MYCOBACTERIUM TUBERCULOSIS Overview
Like other mycobacteria, MTB cells are bacilli with a gram-positive cell wall structure requiring an acid-fast stain for demonstration. Tuberculosis is a systemic infection the most common form of which is a chronic pneumonia with fever, cough, bloody sputum, and weight loss. The natural history follows a course of chronic fever and wasting to death aptly labeled “consumption” in the 19th century. Disease outside the lung also occurs and is particularly devastating when MTB reaches the central nervous system causing tuberculous meninigitis. Most of those infected never develop disease manifesting infection only by the presence of a skin test or other evidence of an immune response. Although disease may appear immediately following primary infection, in most instances it follows a latent period lasting months, years, and even decades. MTB is not known to produce any classic virulence factors such as toxins. The tissue destruction is due to the destructive effects of unremitting delayed-type hypersensitivity in a host whose Th1 cellular immune responses are unable to restrict growth of MTB. Methods for culture diagnosis are sensitive but require specialized expertise. Effective antimicrobial therapy has long been available but multiple drugs are required and the treatment course prolonged. Together these make tuberculosis controllable but only in countries that can afford it. It is still the leading cause of premature death by bacterial infection in the world.
MTB is a slim, strongly acid–alcohol–fast rod. It frequently shows irregular beading in its staining, appearing as connected series of acid-fast granules (Figure 27–2). It grows at 37°C, but not at room temperature, and it requires enriched or complex media for primary growth. The classic medium, Löwenstein-Jensen, contains homogenized egg in nutrient base with dyes to inhibit the growth of nonmycobacterial contaminants. Growth is very slow, with a mean generation time of 12 to 24 hours. The dry, rough, buff-colored colonies usually appear after 3 to 6 weeks of incubation. Growth is more rapid in semisynthetic (oleic acid–albumin) and liquid media. The major phenotypic tests for identification are summarized in Table 27–1. Of particular importance is the ability of MTB to produce large quantities of niacin, which is uncommon in other mycobacteria.
✺ Niacin test distinguishes from other mycobacteria
Because of its hydrophobic lipid surface, MTB is unusually resistant to drying, to most common disinfectants, and to acids and alkalis. Tubercle bacilli are sensitive to heat, including pasteurization, and individual organisms in droplet nuclei are susceptible to inactivation by ultraviolet light. As with other mycobacteria, the MTB cell wall structure is dominated by mycolic acids and LAM. Its antigenic makeup includes many protein and polysaccharide antigens, of which a boiled extract from MTB called tuberculin is the most studied. It consists of heat-stable proteins liberated into liquid culture media. A purified protein derivative (PPD) of tuberculin is used for skin testing and is standardized in tuberculin units according to skin test activity.
Unusual resistance to drying and disinfectants but not to heat
✺ Tuberculin PPD is a mix of MTB proteins
A recognized disease of antiquity, tuberculosis first reached epidemic proportions in the Western world during the Industrial Revolution beginning in the 18th and 19th centuries. Associated with urbanization and crowding, consumption accounted for 20% to 30% of all deaths in cities, winning tuberculosis the appellation of “the captain of all the men of death.” Morbidity rates were many times higher. The disease has had major sociologic impacts, flourishing with ignorance, poverty, and poor hygiene, particularly during the social disruptions of war and economic depression. Under these conditions, the poor are the major victims, but all sectors of society are at risk. Chopin, Paganini, Rousseau, Goethe, Chekhov, Thoreau, Keats, Elizabeth Barrett Browning, and the Brontës, to name but a few, were all lost to tuberculosis in their prime. With knowledge of the cause and transmission of the disease and the development of effective antimicrobial agents, tuberculosis was increasingly brought under control in developed countries. Unfortunately, morbidity and mortality remain at 19th-century levels in many developing countries. Today, a third of the world is infected, 30 million with active disease, and over 8 million new cases every year. There are more than 30 thousand tuberculosis deaths every week. As shown in Figure 27–3 the global distribution is unequal largely due to the relative availability of the public health and medical resources necessary to control tuberculosis. Twenty-two high-burden countries account for 80% of active cases.
