Rocsanna Namdar, Michael Lauzardo, and Charles A. Peloquin
KEY CONCEPTS
Tuberculosis (TB) is the most prevalent communicable infectious disease on earth. It is the leading cause of death in human immunodeficiency virus (HIV) infection worldwide. It remains out of control in many developing nations. These nations require medical and financial assistance from developed nations in order to control the spread of TB globally.
In the United States, TB disproportionately affects ethnic minorities as compared with whites, reflecting greater ongoing transmission in ethnic minority communities. Additional TB surveillance and preventive treatment are required within these communities.
Coinfection with HIV and TB accelerates the progression of both diseases, thus requiring rapid diagnosis and treatment of both diseases.
Mycobacteria are slow-growing organisms; in the laboratory, they require special stains, special growth media, and long periods of incubation to isolate and identify.
TB can produce atypical signs and symptoms in infants, the elderly, and immunocompromised hosts, and it can progress rapidly in these patients.
Latent TB infection (LTBI) can lead to reactivation disease years after the primary infection occurred.
The patient suspected of having active TB disease must be isolated until the diagnosis is confirmed and the patient is no longer contagious. Often, isolation takes place in specialized “negative-pressure” hospital rooms to prevent the spread of TB.
Isoniazid and rifampin are the two most important TB drugs; organisms resistant to both these drugs (multidrug-resistant TB [MDR-TB]) are much more difficult to treat.
Directly observed treatment (DOT) is considered the standard of care. DOT should be used whenever possible to reduce treatment failures and the selection of drug-resistant isolates.
Never add a single drug to a failing TB treatment regimen!
INTRODUCTION
Tuberculosis (TB) remains a leading infectious killer globally. TB is caused by Mycobacterium tuberculosis, which can produce either a silent, latent infection or a progressive, active disease.1 Left untreated or improperly treated, TB causes progressive tissue destruction and, eventually, death. Because of renewed public health efforts, TB rates in the United States continue to decline. In contrast, TB remains out of control in many developing countries—to the point that one third of the world’s population currently is infected.1 Given increasing drug resistance, it is critical that a major effort be made to control TB before the most potent drugs are no longer effective.
TB rates generally have risen with increasing urbanization and overcrowding because it is easier for an airborne disease to spread when people are packed closely together. Hence, TB became a significant pathogen in Europe during the Middle Ages and peaked during the Industrial Revolution, when it caused approximately 25% of all deaths in Europe and in the United States.1,2 This dire threat led to the rise of public health departments and to procedures such as the isolation of infected patients. Thus, TB was directly responsible for many of the healthcare practices that we take for granted today. Unfortunately, in developing nations, some of these practices are not widely available, and TB continues to rage unabated.
EPIDEMIOLOGY
Globally, roughly 2 billion people are infected by M. tuberculosis, and roughly 2 million people die from active TB each year despite the fact that it is curable.1,2 In the United States, an estimated 9 to 14 million people are latently infected with M. tuberculosis, meaning that they are not currently sick but that they could fall ill with TB at any time. In 2011, a total of 10,521 new TB cases were reported in the United States, an incidence of 3.4 cases per 100,000 population, which is 6.4% lower than the rate in 2010. This is the lowest rate recorded since national reporting began in 1953.3 (For detailed data analysis, visit the Centers for Disease Control and Prevention [CDC] website at www.cdc.gov/nchstp/tb.) The annual incidence of TB in the United States declined by approximately 5% per year from 1953 to 1983 (Fig. 90–1).3 In 1984, this decline slowed, and then the incidence of TB rose from 1988 to 1992, reaching 10.5 cases per 100,000 population. Since 1992, more effective infection control practices and treatment protocols have reduced TB rates significantly as mentioned above. Despite this good news, the eradication of TB from the United States remains very difficult. One reason is that we continue to import new cases from countries where TB remains out of control.3,4
FIGURE 90-1 Reported TB Cases, United States, 1982–2011.
*Updated as of June 25, 2012. (From reference 3.)
Risk Factors for Infection
Location and Place of Birth
Four states (California, Florida, New York, and Texas) continued to report more than 500 cases each in 2011. Combined, these four states accounted for 5,299 TB cases or approximately half (50.4%) of all TB cases reported in 2011.3 Within these states, TB is most prevalent in large urban areas.3
The TB rate among foreign-born persons was 12 times that of U.S.-born persons in 2011.3 The percentage of foreign-born TB patients in the United States has increased annually since 1986, reaching 62.5% in 2011.3 The 17.3 per 100,000 population TB rate among foreign-born persons was a 4.8% decrease since 2010 and a 49% decrease since 1993. In 2011, 54.1% of foreign-born persons with TB originated from five countries: Mexico (1,392 cases), the Philippines (750 cases), Vietnam (537 cases), India (498 cases), and China (365 cases).3 Therefore, healthcare workers must “think TB” when caring for patients from these countries who experience symptoms such as cough, fever, and weight loss.
Close contacts of pulmonary TB patients are most likely to become infected.2–4 These include family members, coworkers, or coresidents in places such as prisons, shelters, or nursing homes. The more prolonged the contact, the greater is the risk, with infection rates as high as 30%.3,4 Although many circumstances exist, TB patients frequently have limited access to healthcare, live in crowded conditions, or are homeless.2–4 Many patients have histories of alcohol abuse or illicit drug use, and many are coinfected with hepatitis B or human immunodeficiency virus (HIV). These concurrent social and health problems make treating some TB patients particularly difficult.
Race, Ethnicity, Age, and Gender
In the United States, TB disproportionately affects ethnic minorities. In 2011, for the first time since the current reporting system began in 1993, non-Hispanic Asians surpassed Hispanics as the largest ethnic group among TB patients. Compared with non-Hispanic whites, the TB rate among non-Hispanic Asians was 25 times greater, and rates among non-Hispanic blacks and Hispanics were 8 and 7 times greater, respectively. Among U.S.-born ethnic groups, the greatest disparity in TB rates occurred among non-Hispanic blacks, whose rate was six times the rate for non-Hispanic whites.3 TB is most common during early adulthood primarily in the 25- to 44-year age group. In 2010, 6% of cases in the United States were children under 15 years of age, 11% were age 15 to 24, 33% were age 25 to 44, 31% were age 45 to 64, and 20% were at least 65 years old.4 TB is more common in older whites and Asians compared with younger people from these groups. This reflects reactivation of latent infection acquired many years earlier when TB was very common. Older blacks and Hispanics also have more TB than younger individuals, but the differences by age are not as pronounced.5 This reflects a greater recent transmission among younger blacks and Hispanics compared with younger whites and Asians. Until the age of 15 years, TB rates are similar for males and females, but after that, the male predominance increases with each decade of life.5
Coinfection with Human Immunodeficiency Virus
HIV is the most important risk factor for active TB, especially among people 25 to 44 years of age.2,4–6 TB and HIV seem to act synergistically within patients and across populations, making each disease worse than it might otherwise be. In 2011, 7.9% of incident cases of TB in the United States were coinfected with HIV.3 This increase in percentage over previous years was felt to be due largely to improved reporting of HIV status to state TB programs. These numbers are estimates because laws and regulations in some states prohibit sharing HIV status of TB patients with the TB program. HIV coinfection may not increase the risk of acquiring M. tuberculosis infection, but it does increase the likelihood of progression to active disease.1,6 There is evidence for higher mortality rates in HIV coinfected with multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB.7
Risk Factors for Disease
Once infected with M. tuberculosis, a person’s lifetime risk of active TB is approximately 10%.2,4,6 The greatest risk for active disease occurs during the first 2 years after infection. Children younger than 2 years of age and adults older than 65 years of age have two to five times greater risk for active disease compared with other age groups. Patients with underlying immune suppression (e.g., renal failure, cancer, and immunosuppressive drug treatment) have 4 to 16 times greater risk than other patients. Finally, HIV-infected patients with M. tuberculosis infection are 100 times more likely to develop active TB than normal hosts.4,8 HIV-infected patients have an annual risk of active TB of approximately 10%, rather than a lifetime risk at that rate. Therefore, all patients with HIV infection should be screened for tuberculous infection, and those known to be infected with M. tuberculosis should be tested for HIV infection.
ETIOLOGY
M. tuberculosis is a slender bacillus with a waxy outer layer.2,6 It is 1 to 4 μm in length, and under the microscope, it is either straight or slightly curved in shape.1,9,10 It does not stain well with Gram stain, so the Ziehl-Neelsen stain or the fluorochrome stain must be used instead.1,2,6 After Ziehl-Neelsen staining with carbol-fuchsin, mycobacteria retain the red color despite acid–alcohol washes. Hence, they are called acid-fast bacilli (AFB).9 After staining, microscopic examination (“smear”) detects about 8,000 to 10,000 organisms per milliliter (8 × 106/L to 10 × 106/L) of specimen, so a patient can be “smear negative” but still grow M. tuberculosis on culture. Microscopic examination also cannot determine which of the more than 100 mycobacterial species is present or whether the organisms in the original samples were alive or dead.1,9,10 On smear, they are all dead. On culture, M. tuberculosis grows slowly, doubling about every 20 hours. This is slow compared with gram-positive and gram-negative bacteria, which double about every 30 minutes.
