Tuberculosis written report

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Level II Block V Module 1 – RESPIRATORY SYSTEM

Case 4: “Bloody Mary”

1. What is hemoptysis? What causes hemoptysis?

Hemoptysis is defined as the expectoration of blood from the respiratory tract, a spectrum that varies from blood-streaking of sputum to coughing up large amounts of pure blood. The most common site of bleeding is the airways, i.e., the tracheobronchial tree, which can be affected by inflammation (acute or chronic bronchitis, bronchiectasis) or by neoplasm (bronchogenic

carcinoma, endobronchial metastatic carcinoma, or bronchial carcinoid tumor). The bronchial arteries, which originate either from the aorta or from intercostal arteries and are therefore part of the high-pressure systemic circulation, are the source of bleeding in bronchitis or

bronchiectasis or with endobronchial tumors. Blood originating from the pulmonary parenchyma can be either from a localized source, such as an infection (pneumonia, lung abscess, tuberculosis), or from a process diffusely affecting the

parenchyma (as with a coagulopathy or with an autoimmune process such as Goodpasture’s syndrome). Disorders primarily affecting the pulmonary vasculature include pulmonary embolic disease and those conditions associated with elevated pulmonary venous and capillary pressures, such as mitral

stenosis or left ventricular failure. Although the relative frequency of the different etiologies of hemoptysis varies from series to series, most recent studies indicate that bronchitis and bronchogenic carcinoma are the two most

common causes. Despite the lower frequency of tuberculosis and bronchiectasis seen in recent compared to older series, these two disorders still represent the most common causes of massive hemoptysis in several

series. Even after extensive evaluation, a sizable proportion of patients (up to 30% in some series) have no identifiable etiology for their hemoptysis. These patients are classified as having idiopathic or cryptogenic hemoptysis, and subtle airway or parenchymal disease is presumably responsible for the bleeding.

(Harrison’s Principles of Internal Medicine 16th Edition)

1.1 What are the conditions that present with hemoptysis?

Differential Diagnosis of Hemoptysis

A. Source other than the lower respiratory tract1. Upper airway (nasopharyngeal) bleeding2. Gastrointestinal bleeding

B. Tracheobronchial source1. Neoplasm (bronchogenic carcinoma, endobronchial metastatic tumor,2. Kaposi’s sarcoma, bronchial carcinoid)3. Bronchitis (acute or chronic)4. Bronchiectasis5. Broncholithiasis6. Airway trauma7. Foreign body

C. Pulmonary parenchymal source1. Lung abscess2. Pneumonia3. Tuberculosis4. Mycetoma (“fungus ball”)5. Goodpasture’s syndrome6. Idiopathic pulmonary hemosiderosis7. Wegener’s granulomatosis8. Lupus pneumonitis9. Lung contusion

D. Primary vascular source1. Arteriovenous malformation2. Pulmonary embolism3. Elevated pulmonary venous pressure (esp. mitral stenosis)4. Pulmonary artery rupture secondary to balloon-tip pulmonary artery catheter manipulation

E. Miscellaneous/rare causes1. Pulmonary endometriosis2. Systemic coagulopathy or use of anticoagulants or thrombolytic agents


1.2 Differentiate massive from non-massive hemoptysis.

Massivehemoptysis is variably defined as the expectoration of >100 to >600 mL over a 24-h period, although the patient’s estimation of the amount of blood is notoriously unreliable. Expectoration of even relatively small amounts of blood is a frightening symptom and can be a marker for potentially serious disease, such as bronchogenic carcinoma. Massive hemoptysis, on the other hand, can represent an acutely lifethreatening problem. Large amounts of blood can fill the airways and the alveolar spaces.


1.3 Differentiate hemoptysis from hematemesis.

Hematemesis is vomitus of red blood or “coffee-grounds” material. Because blood originating from the nasopharynx or the gastrointestinal tract can mimic blood coming from the lower respiratory tract, it is important to determine initially that the blood is not coming from one of these alternative sites. Clues that the blood is originating from the gastrointestinal tract include a dark red appearance and an acidic pH, in contrast to the typical bright red appearance and alkaline pH of true hemoptysis.


2. What is pulmonary tuberculosis?

Pulmonary Tuberculosis

Pulmonary tuberculosis can be categorized as primary or postprimary (secondary).

Primary Disease

Primary pulmonary tuberculosis occurs soon after the initial infection with tubercle bacilli. In areas of high tuberculosis transmission, this form of disease is often seen in children. Because most inspired air is distributed to the middle and lower lung zones, these areas of the lungs are most commonly involved in primary tuberculosis. The lesion forming after infection is usually peripheral and accompanied in more than half of cases by hilar or paratracheal lymphadenopathy, which may not be detectable on chest radiography. In the majority of cases, the lesion heals spontaneously and may later be evident as a small calcified nodule (Ghon lesion). In children and in persons with impaired immunity (e.g., those with malnutrition or HIV infection), primary pulmonary tuberculosis may progress rapidly to clinical illness. The initial lesion increases in size and can evolve in different ways. Pleural effusion, which is found in up to two-thirds of cases, results from the penetration of bacilli into the pleural space from an

adjacent subpleural focus.

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In severe cases, the primary site rapidly enlarges, its central portion undergoes necrosis, and cavitation develops (progressive primary tuberculosis). Tuberculosis in young children is almost invariably accompanied by hilar or mediastinal lymphadenopathy due to the spread of bacilli from the lung parenchyma through lymphatic vessels. Enlarged lymph nodes may compress bronchi, causing obstruction and subsequent segmental or lobar collapse. Partial obstruction may cause obstructive emphysema, and bronchiectasis may also develop. Hematogenous dissemination, which is common and often asymptomatic, may result in the most severe manifestations of primary M. tuberculosis infection. Bacilli reach the bloodstream from the pulmonary lesion or the lymph nodes and disseminate into various organs, where they may produce granulomatous lesions. Although healing frequently takes place, immunocompromised persons (e.g., patients with HIV infection) may develop miliary tuberculosis and/or tuberculous meningitis.

Postprimary Disease (Secondary)

Also called adult-type, reactivation, or secondary tuberculosis, postprimary disease results from endogenous reactivation of latent infection and is usually localized to the apical and posterior segments of the upper lobes, where the substantially higher mean oxygen tension (compared with that in the lower zones) favors mycobacterial growth.

In addition, the superior segments of the lower lobes are frequently involved. The extent of lung parenchymal involvement varies greatly, from small infiltrates to extensive cavitary disease. With cavity formation, liquefied necrotic contents are ultimately discharged into the airways, resulting in satellite lesions within the lungs that may in turn undergo cavitation. Massive involvement of pulmonary segments or lobes, with coalescence of lesions, produces tuberculous pneumonia. While up to one-third of untreated patients reportedly succumb to severe

pulmonary tuberculosis within a few weeks or months after onset (the classical "galloping consumption" of the past), others undergo a process of spontaneous remission or proceed along a chronic, progressively debilitating course ("consumption").

Under these circumstances, some pulmonary lesions become fibrotic and may later calcify, but cavities persist in other parts of the lungs. Individuals with such chronic disease continue to discharge tubercle bacilli into the environment. Most patients respond to treatment, with defervescence, decreasing cough, weight gain, and a general improvement in well-being within several weeks. Early in the course of disease, symptoms and signs are often nonspecific and insidious, consisting mainly of fever and night sweats, weight loss, anorexia, general malaise, and weakness. However, in the majority of cases, cough eventually develops often initially nonproductive and subsequently accompanied by the production of purulent sputum, sometimes with blood streaking. Massive hemoptysis may ensue as a consequence of the erosion of a blood vessel in the wall of a cavity. Hemoptysis, however, may also result from rupture of a dilated vessel in a cavity (Rasmussen's aneurysm) or from aspergilloma formation in an old cavity. Pleuritic chest pain sometimes develops in patients with subpleural parenchymal lesions. Extensive disease may produce dyspnea and, in rare instances, adult respiratory distress syndrome (ARDS). Physical findings are of limited use in pulmonary tuberculosis. Many patients have no abnormalities detectable by chest examination, whereas others have detectable rales in the involved areas during inspiration, especially after coughing. Occasionally, rhonchi due to partial bronchial obstruction and classic amphoric breath sounds in areas with large cavities may be heard. Systemic features include fever (often low-grade and intermittent) in up to 80% of cases and wasting. Absence of fever, however, does not exclude tuberculosis. In some cases, pallor and finger clubbing develop. The most common hematologic findings are mild anemia and leukocytosis. Hyponatremia due to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) has also been reported.


2.1 Give the staining and cultural characteristics used to identify Mycobacterium tuberculosis.

Staining Characteristics

The Ziehl-Neilsen/Neelsen acid-fast stain is useful in staining organisms either from cultures or from clinical material. With this stain, the bacilli appear as brilliantly staining red rods against blue background. The best explanation of the acid-fastness of mycobacteria is based on a lipid-barrier principle in which an increased hydrophobicity of the surface layers follows the complexity of dye with

mycolic acid residues that are present in the cell wall. This prevents the carbolfuchsin that has become trapped in the interior of the cell. Tubercle bacilli are difficult to stain with the Gram stain although they are usually considered to be gram (+), staining is poor and irregular because failure of the dye to penetrate the cell wall. Gram stains of clinical material are thus invalid for the identification of mycobacteria.

Cultural Characteristics

Colonies are small, dry, and scaly in appearance.

(Zinsser Microbiology 20th Edition)

2.2 What are the physiologic, cultural, antigenic and virulent properties of Mycobacterium tuberculosis?

a. Physiologic Properties

Cultural Characteristics

o Mycobacterium tuberculosis is an obligate aerobe and will not grow in the absence of oxygen.o Tubercle bacilli will grow on a very simple synthetic medium but for 1° isolation from clinical material, a more complex medium containing either egg-potato base or a serum agar base

is required.o The organisms are very slow growing even under optimal growth conditions and 10-20 days of incubation at 37°C is required before growth can be visualized.o Aeration of cultures by rotary shaking markedly increases the growth rate and shortens the lag phase of growth.o Growth is enhanced by an increased CO2 tension.o The optimal pH range is 6.0-7.6 will permit growth.

Metabolism

o The mycobacteria are strictly aerobic organisms that fulfill their energy requirements by the complete oxidation of glucose or glycerol to CO2 and water.o Catalase and peroxidise are present in all mycobacteria for the disposal of H2O2 generated in the final reaction of the terminal respiratory chain.o Catalasese that are different with respect to their heat stability have been identified in various species of the mycobacteria.o Under optimal culture conditions, the doubling time of tubercle bacilli is 14-15 hours.

b. Antigenic Properties

Old Tuberculin (OT)

o OT is the original test reagent for the tuberculin test, a diagnostic skin test for tuberculous infection.o Tuberculin is an antigenically crude extract prepared from 6-week-old broth cultures by boiling the culture, filtering off the organisms and concentrating the filtrate 10 fold by streaming.o The active component of this preparation is a heat-stable protein.

Purified Protein Derivative (PPD)

o PPD is a partially purified preparation of OT prepared ammonium sulphate fractionation.o Currently, PPD is the test reagent used for tuberculin skin testing.

c. Virulent Properties

o Mycobacterium tuberculosis produces neither exotoxin.o No single structure, antigen or mechanism of action can explain the virulence of the organism.

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o A number of properties however, are usually associated with the capacity of virulent strains of Mycobacterium tuberculosis to produce progressive disease., although none of these, either singly or together can account completely for virulence, each undoubtedly plays a crucial role in the pathogenesis of infection.

Cord Factor

o There is a high correlation between the virulence of strains of tubercle bacilli and their morphologic appearance in culture in the form of serpentine cords consisting of bacilli in close parallel arrangements.

Sulfatides

o They are peripherally located glycolipids responsible for the neutral red reactivity associated with virulent strains of Mycobacterium tuberculosis.o Although sulfatides are not toxic themselves, when administered simultaneously with cord factor, they potentiate synergistically the toxicity of the cord factor.

(Zinsser Microbiology 20th Edition)

2.3 Name the other types of mycobacteria that can cause pulmonary infections, their morphology and cultural characteristics.

Mycobacterium bovis

Although most cases of TB are caused by mycobacterium tuberculosis, 2 additional species, Mycobacterium bovis and Mycobacterium africanum also cause tuberculosis in humans. Mycobacterium africanum has been isolated only remains in certain parts in Africa but there remains a substantial residue of infection with Mycobacterium bovis in many countries where raw

milk is ingested.

Morphologic and Cultural Characteristics

This species is often shorter and plumper than the human tubercle bacillus and its primarily isolation is usually more difficult. Strains of Mycobacterium bovis grow more slowly and the colonies are smaller than most clinical isolates of the human species. In general, Mycobacterium bovis is less aerotolerant than Mycobacterium tuberculosis but is more pathogenic for experimental animals. In the laboratory, the most useful single test for differentiating Mycobacterium bovis from Mycobacterium tuberculosis is the niacin test, a test based on the difference between the amount of

free nicotinic acid produced by the 2 species.