Epidemic peak in 18th and 19th centuries
Attack rates relate to health resources
The worldwide incidence and distribution of tuberculosis. (Reproduced with permission from Willey JM: Prescott, Harley, & Klein’s Microbiology, 7th edition. McGraw-Hill, 2008.)
The majority of tuberculous infections are contracted by inhalation of droplet nuclei carrying the causative organism (Figure 27–4). Humans may also be infected through the gastrointestinal tract after ingestion of milk from tuberculous cows (now uncommon because of pasteurization) or, rarely, through abraded skin. Although a number of animals may be infected, humans are the primary reservoir for MTB. It has been estimated that a single cough can generate as many as 3000 infected droplet nuclei which dry while airborne and remain suspended for long periods. It is estimated that less than 10 bacilli may initiate a pulmonary infection in a susceptible individual. The likelihood of acquiring infection thus relates to the numbers of organisms in the sputum of an open case of the disease, the frequency and efficiency of the coughs, the closeness of contact, and the adequacy of ventilation in the contact area. Epidemiologic data indicate that large doses or prolonged exposure to smaller infecting doses is usually needed to initiate infection. In some closed environments, such as a submarine or a crowded nursing home, a single open case of pulmonary tuberculosis can infect the majority of nonimmune individuals sharing sleeping accommodations. Infection outdoors is less likely due to ventilation and the susceptibility of MTB to ultraviolet light.
✺ Infection by respiratory droplet route
✺ Repeated coughing generates infectious dose into air
Poor ventilation increases risk
Tuberculosis. A. Primary tuberculosis. Mycobacterium tuberculosis is inhaled in droplet nuclei from an active case of tuberculosis. Initial multiplication is in the alveoli with spread through lymphatic drainage to the hilar lymph nodes. After further lymphatic drainage to the bloodstream, the organisms are spread throughout the body. B. Alveolar macrophage. The two-front battle being carried out between A and C is shown. Ingested bacteria multiply in the nonactivated macrophage. (1) TH1 cellular immune responses attempt to activate the macrophage by secreting cytokines (interferon gamma [IFN-γ]). If successful, the disease is arrested. (2) Inflammatory elements of delayed-type hypersensitivity (DTH) are attracted and cause destruction. If activation is not successful, DTH injury and disease continue. C. Reactivation tuberculosis. Reactivation typically starts in the upper lobes of the lung with granuloma formation. DTH-mediated destruction can form a cavity, which allows the organisms to be coughed up to infect another person.
The AIDS pandemic and the spread of MTB strains resistant to multiple drugs have added to the tuberculosis burden. It is estimated that patients with latent tuberculosis increase their risk of reactivation disease by a factor 200 to 300 times with the development of HIV coinfection. HIV-infected persons are also at particularly high risk for primary infection even in the first year when their CD4+ T cell counts are still high. With this dark synergy, tuberculosis and AIDS are the leading causes of premature death in the world, and 30% of these deaths are HIV infected.
✺ AIDS and drug resistance enhance spread
MTB is a facultative intracellular pathogen whose success depends on avoiding the killing mechanisms of professional phagocytes. Primary tuberculosis is the initial infection in which inhaled droplet nuclei containing tubercle bacilli are deposited in the peripheral respiratory alveoli, most frequently those of the well-ventilated midlung zones of the middle and lower lobes. At the earliest stages surface proteins (ESAT-6) may facilitate binding to laminin in the basement membrane of alveolar epithelial cells. In the alveoli the bacteria are recognized by alveolar macrophage complement receptors (CR1, CR3, CR4) and phagocytosed. This inaugurates a two-stage battle within the macrophage, which may be resolved in weeks or last for decades. The first stage is MTB’s interference with phagosome/lysosome fusion and with the digestive mechanisms of the macrophage. In this process, MTB has the upper hand through the ability of its urease to interfere with the acidification required for maximal efficiency of lysosomal enzymes. The production of antioxidants like superoxide dismutase which interfere with reactive oxygen bactericidal mechanisms is also important. These actions allow the bacteria to multiply freely in the phagosome of the nonactivated macrophage (Figure 27–4). The second stage is the triggering of TH1 immune responses, beginning with digestion and surface presentation of mycobacterial components and ending with cytokine activation of the macrophages. The short- and long-term outcomes of the infection depend on the ability of the macrophage activation process to reverse the intracellular edge that MTB has as a result of its ability to block bactericidal mechanisms inside the phagosome.