Culture and Susceptibility Testing
Direct susceptibility testing involves inoculating specialized media with organisms taken directly from a concentrated, smear-positive specimen.1,9,10 This approach produces susceptibility results in 2 to 3 weeks. Indirect susceptibility testing involves inoculating the test media with organisms obtained from a pure culture of the organisms, which can take several more weeks. The most common agar method, known as the proportion method, uses the ratio of colony counts on drug-containing agar to that on drug-free agar.1,10 In the United States, the critical proportion for resistance is 1%. That means that if a drug-containing plate shows only 2% of the growth seen on a drug-free plate, some of the organisms from the specimen were resistant to that drug. Therefore, it is likely that many of the organisms in the patient also are resistant to that drug, and it should not be used to treat that patient.
The proportion method’s limitations include many weeks to obtain results, drug degradation during the incubation, and a qualitative result (susceptible or resistant). The newer mycobacterial growth indicator tube (MGIT) (Becton Dickson, Sparks, MD) systems use liquid media and detect live mycobacteria in as few as 9 to 14 days.11,12
Rapid-identification tests are now available. Nucleic acid probes such as the AccuProbe (Gen-Probe, San Diego, CA) use DNA probes to identify the presence of complementary ribosomal ribonucleic acid (rRNA) for several mycobacterial species.6,9,13 DNA fingerprinting using restriction-fragment-length polymorphism analysis has been used to identify clusters of cases.1,9,13 Amplification of the genetic material can be achieved through polymerase chain reaction (PCR) (Roche Molecular Systems, Branchburg, NJ), the amplified M. tuberculosis direct (MTD) test (Gen-Probe), and strand-displacement amplification (SDA; Becton-Dickinson, Sparks, MD).9,12 Thin-layer chromatography, high-performance liquid chromatography for mycolic acid identification, and gas chromatography for short-chain fatty acids (methyl esters) have been used to speciate mycobacterial isolates.1,9,13 Other tests are designed to detect common genetic changes associated with drug resistance, such as changes in the katG gene associated with isoniazid resistance and the rpoB gene associated with rifampin resistance.6,12,14,15 Two tests, the Gene X-pert (Cepheid, Sunnyvale, CA) and the Hain test (Hain Lifescience, Nehren, Germany), have entered into limited clinical use in the United States. These tests offer clinicians a chance to know rapidly if resistance to rifampin is present (both tests) and what drugs might be good initial choices (Hain Test).
Transmission
M. tuberculosis is transmitted from person to person by coughing or other activities that cause the organism to be aerosolized.2,6,11 These particles, called droplet nuclei, contain one to three bacilli and are small enough (1 to 5 mm) to reach the alveolar surface. This produces “droplet nuclei” that are dispersed in the air. Each droplet nuclei contains one to three organisms. Approximately 30% of individuals who experience prolonged contact with an infectious TB patient will become infected.
A person with cavitary, pulmonary TB and a cough may infect roughly one person per month until that person is treated effectively, although this number can vary significantly. A person with the uncommon laryngeal form of TB can spread organisms even when talking, so the transmission rates can be even higher.
PATHOPHYSIOLOGY
Immune Response
T-lymphocyte responses are essential to controlling M. tuberculosis infections.2,6,16,17 In the mouse model, two different T-cell responses—the T-helper type 1 (TH1) response and the T-helper type 2 (TH2) response—have been described. The TH1 response is the preferred response to TB, and the TH2 response, including the potentially subversive influence of interleukin (IL) 4, is undesirable.2,16,17 Some workers have argued that this dichotomy is clearer in the mouse model, and in many humans, the T-cell response may be classified as TH0 (elements of both TH1 and TH2).16 In either case, T lymphocytes activate macrophages that, in turn, engulf and kill mycobacteria. T lymphocytes also destroy immature macrophages that harbor M. tuberculosis but are unable to kill the invaders.16,17 CD4+ cells are the primary T cells involved, with contributions by γδ T cells and CD8+ T cells.20 CD4+ T cells produce interferon-γ (INF-γ) and other cytokines, including IL-2 and IL-10, that coordinate the immune response to TB.16 Because CD4+ cells are depleted in HIV-infected patients, these patients are unable to mount an adequate defense to TB.16,17
Although B-cell responses and antibody production can be demonstrated in TB-infected mammals, these humoral responses do not appear to contribute much to the control of TB within the host.2,6,16 Tumor necrosis factor-α(TNF-α) and INF-γ are important cytokines involved in coordinating the host’s cell-mediated response. Rheumatoid arthritis patients treated with TNF-α inhibitors (such as infliximab) have high rates of reactivation TB.18 Therefore, patients known to be deficient in the activity of TNF-α or INF-γ should be screened for TB infection and offered appropriate treatment.
M. tuberculosis has several ways of evading or resisting the host immune response.16,17 In particular, M. tuberculosis can inhibit the fusion of lysosomes to phagosomes inside macrophages. This prevents the destructive enzymes found in the lysosomes from getting to the bacilli captured in the phagosomes. This inhibition of destructive mechanisms allows time for M. tuberculosis to escape into the cytoplasm. Virulent M. tuberculosis is able to multiply in the macrophage cytoplasm, thus perpetuating their spread. Finally, lipoarabinomannan (LAM), the principal structural polysaccharide of the mycobacterial cell wall, inhibits the host immune response.16,17 LAM induces immunosuppressive cytokines, thus blocking macrophage activation; additionally, LAM scavenges O2, thus preventing attack by superoxide anions, hydrogen peroxide, singlet oxygen, and hydroxyl radicals.16,17 These survival mechanisms make M. tuberculosis a particularly difficult organism to control. Any defects in the host immune system make it likely that M. tuberculosis will not be controlled and that active disease will ensue.
Primary Infection
Primary infection usually results from inhaling airborne particles that contain M. tuberculosis.2,6,17 The progression to clinical disease depends on three factors: (a) the number of M. tuberculosis organisms inhaled (infecting dose), (b) the virulence of these organisms, and (c) the host’s cell-mediated immune response.2,3,6,11,17,19 At the alveolar surface, the bacilli that were delivered by the droplet nuclei are ingested by pulmonary macrophages.22 If these macrophages inhibit or kill the bacilli, infection is aborted.17 If the macrophages cannot do this, the organisms continue to multiply. The macrophages eventually rupture, releasing many bacilli, and these mycobacteria are then phagocytized by other macrophages. This cycle continues over several weeks until the host is able to mount a more coordinated response.17 During this early phase of infection, M. tuberculosis multiplies logarithmically.17
Some of the intracellular organisms are transported by the macrophages to regional lymph nodes in the hilar, mediastinal, and retroperitoneal areas. The cycle of phagocytosis and cell rupture continues. During lymph node involvement, the mycobacteria may be held in check. More frequently, M. tuberculosis spreads throughout the body through the bloodstream.2,6,17 When this intravascular dissemination occurs, M. tuberculosis can infect any tissue or organ in the body. Most commonly, M. tuberculosis infects the posterior apical region of the lungs. This may be so because of the high oxygen content, and it may be because of a less vigorous immune response in this area.
After about 3 weeks of infection, T lymphocytes are presented with M. tuberculosis antigens. These T cells become activated and begin to secrete INF-γ and the other cytokines noted earlier. The processes described in Immune Response above then begin to occur. First, T lymphocytes stimulate macrophages to become bactericidal.17 Large numbers of activated microbicidal macrophages surround the solid caseous (cheese-like) tuberculous foci (the necrotic area of infection).17 This process of creating activated microbicidal macrophages is known as cell-mediated immunity (CMI).17
At the same time that CMI occurs, delayed-type hypersensitivity (DTH) also develops through the activation and multiplication of T lymphocytes. DTH refers to the cytotoxic immune process that kills nonactivated immature macrophages that are permitting intracellular bacillary replication.17 These immature macrophages are killed when the T lymphocytes initiate Fas-mediated apoptosis (programmed cell death).17 The bacilli released from the immature macrophages then are killed by the activated macrophages.17
By this time (>3 weeks), macrophages have begun to form granulomas to contain the organisms. In a typical tuberculous granuloma, activated macrophages accumulate around a caseous lesion and prevent its further extension.17At this point, the infection is largely under control, and bacillary replication falls off dramatically. Depending on the inflammatory response, tissue necrosis and calcification of the infection site plus the regional lymph nodes may occur.
Over 1 to 3 months, activated lymphocytes reach an adequate number, and tissue hypersensitivity results. This is shown by a positive tuberculin skin test. Any remaining mycobacteria are believed to reside primarily within granulomas or within macrophages that have avoided detection and lysis, although some residual bacilli have been found in various types of cells.2,6,16
Approximately 90% of infected patients have no further clinical manifestations. Most patients only show a positive skin test (70%), whereas some also have radiographic evidence of stable granulomas. This radiodense area on chest radiograph is called a Ghon’s complex. Approximately 5% of patients (usually children, the elderly, and the immunocompromised) experience “progressive primary” disease that occurs before skin test conversion, which presents as a progressive pneumonia, usually in the lower lobes.20 Disease frequently spreads, leading to meningitis and other severe forms of TB.20 Because of this risk of severe disease, very young, elderly, and immunocompromised patients, including those with HIV, should be evaluated and treated for latent or active TB.