Bacillus of Calmette and Guerin (BCG)

BCG is an attenuated mutant of Mycobacterium bovis by repeated subculture on a glycerol-potato-bile medium. Subcultures of the original isolate are maintained as Mycobacterium bovis strain BCG and used as an immunizing agent against tuberculosis and in cancer immunotherapy.

Mycobacterium kansasii

Mycobacterium kansasii organisms are usually longer and wider than tubercle bacilli and with the acid-fast stain, characteristically stain unevenly to give a barred or beaded appearance. The organisms are usually arranged in curving strands. Mycobacterium kansasii is photochromogenic. Colonies which are demonstrable after 1-2 weeks of incubation in the dark on glycerol egg slants are usually smooth and ivory in color. If grown in the light, the colonies are lemon yellow becoming orange or reddish orange with age.

Clinical Manifestations

Pulmonary disease is the most common clinical form of Mycobacterium kansasii infection. It occurs primarily in middle-aged or elderly white men, most of whom have some pre-existing form of lung disease. It resembles tuberculosis except that symptoms when present, tend to be mild.

Mycobacterium simae

The organism is photochromogenic, producing small dysgenic colonies which are initially buff in color but which gradually turn yellow on exposure to light. Its most distinctive property is the production of niacin, a trait not seen in the other non-tuberculous mycobacteria.

Clinical Infection

Disease in some patients has been markedly by rapid progression and extensive pulmonary cavitation but in most patients the clinical picture has been confused by the simultaneous use of corticosteroids or by the presence of other underlying disease.

Mycobacterium avium – Mycobacterium intracellulare

There is considerable overlap between the properties of the 2 major nonphotochromogenic pathogens, Mycobacterium avium and Mycobacterium intracellulare, making speciation of strains extremely difficult.

Morphologic and Cultural Characteristics

The organisms are pleomorphic but on culture media they usually appear as short rods with bipolar acid-fast granules. Most virulent avian strains grow better at 44°C than at 37°C, whereas most strains of Mycobacterium intracellulare prefer the lower temperature. Colonies of primary isolates are predominantly thin, translucent and smooth but a few rough colonies are also often produced. On subculture, colonies become more opaque and domed. (Zinsser Microbiology 20th Edition)

3. What is the epidemiology of PTB in the:

3.1 Philippines, Western Pacific Region, Worldwide

Tuberculosis (TB) is still a major public health concern in the Philippines, ranking as the 6th (previously 5th) leading cause of morbidity and mortality based on recent local data. Globally, the Philippines is 9th (previously ranked 7th) among 22 high burden countries and ranked 3 rd (previously 2nd) in the Western Pacific region based on its national incidence of 133 new

sputum smear-positive cases per 100,000 population in 2004 (from 145 new cases per 100,000 in 2002). The Philippine Health Statistics recorded a total of 27,000 deaths from tuberculosis, at the turn of the century. The National Tuberculosis Program (NTP) reported 130,000 to 140,000 TB cases, mainly discovered and treated in government health units, of which 60% are highly infectious smear-positive

cases. As of 2004, the case detection rate (CDR) improved from 53% in 2003 to 68% and the cure rate increased from 75% in 2003 to 80.6%. Both are however still below global targets of 70% and 78% respectively.

(Diagnosis, Treatment, Prevention & Control of Tuberculosis: 2006 Update)

More than 3.8 million new cases of tuberculosis of all forms (pulmonary and extrapulmonary), 90% of them from developing countries were reported to the World Health Organization (WHO) in 2001.

However, because of a low level of case detection and incomplete notifications, reported cases represent only a fraction of the total. It is estimated that 8.5 million new cases of tuberculosis occurred worldwide in 2001, 95% of them in developing countries of Asia (5 million), Africa (2 million), the Middle East (0.6 million), and

Latin America (0.4 million).

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It is also estimated that 1.8 million deaths from tuberculosis occurred in 2000, 98% of them in developing countries. After an increase in the late 1980s, numbers of cases have declined during the past few years in several industrialized countries, including the United States. The increases in the 1980s were largely related to immigration from countries with a high prevalence of tuberculosis; infection with HIV; social problems, such as poverty, homelessness, and

drug abuse; and dismantling of tuberculosis services. With the implementation of stronger control programs in the United States, the decrease resumed in 1993. In 2002, 15,075 cases of tuberculosis (5.2 cases per 100,000 population) were reported to the U.S. Centers for Disease Control and Prevention (CDC) a 43% decrease from the 1992 peak. In the United States, tuberculosis is uncommon among young adults of European descent, who have only rarely been exposed to M. tuberculosis infection during recent decades. In contrast, because of a high risk in the past, the prevalence of M. tuberculosis infection is relatively high among elderly Caucasians, who remain at increased risk of developing active

tuberculosis. Tuberculosis in the United States is also a disease of young adult members of the HIV-infected, immigrant, and disadvantaged/marginalized populations. Similarly, in Europe, tuberculosis has reemerged as an important public health problem, mainly as a result of cases among immigrants from high-prevalence countries. Recent tuberculosis trends in developing countries indicate a stable situation, with almost no decline. There are two exceptions.

o First, in sub-Saharan Africa, the spread of the HIV epidemic has resulted in doubling or tripling of the number of reported cases of tuberculosis during the past 15 years. o Second, in countries of the former Soviet Union and in Romania, numbers of cases have increased by two- or threefold in the past 10 years, largely as the result of deterioration in

socioeconomic conditions and the health care infrastructure.


4. Name the factors that contribute to the spread of tuberculosis and the different ways to contain the spread of the disease. What is the pathogenesis of the disease?

Tuberculosis foourishes wherever there is poverty, crowding, and chronic debilitating illness. In the United States, tuberculosis is mainly a disease of the elderly, the urban poor and people with AIDS. Certain disease states also increase the risk: diabetes mellitus, Hodgkin’s lymphoma, chronic lung disease (particularly silicosis), chronic renal failure, malnutrition, alcoholism and

immunosuppression. Most infections are acquired by person-to-person transmission of airborne droplets of organisms from an active case to a susceptible host.

Pathogenesis:

The pathogenesis of TB in a previously unexposed, immunocompetent person depends on the development of anti-mycobacterial cell-mediated immunity, which confers resistance to the bacteria and results in development of hypersensitivity of tubercular antigens.

The pathological manifestations of tuberculosis, such as caseating granulomas and cavitation, are the result of the hypersensitivity that is part and parcel of the host immune response. Because the effector cells that mediate immunity also mediate hypersensitivity and tissue destruction, the appearance of hypersensitivity also signals the acquisistion of immunity to the organism.

Macrophages are the primary cells infected by Mycobacterium tuberculosis. In early infection, tuberculosis bacilli replicate essentially unchecked, while later in infection, the T-helper response stimulates macrophages to contain the proliferation of the bacteria.

Steps:

Mycobacterium TB enters macrophages by endocytosis mediated by several macrophage receptors: mannose receptors bind lipoarabinomannan, a glycolipid in the bacterial cell wall, and complement receptors bind opsonized bacteria.

Once inside the macrophage, Mycobacterium TB replicates within the phagosome by blocking fusion of the phagosome and lysosome. This is an active process as live, but not dead, mycobacteria block phagolysosome formation. Mycobacterium TB has several mechanisms for blocking phagolysosome formation, including inhibition of Ca++ signals and blocking recruitment and assembly of the proteins which mediate

phagosome-lysosome fusion. Thus the earliest stage of primary tuberculosis (<3weeks) in the nonsensitized individual is characterized by proliferation of bacteria in the pulmonary alveolar macrophages and air-spaces, with

resulting bacteremia and seeding of multiple sites. Despite bacteremia, most patients at this stage are asymptomatic or have a mild flu-like illness. The genetic make-up of the host may influence the course of the disease. In some people with polymorphisms in the NRAMP1 gene, the disease may progress from this point without development of an effective immune response. NRAMP1 protein is a transmembrane protein found in endosomes and lysosomes that pumps divalent cations into the lysosome. This may have role in generation of anti-microbial oxygen radicals. About 3 weeks after infection, a TH1 response against Mycobacterium TB is mounted that activates macrophages to become bactericidal. TH1 cells are stimulated by mycobacterial antigens drained to the lymph node, which are presented with class II major histocompatibility proteins by antigen presenting cells. Differentiation of TH1 cells depends on the presence of IL-2, which is produced by antigen presenting cells that have encountered the mycobacteria. Mature TH1 cells, both in lymph nodes and in the lung, produce IFN-y. IFN-y is the critical mediator which drives macrophages to become competent to contain the Mycobacterium TB infection. IFN-y stimulates formation of the phagolysosome in infected macrophages, exposing the bacteria into an inhospitable acidic environment. IFN-y also stimulates expression of inducible nitric oxide synthase (iNOS), which produces nitric oxide (NO). NO generates reactive nitrogen and other free radicals capable of oxidative destruction of

several mycobacterial constituents, from cell wall to DNA. In addition to stimulating macrophages to kill mycobacteria, the TH1 response orchestrates the formation of granulomas and caseous necrosis. Activated macrophages, stimulated by IFN-y, produce TNF, which recruits monocytes. These monocytes differentiate into the “epithelioid histiocytes” that characterize the granulomatous response. In many people, this response contains the bacteria and doesn’t cause significant tissue destruction or illness. In other people, the infection progressed due to age or immunosuppression, and the

ongoing immune response results in tissue destruction due to caseation and cavitation. The importance of TNF in this response is underscored by the fact that patients with rheumatoid arthritis who are treated with a TNF antagonist have an increased risk of tuberculosis reactivation. In addition to the TH1 response, unusual T cells which recognize mycobacterial lipid antigens bound to CD1 on antigen presenting cells, or which express a gamma-delta T cell receptor, also make

IFN-y. However, it is clear that TH1 cells have a central role in this process as defects in any of the steps in generating a TH1 response results in absence of resistance and disease progression.

From Exposure to Infection

M. tuberculosis is most commonly transmitted from a patient with infectious pulmonary tuberculosis to other persons by droplet nuclei, which are aerosolized by coughing, sneezing, or speaking. The tiny droplets dry rapidly; the smallest (<10 μm in diameter) may remain suspended in the air for several hours and may gain direct access to the terminal air passages when inhaled. There may be as many as 3000 infectious nuclei per cough. Other routes of transmission of tubercle bacilli, such as through the skin or the placenta, are uncommon and of no epidemiologic

significance. The probability of contact with a case of tuberculosis, the intimacy and duration of that contact, the degree of infectiousness of the case, and the shared environment of the contact are all important

determinants of transmission. Several studies of close contacts have clearly demonstrated that tuberculosis patients whose sputum contains AFB visible by microscopy play the greatest role in the spread of infection. These patients often have cavitary pulmonary disease or tuberculosis of the respiratory tract (endobronchial or laryngeal tuberculosis) and produce sputa containing as many as 105 AFB/mL. Patients with sputum smear–negative/culture-positive tuberculosis are less infectious, and those with culture-negative pulmonary disease and extrapulmonary tuberculosis are essentially

noninfectious. The frequent absence of cavities among HIV-infected patients may reduce their infectiousness. Crowding in poorly ventilated rooms is one of the most important factors in the transmission of tubercle bacilli, since it increases theintensity of contact with a case. In short, the risk of acquiring M. tuberculosis infection is determined mainly by exogenous factors. Because of delays in seeking care and in diagnosis, it is estimated that up to 20 contacts may be infected by each AFB-positive case before detection in high-prevalence settings.

From Infection to Disease

Unlike the risk of acquiring infection with M. tuberculosis, the risk of developing disease after being infected depends largely on endogenous factors, such as the individual’s innate susceptibility to disease and level of function of cell-mediated immunity.

Clinical illness directly following infection is classified as primary tuberculosis and is common among children up to 4 years of age. Although this form may be severe and disseminated, it is usually not transmissible. When infection is acquired later in life, the chance is greater that the immune system will contain it, at least temporarily.

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The majority of infected individuals who ultimately develop tuberculosis do so within the first year or two after infection. Dormant bacilli, however, may persist for years before reactivating to produce secondary (or postprimary) tuberculosis, which is often infectious. Overall, it is estimated that ~10% of persons infected in their youth will eventually develop active tuberculosis. This risk, however, is greatly increased among HIV-infected persons. Reinfection of a previously infected individual, which is common in areas with high rates of tuberculosis transmission, may also favor the development of disease. Molecular typing and comparison of strains of M. Tuberculosis have suggested that up to one-third of cases of active tuberculosis in U.S. inner-city communities are due to recent transmission rather

than to reactivation of latent infection. Age is an important determinant of the risk of disease after infection. Among infected persons, the incidence of tuberculosis is highest during late adolescence and early adulthood; the reasons are unclear. The incidence among women peaks at 25 to 34 years of age. In this age group rates among women are usually higher than those among men, while at older ages the opposite is true. The risk may increase in the elderly, possibly because of waning immunity and comorbidity. A variety of diseases and conditions favor the development of active tuberculosis. The most potent risk factor for tuberculosis among infected individuals is clearly HIV co-infection, which suppresses cellular immunity. The risk that latent M. tuberculosis infection will proceed to active disease is directly related to the patient’s degree of immunosuppression. In a study of HIV-infected, PPD-positive persons, this risk varied from 2.6 to 13.3 cases per 100 personyears and depended upon the CD4+ cell count.