✺ MTB multiplies in alveolar macrophages
✺ Acidification, reactive oxygen mechanisms of phagosome blocked
✺ TH1 immune responses triggered
In the early stages of infection, MTB-laden macrophages are transported through lymphatic channels to the hilar and mediastinal lymph nodes draining the infected site. From there, a low-level bacteremia disseminates the bacteria to a number of tissues, including the liver, spleen, kidney, bone, brain, meninges, and apices of the lung. Although the primary site of infection and enlarged hilar lymph nodes can be detected radiologically, the distant sites usually have no findings. In fact, the primary evidence for their existence is reactivation at nonpulmonary sites later in life. Tuberculous meningitis is the most serious of these. Despite this widespread dissemination, less than 10% of immunocompetent persons who undergo primary infection will experience disease at any time in their life.
✺ MTB disseminates to lymph nodes and bloodstream
✺ Less than 10% ever suffer disease
In the primary lesion as MTB cells multiply, macrophages and dendritic cells release cytokines (tumor necrosis factor, interleukin 12 [IL-12], interferon gamma [IFN-γ]), which attract T cells and other inflammatory cells to the site. The recruited CD4+ T cells initiate the TH1-type immune response over the following 3 to 9 weeks in which IFN-γ is the primary activator of macrophages. This includes CD8+ cytotoxic T cells which recognize and destroy MTB-infected macrophages. MTB multiplication also generates mycobacterial proteins which trigger a delayed-type hypersensitivity (DTH) response with its phagocytes, fluid, and release of digestive enzymes. This adds a destructive component to the process and is the sole known source of injury in tuberculosis. The magnitude of the DTH is directly related to the size of the MTB population. If the TH1 immune process is effective, the antigenic source of DTH stimulation wanes and the disease resolves. In the IFN-γ activated macrophages a specific subset of genes have been modulated to generate a cell-mediated immune response to mycobacterial proteins. Stimulation of the DTH component of this response is the basis of the tuberculin skin test (see Diagnosis).
✺ Cytokines attract T cells and TH1 immune response
✺ MTB proteins also trigger DTH and injury
The mixture of the TH1 immune and DTH responses is manifest in a microscopic structure called a granuloma, which is composed of lymphocytes, macrophages, epithelioid cells (activated macrophages), fibroblasts, and multinucleated giant cells (fused macrophages) all in an organized pattern (Figure 27–5). As the granuloma grows, the destructive nature of the hypersensitivity component leads to necrosis usually in the center of the lesion. This is termed caseous necrosis because of the cheesy, semisolid character of material at the center of large gross lesions, but the term fits the smooth glassy appearance of microscopic granulomas as well.
✺ The granuloma includes activated macrophages, lymphocytes, and fibroblasts
✺ Caseous necrosis is due to DTH
Tuberculous granulomas. A. Early granuloma with lymphocytes, epithelioid cells, and fibroblasts organizing around a central focus. The multinucleate giant cell in the center is typical of granulomas but not exclusive to Mycobacterium tuberculosis. B. Multiple granulomas surround and invade a vein near the lung hilum. Central degeneration is starting to appear and will eventually become caseous necrosis. (Reproduced with permission from Connor DH, Chandler FW, Schwartz DQ, et al: Pathology of Infectious Diseases. Stamford, CT: Appleton & Lange, 1997.)
Primary infections are handled well once the TH1 immune response halts the intracellular growth of MTB. Bacterial multiplication ceases, the lesions heal by fibrosis, and the organisms appear to slowly die. This sequence occurs in infections with multiple other infectious agents for which it is the end of the story. In tuberculosis, some of the organisms, when faced with oxygen and nutrient deprivation, instead of dying enter a prolonged dormant state called latency. Some view the arrival of MTB specific T cells 3 to 4 weeks after infection as the start of containment rather than cure. Specific factors facilitating survival are not known but the waxy nature of the MTB cell wall must be of aid as it is in the environment. It has long been assumed that these latent bacilli are primarily in healed granulomas in the lung, but we now know they are widely distributed with or without evidence of local granulomatous inflammation. This surviving MTB subpopulation in the lung and elsewhere lies waiting for reactivation months, years, or decades later. For the vast majority of persons who undergo a primary infection this never happens, either because of the complete killing of the original population or the failure of factors favoring latency or reactivation to materialize. The activation of a large set of MTB genes associated with a shift to the nonreplicating latent state is triggered by hypoxic conditions in the granuloma. A major feature of this state is the intracellular accumulation of lipids derived from host fatty acids and cholesterol which could serve as a durable energy source for the bacteria. This is manifest by the “foamy macrophages” seen in granulomas and occasionally the sputum of tuberculous patients.