Reactivation Disease
Roughly 10% of infected patients develop reactivation disease at some point in their lives. Nearly half of these cases occur within 2 years of infection.2,6,11 In the United States, most cases of TB are believed to result from reactivation. Reinfection is uncommon in the United States because of the low rate of exposure and because previously sensitized individuals possess some degree of immunity to reinfection.2,17 Exceptions include patients coinfected with HIV who live in areas of higher exposure to M. tuberculosis.
The apices of the lungs are the most common sites for reactivation (85% of cases).2 For reasons that are not entirely known (waning cellular immunity, loss of specific T-cell clones, blocking antibody), organisms within granulomas emerge and begin multiplying extracellularly.17 The inflammatory response produces caseating granulomas, which eventually will liquefy and spread locally, leading to the formation of a hole (cavity) in the lungs.
The immune response contributes to the severity of the lung damage, and DTH allows for intracellular mycobacterial multiplication.16,17 In addition, there is “innocent bystander” killing of host cells and locally thrombosed blood vessels.17 The killing of mycobacteria, macrophages, and neutrophils that have entered the battle releases cytokines and lysozymes into the infectious foci. This toxic mixture can be too much for the surrounding alveoli and airway cells, causing regional necrosis and structural collapse.2,17 These unstable foci liquefy, spreading the infection to neighboring areas of the lung, creating a cavity. Some of this necrotic material is coughed out, producing droplet nuclei. Bacterial counts in the cavities can be as high as 108 per milliliter of cavitary fluid. Partial healing may result from fibrosis, but these lesions remain unstable and may continue to expand.2,17 If left untreated, pulmonary TB continues to destroy the lungs, resulting in hypoxia, respiratory acidosis, and eventually death.
Extrapulmonary and Miliary Tuberculosis
Caseating granulomas at extrapulmonary sites can undergo liquefaction, releasing tubercle bacilli and causing symptomatic disease.2,6 Extrapulmonary TB without concurrent pulmonary disease is uncommon in normal hosts but more common in HIV-infected patients. Because of these unusual presentations, the diagnosis of TB is difficult and often delayed in immunocompromised hosts.2,6 Lymphatic and pleural diseases are the most common forms of extrapulmonary TB, followed by bone, joint, genitourinary, meningeal, and other forms.2,6 Occasionally, a massive inoculum of organisms enters the bloodstream, causing a widely disseminated form of the disease known as miliary TB. It is named for the millet seed appearance of the small granulomas seen on chest radiographs, and it can be rapidly fatal.16 Miliary TB is a medical emergency requiring immediate treatment.
Influence of HIV Infection on Pathogenesis
HIV infection is the strongest single risk factor for active TB.2,6,16 As CD4+ lymphocytes multiply in response to the mycobacterial infection, HIV multiplies within these cells and selectively destroys them. In turn, the TB-fighting lymphocytes are depleted.16 This vicious cycle puts HIV-infected patients at 100 times the risk of active TB compared with HIV-negative people.21 In addition, the combination of HIV infection and certain social behaviors increases the risk of newly acquired TB. In select areas of the United States during the resurgence of TB during the early 1990s, up to 50% of new TB cases were the result of recent infection, particularly among HIV-infected individuals.21,22
As mycobacteria spread throughout the body, HIV replication accelerates in lymphocytes and macrophages. This leads to progression of HIV disease.16,23 HIV-infected patients who are infected with TB deteriorate more rapidly unless they receive antimycobacterial chemotherapy.24,25 Most clinicians now recommend beginning TB treatment first, and shortly after, beginning HIV treatment. However, this needs to be individualized based on degree of immunosuppression from HIV and the patient’s tolerance of the treatment regimen. Some patients will experience paradoxical worsening of the TB.11,23 This appears to result from a reinvigorated inflammatory response to TB. Because TB can be very dangerous in HIV-positive patients, they should be screened for tuberculous infection or disease soon after they are shown to be HIV-positive.2,6,16
CLINICAL PRESENTATION
The classical presentation of TB is shown in Clinical Presentation of Tuberculosis above. The onset of TB may be gradual, and the diagnosis may not be considered until a chest radiograph is performed. Unfortunately, many patients do not seek medical attention until more dramatic symptoms, such as hemoptysis, occur. At this point, patients typically have large cavitary lesions in the lungs. These cavities are loaded with M. tuberculosis. Expectoration or swallowing of infected sputum may spread the disease to other areas of the body.1,2,6,19 Physical examination is nonspecific but suggestive of progressive pulmonary disease. 
Patients coinfected with HIV may have atypical presentations.1,2,6,19 As their CD4+ counts decline, HIV-positive patients are less likely to have positive skin tests, cavitary lesions, or fever. Pulmonary radiographic findings may be minimal or absent. HIV-positive patients have a higher incidence of extrapulmonary TB and are more likely to present with progressive primary disease. Because their symptoms are not specific to TB, a thorough workup for TB is essential.2,6,16,19
CLINICAL PRESENTATION Tuberculosis
Signs and Symptoms
• Patients typically present with weight loss, fatigue, a productive cough, fever, and night sweats.1,2,6,19
• Frank hemoptysis.
Physical Examination
• Dullness to chest percussion, rales, and increased vocal fremitus are observed frequently on auscultation.
Laboratory Tests
• Moderate elevations in the white blood cell (WBC) count with a lymphocyte predominance
Diagnostic Considerations
• Positive sputum smear
• Fiber-optic bronchoscopy (if sputum tests are inconclusive and suspicion is high)
Chest Radiograph
• Patchy or nodular infiltrates in the apical areas of the upper lobes or the superior segment of the lower lobes2,6,19
• Cavitation that may show air–fluid levels as the infection progresses
Extrapulmonary TB typically presents as a slowly progressive decline in organ function.2,6,19 Patients may have low-grade fever and other constitutional symptoms. Patients with genitourinary TB may present with sterile pyuria and hematuria. Lymphadenitis often involves the cervical and supraclavicular nodes and may appear as a neck mass with spontaneous drainage. Tuberculous arthritis and osteomyelitis occur most commonly in the elderly and usually affect the lower spine and weight-bearing joints. TB of the spine is known as Pott’s disease.2 Abnormal behavior, headaches, or convulsions suggest tuberculous meningitis. Involvement of the peritoneum, pericardium, larynx, and adrenal glands also occurs.2,6,19
The Elderly
TB in the elderly is easily confused with other respiratory diseases. Many clinical findings are muted or absent altogether. Compared with younger patients, TB in the elderly is far less likely to present with positive skin tests, fevers, night sweats, sputum production, or hemoptysis.2,19,24 Weight loss may occur but is nonspecific. In contrast, mental status changes are twice as common in the elderly, and mortality is six times higher.2,19,24 TB is a preventable cause of death in the elderly that should not be overlooked.
Children
TB in children, especially those younger than 12 years of age, may present as a typical bacterial pneumonia and is called progressive primary TB.19,20 Clinical disease often begins 1 to 2 months after exposure and precedes skin-test positivity. Unlike adults, pulmonary TB in children often involves the lower and middle lobes.19,20 Dissemination to the lymph nodes, GI and genitourinary tracts, bone marrow, and meninges is common. Because of delays in recruitment of cellular immunity, cavitary disease is infrequent, and the number of organisms present typically is smaller than in an adult. Because cavitary lesions are uncommon, children do not spread TB readily. However, TB can be rapidly fatal in a child, and it requires prompt chemotherapy.
DIAGNOSIS
Diagnostic Testing
The key to stopping the spread of TB is early identification of infected individuals.1,2,6,19 Table 90–1 lists the populations most likely to benefit from testing (column 1 patients are at highest risk for TB, followed by those in column 2). Members of these high-risk groups should be tested for TB infection and educated about the disease.
TABLE 90-1 Criteria for Tuberculin Positivity by Risk Group
The Mantoux test is a TB skin test. It uses tuberculin purified protein derivative (PPD), and unlike the Heaf or tine test, the Mantoux test is quantitative. The standard 5-tuberculin-unit PPD dose is placed intracutaneously on the volar aspect of the forearm with a 26- or 27-gauge needle.2,19,24 This injection should produce a small, raised, blanched wheal. An experienced professional should read the test in 48 to 72 hours. The area of induration (the “bump”) is the important end point, not the area of redness. Table 90–1 lists the criteria for interpretation.1,2,6,19,24 The CDC does not recommend the routine use of anergy panels.24,26 Aplisol and Tubersol 5-tuberculin-unit products are available commercially and are similar in sensitivity, specificity, and reactivity. It is important, however, to use one product and notify appropriate users when switching between products.27,28
The “booster effect” occurs for patients who do not respond to an initial skin test but show a positive reaction if retested about a week later.19,26 Patients with past M. tuberculosis infection and some patients with past immunization with bacillus Calmette-Guérin (BCG) vaccine or past infection with other mycobacteria may “boost” with a second skin test. Individuals who require periodic skin testing, such as healthcare workers, should receive a two-stage test initially.19,26,29 Once they are shown to be skin-test negative, any positive skin test later shows recent infection, and this requires treatment.
The PPD skin test is an imperfect diagnostic tool. Up to 20% of patients with active TB are falsely skin-test negative, presumably because their immune systems are overwhelmed.16,26 False-positive results are more common in low-risk patients and those recently vaccinated with BCG. Despite BCG vaccination, one should not ignore a positive PPD result. These patients require careful evaluation for active disease, and they may be offered preventive treatment because many come from areas where TB infection is common.