PATHOGENESIS AND IMMUNITY

The interaction of M. tuberculosis with the human host begins when droplet nuclei containing microorganisms from infectious patients are inhaled. While the majority of inhaled bacilli are trapped in the upper airways and expelled by ciliated mucosal cells, a fraction (usually <10%) reach the alveoli. There, nonspecifically activated alveolar macrophages ingest the bacilli. Invasion of macrophages by mycobacteria may result in part from association of C2a with the bacterial cell wall followed by C3b opsonization of the bacteria and recognition by the macrophages. The balance between the bactericidal activity of the macrophage and the number and virulence of the bacilli (with virulence partially linked to the bacterium’s lipid-rich cell wall and to its glycolipid

capsule, both of which confer resistance to complement and free radicals of the phagocyte) determines the events following phagocytosis. Several genes thought to confer virulence to M. tuberculosis have been identified; katG encodes for catalase, an enzyme protective against oxidative stress; rpoV is the main sigma factor initiating

transcription of several genes. Defects in these two genes result in loss of virulence. The erp gene, encoding a protein required for multiplication, also contributes to virulence. Outbreaks of tuberculosis in Tennessee and Kentucky in 1994 through 1996 exemplify how infection with virulent strains can result in enhanced transmission with high rates of disease. Strains of the Beijing/W genotype family have been identified in outbreak conditions in a variety of settings worldwide and have been associated with high mortality and drug resistance. Several observations suggest that genetic factors play a key role in innate nonimmune resistance to infection with M. tuberculosis. The existence of this resistance is suggested by the differing degrees of susceptibility to tuberculosis in different populations. In mice, a gene called Nramp1 (natural resistance–associated macrophage protein 1) has a regulatory role in resistance/susceptibility to mycobacteria. The human homologue NRAMP1, cloned to chromosome 2q, may have a role in determining susceptibility to tuberculosis, as is suggested by a study among West Africans. In the initial stage of host-bacterium interaction, either the host’s macrophages contain bacillary multiplication by producing proteolytic enzymes and cytokines or the bacilli begin to multiply. If the bacilli multiply, their growth quickly kills the macrophages, which lyse. Nonactivated monocytes attracted from the bloodstream to the site by various chemotactic factors ingest the bacilli released from the lysed macrophages. These initial stages of infection are usually asymptomatic. About 2 to 4 weeks after infection, two additional host responses to M. tuberculosis develop: a tissue-damaging response and a macrophage-activating response. The tissue-damaging response is the result of a delayed-type hypersensitivity (DTH) reaction to various bacillary antigens; it destroys nonactivated macrophages that contain multiplying bacilli. The macrophage-activating response is a cell-mediated phenomenon resulting in the activation of macrophages that are capable of killing and digesting tubercle bacilli. Although both of these responses can inhibit mycobacterial growth, it is the balance between the two that determines the form of tuberculosis that will develop subsequently. With the development of specific immunity and the accumulation of large numbers of activated macrophages at the site of the primary lesion, granulomatous lesions (tubercles) are formed. These lesions consist of lymphocytes and activated macrophages, such as epithelioid cells and giant cells. Initially, the newly developed tissue-damaging response is the only event capable of

limiting mycobacterial growth within macrophages. This response, mediated by various bacterial products, not only destroys macrophages but also produces early solid necrosis in the center of the tubercle. Although M. tuberculosis can survive, its growth is inhibited within this necrotic environment by low oxygen tension and low pH. At this point, some lesions may heal by fibrosis and calcification, while others undergo further evolution. Cell-mediated immunity is critical at this early stage. In the majority of infected individuals, local macrophages are activated when bacillary antigens processed by macrophages stimulate T

lymphocytes to release a variety of lymphokines. These activated cells aggregate around the lesion’s center and effectively neutralize tubercle bacilli without causing further tissue destruction. In the central part of the lesion, the necrotic material resembles soft cheese (caseous necrosis)—a phenomenon that may also be observed in other conditions, such as neoplasms. Even when healing takes place, viable bacilli may remain dormant within macrophages or in the necrotic material for years or even throughout the patient’s lifetime. These “healed” lesions in the lung parenchyma and hilar lymph nodes may later undergo calcification. In a minority of cases, the macrophage-activating response is weak, and mycobacterial growth can be inhibited only by intensified DTH reactions, which lead to tissue destruction. The lesion tends to enlarge further, and the surrounding tissue is progressively damaged. At the center of the lesion, the caseous material liquefies. Bronchial walls as well as blood vessels are invaded and destroyed, and cavities are formed. The liquefied caseous material, containing large numbers of bacilli, is drained through bronchi. Within the cavity, tubercle bacilli multiply well and spread into the airways and the environment through expectorated sputum. In the early stages of infection, bacilli are usually transported by macrophages to regional lymph nodes, from which they disseminate widely to many organs and tissues. The resulting lesions may undergo the same evolution as those in the lungs, although most tend to heal. In young children with poor natural immunity, hematogenous dissemination may result in fatal miliary tuberculosis or tuberculous meningitis. Cell-mediated immunity confers partial protection against M. tuberculosis, while humoral immunity has no defined role in protection. Two types of cells are essential: macrophages, which directly phagocytize tubercle bacilli, and T cells (mainly CD4_lymphocytes), which induce protection through the production of lymphokines,

especially interferon y (IFN-y). After infection with M. tuberculosis, alveolar macrophages secrete a number of cytokines: interleukin (IL) 1 contributes to fever; IL-6 contributes to hyperglobulinemia; and tumor necrosis factor α

(TNF-α) contributes to the killing of mycobacteria, the formation of granulomas, and a number of systemic effects, such as fever and weight loss. Macrophages are also critical in processing and presenting antigens to T lymphocytes; the result is a proliferation of CD4+ lymphocytes, which are crucial to the host’s defense against M.

tuberculosis. Qualitative and quantitative defects of CD4+ T cells explain the inability of HIV-infected individuals to contain mycobacterial proliferation. Reactive CD4+ lymphocytes produce cytokines of the TH1 pattern and participate in MHC class II–restricted killing of cells infected with M. tuberculosis. TH1 CD4+ cells produce IFN-γ and IL-2 and promote cell-mediated immunity. TH2 cells produce IL-4, IL-5, and IL-10 and promote humoral immunity. The interplay of these various cytokines and their cross-regulation determine the host’s response. The role of cytokines in promoting intracellular killing of mycobacteria has not been entirely elucidated. IFN-γ may induce release of nitric oxide, and TNF-α also seems to be important. Observations in transgenic knockout mice suggest that other T cell subsets (especially CD8+ cells) restricted by alternative antigen-presenting molecules containing a β2-microglobulin subunit may

play an important role. Lipids have been involved in mycobacterial recognition by the innate immune system, and lipoproteins have been proven to trigger potent signals through Toll-like receptors. Finally, a recently described subset of T cells capable of recognizing lipid elements of the bacillus presented by CD1 molecules may be implicated in protection. M. tuberculosis possesses various protein antigens. Some are present in the cytoplasm and cell wall; others are secreted. That the latter are more important in eliciting a T lymphocyte response is suggested by experiments documenting the appearance of protective immunity in animals after immunization with live,

protein-secreting mycobacteria. Among the antigens with a potential protective role are the 30-kDa (or 85B) and the ESAT-6 antigens. Protective immunity is probably the result of reactivity to a large number of different mycobacterial antigens. Coincident with the appearance of immunity, DTH to M. tuberculosis develops. This reactivity is the basis of the PPD skin test, which is used primarily for the detection of M. tuberculosis infection in persons without symptoms. The cellular mechanisms responsible for PPD reactivity are related mainly to previously sensitized CD4+ lymphocytes, which are attracted to the skin-test site. There, they proliferate and produce cytokines. While DTH is associated with protective immunity (PPD-positive persons being less susceptible to a new M. tuberculosis infection than PPD-negative persons), it by no means guarantees protection

against reactivation. In fact, severe cases of active tuberculosis are often accompanied by strongly positive skin-test reactions.

6

(Robbins and Cotran Pathologic Basis of Disease 7th Edition)

4.1 What is primary tuberculosis? Gohn’s Complex? Simon foci?

Clinical Features:

Primary TB is the form of disease that develops in a previously unexposed, and therefore unsensitized, person. About 5 % of newly infected people develop clinically significant disease. The elderly and profoundly immunosuppressed persons may lose their immunity to the tubercle bacillus and so may develop primary TB more that once. With primary TB, the source of the organism is exogenous. While most patients with primary TB go on to have latent disease, progressive infection, with continued lung pathology, occurs in some. The diagnosis of progressive primary TB in adults can be difficult. Contrary to the usual picture of “adult type” (or reactivation) TB (apical disease with cavitation), progressive primary TB more often resembles and acute bacterial pneumonia, with lower and

middle lobe consolidation, hilar adenopathy, and pleural effusion; cavitation is rare, especially in patients with severe immunosuppression. Lymphohematogenous dissemination is a dreaded complication and may result in the development of tuberculous meningitis and military TB. Similar lesions also occur following progression of secondary TB.

Gross morphology:

The inhaled bacilli implant in the distal airspaces of the lower part of the upper lobe or the upper part of the lower lobe, usually close to the pleura. As sensitization develops, a 1-1.5cm area of gray-white inflammatory consolidation emerges, known as the Ghon focus. Tubercle bacilli, either free of within phagocytes, drain to the regional nodes, which also often caseate. This combination of parenchymal lung lesion and nodal involvement is referred to as the Ghon complex. During the 1st few weeks, there is also lymphatic and hematogenous dissemination to other parts of the body. In approximately 95% of cases, development of cell-mediated immunity controls the infection. Hence, the Ghon complex undergoes progressive fibrosis, often followed by radiologically detectable calcification (Ranke complex), and despite seeding of other organs, no lesions develop.

Histologic morphology:

Sites of active involvement are marked by a characteristic granulomatous inflammatory reaction that forms both caseating and non-caseating tubercles. Individual tubercles are microscopic; it is only when multiple granulomas coalesce that they become macroscopically visible. The granulomas are usually enclosed within a fibroblastic rim

punctuated by lymphocytes. Multinucleate giant cells are present in the granulomas. Immunocompromised people do not form the characteristic granulomas.


PRIMARY DISEASE

Primary pulmonary tuberculosis results from an initial infection with tubercle bacilli. In areas of high tuberculosis prevalence, this form of disease is often seen in children and is frequently localized to the middle and lower lung zones. The lesion forming after infection is usually peripheral and accompanied by hilar or paratracheal lymphadenopathy, which may not be detectable on chest radiography. In the majority of cases, the lesion heals spontaneously and may later be evident as a small calcified nodule (Ghon lesion). In children and in persons with impaired immunity (e.g., those with malnutrition or HIV infection), primary pulmonary tuberculosis may progress rapidly to clinical illness. The initial lesion increases in size and can evolve in different ways. Pleural effusion, a frequent finding, results from the penetration of bacilli into the pleural space from an adjacent subpleural focus. In severe cases, the primary site rapidly enlarges, its central portion undergoes necrosis, and acute cavitation develops (progressive primary tuberculosis). Tuberculosis in young children is almost invariably accompanied by hilar or mediastinal lymphadenopathy due to the spread of bacilli from the lung parenchyma through lymphatic vessels. Enlarged lymph nodes may compress bronchi, causing obstruction and subsequent segmental or lobar collapse. Partial obstruction may cause obstructive emphysema, and bronchiectasis may also develop. Hematogenous dissemination, which is common and is often asymptomatic, may result in the most severe manifestations of primary M. tuberculosis infection. Bacilli reach the bloodstream from the pulmonary lesion or the lymph nodes and disseminate into various organs, where they may produce granulomatous lesions. Although healing frequently takes place, immunocompromised persons (e.g., patients with HIV infection) may develop military tuberculosis and/or tuberculous meningitis.


4.2 What is secondary PTB?

Clinical Features:

Secondary TB is the pattern of disease that arises on a previously sensitized host. It may follow shortly after primary TB, but more commonly, it arises from reactivation of dormant primary lesion many decades after initial infection, particularly when host resistance is

weakened. It may also result from exogenous re-infection because of waning of the protection afforded by the primary disease or because of a large inoculum of virulent bacilli. Reactivation of TB is more common in low-prevalence areas, while re-infection plays an important role in regions of high contagion. Secondary PTB is classically localized to the apex of the upper lobes of one or both lungs. This may be because the high oxygen tension in the apices promotes growth of the bacteria. Because of the pre-existence of hypersensitivity, the bacilli elicit a prompt and marked tissue response that tends to wall off the focus of infection. As a result of this localization, the regional lymph nodes are less prominently involved early in the secondary disease than they are in primary TB. On the other hand, cavitation occurs readily in the secondary form, resulting in dissemination of mycobacteria along the airways. Indeed, cavitation is almost inevitable in neglected secondary

TB, and erosion into an airway becomes an important source of infection because the patient now coughs sputum that contains bacilli. Localized secondary TB may be asymptomatic. When manifestations appear, they are usually insidious in onset. Systemic symptoms, probably related to cytokines released by activated macrophages (eg. TNF and IL-1), often appear early in the course and include malaise, anorexia, weight loss, and

fever. Commonly, the fever is low grade and remittent (appearing late each afternoon and then subsiding), and night sweats occur. With progressive pulmonary involvement, increasing amounts of sputum, at first mucoid and later purulent, appear. Some degree of hemoptysis is present in about half of all cases of PTB. Pleuritic pain may result from extension of the infection to the pleural surfaces. Extrapulmonary manifestations of TB are legion and depend on the organ system involved.

