracting TB from patient contact, the risk estimated to be < 0.3%.29

Patient Education

The following recommendations are from the CDC74:

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 the above criteria are met, patients with TB disease can 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 not to 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 in 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.

NH: 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 Tuberculosis

The only TB vaccine that is currently available is Bacillus Calmette-Guérin (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.52,75

Children: Children with a negative tuberculin skin test who are in a living situation in which the likelihood of exposure to TB is high, and the child cannot be removed from that situation. Vaccination should also be done if the child is continually exposed to TB and cannot be treated or if the child has TB that is resistant to INH and rifampin. The vaccine has been shown to be 70%-80% effective.75

Healthcare workers: Healthcare workers who are exposed to a high percentage of patients 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.

The BCG vaccine is much less effective for older children and adults, and this is likely due to differences in immune status between infants and these groups and because older children and adults are more likely to have had prior exposure to TB.75

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) as these patients may develop serious systemic adverse effects.

BCG vaccination should not be given during pregnancy. Even though no harmful effects of BCG vaccination on the fetus have been observed, BCG is a live vaccine, so its use in pregnant women is contraindicated.

BCG is relatively safe. Large local reactions at the injection site are common, and they may become ulcerated and painful and leave a permanent.75 Osteitis and osteomyelitis can occur after a BCG injection, but these are rare adverse effects. Disseminated BCG infections in the liver, lymphatic issue, skeletal system, the CNS, and other sites can also occur, most often in patients who are immunocompromised and disseminated BCG disease has been reported to occur in 33% of immunocompromised infants.75,76

Vaccination with BCG can cause a false-positive TB skin test.77 The IRGA test is not affected by BCG vaccine.75,78

Disseminated Tuberculosis

Disseminated TB, which is sometimes referred to as military TB, is defined as TB caused by hematogenous dissemination of M tuberculosis and is present in two or more non-contiguous sites.79 Disseminated TB is an uncommon condition. It accounts for 2%-3% of all cases of TB,79 and disseminated TB can affect organs and tissues, including (but not limited to) the bone marrow, eyes, kidneys, and liver.7,79 Disseminated TB may be caused by reactivation of latent TB, the progression of active TB, or it may be iatrogenic. Disseminated TB occurs most often in patients who have specific risks factors, and people who are immunocompromised or have an HIV infection are particularly susceptible.7,79

Treatment in TB infected Children

Tuberculosis is a serious disease for children. Children are more susceptible to the transmission of TB, and they should be screened if they have had close contact with someone who has the disease or if they have risk factors, e.g., an HIV infection, that increases their risk of becoming infected. For children, brief contact with an infected adult may result in infection, the risk of progression to the active disease after exposure to TB is quite high, up to 50% in children < two years of age80 and children are more likely than adults to develop severe and/or extra-pulmonary TB.81 Worldwide, tuberculosis is commonly occurring disease but in the United States pediatric cases of TB are rare; in 2016 there were only 387 reported cases of TB in children and adolescents under the age of 15.12

Active TB in children is treated with a two-month initiation phase and a four-month continuation phase. The recommended dosing for INH differs slightly depending on the source (The recommendation from the WHO is 7-15 mg/kg, the other sources are 10-20 mg) and the dosing of the TB drugs can be done once, twice, or three times a week dosing; the decision to which to use depends on the incidence of TB in the area, the HIV status of the child, and other factors. The regimen listed below36,82:

Initiation

INH: Daily dosing, 10-15 mg/kg. Twice a week dosing, 20-30 mg/kg. The 24-hour maximum dose is 300 mg.

Rifampin: Once a day or twice a week dosing, 15-20 mg/kg, 600 mg maximum daily dose.

Pyrazinamide: Daily dosing, 30-40 mg/kg. Twice a week dosing, 50 mg/kg. For both. The 24-hour maximum dose is 2 grams.

Ethambutol: 15-25 mg/kg, the 24-hour maximum dose is 1 gram. Twice a week dosing, 50 mg/kg with a 24-hour maximum dose of 2.5 grams.

Continuation

INH: Daily dosing, 10-15 mg/kg. Twice a week dosing, 20-30 mg/kg. The 24-hour maximum dose is 300 mg.

Rifampin: Once a day or twice a week dosing, 15-20 mg/kg, 600 mg maximum daily dose.

Children with suspected or confirmed pulmonary tuberculosis or tuberculous 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 (INH, rifampicin, and pyrazinamide) for 2 months followed by a two-drug (INH and rifampicin) regimen for 4 months using the aforementioned doses/dosing schedule.82

Children with suspected or confirmed pulmonary TB or tuberculosis peripheral lymphadenitis and/or children who have extensive pulmonary disease, living in settings where the prevalence of HIV is high and/or where INH resistance is high should be treated with the aforementioned four-drug/two months, two-drug/four months regimen.82

Infants aged 0–3 months with suspected or confirmed pulmonary tuberculosis or tuberculous peripheral lymphadenitis should be treated with regimens that were previously outlined. Dose adjustments may be needed, and these should be determined by a clinician who is experienced in managing pediatric tuberculosis.82

Children with suspected or confirmed pulmonary tuberculosis or tuberculosis peripheral lymphadenitis living in settings with a high HIV prevalence or who have a confirmed HIV infection should not be treated with intermittent regimens twice-weekly or thrice-weekly regimens. If the child does not have an HIV infection and DOT can be done, a thrice-weekly regimen can be used.82

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

Children who are being treated for drug-susceptible TB do not need to take pyridoxine.83

Treatment of children who have MDR-TB is essentially the same as it is for adults,66,83 but there are several considerations to keep in mind when treating children for MDR-TB.