Interferon-γ release assays (IGRA) measure the release of INF-γ in blood in response to the TB antigens.30 They may provide quick and specific results for identifying M. tuberculosis. IGRAs do not trigger a booster effect and are more specific for testing M. tuberculosis than the PPD. The QuantiFERON-TB Gold test (QFT-G) is an enzyme-linked immunosorbent assay (ELISA) and was approved by the U.S. FDA in 2005.30 The T-SPOT.TB, an enzyme-linked immunospot assay, was approved by the U.S. FDA in 2008.31 Both tests can be used for diagnosing latent TB infection (LTBI) and TB disease caused by M. tuberculosis. The antigenic proteins are absent from BCG vaccine strains and from most non-TB mycobacteria. Therefore, QFT-G does not trigger a booster effect and is more specific for testing of M. tuberculosis than the PPD. Although these tests can provide results to diagnose both latent infection and disease, they cannot differentiate between the two. Results are available within <24 hours, instead of the 2 to 3 days required for the traditional PPD skin test. Therefore, the patient does not have to return to the clinic as required by the PPD skin test, making it more convenient. The CDC has approved the use of these tests in all circumstances in which the PPD is currently used; however, the sensitivity for young children (<5 years) and in immunocompromised patients has not been determined.32–35
Additional Tests
When active TB is suspected, attempts should be made to isolate M. tuberculosis from the site of infection.2,6,19,26 Sputum collected in the morning usually has the highest yield.2,9,19 Daily sputum collection over 3 consecutive days is recommended.
For patients unable to expectorate, sputum induction with aerosolized hypertonic saline may produce a diagnostic sample. Bronchoscopy, or aspiration of gastric fluid via a nasogastric tube, may be attempted for select patients.19For patients with suspected extrapulmonary TB, samples of draining fluid, biopsies of the infected site, or both may be attempted. Blood cultures are positive occasionally, especially in AIDS patients.19,36
TREATMENT
Desired Outcomes
The desired outcomes during the treatment of TB are:
1. Rapid identification of a new TB case
2. Initiation of specific anti-TB treatment
3. Prompt resolution of the signs and symptoms of disease
4. Achievement of a noninfectious state in the patient, thus ending isolation
5. Adherence to the treatment regimen by the patient
6. Cure of the patient as quickly as possible (generally at least 6 months of treatment)
It is also important that patients with active disease are isolated to prevent spread of the disease and that appropriate samples for smears and cultures are collected. Secondary goals are identification of the index case that infected the patient, identification of all persons infected by both the index case and the new case of TB (“contact investigation”), and completion of appropriate treatments for those individuals.
General Approaches to Treatment
Drug treatment is the cornerstone of TB management.2,6,11,37 Monotherapy can be used only for infected patients who do not have active TB (latent infection, as shown by a positive skin test). Once active disease is present, a minimum of two drugs, and generally three or four drugs, must be used simultaneously.2,6,11,37 The duration of treatment depends on the condition of the host, extent of disease, presence of drug resistance, and tolerance of medications. The shortest duration of treatment generally is 6 months, and 2 to 3 years of treatment may be necessary for cases of MDR-TB.2,6,11,37 Because the duration of treatment is so long and because many patients feel better after a few weeks of treatment, careful followup is required. Directly observed therapy (DOT) by a healthcare worker is a cost-effective way to ensure completion of treatment and is considered the standard of care.2,6,11,37–39
Principles for Treating Latent Infection and for Treating Disease
Asymptomatic patients with tuberculous infection have a bacillary load of about 103 organisms, compared with 1011 organisms in a patient with cavitary pulmonary TB.2,6 As the number of organisms increases, the likelihood of naturally occurring drug-resistant mutants also increases. Naturally occurring resistant mutants are found at rates of 1 in 106 to 1 in 108 organisms for the anti-TB drugs.2,37 When treating asymptomatic latent infection with isoniazid monotherapy, the risk of selecting out isoniazid-resistant organisms is low. The isoniazid mutation rate is about 1 in 106, but only about 103 organisms are present in the body. In contrast, the risk of selecting out isoniazid-resistant organisms is unacceptably high for patients with cavitary TB. One can prevent selection of these resistant mutants by adding more drugs because the rates for resistance mutations to multiple drugs are additive functions of the individual rates. For example, only 1 in 1013 organisms would be naturally resistant to both isoniazid (1 in 106) and rifampin (1 in 107).2,37 It is unlikely that such rare organisms are present in a previously untreated patient.
Combination chemotherapy is required for treating active TB disease. The patient should receive at least two drugs to which the isolate is susceptible, and, generally, four drugs are given at the outset of treatment. Rifampin and isoniazid are the best drugs for preventing drug resistance, followed by ethambutol, streptomycin, and pyrazinamide.2,6,37,40
Three subpopulations of mycobacteria are proposed to exist within the body, and each appears to respond to certain drugs.2,37 Most numerous are the extracellular, rapidly dividing bacteria, often found within cavities (about 107to 109 organisms). These are killed most readily by isoniazid, followed by rifampin, streptomycin, and the other drugs. A second group resides within caseating granulomas (possibly 105 to 107 organisms). These organisms appear to be in a semidormant state, with occasional bursts of metabolic activity. Pyrazinamide, through its conversion within M. tuberculosis to pyrazinoic acid, appears most active against these organisms. Rifampin and isoniazid also may be active against this subpopulation. The third subset is the intracellular mycobacteria present within macrophages (104 to 106). Rifampin, isoniazid, and the quinolones appear to be most active against intracellular M. tuberculosis. While this appears to explain what happens during the treatment of TB, there is no practical way to quantitate these populations within a given patient.
Nonpharmacologic Therapy
Nonpharmacologic interventions aim to (a) prevent the spread of TB, (b) find where TB has already spread using contact investigation, and (c) replenish the weakened (consumptive) patient to a state of normal weight and well-being. The first two items are performed by public health departments. Clinicians involved in the treatment of TB should verify that the local health department has been notified of all new cases of TB.
Workers in hospitals and other institutions must prevent the spread of TB within their facilities.2,11,24 All such workers should learn and follow each institution’s infection control guidelines. This includes using personal protective equipment, including properly fitted respirators, and closing doors to “negative-pressure” rooms. These hospital isolation rooms draw air in from surrounding areas rather than blowing air (and M. tuberculosis) into these surrounding areas. The air from the isolation room may be treated with ultraviolet lights and then vented safely outside. However, these isolation rooms work properly only if the door is closed.
Debilitated TB patients may require therapy for other medical problems, including substance abuse and HIV infection, and some may need nutritional support. Therefore, clinicians involved in substance abuse rehabilitation and nutritional support services should be familiar with the needs of TB patients. Surgery may be needed to remove destroyed lung tissue, space-occupying infected lesions (tuberculomas), and certain extrapulmonary lesions.2,11,37 BCG is the only clinically relevant vaccine for TB in use today. Although it is one of the most commonly administered vaccines in history, it is of limited value, and cannot prevent infection by M. tuberculosis. BCG (discussed below) may prevent extreme forms of TB in infants.37,41
Pharmacologic Therapy
Treating Latent Infection
Isoniazid is the preferred drug for treating LTBI.2,6,11,37 Generally, isoniazid alone is given for 9 months. The treatment of LTBI reduces a person’s lifetime risk of active TB from approximately 10% to approximately 1%. Because TB is spread easily through the air, each case prevented also prevents a second wave of cases that each prevented case would have produced. Historically, the treatment of LTBI has been called prophylaxis. Table 90–2 lists the LTBI treatment options.
TABLE 90-2 Recommended Drug Regimens for Treatment of Latent Tuberculosis (TB) Infection in Adults
Because young children, the elderly, and HIV-positive patients are at greater risk of active disease once infected with M. tuberculosis, they require careful evaluation. Once active TB is ruled out, they should receive treatment for latent infection.2,18,19,37
The keys to successful treatment of LTBI are (a) infection by an isoniazid-susceptible isolate, (b) adherence to the regimen, and (c) no exogenous reinfection.2 Isoniazid adult doses are usually 300 mg daily (5 to 10 mg/kg of body weight)37 (see Table 90–2). Lower doses are less effective.2,42,43 Isoniazid should be given on an empty stomach, and antacids should be avoided within 2 hours of dosing. Rifampin 600 mg daily for 4 months can be used when isoniazid resistance is suspected or when the patient cannot tolerate isoniazid.2,37 There is a growing body of evidence that 4 months of rifampin may be a safer and more cost-effective alternative to 9 months of isoniazid. Menzies and colleagues showed that 4 months of rifampin was significantly cheaper per patient completing treatment because of better completion and fewer adverse events.44 The combination of pyrazinamide plus rifampin is no longer recommended because of higher than expected rates of hepatotoxicity. Rifabutin 300 mg daily might be substituted for rifampin for patients at high risk of drug interactions. When resistance to isoniazid and rifampin is suspected in the isolate causing infection, there is no regimen proved to be effective.2,37 Regimens that mightbe effective include ethambutol plus levofloxacin, but data regarding efficacy are lacking.