Gross morphology:

The initial lesion is usually a small focus of consolidation, less than 2 cm in diameter, within 1-2 cm of the apical pleura. Such foci are sharply circumscribed, firm, gray-white to yellow areas that have a variable amount of central caseation and peripheral fibrosis. In favorable cases, the initial parenchymal focus undergoes progressive fibrous encapsulation, leaving only fibrocalcific scars.

Histologic morphology:

The active lesions show characteristic coalescent tubercles with central caseation. Although tubercle bacilli can be demonstrated by appropriate methods in early exudative and caseous phases of granuloma formation, it is usually impossible to find them in the late,

fibrocalcific stages.

7

Localized, apical, secondary PTB may heal with fibrosis either spontaneously or after therapy, or the disease may progress and extend along several different pathways.


POSTPRIMARY DISEASE

Also called adult-type, reactivation, or secondary tuberculosis, postprimary disease results from endogenous reactivation of latent infection and is usually localized to the apical and posterior segments of the upper lobes, where the high oxygen concentration favors mycobacterial growth.

In addition, the superior segments of the lower lobes are frequently involved. The extent of lung parenchymal involvement varies greatly, from small infiltrates to extensive cavitary disease. With cavity formation, liquefied necrotic contents are ultimately discharged into the airways, resulting in satellite lesions within the lungs that may in turn undergo cavitation. Massive involvement of pulmonary segments or lobes, with coalescence of lesions, produces tuberculous pneumonia. While up to one-third of untreated patients reportedly succumb to severe pulmonary tuberculosis within a few weeks or months after onset, others undergo a process of spontaneous remission

or proceed along a chronic, progressively debilitating course (“consumption”). Under these circumstances, some pulmonary lesions become fibrotic and may later calcify, but cavities persist in other parts of the lungs. Individuals with such chronic disease continue to discharge tubercle bacilli into the environment. Most patients respond to treatment, with defervescence, decreasing cough, weight gain, and a

general improvement in well-being within several weeks. Early in the course of disease, symptoms and signs are often nonspecific and insidious, consisting mainly of fever and night sweats, weight loss, anorexia, general malaise, and weakness. However, in the majority of cases, cough eventually develops often initially nonproductive and subsequently accompanied by the production of purulent sputum. Blood streaking of the sputum

is frequently documented. Massive hemoptysis may ensue as a consequence of the erosion of a fully patent vessel located in the wall of a cavity. Hemoptysis, however, may also result from rupture of a dilated vessel in a cavity (Rasmussen’s aneurysm) or from aspergilloma formation in an old cavity. Pleuritic chest pain sometimes develops in patients with subpleural parenchymal lesions but can also result from muscle strain due to persistent coughing. Extensive disease may produce dyspnea and (occasionally) adult respiratory distress syndrome (ARDS). Physical findings are of limited use in pulmonary tuberculosis. Many patients have no abnormalities detectable by chest examination, while others have detectable rales in the involved areas during inspiration, especially after coughing. Occasionally, rhonchi due to partial bronchial obstruction and classic amphoric breath sounds in areas with large cavities may be heard. Systemic features include fever (often low-grade and intermittent) and wasting. In some cases, pallor and finger clubbing develop. The most common hematologic findings are mild anemia and leukocytosis. Hyponatremia due to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) has also been

reported.


4.3 What is progressive PTB?

Progressive PTB may ensue in the elderly and immunosuppressed.

Morphology:

The apical lesion enlarges with expansion of the area of caseation. Erosion into a bronchus evacuates the caseous center, creating a ragged, irregular cavity lined by casseous material that is poorly walled off by fibrous tissue. Erosion of blood vessels results in hemoptysis. With adequate treatment, the process may be arrested, although healing by fibrosis often distorts the pulmonary architecture. Irregular cavities, now free of caseation necrosis, may remain or collapse in the surrounding fibrosis. If the treatment is inadequate or if host defenses are impaired, the infection may spread by direct expansion via dissemination through airways, lymphatic channels, or the vascular system.


4.4 What is latent TB infection (LTB)?

Latent TB means that you have the TB bacteria in your body, but your body’s defenses (immune system) fight the infection and try to keep it from turning into active TB. This means that you don't have any symptoms of TB right now and can't spread the disease to others. If you have latent TB, it can become active TB.

(WebMD http://www.webmd.com/a-to-z-guides/tuberculosis-tb-topic-overview)

“Latent tuberculosis” is the term used for people who test positive for tuberculosis (most commonly with a positive tuberculin skin test), but do not have any evidence of active infection. Currently one in three people worldwide are felt to harbor tuberculosis bacilli. Tuberculosis is transmitted through airborne spread of Mycobacterium tuberculosis. When a person with active pulmonary TB coughs, aerosolized droplets containing bacilli can invade the lungs of close contacts. In 90-95% of cases, the infected person's immune system halts growth of the bacteria and active disease does not develop, although skin or serological testing for TB will convert to positive. Once positive, a person's TB test will generally remain positive for life.

(http://ethnomed.org/clin_topics/tb/firland/screening/latent_tb_faqs/latent_tb_faqs.htm)

5. Name the different diagnostic examinations for the identification of Mycobacterium tuberculosis.5.1 Discuss the role and indication of tuberculin skin test. Perform a tuberculin skin test. Read, record and internet the results.5.2 What is the role of chest x-ray in PTB? What is its sensitivity and specificity.5.3 What is the role of sputum examination in PTB? How is sputum collection done? What is its sensitivity and specificity?5.4 What is the role of culture and sensitivity? How is culture and sensitivity done? What is its sensitivity and specificity?

DIAGNOSIS

The key to the diagnosis of tuberculosis is a high index of suspicion. Diagnosis is not difficult with a high-risk patient; e.g., a homeless alcoholic who presents with typical symptoms and a classic chest radiograph showing upper lobe infiltrates with cavities On

the other hand, the diagnosis can easily be missed in an elderly nursing-home resident or a teenager with a focal infiltrate. Often, the diagnosis is first entertained when the chest radiograph of a patient being evaluated for respiratory symptoms is abnormal. If the patient has no complicating medical conditions that favor immunosuppression, the chest radiograph may show the typical picture of upper lobe infiltrates with cavitation. The longer the delay between the onset of symptoms and the diagnosis, the more likely is the finding of cavitary disease. In contrast, immunosuppressed patients, including those with HIV infection, may have “atypical” findings on chest radiography; e.g., lower-zone infiltrates without cavity formation.

AFB Microscopy

A presumptive diagnosis is commonly based on the finding of AFB on microscopic examination of a diagnostic specimen such as a smear of expectorated sputum or of tissue (for example, a lymph node biopsy).

Most modern laboratories processing large numbers of diagnostic specimens use auramine-rhodamine staining and fluorescence microscopy. The more traditional method; light microscopy of specimens stained with Kinyoun or Ziehl-Neelsen basic fuchsin dyes is satisfactory, although more time-consuming. For patients with suspected pulmonary tuberculosis, three sputum specimens, preferably collected early in the morning, should be submitted to the laboratory for AFB smear and

mycobacteriology culture. If tissue is obtained, it is critical that the portion of the specimen intended for culture not be put in formaldehyde. The use of AFB microscopy on urine or gastric lavage fluid is limited by the presence of mycobacterial commensals, which can cause false-positive results.

8

Mycobacterial Culture

Definitive diagnosis depends on the isolation and identification of M. tuberculosis from a diagnostic specimen in most cases, a sputum specimen obtained from a patient with a productive cough.

Specimens may be inoculated onto egg- or agar-based medium (e.g., Lo¨wenstein-Jensen or Middlebrook 7H10) and incubated at 37 degrees Celcius under 5% CO2. Because most species of mycobacteria, including M. tuberculosis, grow slowly, 4 to 8 weeks may be required before growth is detected. Although M. tuberculosis may be presumptively identified on the basis of growth time and colony pigmentation and morphology, a variety of biochemical tests have traditionally been used to

speciate mycobacterial isolates. In today’s laboratories, the use of liquid media for isolation and speciation by nucleic acid probes or high-pressure liquid chromatography of mycolic acids has replaced the traditional methods

of isolation on solid media and identification by biochemical tests. These new methods have decreased the time required for bacteriologic confirmation to 2 to 3 weeks.

Nucleic AcidAmplification

Several test systems based on amplification of mycobacterial nucleic acid are available. These systems permit the diagnosis of tuberculosis in as little as several hours. However, their applicability is limited by low sensitivity (lower than culture, but higher than AFB smear microscopy) and high cost. At present, these tests are most useful for the rapid confirmation of tuberculosis in persons with AFB-positive sputa. However, they may also have utility for the diagnosis of AFB-negative pulmonary and extrapulmonary tuberculosis in selected patients.

Drug Susceptibility Testing

In general, the initial isolate of M. tuberculosis should be tested for susceptibility to isoniazid, rifampin, and ethambutol. In addition, expanded susceptibility testing is mandatory when resistance to one or more of these drugs is found or the patient either fails to respond to initial therapy or has a relapse after the

completion of treatment. Susceptibility testing may be conducted directly (with the clinical specimen) or indirectly (with mycobacterial cultures) on solid or liquid medium. Results are obtained most rapidly by direct susceptibility testing on liquid medium, with an average reporting time of 3 weeks. With indirect testing on solid medium, results may not be available for >8 weeks. Molecular methods for the rapid identification of drug resistance are becoming available. One of the most promising uses polymerase chain reaction (PCR) to detect mutations in the rpoB gene associated with resistance to rifampin.

Radiographic Procedures

As noted above, the initial suspicion of pulmonary tuberculosis is often based on abnormal chest radiographic findings in a patient with respiratory symptoms. Although the “classic” picture is that of upper lobe disease with infiltrates and cavities, virtually any radiographic pattern from a normal film or a solitary pulmonary nodule to diffuse alveolar

infiltrates in a patient with ARDS may be seen. In the era of AIDS, no radiographic pattern can be considered pathognomonic.

PPD Skin Testing andDiagnosis of Latent Tuberculosis Infection

In 1891, Robert Koch discovered components of M. tuberculosis in a concentrated liquid culture medium. Subsequently named “old tuberculin” (OT), this material was initially believed to be useful in the treatment of tuberculosis (although this idea was later disproved). It soon became clear that OT was capable of eliciting a skin reaction when injected subcutaneously into patients with tuberculosis. In 1932, Seibert and Munday purified this product by ammonium sulfate precipitation. The result was an active protein fraction known as tuberculin PPD. However, the complexity and diversity of the constituents of PPD rendered its standardization difficult. PPD-S, developed by Seibert and Glenn in 1941, was chosen as the international

standard. Later, the WHOand UNICEF sponsored large-scale production of a master batch of PPD, termed RT23, and made it available for general use. The greatest limitation of PPD is its lack of mycobacterial species specificity, a property that is due to the large number of proteins in this product that are highly conserved in the various

species of mycobacteria. Skin testing with PPD is most widely used in screening for M. tuberculosis infection. The test is of limited value in the diagnosis of active tuberculosis because of its low sensitivity and specificity. False-negative reactions are common in immunosuppressed patients and in those with overwhelming tuberculosis. Positive reactions are obtained when patients have been infected with M. tuberculosis but do not have active disease and when persons have been sensitized by nontuberculous mycobacteria

or bacille Calmette-Gue´rin (BCG) vaccination. Although BCG vaccine is not used in the United States for tuberculosis prevention, many immigrants will have received it. In the absence of a history of BCG vaccination, a positive skin test may provide additional support for the diagnosis of tuberculosis in culture-negative cases. Because results of anergy testing in HIV-infected populations do not seem useful to clinicians making decisions about preventive therapy, anergy testing based on other DTH antigens is no

longer recommended as a routine component of tuberculosis screening among HIV-infected persons. However, some experts support the use of anergy testing to help guide individual decisions regarding preventive therapy, and some recommend that PPD skin testing be performed for

patients previously classified as anergic if evidence indicates that these patients’ immune systems have responded to therapy with antiretroviral drugs.

Cytokine Release Assays

A commercially available whole-blood cytokine assay, the QuantiFERON-TB test (Cellestis Ltd), has been approved by the U.S. Food and Drug Administration (FDA) as an aid in the diagnosis of latent tuberculosis infection. The test requires overnight incubation of a peripheral-blood sample with PPD and control antigens followed by measurement of IFN-y released by sensitized lymphocytes in an enzyme-linked

immunosorbent assay (ELISA). A multicenter study conducted by the CDC indicated good agreement between this assay and the PPD skin test, although the assay’s ability to predict the development of active tuberculosis is

not known. At present, the QuantiFERON-TB test is recommended for screening for latent tuberculosis infection in populations at low to moderate risk of tuberculosis. Studies are under way to assess the performance of this test in contact investigations, persons with suspected tuberculosis disease, HIV-infected persons, and children. The test’s performance will probably be enhanced by the use of antigens such as ESAT-6 and CPF10 that are present in M. tuberculosis but absent from BCG strains and most

nontuberculous mycobacteria.