✺ Primary lesions heal once immunity develops
✺ Some MTB enter latent state rather than dying
Reactivation (Adult) Tuberculosis
Although mycobacterial factors have been identified (resuscitation-promoting factor), little is known of the mechanisms of reactivation of these latent foci. It has generally been attributed to some selective waning of immunity. The new foci are usually located in body areas of relatively high oxygen tension that would favor growth of the aerobe MTB. The apex of the lung is the most common, with spreading, coalescing granulomas, and large areas of caseous necrosis. Necrosis often involves the wall of a small bronchus from which the necrotic material is discharged, resulting in a pulmonary cavity and bronchial spread. Frequently, small blood vessels are also eroded. The destructive nature of these lesions cannot be directly attributed to any products or structural components of MTB. The damage is due to the failure of the host to control growth of MTB and thus the rising load of mycobacterial proteins which stimulate the autodestructive DTH response.
✺ Latent MTB reactivates at aerobic sites
✺ DTH-mediated destruction forms pulmonary cavities
Humans generally have a high innate immunity to the development of disease. This was tragically illustrated in the Lübeck disaster of 1926, in which infants were administered wild-type MTB instead of an intended vaccine strain. Despite the large dose, only 76 of 249 died and most of the others developed only minor lesions. As stated earlier, over 90% of immunocompetent persons infected with MTB never develop active disease. There is epidemiologic and historic evidence for differences in the immunity in certain population groups and between identical and nonidentical twins. What is known of the mechanisms of innate immunity is similar to that with other pathogenic bacteria. These include Toll-like receptor responses generated by the recognition of components of the MTB cell wall and phagocytic responses.
Innate immunity is high and genetically variable
Adaptive immunity to tuberculosis is primarily related to the development of reactions mediated through CD4+ T lymphocytes via TH1 pathways. Intracellular killing of MTB by macrophages activated by INF-γ and the CD8+ mediated killing of infected macrophages are the essential steps. The specific components of MTB that are important in initiating these reactions are not known. Although antibodies are formed in the course of disease, there is no evidence they play any role in immunity.
✺ TH1 immunity is most important
✺ Cytotoxic CD8+ lymphocytes also participate
TUBERCULOSIS: CLINICAL ASPECTS
Primary tuberculosis is either asymptomatic or manifest only by fever and malaise. Radiographs may show infiltrates in the mid-zones of the lung (Ghon focus) and later enlarged draining lymph nodes in the area around the hilum. When these lymph nodes fibrose and sometimes calcify, they produce a characteristic radiologic picture (Ghon complex). In less than 5% of patients, the primary disease is not controlled and merges into the reactivation type of tuberculosis, or disseminates to many organs. The latter may also result from a necrotic tubercle eroding into a small blood vessel.
✺ Mid-lung infiltrates and adenopathy
Primary infection may progress to reactivation or dissemination
The times of life when persons infected with MTB are most likely to develop clinical disease are infancy (primary), young adult (primary or reactivation), or old age (reactivation). In Western countries, reactivation of previous quiescent lesions occurs most often after age 50 and is more common in men. Reactivation is associated with a period of immunosuppression precipitated by malnutrition, alcoholism, diabetes, old age, or a dramatic change in the individual’s life, such as loss of a spouse. In areas in which tuberculosis is more prevalent, reactivation is more frequently seen in young adults experiencing the immunosuppression that accompanies puberty and pregnancy. Recently, reactivation and progressive primary tuberculosis among younger adults have increased as a complication of AIDS.
Reactivation is most common in older men
✺ Predisposing factors include underlying disease and life events
How can it take this long for disease to develop?