In 2011, a randomized controlled trial conducted in Brazil, Spain, Canada, and the United States compared 12 weeks of once-weekly isoniazid and rifapentine by DOT with daily self-administered isoniazid for 9 months.45 This study, with over 8,000 participants, showed that the 12 weeks of weekly isoniazid and rifapentine given by DOT was not inferior in efficacy to 9 months of self-administered isoniazid, had a significantly higher completion rate (82% vs. 69%), and was associated with fewer grade 3 or 4 adverse reactions (1.6% vs. 3%).45 It should be noted however that hypersensitivity reactions were more common with the isoniazid/rifapentine regimen and close clinical followup should be undertaken while experience is gained with this new regimen for LTBI therapy. The CDC now recommends the 12-week isoniazid/rifapentine regimen as an equal alternative to 9 months of daily isoniazid for treating LTBI in otherwise healthy patients aged ≥12 years who have a predictive factor for greater likelihood of TB developing, which included recent exposure to contagious TB, conversion from negative to positive on an indirect test for infection (i.e., IGRA or tuberculin skin test), and radiographic findings of healed pulmonary TB.46 HIV-infected patients who are otherwise healthy and are not taking antiretroviral medications are also included in this category. However, precautions should be taken as HIV-infected patients are more likely to have extrapulmonary TB or pulmonary TB with normal findings on chest radiograph. For recent skin-test converters of all ages, the risk of active TB outweighs the risk for drug toxicity.24,37 Pregnant women, alcoholics, and patients with poor diets who are treated with isoniazid should receive pyridoxine (vitamin B6) 10 to 50 mg daily to reduce the incidence of CNS effects or peripheral neuropathies. All patients who receive treatment of LTBI should be monitored monthly for adverse drug reactions and for possible progression to active TB.
Treating Active Disease
The CDC, American Thoracic Society (ATS), and the Infectious Diseases Society of America have published an algorithm for the treatment of TB (Fig. 90–2). The treatment of active TB requires the use of multiple drugs. There are two primary anti-TB drugs, isoniazid and rifampin, with the rest of the drugs having specific roles.37,40 Isoniazid and rifampin should be used together whenever possible. Typically, M. tuberculosis is either very susceptible or very resistant to a given drug. Theoretically, minimal inhibitory concentration (MIC) results could be used to guide dosing in the treatment of moderately resistant M. tuberculosis, but this remains to be studied prospectively.2,11,37
FIGURE 90-2 Treatment algorithm for tuberculosis. Note: Patients in whom tuberculosis is proved or strongly suspected should have treatment initiated with isoniazid, rifampin, pyrazinamide, and ethambutol for the initial 2 months. A repeat smear and culture should be performed when 2 months of treatment has been completed. If cavities were seen on the initial chest radiograph or the acid-fast smear is positive at completion of 2 months of treatment, the continuation phase of treatment should consist of isoniazid and rifampin daily or twice weekly for 4 months to complete a total of 6 months of treatment. If cavitation was present on the initial chest radiograph and the culture at the time of completion of 2 months of therapy is positive, the continuation phase should be lengthened to 7 months (total of 9 months of treatment). If the patient has HIV infection and the CD+ cell count is <100/μL (<100 × 106/L), the continuation phase should consist of daily or three-times-weekly isoniazid and rifampin. In HIV-uninfected patients having no cavitation on chest radiograph and negative acid-fast smears at completion of 2 months of treatment, the continuation phase may consist of either once-weekly isoniazid and rifapentine, or daily or twice-weekly isoniazid and rifampin, to complete a total of 6 months (bottom). Patients receiving isoniazid and rifapentine, and whose 2-month cultures are positive, should have treatment extended by an additional 3 months (total of 9 months). (CXR, chest radiograph; EMB, ethambutol; INH, isoniazid; PZA, pyrazinamide; RIF, rifampin; RPT, rifapentine.) aEMB may be discontinued when results of drug susceptibility testing indicate no drug resistance. bPZA may be discontinued after it has been taken for 2 months (56 doses). cRPT should not be used in HIV-infected patients with tuberculosis or in patients with extrapulmonary tuberculosis. dTherapy should be extended to 9 months if the 2-month culture is positive. (From: American Thoracic Society, Centers for Disease Control and Prevention, Infectious Diseases Society of America. Treatment of tuberculosis. MMWR Recomm Rep 2003;52(RR-11):1-77.)
Drug susceptibility testing should be done on the initial isolate for all patients with active TB. These data should guide the selection of drugs over the course of treatment.2,6,11,37 However, some patients are unable to provide a suitable specimen for laboratory testing. If susceptibility data are not available for a given patient, the drug susceptibility data for the suspected source case or regional susceptibility data should be used.2,37
Drug resistance should be expected for patients presenting for the retreatment of TB. These patients require retesting of drug susceptibility using freshly collected specimens. It is imperative to learn what drugs the patient received and for how long the patient received them.2,11,37 A treatment history, often called a “drug-o-gram,” shows the start and stop dates of all antimycobacterial drugs on a horizontal bar graph.2,37 A drug-o-gram should be constructed for all retreatment patients.
The standard TB treatment regimen is isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months, followed by isoniazid and rifampin for 4 months, a total of 6 months of treatment.2,11,37 If susceptibility to isoniazid, rifampin, and pyrazinamide is shown, ethambutol can be stopped at any time. Without pyrazinamide, a total of 9 months of isoniazid and rifampin treatment is required. Table 90–3shows the recommended treatment regimens. When intermittent therapy is used, DOT is essential. Doses missed during an intermittent TB regimen decrease its efficacy and increase the relapse rate. Note that Table 90–3 shows recommendations that differ for HIV-negative and HIV-positive patients. HIV-positive patients should not receive highly intermittent regimens. In general, regimens given daily five times each week or three times weekly can be used for HIV-positive patients. Less frequent dosing is associated with higher failure and relapse rates and the selection of rifampin-resistant organisms.37
TABLE 90-3 Drug Regimens for Culture-Positive Pulmonary Tuberculosis Caused by Drug-Susceptible Organisms
When a patient’s sputum smears convert to a negative, the risk of the patient infecting others is greatly reduced, but it is not zero.2,17,37 Such patients can be removed from respiratory isolation, but they must be careful not to cough on others and should meet with others only in well-ventilated places. Smear-negative patients still may be culture positive, so they still can transmit TB to others.
Clinical Controversy…
Although very effective therapy exists for the treatment of TB, it continues to be a problem in the developing world. Cure rates of 95% to 98% are achievable with appropriate treatment; however, the right social, economic, and political conditions must exist in order for the prolonged, complicated regimen to be administered appropriately. Although individual case management (susceptibility testing, TDM, close followup) is ideal, it is difficult to implement in countries that bear the highest burden of TB. DOT exists in many developing countries, but due to limited resources and other social and political barriers, true DOT is not the standard of care.
Patients who are slow to respond clinically, those who remain culture positive at 2 months of treatment, those with cavitary lesions on chest radiograph, and perhaps HIV-positive patients should be treated for a total of 9 months and for at least 6 months from the time that they convert to smear and culture negativity.2,6,11,37 Some authors recommend therapeutic drug monitoring (TDM) for such patients.2,11,40,42When isoniazid and rifampin cannot be used, treatment durations become 2 years or more regardless of immune status.2,11,37,40
Adjustments to the regimen should be made once the susceptibility data are available.2,11,37 If the organism is drug-resistant, careful consideration of the remaining therapeutic options must be made. Two or more drugs with in vitro activity against the patient’s isolate and that the patient has not received previously should be added to the regimen, as needed.2,11,37 
There is no standard regimen for MDR-TB.2,11,37 Each patient’s exposure history, previous treatment history (including toxicity and adherence issues), and current susceptibility data must be considered simultaneously. It is critical to avoid monotherapy, and it is critical to avoid adding a single drug to a failing regimen.2,11,37 Adding one drug at a time leads to the sequential selection of drug resistance until there are no drugs left. TB specialists should be consulted regarding cases of MDR-TB. It may take several months for a patient with MDR-TB to become culture negative because the drugs used lack the potency of isoniazid and rifampin.2,40Consequently, prolonged respiratory isolation may be required.