Either the short duration or the long duration of treatment can be used, but there is less clinical experience with the shorter duration.66 Bedaquiline can be used in children down to six years of age, and delamanid in children down to three years of age.66 Amikacin and streptomycin are ototoxic and nephrotoxic, and they should be given to children who have MDR-TB only if there is no other option, monitoring for otic and renal adverse effects cannot be done, and the TB strain the child has is susceptible to these drugs.66,83

Treatment of children who have or are suspected of having latent TB is not significantly different from the treatment for adults. If the diagnosis of latent TB is made, there are four treatment regimens that can be used.80,84 There is no evidence that any one regimen is superior to another, so the clinician should use the approach that is likely to promote adherence is the least toxic to the child. Daily pyridoxine supplementation for children taking INH is not needed unless the child is exclusively breastfed, the child has an HIV infection and is symptomatic, he/she has a milk/meat deficient diet, or if the child had a nutritionally deficient diet.84

INH: Once a day at 10 to 15 mg/kg. The duration of therapy is nine months, and the daily dose should not exceed 300 mg. INH can also be given at a dose of 20 to 30 mg/kg, twice a week for nine months, the daily dose not to exceed 900 mg. The latter approach requires DOT.

INH and rifampin: INH is given at 10 to 15 mg/kg a day, the daily dose should not exceed 300 mg. Rifampin is dosed at 10 to 20 mg/kg a day, the daily dose should not exceed 600 mg. The duration of therapy is three months.

INH and rifapentine: INH is given once a week for three months at a dose of 15 mg/g. The dose should be rounded up to the nearest 50 or 100 mg, and the daily dose should not exceed 900 mg. The rifapentine dose depends on patient weight, and it is given once a week for three months, DOT is preferred for this approach.

  • 10-14 kg: 300 mg
  • 14.1-25 kg: 450 mg
  • 25.1-32 kg: 600 mg
  • 32.1-49.9 kg: 750 mg
  • ≥ 50 kg: 900 mg, maximum

Rifampin: 10 to 20 mg/kg a day for four months. The daily dose should not exceed 600 mg.

Case Study #1

A 45-year-old female recently emigrated to the United States from Southeast Asia, visits a primary care clinic because she has had a headache and an occasional cough for the past three days. The patient states she has no chronic medical problems; she does not smoke, abuse alcohol, or use illicit drugs. She does not take any prescription medications, and aside from the headache and cough, she has been in good health. The patient states that she has never been tested for the presence of tuberculosis, she thinks – but is not sure – that close relatives with whom she lived with may have been treated for TB, and she does not know if she had been given the BCG vaccine when she was a child.

The nurse practitioner diagnoses the patient as having a stress headache and that the cough may be likely caused by mild reactive airway disease. She consults with an infectious disease specialist. The infectious disease specialist notes that the patient has been living in an area where TB is endemic and access to anti-tuberculars may be difficult. She recommends that the patient be tested for hepatitis B and C, HIV, pregnancy, and TB; a TST or IRGA can be used, but the IRGA is preferable if it is likely that the patient may not return for a TST reading within the prescribed time. In addition, a CXR and liver function tests are done, and the patient’s visual acuity is checked.

The IRGA is positive. The CXR and liver function tests are normal as is her visual acuity, and the patient does not have hepatitis B or C, or HIV, and she is not pregnant. The infectious disease specialist is consulted again, and because of the patient’s place of origin and because it is possible that she had close contact with someone who may have had active TB, she is at risk for progression of her (likely) latent TB to the active disease. Rifampin, 10 mg/kg taken once a day for four months, is prescribed. The patient is evaluated monthly at the clinic, and at the end of the drug therapy, there is no clinical evidence that she has active TB.

Case Study #2

A 19-year-old male self-refers to an emergency room complaining of cough, fever, and night sweats, duration approximately two weeks. The patient has PMH of alcohol abuse and IV drug use, he has a chronic hepatitis C infection (untreated), he is taking ART for his HIV infection, and he is currently homeless. The patient is admitted to the hospital, placed in a private room, and standard and respiratory precautions are put in place.

The CXR is suggestive of but not diagnostic for cavitary disease of TB, the results of all laboratory tests are normal except for an elevated WBC and mildly elevated ALT, 99 IU/L (it is not known if the patient’s baseline ALT is elevated), and his TST result is > 5 mm (Note: He has not been previously had a TST. He does not have hepatitis B.

Because there is a high index of suspicion that the patient has active TB, an empiric regimen of INH, ethambutol, rifampin, and pyrazinamide is suggested as well as a daily supplement of pyridoxine. Because the patient is on ART, a clinical pharmacologist is consulted prior to beginning the TB drug therapy to determine what doing adjustments should be made in the TB drug therapy and the ART and if rifampin can be used. A sputum culture confirms the presence of TB, and drug susceptibility determines that the patient does not have MDR-TB or XDR-TB, and drug therapy is started. It is decided to delay treatment of his hepatitis C for the time. The public health department is notified of the case, and efforts are made to locate people who had contact with the patient and would be at risk for transmission of TB. The patient’s condition stabilizes, two AFB smears are negative, and he is discharged to a supervised living. DOT at a local health clinic is arranged.

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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