Additional Diagnostic Procedures

Other diagnostic tests may be used when pulmonary tuberculosis is suspected. Sputum induction by ultrasonic nebulization of hypertonic saline may be useful for patients unable to produce a sputum specimen spontaneously. Frequently, patients with radiographic abnormalities that are consistent with other diagnoses (e.g., bronchogenic carcinoma) undergo fiberoptic bronchoscopy with bronchial brushings or

transbronchial biopsy of the lesion. Bronchoalveolar lavage of a lung segment containing an abnormality may also be performed. In all cases, it is essential that specimens be submitted for AFB smear and mycobacterial culture. For the diagnosis of primary pulmonary tuberculosis in children, who often do not expectorate sputum, specimens from early-morning gastric lavage may yield positive cultures. Invasive diagnostic procedures are indicated for patients with suspected extrapulmonary tuberculosis. In addition to specimens of involved sites (e.g., CSF for tuberculous meningitis, pleural fluid and biopsy samples for pleural disease), bone marrow and liver biopsy and culture have a good

diagnostic yield in disseminated (miliary) tuberculosis, particularly in HIV-infected patients, who also have a high frequency of positive blood cultures. In some cases, cultures will be negative, but a clinical diagnosis of tuberculosis will be supported by consistent epidemiologic evidence (e.g., a history of close contact with an infectious

patient), a positive PPD skin test, and a compatible clinical and radiographic response to treatment. In the United States and other industrialized countries with low rates of tuberculosis, some patients with limited abnormalities on chest radiographs and sputum positive for AFB are infected

with organisms of the M. avium complex or M. kansasii.

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Factors favoring the diagnosis of nontuberculous mycobacterial disease over tuberculosis include an absence of risk factors for tuberculosis, a negative PPD skin test, and underlying chronic obstructive pulmonary disease.

Patients with HIV-associated tuberculosis pose several diagnostic problems, as noted above in the description of clinical manifestations. Moreover, HIV-infected patients with sputum culture–positive and AFB-positive tuberculosis may present with a normal chest radiograph. With the advent of highly active antiretroviral therapy (HAART), the occurrence of disseminated M. avium complex disease that can be confused with tuberculosis has become much less

common.

Adjunctive Diagnostic Tests

A number of methods have been evaluated as adjuncts to standard laboratory diagnosis. The most thoroughly investigated is serologic diagnosis based on detection of antibody to a variety of mycobacterial antigens. However, tests with most of the target antigens have a low predictive value when used in a population with a low probability of disease. Tests aimed at detection of mycobacterial antigen by serologic methods have generally been insufficiently sensitive to be useful.


Bacteriology (result of sputum smear) in pulmonary TB. Defining the smear result in pulmonary cases is important to:

o Identify smear-positive cases, because they are the most infectious cases and usually have higher mortality.o Record, report and evaluate programme performance (smear-positive cases are the cases for which bacteriological monitoring of treatment progress is most practicable).

Although culture is useful to diagnose TB, it is not as important as smear microscopy for TB control. Culture facilities are not universally available and the results take several weeks or months, which is too late to monitor progress. Smear-negative, culture-positive patients are less infectious and, except in immunodepressed individuals, have fewer bacilli. In general, the treatment regimens are the same for culture-positive and culture-negative patients. The flow chart in Annex 1 shows the recommended diagnostic procedure for suspected pulmonary TB. The following definitions are used:

o Pulmonary tuberculosis, sputum smear-positive (PTB+)a. Two or more initial sputum smear examinations positive for AFB.b. One sputum smear examination positive for AFB plus radiographic abnormalities consistent with active PTB as determined by a clinician, or c. One sputum smear positive for AFB plus sputum culture positive for M. tuberculosis.

o Pulmonary tuberculosis, sputum smear-negative (PTB-) Case of PTB that does not meet the above definition for smear-positive TB. This group includes cases without smear result, which should be exceptional in adults but are relatively more frequent in children. Note that in keeping with good clinical and public health practice, diagnostic criteria for PTB-should include:

o At least three sputum specimens negative for AFB.o Radiographic abnormalities consistent with active PTB.o No response to a course of broad-spectrum TB antibiotics.o Decision by a clinician to treat with a full course of antituberculosis chemotherapy.

Under programme conditions, when microscopy laboratory services are available and diagnostic criteria are properly applied, PTB smear-positive cases represent at least 65% of the total of PTB cases in adults, and 50% or more of all TB cases.

Note that these proportions may be lower in high HIV-incidence populations. It is apparent from the above definitions that in the absence of culture, standard chest radiography is necessary to document cases of smear-negative PTB. Fluoroscopy examination results are not acceptable as documented evidence of PTB.

(WHO Guidelines for National Programmes)

6. Discuss the classification of PTB and treatment strategies based on:6.1 Diagnosis, Treatment, Prevention and Control of Tuberculosis: 2006 Update6.2 What is TB DOTS? What are its components? What is the responsibility of the physician in the diagnosis and treatment of PTB patients?

What is TB Network?

1. It is the official communication handle of the National Tuberculosis Control Program or NTP that will stand for DOH’s re-energized fight against TB.2. It is a product of DOH’s collaboration with the LGUs, PhilCAT, and Philhealth.3. It is a “special group” dedicated to help/ take care of TB symptomatics and TB patients.

a. Initially, it comprises regular health workers in the RHUs, MHOs and PHOs. b. Eventually, it will include everyone in the community who wish to help in the administration and financing of D.O.T.S.; family and relatives of TB symptomatics / patients, church, church organizations, civic organizations, NGOs, schools, companies/corporations.

1. TB Network comes with several information materials, such as print ads, radio and TV commercials. Poster of this TB Network as endorsed by Secretary Dayrit himself and with its battle cry “Kakampi Laban sa TB” will also be distributed as soon as ready.

2. It is participated in by the different stakeholders like donor agencies, private sector, non-government organizations, academe, professional societies, pharmaceutical companies and other TB DOTS partners and individual advocates united as one for a common cause.

2. Members of TB Network have also expanded to a huge number of other government agencies as also members of the Comprehensive & Unified Policy for TB Control in the Philippines or C.U.P.

3. DOH in cooperation with all the involved agencies as members of TB Network continuously works hand-in-hand in increasing case detection and cure rates in accordance with the NTP Targets every year.

4. In the end, it can blossom into a systematic, well-oiled, nationwide movement for the eventual complete eradication and/or control of TB-spearheaded by DOH.

Creative Considerations

1. Create a strong branding for NTP.2. Establish a human connection between the NTP and Target Audiences.3. Employ a unique visual device that is attractive, impactful, and memorable.

10 Roles of a TB-D.O.T.S. Advocate

1. Shares experiences and accomplishments in terms of cure and referral to TB Network.2. Disseminates right information on TB through available Information, Education, and Communication (IEC) campaign materials.3. Serves as moral support to TB patients and fellow advocates.4. Refers individuals with cough for two weeks or more to the nearest D.O.T.S. center for proper management.5. Conducts health education activities on how TB disease is acquired and developed.6. Promotes D.O.T.S. services of TB Partners including private sector.7. Advocates D.O.T.S. as the Strategy for curing TB.8. Participates during NTP activities including National Health Events, if possible.9. Encourages other people from different sectors to be a TB D.O.T.S. Advocate.10. Assists the treatment partner or may serve as the treatment partner, if necessary.

TB vs. NTP-D.O.T.S

What is TB?

10

Tuberculosis is an infectious disease caused by TB bacteria ( tuberculosis) that primarily affects the lungs. This condition is known as pulmonary tuberculosis (PTB). You may also have tuberculosis in the bones, meninges, joints, genito-urinary tract, liver, kidneys, intestines and heart and this is called extra-pulmonary tuberculosis.

What are some of the relevant TB statistics?

The Philippines is among the 22 high-burdened countries in the world according to W.H.O. TB is the 6th leading cause of illness and the 6th leading cause of deaths among the Filipinos. Most TB patients belong to the economically productive age- group (15-54 years-old) according to the 2nd National Prevalence Survey in 1997.

How does one get TB?

One gets infected with TB if he inhales the germs released from air droplets when a pulmonary TB patient coughs, sneezes and spits. A PTB patient whose sputum is positive for the TB germs/bacteria, if left untreated, may infect approximately 10-20 persons in two years.

How is TB diagnosed?

Pulmonary TB is suspected if a person has symptoms of cough for more than 2 weeks, fever, chest and back pains, poor appetite, loss of weight and hemoptysis. He should seek medical consultation and his sputum should be examined to detect the presence of TB germs/bacteria.

How is TB treated?

Tuberculosis is a curable disease. Patients are prescribed with appropriate regimen to render them non-infectious and cured, as early as possible. The treatment for TB is a combination of 3-4 anti-TB drugs. NEVER should we prescribe a SINGLE DRUG for TB treatment! This will worsen the patient’s condition.

What is D.O.T.S.?

D.O.T.S. stands for Directly-Observed Treatment Short-course. It is a comprehensive strategy endorsed by the World Health Organization (WHO) and International Union Against Tuberculosis and Lung Diseases (IUATLD) to detect and cure TB patients. There are five elements of DOTS that need to be fulfilled. These are:

1. Political commitment2. Quality sputum microscopy for diagnosis3. Regular supply of anti-TB drugs4. Standardized recording and reporting of TB data5. Supervised treatment by a treatment partner

According to the WHO Report on the TB Epidemic, 1997: A DOTS cure TB patients and it can produce cure rates as high as 95% even in the poorest countries. A DOTS prevent new infections among children and adults. A DOTS can stop resistance to anti-TB drugs. A DOTS is cost-effective.

How can we avail of D.O.T.S. Services?

DOTS services are available in the rural health units, city health centers and govern ment hospitals around the country. Currently, there are also private facilities that are offering DOTS services to their clients.

Is TB curable?

YES! TB can be cured through D.O.T.S.

What is the National TB Program of the Government?

The National TB Program (NTP) is the Government’s commitment to address the TB problem in the country. The NTP is being implemented nationwide in all government health centers and government hospitals. Its objectives are to detect active TB cases (at least 70%) and cure them (at least 85%). Achieving and sustaining targets will eventually result to the decline of the TB problem in the Philippines.

(http://www.doh.gov.ph/programs/tb_network)

7. Discuss the different drugs used in the treatment of PTB based on the chemical characteristics, mechanism of action, pharmacodynamics, pharmacokinetics, mechanism of resistance and the dose. Identify the 1st line and the 2nd line drugs.

7.1 Rifampicin

The rifamycins (rifampin, rifabutin, rifapentine) are a group of structurally similar, complex macrocyclic antibiotics produced by Amycolatopsis mediterranei; rifampin (RIFADIN; RIMACTANE) is a semisynthetic derivative of one of these¾rifamycin B.

Rifamycins were first isolated by Lepetit Research Laboratories from cultures obtained from a pine forest near Nice, France. Rifampin is soluble in organic solvents and in water at acidic pH.

Antibacterial Activity

Rifampin inhibits the growth of most gram-positive bacteria as well as many gram-negative microorganisms such as Escherichia coli, Pseudomonas, indole-positive and indole-negative Proteus, and Klebsiella.

Rifampin is very active against Staphylococcus aureus and coagulase-negative staphylococci. The drug also is highly active against Neisseria meningitidis and Haemophilus influenzae; minimal inhibitory concentrations range from 0.1 to 0.8 mg/ml. Rifampin inhibits the growth of Legionella species in cell culture and in animal models. Rifampin in concentrations of 0.005 to 0.2 mg/ml inhibits the growth of M. tuberculosis in vitro. Among nontuberculous mycobacteria, M. kansasii is inhibited by 0.25 to 1 mg/ml. The majority of strains of Mycobacterium scrofulaceum, Mycobacterium intracellulare, and M. avium are suppressed by concentrations of 4 mg/ml, but certain strains may be resistant to 16

mg/ml. Mycobacterium fortuitum is highly resistant to the drug. Rifampin increases the in vitro activity of streptomycin and isoniazid, but not that of ethambutol, against M. tuberculosis.

Bacterial Resistance

Microorganisms, including mycobacteria, may develop resistance to rifampin rapidly in vitro as a one-step process, and one of every 107 to 108 tubercle bacilli is resistant to the drug. Microbial resistance to rifampin is due to an alteration of the target of this drug, DNA-dependent RNA polymerase, with resistance in most cases being due to mutations between codons 507

and 533 of the polymerase rpoB gene (Blanchard, 1996); the mutations reduce binding of the drug to the polymerase. As a consequence, the antibiotic must not be used alone in the chemotherapy of tuberculosis.

11

When rifampin has been used to eradicate the meningococcal carrier state, failures have been due to the appearance of drug-resistant bacteria after treatment for as few as 2 days. Certain rifampin-resistant bacterial mutants have decreased virulence. Tuberculosis caused by rifampin-resistant mycobacteria has been described in patients who had not received prior chemotherapy, but this is very rare.