Drug resistance should be considered in the following situations:
1. Patients who have received prior therapy for TB
2. Patients from areas with a high prevalence of resistance (South Africa, Dominican Republic, Peru, Southeast Asia, the Baltic countries, and the former Soviet states)
3. Patients who are homeless, institutionalized, IV drug abusers, or infected with HIV
4. Patients who still have AFB-positive sputum smears after 1 to 2 months of therapy
5. Patients who still have positive cultures after 2 to 4 months of therapy
6. Patients who fail treatment or relapse after treatment
7. Patients known to be exposed to MDR-TB cases
Empirical therapy with four or more drugs may be needed for acutely ill patients.2,11,37 These regimens may be altered when the susceptibility pattern becomes known. If the index case is known, then the same effective regimen should be employed for the new case. Again, MDR-TB cases should be referred to specialists. A new term in use, XDR-TB, refers to “extensively drug-resistant TB.” Such organisms are resistant to at least isoniazid, rifampin, a fluoroquinolone, and one second-line injectable drug (amikacin, capreomycin, or kanamycin).47
Special Populations
Tuberculous Meningitis and Extrapulmonary Disease Patients with CNS TB usually are treated for longer periods (9 to 12 months instead of 6 months).2,11,37 In general, isoniazid, pyrazinamide, ethionamide, and cycloserine penetrate the cerebrospinal fluid readily, but rifampin, ethambutol, and streptomycin have variable CNS penetration.43 Of the quinolones, levofloxacin may be preferred based on current data. Extrapulmonary TB of the soft tissues can be treated with conventional regimens.2,11,37 TB of the bone typically is treated for 9 months, occasionally with surgical debridement.2,11,37
Children TB in children may be treated with regimens similar to those used in adults, although some physicians still prefer to extend treatment to 9 months.2,11,19,20,37 Pediatric doses of isoniazid and rifampin on a milligram-per-kilogram basis are higher than those used in adults (Table 90–4).37
TABLE 90-4 Dosesa of Antituberculosis Drugs for Adults and Childrenb,c
Pregnancy Women with TB should be cautioned against becoming pregnant because the disease poses a risk to the fetus and to the mother. If already pregnant, the usual treatment is isoniazid, rifampin, and ethambutol for 9 months.47 Isoniazid and ethambutol are relatively safe for use in pregnant women.2,37,43,48 B vitamins are particularly important during pregnancy and should be provided to women being treated for TB. Rifampin is associated rarely with birth defects, including limb reduction and CNS lesions.43 In general, rifampin is used in pregnant women with TB. Pyrazinamide has not been studied in large numbers of pregnant women, but anecdotal data suggest that it may be safe.37
Streptomycin use during pregnancy may lead to hearing loss in the newborn, including complete deafness. Streptomycin and the other aminoglycosides must be reserved for critical situations where alternatives do not exist.2,37Although the polypeptide capreomycin has not been studied, it probably carries the same risks.
Ethionamide may cause premature delivery and congenital deformities when used during pregnancy.37,43 Down’s syndrome also has been reported with ethionamide, so it cannot be recommended in this setting. p-Aminosalicylic acid has been used safely in pregnancy, but specific data are lacking.37,43 Cycloserine is known to cross the placenta, but the effects on the developing fetus are not known. Therefore, cycloserine generally cannot be recommended during pregnancy.43
Ciprofloxacin, levofloxacin, moxifloxacin, and the other quinolones are associated with permanent damage to cartilage in the weight-bearing joints of immature animals, especially dogs and rabbits.37,43Although these drugs do not frequently cause joint problems in humans, other anti-TB agents should be used during pregnancy.
Pregnant women with LTBI are not at the same level of risk compared with those with active disease. Therapy with isoniazid for LTBI may be delayed until after pregnancy or, if recent skin-test conversion has occurred, started during the second trimester of pregnancy.37,43,48 Although most anti-TB drugs are excreted in breast milk, the amount of drug received by the infant through nursing is insufficient to cause toxicity. Quinolones should be avoided in nursing mothers, if possible.
HIV Infection Patients with AIDS and other immunocompromised hosts may be managed with chemotherapeutic regimens similar to those used in immunocompetent individuals, although treatment is often extended to 9 months (see Table 90–3).2,11,37 The precise duration to recommend remains a matter of debate. Highly intermittent regimens (twice or once weekly) are not recommended for HIV-positive TB patients. Prognosis has been particularly poor for HIV-infected patients infected with MDR-TB, so all efforts should be made to reduce the time between clinical presentation, diagnosis of TB, and start of appropriate treatment. Recommendations for management of HIV and TB published by the World Health Organization and others have provided guidance on monitoring of treatment, side effects, and drug interactions of HIV and TB, MDR, XDR-TB.7,49 Differentiation must be made between infection with M. tuberculosis and nontuberculous mycobacteria, such as Mycobacterium avium complex (MAC), because the drugs used are different. While awaiting laboratory results, the patient can be treated empirically for TB if there is any doubt about the causative organism. Some patients with AIDS malabsorb their oral medications; this is discussed in Therapeutic Drug Monitoring below.2,37,40,42 The major issue of drug interactions is discussed in Rifampin below.
Renal Failure For nearly all patients, isoniazid and rifampin do not require dose modification in renal failure. They are eliminated primarily by the liver.40,43,50 In the unlikely event that peripheral neuropathies develop, the frequency of isoniazid dosing may be reduced. Pyrazinamide and ethambutol typically require a reduction in dosing frequency from daily to three times weekly (Table 90–5).37,50
TABLE 90-5 Dosing Recommendations for Adult Patients with Reduced Renal Function and for Adult Patients Receiving Hemodialysis
Renally cleared TB drugs include the aminoglycosides (amikacin, kanamycin, and streptomycin), capreomycin, ethambutol, cycloserine, and levofloxacin.37,43,51 Dosing intervals need to be extended for these drugs (Table 90–5). Ciprofloxacin and moxifloxacin are approximately 50% cleared by the kidneys but may not require a change in dose from once daily, as used for TB. The metabolites of isoniazid, pyrazinamide, and p-aminosalicylic acid are cleared primarily by the kidneys. The role of these metabolites in causing toxicity is unknown, so their accumulation in renal failure may carry some risk.
Ethionamide and its sulfoxide metabolite are hepatically cleared, so dosing is unchanged.37,51 p-Aminosalicylic acid is converted largely to metabolites prior to renal elimination; these metabolites may accumulate in renal failure.51 For patients on hemodialysis, the usual 12-hour dosing interval for p-aminosalicylic acid granules seems to be safe. Dialysis will remove the metabolites. Serum concentration monitoring must be performed for cycloserine to avoid dose-related toxicities in renal failure patients.40,42,51
Hepatic Failure Anti-TB drugs that rely on hepatic clearance for most of their elimination include isoniazid, rifampin, pyrazinamide, ethionamide, and p-aminosalicylic acid.43 Ciprofloxacin and moxifloxacin are approximately 50% cleared by the liver. Elevations of serum transaminase concentrations generally are not correlated with the residual capacity of the liver to metabolize drugs, so these markers cannot be used as guides for drug dosing. Furthermore, isoniazid, rifampin, pyrazinamide, and, to a lesser degree, ethionamide, p-aminosalicylic acid, and, rarely, ethambutol may cause hepatotoxicity.37,40,43 For some patients with drug-susceptible TB, a “liver-sparing” regimen of streptomycin, levofloxacin, and ethambutol may be used, at least temporarily.37,40,43 Because this regimen requires 18 or more months of treatment to be successful, patients usually are switched to isoniazid- and rifampin-containing regimens as soon as they are able.
Morbid Obesity Data are not available for dosing the TB drugs for patients with morbid obesity.43 Relatively hydrophilic drugs (isoniazid, pyrazinamide, the aminoglycosides, capreomycin, ethambutol, p-aminosalicylic acid, and cycloserine) can be dosed initially based on ideal body weight. Very low or very high serum concentrations can be avoided by checking the serum concentrations.
The TB Drugs
The interested reader is referred to several other publications for more detailed information regarding these drugs.2,10,37,40,42,43 Note that although the ATS/CDC guidelines recommend “maximum” doses (see Table 90–4),37 in the authors’ view, the “maximum” dose for a given patient is the dose that produces the desired response with an acceptable level of toxicity.40,42 This can only be determined on a case-by-case basis. Artificially capping doses may deprive patients of needed drug.
Primary Antituberculosis Drugs
Isoniazid Isoniazid is one of the two most important TB drugs. It is highly specific for mycobacteria, with a MIC against M. tuberculosis of 0.01 to 0.25 mcg/mL (mg/L). It is bactericidal and is thought to inhibit mycolic acid synthesis and disruption of the cell wall in susceptible organisms. Most nontuberculous mycobacteria such as M. avium are resistant to isoniazid, although M. kansasii and Mycobacterium xenopi are susceptible. The most common mechanisms of resistance result from mutations in the katG or inhA genes.
Isoniazid is readily absorbed from the GI tract and from intramuscular injection sites. It also can be given as a short IV infusion over 5 minutes if diluted in about 20 mL of normal saline.52 Isoniazid should be given on an empty stomach whenever possible.53 N-Acetyltransferase 2 forms the principal metabolite acetylisoniazid, which lacks antimycobacterial activity. The rate at which humans acetylate isoniazid is determined genetically; slow acetylation is an autosomal recessive trait and reflects a relative lack of N-acetyltransferase 2. Fast acetylators have isoniazid half-lives of less than 2 hours. Approximately 50% of whites and blacks and 80% to 90% of Asians and Native Alaskans are rapid acetylators. Slow acetylators have isoniazid half-lives of 3 to 4 hours and may be at an increased risk of neurotoxicity. The association of acetylator status and risk of hepatotoxicity, however, appears to be weak.54 Poor absorption and rapid clearance of isoniazid for patients receiving highly intermittent therapy are associated with poor clinical outcomes.55,56
Transient elevations of the serum transaminases occur in 12% to 15% of patients receiving isoniazid and usually occur within the first 8 to 12 weeks of therapy.37 Overt hepatotoxicity, however, occurs in only 1% of cases. Risk factors for hepatotoxicity include patient age, preexisting liver disease, excessive alcohol intake, pregnancy, and the postpartum state. Isoniazid also may result in neurotoxicity, most frequently presenting as peripheral neuropathy or, in overdose, as seizures and coma. Patients with pyridoxine deficiency, such as pregnant women, alcoholics, children, and the malnourished, are at increased risk. Isoniazid may inhibit the metabolism of phenytoin, carbamazepine, primidone, and warfarin.40 Patients who are being treated with these agents should be monitored closely, and appropriate dose adjustments should be made when necessary.