Cough is the universal symptom of tuberculosis. It is initially dry, but as the disease progresses sputum is produced, which even later is mixed with blood (hemoptysis). Fever, malaise, fatigue, sweating, and weight loss all progress with continuing disease. Radiographically, infiltrates appearing in the apices of the lung coalesce to form cavities with progressive destruction of lung tissue. Less commonly, reactivation tuberculosis can also occur in other organs, such as the kidneys, bones, lymph nodes, brain, meninges, bone marrow, and bowel. Disease at these sites ranges from a localized tumor-like granuloma (tuberculoma) to a fatal chronic meningitis. Untreated, the progressive cough, fever, and weight loss of pulmonary tuberculosis creates an internally consuming fire that usually takes 2 to 5 years to cause death. The course in AIDS and other T-cell–compromised patients is more rapid.
✺ Cough is universal
✺ Cavities form in lung apices
Multiple organs are involved
The tuberculin skin test (Figure 27–6) measures DTH to an international reference tuberculoprotein preparation called PPD. The test involves an intradermal injection that is read 48 to 72 hours later. An area of induration of 15 mm or more accompanied by erythema constitutes a positive reaction, and no induration indicates a negative reaction. A positive PPD test indicates that the individual has developed DTH through infection at some time with MTB, but carries no implication as to whether the disease is active. Persons who have been infected with another mycobacterial species or immunized with the bacillus Calmette-Guérin (BCG) vaccine may also be reactive, but the induration is usually in the 5 to 10 mm range. Patients with severe disseminated disease, those on immunosuppressive drugs, or those with immunosuppressive diseases such as AIDS may fail to react or produce 5 to 10 mm reactions due to anergy. A positive PPD should not be attributed to BCG unless the vaccination was recent.
✺ Positive PPD indicates past or current infection
✺ Other mycobacteria or BCG immunization cause intermediate reponses
Immune compromise reduce response
Tuberculin test. The PPD (purified protein derivative) tuberculoprotein was injected intradermally at this site 48 hours previously. The erythema and induration (>10 mm) that are present indicate the development of delayed-type (type IV) hypersensitivity. (Reproduced with permission from Nester EW: Microbiology: A Human Perspective, 6th edition. 2009.)
The predictive value of the tuberculin test depends on the prevalence of tuberculosis and other mycobacterial diseases in the population and public health practices, particularly the use of BCG immunization. In the United States, where BCG is not used, and the disease prevalence is low, a positive test is very strong evidence of previous MTB infection. In countries that use BCG, the skin test can only be used selectively. A new group of tests detect the release of IFN-γ from T cells stimulated with MTB-only proteins. These IFN-γ release assays (IGRA) are not positive in persons immunized with BCG or infected with other mycobacteria but are no better indicator of active tuberculosis than the tuberculin test. Their use is limited by cost but increasing in immigrant populations and as an aid in making isolation decisions in hospitalized patients.
✺ Predictive value of positive PPD depends on prevalence, BCG status
✺ IFN-γ tests are more specific
Think ➱ Apply 27-1. This is due to the long survival of the cells that enter the state of latency. The MTB have been inert but “alive” all this time.
MTB can be detected microscopically in smears of clinical specimens using one of the acid-fast staining procedures discussed in Chapter 4. Because the number of organisms present is often small, specimens such as sputum and cerebrospinal fluid are concentrated by centrifugation before staining to improve the sensitivity of detection. In one of the acid-fast procedures, the stain is fluorescent, which enhances the chances that a microscopist will be able to find just a few acid-fast bacilli (AFB) in an entire smear. Even with the best of concentration and staining methods, little more than half (~65%) of culture-positive sputum samples yield positive smears. The yield from other sites is even lower, particularly from cerebrospinal fluid. The presence of AFB is not specific for MTB because other mycobacteria may have a similar morphology.
✺ AFB detected in 65% of culture-positive sputum
Contaminating mycobacteria may yield “false” positives
Additional caution must be exercised in the interpretation of positive smears from urine or from medical devices (bronchoscope, nasotracheal tube) because contamination with environmental AFB is possible. Despite its challenges, the pursuit of a smear diagnosis is well worth the effort because it allows clinical decision making while awaiting the days to weeks required for culture results.