Mechanism of Action

Rifampin inhibits DNA-dependent RNA polymerase of mycobacteria and other microorganisms by forming a stable drug-enzyme complex, leading to suppression of initiation of chain formation (but not chain elongation) in RNA synthesis.

More specifically, the b subunit of this complex enzyme is the site of action of the drug, although rifampin binds only to the holoenzyme. Nuclear RNA polymerases from a variety of eukaryotic cells do not bind rifampin, and RNA synthesis is correspondingly unaffected in eukaryotic cells. High concentrations of rifamycin antibiotics can inhibit RNA synthesis in mammalian mitochondria, viral DNA-dependent RNA polymerases, and reverse transcriptases. Rifampin is bactericidal

for both intracellular and extracellular microorganisms.

Absorption, Distribution, and Excretion

The oral administration of rifampin produces peak concentrations in plasma in 2 to 4 hours; after ingestion of 600 mg, this value is about 7 mg/ml, but there is considerable variability. Aminosalicylic acid may delay the absorption of rifampin and cause a failure to reach adequate plasma concentrations. If aminosalicylate and rifampin are used concurrently, they should be given separately at an interval of 8 to 12 hours. Following absorption from the gastrointestinal tract, rifampin is eliminated rapidly in the bile, and an enterohepatic circulation ensues. During this time, the drug is progressively deacetylated, such that after 6 hours, nearly all of the antibiotic in the bile is in the deacetylated form, which retains essentially full antibacterial

activity. Intestinal reabsorption is reduced by deacetylation (as well as by food), and thus metabolism facilitates elimination of the drug. The half-life of rifampin varies from 1.5 to 5 hours and is increased by hepatic dysfunction; the half-life may be decreased in patients receiving isoniazid concurrently who are slow inactivators

of isoniazid. The half-life of rifampin is progressively shortened by about 40% during the first 14 days of treatment, owing to induction of hepatic microsomal enzymes that accelerate rifampin deacetylation.

Up to 30% of a dose of the drug is excreted in the urine and 60% to 65% in the feces; less than half of this may be unaltered antibiotic. Adjustment of dosage is not necessary in patients with impaired renal function. Rifampin is distributed throughout the body and is present in effective concentrations in many organs and body fluids, including the CSF. This is perhaps best exemplified by the fact that the

drug may impart an orange-red color to the urine, feces, saliva, sputum, tears, and sweat; patients should be so warned.

Therapeutic Uses

Rifampin for oral administration is available alone and as a fixed-dose combination with isoniazid (150 mg of isoniazid, 300 mg of rifampin; RIFAMATE) or with isoniazid and pyrazinamide (50 mg of isoniazid, 120 mg of rifampin, and 300 mg pyrazinamide; RIFATER).

A parenteral form of rifampin is available for use when the drug cannot be taken by mouth. Rifampin and isoniazid are the most effective drugs available for the treatment of tuberculosis. The dose of rifampin for treatment of tuberculosis in adults is 600 mg, given once daily, either 1 hour before or 2 hours after a meal. Children should receive 10 mg/kg given in the same way. Doses of 15 mg/kg or higher are associated with increased hepatotoxicity in children. Rifampin, like isoniazid, should never be used alone for the treatment of tuberculosis because of the rapidity with which resistance may develop. Despite the long list of untoward effects from rifampin, their incidence is low, and treatment seldom has to be interrupted. The use of rifampin in the chemotherapy of tuberculosis is detailed below. Rifampin also is indicated for the prophylaxis of meningococcal disease and H. influenzae meningitis. To prevent meningococcal disease, adults may be treated with 600 mg twice daily for 2 days or 600 mg once daily for 4 days; children should receive 10 to 15 mg/kg, to a maximum

of 600 mg.

Untoward Effects

Rifampin generally is well tolerated. When given in usual doses, fewer than 4% of patients with tuberculosis have significant adverse reactions; the most common are rash (0.8%), fever (0.5%), and nausea and vomiting (1.5%). Rarely, hepatitis and deaths due to liver failure have been observed in patients who received other hepatotoxic agents in addition to rifampin, or who had preexisting liver disease. Hepatitis from rifampin rarely occurs in patients with normal hepatic function; likewise, the combination of isoniazid and rifampin appears generally safe in such patients. However, chronic liver disease, alcoholism, and old age appear to increase the incidence of severe hepatic problems when rifampin is given alone or concurrently with isoniazid. Rifampin should not be administered on an intermittent schedule (less than twice weekly) and/or in daily doses of 1.2 g or greater because this is associated with frequent side effects. A flulike syndrome with fever, chills, and myalgias develops in 20% of patients so treated. The syndrome also may include eosinophilia, interstitial nephritis, acute tubular necrosis, thrombocytopenia, hemolytic anemia, and shock. Because rifampin potently induces CYP1A2, 2C9, 2C19, and 3A4, its administration results in a decreased half-life for a number of compounds, including HIV protease and non-nucleoside

reverse transcriptase inhibitors, digitoxin, digoxin, quinidine, disopyramide, mexiletine, tocainide, ketoconazole, propranolol, metoprolol, clofibrate, verapamil, methadone, cyclosporine, corticosteroids, oral anticoagulants, theophylline, barbiturates, oral contraceptives, halothane, fluconazole, and the sulfonylureas.

Gastrointestinal disturbances produced by rifampin (epigastric distress, nausea, vomiting, abdominal cramps, diarrhea) have occasionally required discontinuation of the drug. Various symptoms related to the nervous system also have been noted, including fatigue, drowsiness, headache, dizziness, ataxia, confusion, inability to concentrate, generalized numbness, pain in the extremities, and muscular weakness.

Hypersensitivity reactions include fever, pruritus, urticaria, various types of skin eruptions, eosinophilia, and soreness of the mouth and tongue. Hemolysis, hemoglobinuria, hematuria, renal insufficiency, and acute renal failure have been observed rarely; these also are thought to be hypersensitivity reactions. Thrombocytopenia,

transient leukopenia, and anemia have occurred during therapy. Since the potential teratogenicity of rifampin is unknown and the drug is known to cross the placenta, it is best to avoid the use of this agent during pregnancy.

Graber and associates (1973) noted immunoglobulin light-chain proteinuria (either kappa, lambda, or both) in about 85% of patients with tuberculosis treated with rifampin. None of the patients had symptoms or electrophoretic patterns compatible with myeloma. However, renal failure has been associated with light-chain proteinuria. Rifampin is effective for chemoprophylaxis of meningococcal disease and meningitis due to H. influenzae in household contacts of patients with such infections. Combined with a b-lactam antibiotic or vancomycin, rifampin may be useful for therapy in selected cases of staphylococcal endocarditis (on both natural and prosthetic valves) or osteomyelitis,

especially those caused by staphylococci "tolerant" to penicillin. Rifampin may be indicated for treatment of infections in patients with inadequate leukocytic bactericidal activity and for eradication of the staphylococcal nasal carrier state in patients with

chronic furunculosis.

7.2 Isoniazid

Isoniazid (isonicotinic acid hydrazide; NYDRAZID, others) is still considered the primary drug for the chemotherapy of tuberculosis. All patients with disease caused by isoniazid-sensitive strains of the tubercle bacillus should receive the drug if they can tolerate it.

History

The discovery of isoniazid was fortuitous; in 1945 Chorine reported that nicotinamide possesses tuberculostatic action. Examination of the compounds related to nicotinamide revealed that many pyridine derivatives possess tuberculostatic activity; among these were congeners of isonicotinic acid. Because the thiosemicarbazones were known to inhibit M. tuberculosis, the thiosemicarbazone of isonicotinaldehyde was synthesized and studied. The starting material for this synthesis was the methyl ester of isonicotinic acid, and the first intermediate was isonicotinylhydrazide (isoniazid).

Chemistry

Isoniazid is the hydrazide of isonicotinic acid. The isopropyl derivative of isoniazid, iproniazid (1-isonicotinyl-2-isopropylhydrazide), also inhibits the multiplication of the tubercle bacillus. This compound, which potently inhibits monoamine

oxidase, is too toxic for use in human beings. However, its study led to the use of monoamine oxidase inhibitors for the treatment of depression.

12


Isoniazid is bacteriostatic for "resting" bacilli, but is bactericidal for rapidly dividing microorganisms. The minimal tuberculostatic concentration is 0.025 to 0.05 mg/ml. The bacteria undergo one or two divisions before multiplication is arrested. The drug is remarkably selective for mycobacteria, and concentrations in excess of 500 mg/ml are required to inhibit the growth of other microorganisms. Isoniazid is highly effective for the treatment of experimentally induced tuberculosis in animals and is strikingly superior to streptomycin. Unlike streptomycin, isoniazid penetrates cells with ease and is just as effective against bacilli growing within cells as it is against those growing in culture media. Among the various nontuberculous (atypical) mycobacteria, only M. kansasii is sometimes susceptible to isoniazid. However, sensitivity always must be tested in vitro, since the inhibitory concentration required may be rather high.


When tubercle bacilli are grown in vitro in increasing concentrations of isoniazid, mutants are readily selected that are resistant to the drug, even when the drug is present in enormous concentrations. However, cross-resistance between isoniazid and other agents used to treat tuberculosis (except ethionamide, which is structurally related to isoniazid) does not occur.

The most common mechanism of isoniazid resistance is mutations in catalase-peroxidase (katg) that decrease its activity, preventing conversion of the prodrug isoniazid to its active metabolite (Blanchard, 1996). Another mechanism of resistance is related to a mutation in the mycobacterial inhA and KasA genes involved in mycolic acid biosynthesis.

Mutations in NADH dehydrogenase (ndh) also confer isoniazid resistance. Interestingly, isoniazid-resistant strains of M. tuberculosis appear to be less virulent in animal models. As with the other agents described, treatment with isoniazid alone selects for isoniazid-resistant bacteria and leads to the emergence in vivo of resistant strains. The shift from primarily sensitive to mainly insensitive microorganisms occasionally occurs within a few weeks after therapy is started; however, the time of appearance of isoniazid resistance

varies considerably from one case to another. Approximately 1 in 106 tubercle bacilli will be genetically resistant to isoniazid; since tuberculous cavities may contain as many as 107 to 109 microorganisms, it is not surprising that treatment

with isoniazid alone selects for these resistant bacteria. The incidence of primary resistance to isoniazid in the United States until recently had been fairly stable at 2% to 5% of isolates of M. tuberculosis. Resistance currently is estimated at 8% of isolates, but may be much higher in certain populations, including Asian and Hispanic immigrants and in large urban areas and coastal or border

communities.

Mechanism of Action

Isoniazid is a prodrug; mycobacterial catalase-peroxidase converts isoniazid into an active metabolite. A primary action of isoniazid is to inhibit the biosynthesis of mycolic acids¾long, branched lipids that are attached to a unique polysaccharide, arabino galactan, to form part of the

mycobacterial cell wall. The mechanism of action of isoniazid is complex, with resistance mapping to mutations in at least five different genes (katG [coding for the catalase-peroxidase that activates the prodrug

isoniazid], inhA, ahpC, kasA, and ndh). The preponderance of evidence points to inhA as the primary drug target. Indeed, the catalase-peroxidase-activated isoniazid, but not the prodrug, binds to the inhA gene product enoyl-ACP reductase of fatty acid synthase II, which converts D2-unsaturated fatty

acids to saturated fatty acids in the mycolic acid biosynthetic pathway. Mycolic acids are unique to mycobacteria, explaining the high degree of selectivity of the antimicrobial activity of isoniazid. Mutations of the katG gene that result in an inactive catalase-peroxidase cause high-level isoniazid resistance, since the prodrug cannot be activated by the catalase-peroxidase. Isoniazid also inhibits mycobacterial catalase-peroxidase (the isoniazid-activating enzyme), which may increase the likelihood of damage to the mycobacteria from reactive oxygen species and

H2O2. Exposure to isoniazid leads to a loss of acid-fastness and a decrease in the quantity of methanol-extractable lipids in the microorganisms.


Isoniazid is readily absorbed when administered either orally or parenterally. Aluminum-containing antacids may interfere with absorption.Peak plasma concentrations of 3 to 5 mg/ml develop 1 to 2 hours after oral ingestion of usual doses.