Rifampin The introduction of rifampin into routine use during the 1970s allowed for true short-course treatment of TB (6 to 9 months).2,11,37 Without rifampin, treatment is generally 18 months or longer. Drug resistance to rifampin is an ominous prognostic factor because it is frequently associated with isoniazid resistance and leaves the patient with few good therapeutic options. Clinicians must take care to protect susceptibility to rifampin by carefully treating their patients. Rifampin shows bactericidal activity against M. tuberculosis and several other mycobacterial species, including M. bovis and M. kansasii.57It also is active against a broad array of other bacteria. Alteration of the target site on RNA polymerase, primarily through changes in the rpoB gene, leads to most forms of rifampin resistance.37,57
Rifampin usually is given orally, but it also can be given as a 30-minute IV infusion.57 Oral doses are best given on an empty stomach.58 Patients with AIDS, diabetes, and other GI problems appear to have difficulty absorbing rifampin after oral doses, and this has been associated with therapeutic failures in some cases.40,42,56,59 Rifampin is metabolized to 25-desacetyl rifampin, which retains some of rifampin’s activity; most of rifampin and its metabolite are cleared in the bile. Rifampin generally is given at 600 mg daily or intermittently, although this dose does not take full advantage of rifampin’s concentration-dependent killing.40,42 Higher doses should be tested in humans within the context of clinical trials.
Elevations in hepatic enzymes have been attributed to rifampin in 10% to 15% of patients, with overt hepatotoxicity occurring in less than 1%.37,57 More frequent adverse effects of rifampin include rash, fever, and GI distress. Allergic reactions to rifampin have been reported and occur more frequently with intermittent rifampin doses 900 mg or more twice weekly. These reactions may take the form of a flu-like syndrome with development of fever, chills, headache, arthralgias, and, rarely, hypotension and shock.37 Alternatively, hemolytic anemia or acute renal failure may occur, requiring permanent discontinuation.
Rifampin’s potent induction of hepatic enzymes, especially cytochrome P450 3A4, may enhance the elimination of many other drugs, most notably the protease inhibitors used to treat HIV (Table 90–6). HIV-positive patients may benefit from the use of rifabutin instead of rifampin.25,37,49,60 Furthermore, women who use oral contraceptives must use another form of contraception during therapy because increased clearance of the hormones may lead to unexpected pregnancies. Patient records should be reviewed for potential drug interactions before dispensing rifampin. Rifampin may turn urine and other secretions orange-red and may permanently stain some types of contact lenses.
TABLE 90-6 Recommended Regimens for the Concomitant Treatment of Tuberculosis and HIV Infection
Other Rifamycins Rifabutin is used for disseminated M. avium infection in AIDS patients and is quite active against M. tuberculosis. Most rifampin-resistant organisms are resistant to rifabutin. Because rifabutin is a less potent enzyme inducer than rifampin, it may be used for patients who are receiving protease inhibitors.37,49,60,61 For HIV-positive patients, the ATS/CDC recommends regimens with three or more doses of the TB drugs per week (see Table 90–3). Rifapentine is a long-acting rifamycin that can be used once weekly in the continuation phase of treatment (after the first 2 months) in carefully selected HIV-negative patients. It is approximately as potent an enzyme inducer as rifampin, so similar drug interactions are likely.37,49,60,61
Pyrazinamide Adding pyrazinamide to the first 2 months of treatment with isoniazid and rifampin shortens the duration to 6 months for most patients.2,37 Pyrazinamide may be bacteriostatic or bactericidal depending on the concentration and the susceptibility of the organism. It is usually well absorbed and displays a fairly long half-life.62,63 The most common toxicities of pyrazinamide are GI distress, arthralgias, and elevations in the serum uric acid concentrations.37 Most patients do not experience true gout. Hepatotoxicity is the major limiting adverse effect and is dose-related when pyrazinamide is given daily.
A fixed-combination product (Rifater, Aventis) of rifampin 120 mg, isoniazid 50 mg, and pyrazinamide 300 mg is designed to prevent drug resistance by keeping the self-medicating patient from using only one drug at a time. If the patient is receiving DOT, there is no particular advantage to this product. The typical dose of Rifater will be five to six tablets daily. When pyrazinamide is discontinued after 2 months of treatment, the combination product Rifamate (isoniazid 150 mg and rifampin 300 mg) can be substituted.
Ethambutol Ethambutol replaced p-aminosalicylic acid as a first-line agent in the 1960s because it was better tolerated by patients.2,37 It is used as a fourth drug for TB while awaiting susceptibility data.37 If the organism is susceptible to isoniazid, rifampin, and pyrazinamide, ethambutol can be stopped. Ethambutol is active against most mycobacteria, by inhibiting synthesis of metabolites and impairing cell metabolism, and is generally bacteriostatic.
Ethambutol should not be given with antacids.64 For patients with renal failure, the ethambutol dose should be reduced to three times per week.50,65 Retrobulbar neuritis is the major adverse effect. Patients may complain of a change in visual acuity, the inability to see the color green, or both. They should be monitored monthly while on the drug using Snellen wall charts for visual acuity and Ishihara red-green color discrimination cards.31,37
Second-Line Antituberculosis Drugs
Streptomycin Streptomycin is one of three aminoglycoside antibiotics (along with amikacin and kanamycin) that are active against mycobacteria. It is quite active against MAC and several other mycobacteria, enterococci, Brucella, Yersinia, and various other bacteria. Although labeled only for intramuscular dosing, streptomycin can be given safely as IV infusions (100 mL of 5% dextrose in water or normal saline) over 30 minutes, similar to the other aminoglycosides.66 Streptomycin, like other aminoglycosides, is renally cleared by glomerular filtration and must be given less often to patients with renal dysfunction.37,40
Streptomycin occasionally causes nephrotoxicity, although it tends to be mild and reversible. It also is capable of causing ototoxicity (vestibular and cochlear), which may become permanent with continued use.37 Older patients and those receiving long durations of treatment are most likely to experience hearing loss, whereas vestibular toxicity is highly unpredictable.
Resistance to amikacin and kanamycin is frequently linked but independent of resistance to streptomycin and independent of resistance to capreomycin. Therefore, susceptibility tests should guide the selection of these injectable drugs.
p-Aminosalicylic Acid In the United States, only the enteric-coated, sustained-release granule form (Paser) is available.67–69 GI disturbances are the most common adverse effects from p-aminosalicylic acid. Diarrhea is usually self-limited, with symptoms improving after the first 1 to 2 weeks of therapy. Occasionally, a few doses of an opioid will resolve the problem. It also is important to tell the patient that the empty granules will appear in the stool. Although FDA approved for three daily doses, pharmacokinetic data support twice-daily dosing.68
Various types of malabsorption, including steatorrhea, were reported with previous dosage forms of p-aminosalicylic acid. Hypersensitivity and, rarely, severe hepatitis may occur. p-Aminosalicylic acid is known to produce goiter, with or without myxedema, that seems to occur more frequently with concomitant ethionamide therapy.
Cycloserine Cycloserine is only used to treat MDR-TB. It is well absorbed orally and is best taken on an empty stomach.70 It is cleared primarily through the kidneys by glomerular filtration and requires dosage reduction in renal failure. Cycloserine can produce dose-related CNS toxicity, including lethargy, confusion, or unusual behavior. Seizures, although reported, are exceedingly rare in U.S. patients.2,37Therapy is improved by maintaining 2-hour postdose serum concentrations between 20 and 35 mcg/mL (mg/L; 200 and 349 μmol/L).40,42 Most patients reach a maximum dose of 750 mg daily, divided unevenly into two doses. This can be achieved by starting with 250 mg daily for 2 days, followed by 250 mg increments over 2-day intervals. This dose of cycloserine can be maintained if the patient complains of only occasional mild CNS effects, such as difficulty concentrating. Serum concentrations can be checked 1 to 2 weeks into therapy. The addition of pyridoxine 50 mg daily may improve patient tolerance of cycloserine.
Ethionamide Ethionamide shares structural features with two other antimycobacterial agents, isoniazid and, more distantly, thiacetazone, a drug not used in the United States. Prothionamide, the n-propyl derivative of ethionamide, is used in Europe. Ethionamide is only active against organisms of the genus Mycobacterium, and it should be considered primarily bacteriostatic because it is difficult to achieve serum concentrations that would be bactericidal.37,40,42
GI toxicity is the dose-limiting adverse effect. The drug should be introduced gradually in 250 mg increments, as described earlier for cycloserine. Rarely will a patient tolerate more than 1,000 mg daily in divided oral doses. Ethionamide may be administered with a light snack or prior to bedtime to minimize GI intolerance. Food does not affect absorption significantly.71 Little ethionamide is recovered in the urine, so doses remain the same in renal failure. Ethionamide may cause goiter with or without hypothyroidism (especially when given with p-aminosalicylic acid), gynecomastia, alopecia, impotence, menorrhagia, photodermatitis, and acne. The management of diabetes also may be more difficult for patients receiving ethionamide. Because of these problems, ethionamide only is used when necessary.
Clofazimine Clofazimine is a drug with good activity against Mycobacterium leprae and some activity against M. tuberculosis and M. avium. It is used in doses of 100 mg daily in advanced cases of MDR-TB or MAC, especially when therapeutic options are limited.37,40 The drug has a terminal elimination half-life that is weeks long. GI distress and skin discoloration are the most important adverse reactions. Although uncommon, severe GI pain may occur because of deposition of clofazimine crystals within the intestines; this may require surgical correction.