Whether the AFB smear is positive or not, culture of the organism is essential for confirmation and for antimicrobial susceptibility testing. Specimens from sites, such as cerebrospinal fluid, bone marrow, and pleural fluid, can be seeded directly to culture media used for MTB isolation. Samples from sites inevitably contaminated with resident flora, such as sputum, gastric aspirations (cultured when sputum is not available), and voided urine, are chemically treated (alkali, acid, and detergents) using concentrations, experience has shown to kill the bulk of the contaminating flora but allow most mycobacteria to survive. Sputum specimens also require the use of agents to dissolve mucus so the specimen can be concentrated by centrifugation or filtration before inoculation onto the culture media just described.
Material contaminated with resident flora is chemically treated
Mucolytic agents used to concentrate sputum
Cultures on solid media usually take 3 weeks or longer to show visible colonies. Growth is more rapid in liquid media in which detection time may be further decreased by radiometric, flourometric, and colorimetric growth indicator systems. These systems may also be automated and have become the standard for all that can afford them. Identification of the isolated mycobacterium is achieved with a number of cultural and biochemical tests, including those shown in Table 27–1, but the process takes weeks more. Nucleic acid amplification (NAA) procedures targeting both DNA and ribosomal RNA sequences in clinical specimens have been developed and applied worldwide with increasing success. A rapid (less than 2 hours) commercial system shows high specificity for MTB and sensitivities for sputum specimens from patients with positive AFB smears which approach that of culture. Ninety percent of sputum AFB negative cases are also positive and the system also detects resistance to rifampin, a first-line drug (see treatment). Even with improved sensitivity, direct NAA methods cannot yet substitute for culture due to the need for live bacteria to carry out comprehensive antimicrobial susceptibility testing.
✺ Classic culture takes 3+ weeks
Colorimetric indicators speed detection
✺ NAA detects MTB and rifampin resistance
Susceptibility testing essential
Before effective antimycobacterial drugs became available over half the patients with active pulmonary tuberculosis died of their disease, most within 2 years. The search for effective drugs is complicated by the need for them to pass the unusually impermeable lipid-rich mycobacterial cell wall. However, several antimicrobial agents have been shown to be effective in the treatment of MTB infection (Table 27–2). The term first-line is used to describe the primary drugs of choice (isoniazid, ethambutol, rifampin, pyrazinamide) that have long clinical experience to back up their efficacy and to manage their side effects. Second-line agents are less preferred and reserved for use when there is resistance to the first-line agents.
✺ Drugs must penetrate lipid-rich cell wall
✺ Resistance to first-line causes use of second-line drugs
TABLE 27–2Antimicrobics Commonly Used in Treatment of Tuberculosis ||Download (.pdf) TABLE 27–2 Antimicrobics Commonly Used in Treatment of Tuberculosis
|FIRST-LINE DRUG ||SECOND-LINE DRUGa |
|Isoniazid ||para-Aminosalicylic acid |
|Ethambutol ||Ethionamide |
|Rifampin ||Cycloserine |
|Pyrazinamide ||Fluoroquinolones |
The approach with new cases is to start the patient on multiple first-line drugs (often all four) while waiting for the results of susceptibility tests. When these results are available, the regimen is adjusted to two or three agents proven by susceptibility testing to be active against the patient’s isolate.
Isoniazid and rifampin are active against both intra- and extracellular organisms, and pyrazinamide acts at the acidic pH found within cells. The use of streptomycin, the first antibiotic active against MTB, is now limited by resistance, toxicity, and the requirement for parenteral administration. MTB is also susceptible to other drugs that may be used to replace those of the primary group if they are inappropriate because of resistance or drug toxicity. The fluoroquinolones, such as ciprofloxacin and ofloxacin, are active against MTB and penetrate well into infected cells. Their role in the treatment of tuberculosis is promising but they require further clinical evaluation. Isoniazid and ethambutol act on the mycolic acid (isoniazid) and LAM (ethambutol) elements of mycobacterial cell wall synthesis. The molecular targets of the other agents have yet to be defined except for the general antibacterial agents (rifampin, streptomycin, and fluoroquinolones) discussed in Chapter 23.