Isoniazid diffuses readily into all body fluids and cells. The drug is detectable in significant quantities in pleural and ascitic fluids; concentrations in the cerebrospinal fluid (CSF) with inflamed meninges are similar to those in the plasma (Holdiness,

1985). Isoniazid penetrates well into caseous material. The concentration of the agent is initially higher in the plasma and muscle than in the infected tissue, but the latter retains the drug for a long time in quantities well above those required for

bacteriostasis. From 75% to 95% of a dose of isoniazid is excreted in the urine within 24 hours, mostly as metabolites. The main excretory products in humans result from enzymatic acetylation (acetylisoniazid) and enzymatic hydrolysis (isonicotinic acid). Small quantities of an isonicotinic acid conjugate (probably isonicotinyl glycine), one or more isonicotinyl hydrazones, and traces of N-methylisoniazid also are detectable in the urine. The distribution of slow and rapid inactivators of the drug is bimodal owing to differences in the levels and activity of the genetically polymorphic arylamine N-acetyltransferase type 2 (NAT2). The activity of NAT2 enzyme translated from variant alleles is decreased mostly by the impaired stability or a decrease in Vmax. At least 36 NAT2 alleles have been identified, although many

may not be clinically important. As an autosomal recessive trait, only individuals bearing two variant alleles are expected to be prone to impaired acetylation capacity. The rate of acetylation significantly alters the concentrations of the drug that are achieved in plasma and its half-life in the circulation. The half-life of the drug may be prolonged by hepatic insufficiency. The frequency of each acetylation phenotype is dependent upon race but is not influenced by sex or age. Fast acetylation is found in Inuit and Japanese. Slow acetylation is the predominant phenotype in most Scandinavians, Jews, and North African Caucasians. The incidence of "slow acetylators" among various racial types in the United States is about 50%. Since high acetyltransferase activity (fast acetylation) is inherited as an autosomal dominant trait, "fast acetylators" of isoniazid are either heterozygous or homozygous. The average concentration of active isoniazid in the circulation of fast acetylators is about 30% to 50% of that in slow acetylators. In the whole population, the half-life of isoniazid varies from less than 1 to more than 4 hours. The mean half-life in fast acetylators is approximately 70 minutes, whereas 2 to 5 hours is characteristic of slow acetylators. Because isoniazid is relatively nontoxic, a sufficient amount of drug can be administered to fast acetylators to achieve a therapeutic effect equal to that seen in slow acetylators. A dosage

reduction is recommended for slow acetylators with hepatic failure. The clearance of isoniazid is dependent only to a small degree on the status of renal function, but patients who are slow inactivators of the drug may accumulate toxic concentrations if their

renal function is impaired.

Therapeutic Uses

Isoniazid is still the most important drug worldwide for the treatment of all types of tuberculosis. Toxic effects can be minimized by prophylactic therapy with pyridoxine and careful surveillance of the patient. For treatment of active infections, the drug must be used concurrently with

another agent, although it is used alone for prophylaxis. Isoniazid is available for oral and parenteral administration. The commonly used total daily dose of isoniazid is 5 mg/kg, with a maximum of 300 mg; oral and intramuscular doses are identical. Isoniazid usually is given orally in a single daily dose but may be given in two divided doses. Although doses of 10 to 20 mg/kg, with a maximum of 600 mg, occasionally are used in severely ill patients, there is no evidence that this regimen is more effective. Children should receive 10 to 20 mg/kg per day (300 mg maximum). Isoniazid may be used as intermittent therapy for tuberculosis; after a minimum of 2 months of daily therapy with isoniazid, rifampin, and pyrazinamide, for sensitive strains of M. tuberculosis,

patients may be treated with twice-weekly doses of isoniazid (15 mg/kg orally) plus rifampin (10 mg/kg, up to 600 mg per dose) for 4 months. Pyridoxine, vitamin B6, (10 to 50 mg per day) should be administered with isoniazid to minimize the risks of peripheral neuropathy and central nervous system toxicity in malnourished patients

and those predisposed to neuropathy (e.g., the elderly, pregnant women, HIV-infected individuals, diabetics, alcoholics, and uremics).

Untoward Effects

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The incidence of adverse reactions to isoniazid was estimated to be 5.4% among more than 2000 patients treated with the drug; the most prominent of these reactions were rash (2%), fever (1.2%), jaundice (0.6%), and peripheral neuritis (0.2%).

Hypersensitivity to isoniazid may result in fever, various skin eruptions, hepatitis, and morbilliform, maculopapular, purpuric, and urticarial rashes. Hematological reactions also may occur (agranulocytosis, eosinophilia, thrombocytopenia, anemia).

Vasculitis associated with antinuclear antibodies may appear during treatment but disappears when the drug is stopped. Arthritic symptoms (back pain; bilateral proximal interphalangeal joint involvement; arthralgia of the knees, elbows, and wrists; and the "shoulder-hand" syndrome) have been attributed to this

agent. If pyridoxine is not given concurrently, peripheral neuritis (most commonly paresthesias of feet and hands) is the most common reaction to isoniazid and occurs in about 2% of patients

receiving 5 mg/kg of the drug daily. Higher doses may result in peripheral neuritis in 10% to 20% of patients. Neuropathy is more frequent in slow acetylators and in individuals with diabetes mellitus, poor nutrition, or anemia. The prophylactic administration of pyridoxine prevents the development not only of peripheral neuritis, but also of most other nervous system disorders in practically all instances, even when

therapy lasts as long as 2 years. Isoniazid may precipitate convulsions in patients with seizure disorders, and rarely, in patients with no history of seizures. Optic neuritis and atrophy also have occurred during therapy with the drug. Muscle twitching, dizziness, ataxia, paresthesias, stupor, and toxic encephalopathy that may be fatal are other manifestations of the neurotoxicity of isoniazid. A number of mental abnormalities may appear during the use of this drug, including euphoria, transient impairment of memory, separation of ideas and reality, loss of self-control, and florid

psychoses. Isoniazid is known to inhibit the parahydroxylation of phenytoin, and signs and symptoms of toxicity occur in approximately 27% of patients given both drugs, particularly in those who are slow

acetylators. Concentrations of phenytoin in plasma should be monitored and adjusted if necessary. The dosage of isoniazid should not be changed. Although jaundice has been known for some time to be an untoward effect of exposure to isoniazid, not until the early 1970s did it become apparent that severe hepatic injury leading to death

may occur in some individuals receiving this drug. Additional studies in adults and children have confirmed this observation; the characteristic pathological process is bridging and multilobular necrosis. Continuation of the drug after symptoms of hepatic dysfunction have appeared tends to increase the severity of damage. The mechanisms responsible for this toxicity are unknown, although acetylhydrazine, which is a metabolite of isoniazid, causes hepatic damage in adults. Hence, patients who are rapid

acetylators of isoniazid might be expected to be more likely to develop hepatotoxicity than slow acetylators; whether this is true, however, is unresolved. A contributory role of alcoholic hepatitis has been noted, but chronic carriers of the hepatitis B virus tolerate isoniazid. Age appears to be the most important factor in determining the risk of isoniazid-induced hepatotoxicity. Hepatic damage is rare in patients less than 20 years old; the complication is observed in 0.3% of those 20 to 34 years old, and the incidence increases to 1.2% and 2.3% in individuals 35 to

49 and older than 50 years of age, respectively. Up to 12% of patients receiving isoniazid may have elevated plasma aspartate and alanine transaminase activities. Patients receiving isoniazid should be carefully evaluated at monthly intervals for symptoms of hepatitis (anorexia, malaise, fatigue, nausea, and jaundice) and warned to discontinue the drug

if such symptoms occur. Some clinicians also prefer to determine serum aspartate aminotransferase activities at monthly intervals in high-risk individuals (ages 7 to 35, excessive alcohol intake, history of liver disease,

etc.) and recommend that an elevation greater than five times normal is cause for drug discontinuation. Most hepatitis occurs 4 to 8 weeks after the start of therapy. Isoniazid should be administered with great care to those with preexisting hepatic disease. Among miscellaneous reactions associated with isoniazid therapy are dryness of the mouth, epigastric distress, methemoglobinemia, tinnitus, and urinary retention. In persons predisposed to

pyridoxine-deficiency anemia, the administration of isoniazid may result in dramatic anemia, but treatment with large doses of vitamin B6 gradually returns the blood to normal in such cases. A drug-induced syndrome resembling systemic lupus erythematosus has also been reported. Overdose of isoniazid, as in attempted suicide, may result in nausea, vomiting, dizziness, slurred speech, and visual hallucinations followed by coma, seizures, metabolic acidosis, and

hyperglycemia. Pyridoxine is an antidote in this setting; it should be given in a dose that approximates the amount of isoniazid ingested.

7.3 Pyrazinamide

Chemistry

Pyrazinamide is the synthetic pyrazine analog of nicotinamide.


Pyrazinamide exhibits bactericidal activity in vitro only at a slightly acidic pH. Activity at acid pH is ideal, since M. tuberculosis resides in an acidic phagosome within the macrophage. Tubercle bacilli within monocytes in vitro are inhibited or killed by the drug at a concentration of 12.5 mg/ml. Resistance develops rapidly if pyrazinamide is used alone. The target of pyrazinamide appears to be the mycobacterial fatty acid synthase I gene involved in mycolic acid biosynthesis.


Pyrazinamide is well absorbed from the gastrointestinal tract and widely distributed throughout the body. The oral administration of 500 mg produces plasma concentrations of about 9 to 12 mg/ml at 2 hours and 7 mg/ml at 8 hours. The plasma half-life is 9 to 10 hours in patients with normal renal function. The drug is excreted primarily by renal glomerular filtration. Pyrazinamide is distributed widely¾including to the CNS, lungs, and liver¾after oral administration. Penetration of the drug into the CSF is excellent. Pyrazinamide is hydrolyzed to pyrazinoic acid and subsequently hydroxylated to 5-hydroxypyrazinoic acid, the major excretory product.

Therapeutic Uses

Pyrazinamide has become an important component of short-term (6-month) multiple-drug therapy of tuberculosis. Pyrazinamide is available in tablets for oral administration. The daily dose for adults is 15 to 30 mg/kg orally, given as a single dose. The maximum quantity to be given is 2 g per day, regardless of weight. Children should receive 15 to 30 mg/kg per day; daily doses also should not exceed 2 g. Pyrazinamide has been safe and effective when administered twice or thrice weekly (at increased dosages).

Untoward Effects

Injury to the liver is the most serious side effect of pyrazinamide. When a dose of 40 to 50 mg/kg is administered orally, signs and symptoms of hepatic disease appear in about 15% of patients, with jaundice in 2% to 3% and death due to hepatic necrosis in

rare instances. Elevations of plasma alanine and aspartate aminotransferases are the earliest abnormalities produced by the drug. Regimens employed currently (15 to 30 mg/kg per day) are much safer. Prior to pyrazinamide administration all patients should undergo studies of hepatic function and these studies should be repeated at frequent intervals during the entire period of treatment. If

evidence of significant hepatic damage becomes apparent, therapy must be stopped. Pyrazinamide should not be given to individuals with any degree of hepatic dysfunction unless this is absolutely unavoidable. The drug inhibits excretion of urate, resulting in hyperuricemia in nearly all patients; acute episodes of gout have occurred. Other untoward effects that have been observed with pyrazinamide are arthralgias, anorexia, nausea and vomiting, dysuria, malaise, and fever. While some international organizations recommend the use of pyrazinamide in pregnancy, this is not the case in the United States because of inadequate data on teratogenicity.

7.4 Ethambutol

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Chemistry

Ethambutol is a water-soluble and heat-stable compound.

Antibacterial Activity, Mechanism of Action, Resistance

Nearly all strains of M. tuberculosis and M. kansasii as well as a number of strains of MAC are sensitive to Ethambutol. The sensitivities of other nontuberculous organisms are variable. Ethambutol has no effect on other bacteria. It suppresses the growth of most isoniazid- and streptomycin-resistant tubercle bacilli. Resistance to ethambutol develops very slowly in vitro. Mycobacteria take up ethambutol rapidly when the drug is added to cultures that are in the exponential growth phase. However, growth is not significantly inhibited before about 24 hours. Ethambutol inhibits arabinosyl transferases involved in cell wall biosynthesis. Bacterial resistance to the drug develops in vivo via single amino acid mutations in the embA gene when ethambutol is given in the absence of other effective agents.


About 75% to 80% of an orally administered dose of ethambutol is absorbed from the gastrointestinal tract. Concentrations in plasma are maximal in humans 2 to 4 hours after the drug is taken and are proportional to the dose. A single dose of 25 mg/kg produces a plasma concentration of 2 to 5 mg/ml at 2 to 4 hours. The drug has a half-life of 3 to 4 hours. Within 24 hours, 75% of an ingested dose of ethambutol is excreted unchanged in the urine; up to 15% is excreted in the form of two metabolites, an aldehyde and a dicarboxylic acid

derivative. Renal clearance of ethambutol is approximately 7 ml×min-1×kg-1; thus it is evident that the drug is excreted by tubular secretion in addition to glomerular filtration.

Therapeutic Uses

Ethambutol (ethambutol hydrochloride; MYAMBUTOL) has been used with notable success in the therapy of tuberculosis of various forms when given concurrently with isoniazid. Because of a lower incidence of toxic effects and better acceptance by patients, ethambutol has essentially replaced aminosalicylic acid. Ethambutol is available for oral administration in tablets containing the D isomer. The usual adult dose of ethambutol is 15 mg/kg given once a day. Some physicians prefer to treat with 25 mg/kg per day for the first 60 days and then to reduce the dose to 15 mg/kg per day, particularly for those who have received previous therapy.

Ethambutol accumulates in patients with impaired renal function, and adjustment of dosage is necessary. Ethambutol is not recommended for children under 5 years of age, in part because of concern about the ability to test their visual acuity (see below). Children from ages 6 to 12 years should

receive 10 to 15 mg/kg per day.