Thiacetazone Thiacetazone is a weak agent used rarely in parts of the developing world because of its low cost. Skin reactions, including rash and Stevens-Johnson syndrome, may occur. Thiacetazone must be discontinued permanently as soon as a rash appears. Similar to trimethoprim–sulfamethoxazole, the incidence of skin reactions is much higher for AIDS patients.72
Quinolones Levofloxacin, gatifloxacin (outside of the United States), and moxifloxacin are sometimes used to treat MDR-TB because of their excellent activity against M. tuberculosis. Several studies have suggested a potential role for moxifloxacin as a possible replacement for certain first-line agents.2,11,37,40,73–75 Moxifloxacin has been compared with isoniazid and ethambutol during the first 8 weeks of therapy for pulmonary TB. It did not demonstrate a significant increase in 8-week culture negativity when compared with isoniazid. However, shorter time to culture conversion was seen when compared with ethambutol. Quinolones are useful because most are available in oral and IV dosage forms, so they can be used in critically ill patients. However, resistance of MTB to the fluoroquinolones is a major concern. Resistance is attributed to mutations in the gyrA and gyrB genes and can develop in a relatively short period of time.76
Macrolides/Azalides The macrolide clarithromycin and azalide azithromycin represent substantial advances in the treatment of MAC but demonstrate limited activity against M. tuberculosis and are not used frequently for TB.2,11,37,40
New Drugs and Delivery Systems Several promising compounds are currently under development for the treatment of MTB. The nitroimidazole derivatives, OPC67683 (delamanid) and PA824, are chemically related to metronidazole and work through inhibiting mycolic acid synthesis. The diarylquinoline TMC207 (bedaquiline) works through targeting the ATP synthase pump, and does not demonstrate cross-resistance with existing TB drugs. All of these agents have potent in vitro and in vivo activity with very low MICs against M. tuberculosis.77–79 Both TMC-207 and OPC67683 have been evaluated in Phase 2b placebo-controlled, double-blind, randomized trials in patients with newly diagnosed MDR-TB and have shown rapid culture conversion and good tolerance.77,78,80 PA-824 has moved from Phase 1 to Phase 2 trials. Linezolid has been used in some patients with MDR-TB.81 Long-term use of linezolid requires careful monitoring of hematologic indices for potential anemia and thrombocytopenia. It may be possible to reduce the incidences of these toxicities by giving linezolid 600 mg daily or 300 mg twice daily for the slow-growing M. tuberculosis rather than the usual 600 mg twice-daily dose used for gram-positive organisms. Two new compounds in the oxazolidinone class, PNU-100480 and AZD-5847, are currently in Phase 1 studies. Liposomes have been investigated as delivery systems for various agents against mycobacteria, including isoniazid, rifampin, and the aminoglycosides. By changing the pharmacokinetic profile of such agents, their use in the treatment of mycobacterial infections could be enhanced greatly. Currently, no such product is licensed for use against TB.
Corticosteroids Adjunctive therapy with corticosteroids may be of benefit for some patients with tuberculous meningitis or pericarditis to relieve inflammation and pressure.2,37 They should be avoided in most other circumstances because they detract from the immune response to TB.
Bacille Calmette-Guérin Vaccine The BCG vaccine is an attenuated, hybridized strain of M. bovis. It was developed in 1921 and is used as a prophylactic vaccine against TB. Administration of BCG vaccine is compulsory in many developing countries and is officially recommended in many others. Vaccination with BCG produces a subclinical infection resulting in sensitization of T lymphocytes and cross-immunity to M. tuberculosis, as well as cutaneous hypersensitivity and, in many cases, a positive tuberculin skin test.
In the published clinical trials, several different BCG preparations were used, and the efficacy of these vaccinations ranged from negative 56% (some patients did worse with the vaccine) to positive 80%.2,37Trials within the United States and Puerto Rico have shown efficacy rates of 6% to 29%. The primary benefit of BCG vaccination appears to be the prevention of severe forms of TB in children. Data from the BCG trials show that the incidence of tuberculous meningitis and miliary TB is 52% to 100% lower and that the incidence of pulmonary TB is 2% to 80% lower in vaccinated children younger than 15 years of age than it was in unvaccinated controls.
Unfortunately, BCG does not appear to be very reliable in preventing disease by M. tuberculosis in other segments of the population. Side effects occur in 1% to 10% of vaccinated persons and usually include severe or prolonged ulceration at the vaccination site, lymphadenitis, and lupus vulgaris. It is recommended that pregnant women and patients with impaired immune systems, including those with HIV infection, avoid vaccination. The World Health Organization had recommended, however, that in populations where the risk of TB is high, HIV-infected infants who are asymptomatic should receive BCG vaccine at birth or as soon as possible thereafter. Because BCG infection has occurred in AIDS patients given the vaccine, individuals with symptomatic HIV infection should not be vaccinated.2,37
In the United States, BCG vaccination is recommended only for uninfected children who are at unavoidable risk of exposure to TB and for whom other methods of prevention and control have failed or are not feasible.2,37 Its use is very limited.
PERSONALIZED PHARMACOTHERAPY
Health professionals should develop and maintain treatment plans, provide drug information, direct appropriate TDM, and monitor adherence, adverse drug reactions, and interactions to TB therapy through regular assessments. Patients coinfected with HIV will require special attention because of their immunocompromised state and increased risk of drug interactions. TDM may be necessary in certain populations.
Therapeutic Drug Monitoring
TDM, or applied pharmacokinetics, is the use of serum drug concentrations to optimize therapy.37,40,42,82,83 TDM generally should be used if patients are failing appropriate treatment (no clinical improvement after 2 to 4 weeks or smear positive after 4 to 6 weeks). Patients with AIDS, diabetes, cystic fibrosis, various GI disorders, or MDR-TB may be tested prospectively, before problems arise, to ensure adequate treatment (Table 90–6). Blood samples collected at 2 and 6 hours after a dose have been used with some success, although they may not be the optimal sampling times for all the drugs. Finally, TDM of the TB and HIV drugs is perhaps the most logical way to untangle the complex drug interactions that take place.84,85
Clinical Controversy…
Some TB centers employ TDM for many of their patients at the outset of treatment in order to identify drug-delivery problems early. Other centers wait to see how the patient responds and perform TDM only if problems arise. An argument can be made for either approach. The latter can save money, but delays in effective treatment can affect the patient’s outcome adversely.
EVALUATION OF THERAPEUTIC OUTCOMES
Monitoring of the Pharmaceutical Care Plan
The most serious problem with TB therapy is patient nonadherence to the prescribed regimens.86 Unfortunately, there is no reliable way to identify such patients a priori. Noncompliance rates of up to 89% have been reported with TB therapy.86 It is critical to the control of TB that such adherence rates be improved dramatically. The most effective way to achieve this end is with DOT.2,11,37 Despite criticisms that it will cost more money, it is far cheaper in the long run to prevent the further spread of disease with DOT than to track down and treat additional cases of TB continuously.
The homeless and other underprivileged individuals are assumed to constitute the group of patients considered “unreliable,” and DOT should be reserved for them; it is also assumed that “responsible” patients cared for by private physicians may be treated with daily, unsupervised therapy. A study conducted in Baltimore, however, compared outcomes (sputum culture conversion to negative at 3 months) for patients with pulmonary TB who were treated by private physicians with outcomes for patients treated via DOT in a city-run clinic. Surprisingly, 3-month culture conversion occurred in only 40% of the private-care patients, compared with 90% in the city clinic-care patients.82Clearly, expansion of the use of DOT to nearly all patients with TB may be of benefit.
Patients who are AFB smear positive should have sputum samples sent for AFB stains every 1 to 2 weeks until two consecutive smears are negative. This provides early evidence of a response to treatment.37Once on maintenance therapy, sputum cultures can be performed monthly until two consecutive cultures are negative, which generally occurs over 2 to 3 months. If sputum cultures continue to be positive after 2 months, drug susceptibility testing should be repeated, and serum concentrations of the drugs should be checked.
Serum chemistries, including blood urea nitrogen, creatinine, aspartate transaminase, and alanine transaminase, and a complete blood count with platelets should be performed at baseline and periodically thereafter, depending on the presence of other factors that may increase the likelihood of toxicity (e.g., advanced age, alcohol abuse, pregnancy)2,37 (see Table 90–7). Hepatotoxicity should be suspected for patients whose serum transaminases exceed five times the upper limit of normal or whose total bilirubin concentration exceeds 3 mg/dL (51.3 μmol/L) and for patients with symptoms such as nausea, vomiting, or jaundice. At this point, the offending agent(s) should be discontinued. Sequential reintroduction of the drugs with frequent testing of liver enzymes is often successful in identifying the offending agent; other agents may be continued. Alternative agents should be selected as needed. Audiometric testing should be performed at baseline and monthly for patients who must receive aminoglycosides for more than 1 to 2 months. Vision testing (Snellen visual acuity charts and Ishihara color discrimination plates) should be performed on all patients who receive ethambutol. All patients diagnosed with TB should be tested for HIV infection.
TABLE 90-7 Antituberculosis Drug Monitoring Table
ABBREVIATIONS
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