Antimicrobials act intra- and extracellularly
Resistance or toxicity may limit some agents
Because of the high bacterial load and long duration of anti-MTB therapy, the emergence of resistance during treatment is of greater concern than with more acute bacterial infections. For this reason, the use of multiple drugs each with a different mode of action is the norm. Expression of resistance would then theoretically require a double mutant, a very low probability when the frequency of single mutants is 10–7 to 10–10. The percentage of new infections with strains resistant to first-line drugs varies between 5% and 15%, but it is increasing, particularly among those who have been treated previously. Of particular concern is the emergence in the last two decades of multidrug-resistant tuberculosis (MDR-TB) strains, which are resistant to isoniazid and rifampin, the mainstays of primary treatment. MDR-TBs now represent almost 5% of the worldwide cases, and over half of these are concentrated in three countries, China, India, and the Russian Federation. Although still rare, strains that add resistance to one or more second-line drugs (called extensively drug resistant [XDR-TB]) are now being seen.
✺ Multidrug therapy decreases probability of resistance expression
✺ MDR-TB resistant to isoniazid and rifampin
Why doesn’t the mutant lead to a new subpopulation of resistant MTB?
These therapeutic advances make curing tuberculosis a realistic goal for all with active disease. Effective treatment renders the patient noninfectious within 1 or 2 weeks, which has shifted the care of tuberculous patients from isolation hospitals and sanatoriums to the home or the general hospital. The duration of therapy varies, based on some clinical factors but is usually 6 to 9 months. In patients whose organisms display resistance to one or more of these drugs, and in those with HIV infection, a more intensive and prolonged treatment course is used. Chemotherapy for tuberculosis is among the most successful and cost-effective of all health interventions. Failure is most often due to lack of adherence to the regimen by the patient, the presence of resistant organisms, or both.
✺ Treatment lasts 6 to 9 months
Resistance and HIV require longer
✺ Compliance a major problem
Think ➱ Apply 27-2. The mutant cell cannot replicate because it is still susceptible to the action (at a different molecular site) of at least one of the other drugs in the regimen. Expression would require two or three independent mutations in the genome of a single cell.
There are a number of situations in which persons are felt to be at increased risk for tuberculosis even though they have no clinical evidence of disease (healthy + negative chest X-ray). The most common of these situations are close exposure to an open case (particularly a child) and/or conversion of the tuberculin skin test from negative to positive. In these instances, prophylactic chemotherapy with isoniazid (alone) is administered for 6 to 9 months. In the exposed person, the goal is to prevent a primary infection. The PPD-positive person has already had a primary infection; therefore, the goal is to reduce the chance of reactivation tuberculosis by killing all MTB in the body before they enter the nonreplicating latent state. This chemoprophylaxis has clear value for recently exposed persons demonstrating skin test conversion. It is less certain for those whose time of conversion is unknown and could have been many years ago. Isoniazid may cause a form of hepatitis in adults so its administration carries some risk.
✺ Exposure and PPD conversion warrant isoniazid chemoprophylaxis
✺ Goal is eradication prior to latency
BCG is a live vaccine derived originally from a strain of M bovis that was attenuated by repeated subculture. It is administered intradermally to tuberculin-negative subjects and leads to self-limiting local multiplication of the organism with development of tuberculin DTH. The latter negates the PPD as a diagnostic and epidemiologic tool. BCG has been used for the prevention of tuberculosis in various countries since 1923, but its overall efficacy remains controversial. Its ability to prevent disseminated disease in newborns and children is generally acknowledged, but prevention of chronic pulmonary disease in adults is not. Tuberculosis would not be the world leading killer if BCG was effective in preventing pulmonary reactivation disease. The use of BCG in any country is a matter of public health policy balancing the potential protection against the loss of case tracking through the skin test. BCG is not used in the United States, but is in many other counties, particularly those that lack the infrastructure for case tracking. BCG is contraindicated for individuals in whom T-cell–mediated immune mechanisms are compromised, such as those infected with HIV. Current vaccine strategies are focused on boosting the immunogenicity of BCG by the insertion of new recombinant genes. Recently these have included recombinants which inhibit MTB-specific apoptosis or enhance TNF production in macrophages.
✺ BCG live vaccine stimulates tuberculin DTH
✺ Effectiveness in adults variable
Recombinant BCG basis for future vaccines