Untoward Effects

The most important side effect is optic neuritis, resulting in decreased visual acuity and loss of ability to differentiate red from green. The incidence of this reaction is proportional to the dose of ethambutol and is observed in 15% of patients receiving 50 mg/kg per day, in 5% of patients receiving 25 mg/kg per day, and in

fewer than 1% of patients receiving daily doses of 15 mg/kg (the recommended dose for treatment of tuberculosis). The intensity of the visual difficulty is related to the duration of therapy after the decreased visual acuity first becomes apparent and may be unilateral or bilateral. Tests of visual acuity and red-green discrimination prior to the start of therapy and periodically thereafter are thus recommended. Recovery usually occurs when ethambutol is withdrawn; the time required is a function of the degree of visual impairment. Ethambutol produces very few untoward reactions. Fewer than 2% of nearly 2000 patients who received daily doses of 15 mg/kg of ethambutol had adverse reactions: 0.8% experienced diminished visual acuity, 0.5% had a rash, and 0.3%

developed drug fever. Other side effects that have been observed are pruritus, joint pain, gastrointestinal upset, abdominal pain, malaise, headache, dizziness, mental confusion, disorientation, and possible hallucinations.

Numbness and tingling of the fingers owing to peripheral neuritis are infrequent. Anaphylaxis and leukopenia are rare. Therapy with ethambutol results in an increased concentration of urate in the blood in about 50% of patients, owing to decreased renal excretion of uric acid. The effect may be detectable as early as 24 hours after a single dose or as late as 90 days after treatment is started. This untoward effect is possibly enhanced by isoniazid and pyridoxine.

7.5 Streptomycin

History

Streptomycin was the first clinically available effective drug for the treatment of tuberculosis. At first it was given in large doses, but problems related to toxicity and the development of resistant microorganisms seriously limited its usefulness. The antibiotic was then administered in smaller quantities, but streptomycin administered alone still proved to be far from ideal for the management of all forms of the disease. However, the discovery of other compounds that, when administered concurrently with streptomycin, reduced the rate at which microorganisms became drug-resistant enabled physicians to

treat tuberculosis effectively with streptomycin. It is now the least used of the first-line agents in the therapy of tuberculosis.


Streptomycin is bactericidal for the tubercle bacillus in vitro. Concentrations as low as 0.4 mg/ml may inhibit growth. The vast majority of strains of M. tuberculosis are sensitive to 10 mg/ml. M. kansasii is frequently sensitive, but other nontuberculous mycobacteria are only occasionally susceptible. The activity of streptomycin in vivo is essentially suppressive. When the antibiotic is administered to experimental animals prior to inoculation with the tubercle bacillus, the development of disease is not prevented. Infection progresses until the animals' immunological mechanisms respond. The presence of viable microorganisms in abscesses and in the regional lymph nodes adds support to the concept that the activity of streptomycin in vivo is to suppress, not to eradicate, the

tubercle bacillus. This property of streptomycin may be related to the observation that the drug does not readily enter living cells and thus cannot kill intracellular microbes.


Large populations of all strains of tubercle bacilli include a number of cells that are markedly resistant to streptomycin because of mutation. However, primary resistance to the antibiotic is found in only 2% to 3% of isolates of M. tuberculosis. Selection for resistant tubercle bacilli occurs in vivo as it does in vitro. In general, the longer therapy is continued, the greater the incidence of resistance to streptomycin. When streptomycin was used alone, as many as 80% of patients harbored insensitive tubercle bacilli after 4 months of treatment; many of these microorganisms were not inhibited by

concentrations of drug as high as 1 mg/ml.

Therapeutic Uses

Since other effective agents have become available, the use of streptomycin for the treatment of pulmonary tuberculosis has been sharply reduced. Many clinicians prefer to give 4 drugs, of which streptomycin may be one, for the most serious forms of tuberculosis, such as disseminated disease or meningitis. For tuberculosis, adults should be given 15 mg/kg per day in divided doses given by intramuscular injection every 12 hours, not to exceed 1 g per day. Children should receive 20 to 40 mg/kg per day in divided doses every 12 to 24 hours, not to exceed 1 g per day. Therapy usually is discontinued after 2 to 3 months or sooner if cultures become negative.

15

Untoward Effects

In one series of 515 patients with tuberculosis who were treated with this aminoglycoside, 8.2% had adverse reactions; half of these involved the auditory and vestibular functions of the eighth cranial nerve.

Other relatively frequent problems included rash (in 2%) and fever (in 1.4%).

7.6 Ethionamide

Chemistry

Synthesis and study of a variety of congeners of thioisonicotinamide revealed that an a-ethyl derivative¾ethionamide (TRECATOR-SC)¾ is considerably more effective than the parent compound.

It has the following structural formula:

Antibacterial Activity, Resistance

The multiplication of M. tuberculosis is suppressed by concentrations of ethionamide ranging from 0.6 to 2.5 mg/ml. Resistance can develop rapidly in vitro and in vivo when ethionamide is used as a single-agent treatment, and can include low-level cross-resistance to isoniazid . A concentration of 10 mg/ml or less will inhibit approximately 75% of photochromogenic mycobacteria; the scotochromogens are more resistant. Ethionamide is very effective in the treatment of experimental tuberculosis in animals, although its activity varies greatly with the animal model studied.

Mechanism of Action

In the manner of isoniazid, ethionamide is also an inactive prodrug that is activated by a mycobacterial redux system. EtaA, an NADPH-specific, FAD containing monooxygenase, converts ethionamide to a sulfoxide, and thence to 2-ethyl-4-aminopyridine. Although these products are not toxic to mycobacteria, it is believed that a closely related and transient intermediate is the active antibiotic. Ethionamide inhibits mycobacterial growth by inhibiting the activity of the inhA gene product, the enoyl-ACP reductase of fatty acid synthase II. This is the same enzyme that activated isoniazid inhibits. Although the exact mechanisms of inhibition may differ, the results are the same: inhibition of mycolic acid biosynthesis and consequent impairment of cell-wall synthesis. Recent advances in

understanding the mechanisms of activation and action of thioamides may suggest new agents for treating mycobacterial infections.


The oral administration of 1 g of ethionamide yields peak concentrations in plasma of about 20 mg/ml in 3 hours; the concentration at 9 hours is 3 mg/ml. The half-life of the drug is about 2 hours. Approximately 50% of patients are unable to tolerate a single dose larger than 500 mg because of gastrointestinal disturbance. Ethionamide is rapidly and widely distributed; the concentrations in the blood and various organs are approximately equal. Significant concentrations are present in CSF. Ethionamide is cleared by hepatic metabolism; like aminosalicylic acid, ethionamide inhibits the acetylation of isoniazid in vitro. Less than 1% of ethionamide is excreted in an active form in the urine. Therapeutic Uses. Ethionamide is a secondary agent, to be used concurrently with other drugs only when therapy with primary agents is ineffective or contraindicated. Ethionamide is administered only orally. The initial dosage of ethionamide for adults is 250 mg twice daily; it is increased by 125 mg per day every 5 days until a dose of 15 to 20 mg/kg per day is achieved. The maximal dose is 1 g daily. The drug is best taken with meals in divided doses in order to minimize gastric irritation. Children should receive 15 to 20 mg/kg per day in two divided doses, not to exceed 1 g per day.

Untoward Effects

The most common reactions to ethionamide are anorexia, nausea and vomiting, gastric irritation, and a variety of neurologic symptoms. Severe postural hypotension, mental depression, drowsiness, and asthenia are common. Convulsions and peripheral neuropathy are rare. Other reactions referable to the nervous system include olfactory disturbances, blurred vision, diplopia, dizziness, paresthesias, headache, restlessness, and tremors. Pyridoxine (vitamin B6) relieves the neurologic symptoms and its concomitant administration is recommended. Severe allergic skin rashes, purpura, stomatitis, gynecomastia, impotence,

menorrhagia, acne, and alopecia also have been observed. A metallic taste also may be noted. Hepatitis has been associated with the use of the drug in about 5% of cases. The signs and symptoms of hepatotoxicity clear when treatment is stopped. Hepatic function should be assessed at regular intervals in patients receiving ethionamide.

7.7 Aminosalicylic acid


Aminosalicylic acid is bacteriostatic. In vitro, most strains of M. tuberculosis are sensitive to a concentration of 1 mg/ml. The antimicrobial activity of aminosalicylic acid is highly specific, and microorganisms other than M. tuberculosis are unaffected. Most nontuberculous mycobacteria are not inhibited by the drug. Aminosalicylic acid alone is of little value in the treatment of tuberculosis in humans.


Strains of tubercle bacilli insensitive to several hundred times the usual bacteriostatic concentration of aminosalicylic acid can be produced in vitro. Resistant strains of tubercle bacilli also emerge in patients treated with aminosalicylic acid, but much more slowly than with streptomycin.

Mechanism of Action

Aminosalicylic acid is a structural analog of para-aminobenzoic acid, and its mechanism of action appears to be very similar to that of the sulphonamides. Nonetheless, the sulfonamides are ineffective against M. tuberculosis, and aminosalicylic acid is inactive against sulfonamide-susceptible bacteria. This differential sensitivity presumably reflects differences in the enzymes responsible for folate biosynthesis in the various microorganisms.

Absorption, Distribution, and Excretion Aminosalicylic acid is readily absorbed from the gastrointestinal tract. A single oral dose of 4 g of the free acid produces maximal concentrations in plasma of about 75 mg/ml within 1.5 to 2 hours. The sodium salt is absorbed even more rapidly. The drug appears to be distributed throughout the total body water and reaches high concentrations in pleural fluid and caseous tissue but CSF levels are low. The drug has a half-life of about 1 hour, and concentrations in plasma are negligible within 4 to 5 hours after a single conventional dose. Over 80% of the drug is excreted in the urine; more than 50% is in the form of the acetylated compound; the largest portion of the remainder is made up of the free acid. Excretion of aminosalicylic acid is greatly retarded by renal dysfunction, and the use of the drug is not recommended in such patients. Probenecid decreases the renal excretion of this agent.

Therapeutic Uses

Aminosalicylic acid (PASER) is a second-line agent. Its importance in the management of pulmonary and other forms of tuberculosis has markedly decreased since more active and better-tolerated drugs, such as rifampin and ethambutol, have been developed.

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It is administered orally in a daily dose of 10 to 12 g. Because it is a gastric irritant, the drug is best administered after meals, with the daily dose being divided into 2 to 4 equal portions. Children should receive 150 to 300 mg/kg per day in 3 to 4 divided doses.

Untoward Effects

The incidence of untoward effects associated with the use of aminosalicylic acid is approximately 10% to 30%. Gastrointestinal problems¾including anorexia, nausea, epigastric pain, abdominal distress, and diarrhea¾are predominant and often limit patient adherence. Patients with peptic ulcers tolerate the drug especially poorly. Hypersensitivity reactions to aminosalicylic acid are seen in 5% to 10% of patients. High fever may develop abruptly, with intermittent spiking, or it may appear gradually and be low-grade. Generalized malaise, joint pains, and sore throat may be present at the same time. Skin eruptions of various types appear as isolated reactions or accompany the fever. Among the hematological abnormalities that have been observed are leukopenia, agranulocytosis, eosinophilia, lymphocytosis, an atypical mononucleosis syndrome, and thrombocytopenia. Acute hemolytic anemia may appear in some instances.

7.8 Cycloserine

Cycloserine (SEROMYCIN) is a broad-spectrum antibiotic produced by Streptococcus orchidaceus. It was first isolated from a fermentation brew in 1955 and was later synthesized. Currently, cycloserine is used in conjunction with other tuberculostatic drugs in the treatment of pulmonary or extrapulmonary tuberculosis when primary agents (isoniazid, rifampin,

ethambutol, pyrazinamide, streptomycin) have failed.

Chemistry

Cycloserine is D-4-amino-3-isoxazolidone. The drug is stable in alkaline solution but is rapidly destroyed when exposed to neutral or acidic pH.


Cycloserine is inhibitory for M. tuberculosis in concentrations of 5 to 20 mg/ml in vitro. There is no cross-resistance between cycloserine and other tuberculostatic agents. While the antibiotic is effective in experimental infections caused by other microorganisms, studies in vitro reveal no suppression of growth in cultures made in conventional media, which

contain D-alanine; this amino acid blocks the antibacterial activity of cycloserine.

Mechanism of Action

Cycloserine and D-alanine are structural analogs; thus, cycloserine inhibits reactions in which D-alanine is involved in bacterial cell-wall synthesis. The use of medium free of D-alanine reveals that the antibiotic inhibits the growth in vitro of enterococci, E. coli, S. aureus, Nocardia species, and Chlamydia. Absorption, Distribution, and Excretion. When given orally, 70% to 90% of cycloserine is rapidly absorbed. Peak concentrations in plasma are reached 3 to 4 hours after a single dose and are in the range of 20 to 35 mg/ml in children who receive 20 mg/kg; only small quantities are present after 12

hours. Cycloserine is distributed throughout body fluids and tissues. There is no appreciable blood-brain barrier to the drug, and CSF concentrations are approximately the same as those in plasma. About 50% of a parenteral dose of cycloserine is excreted unchanged in the urine in the first 12 hours; a total of 65% is recoverable in the active form over a period of 72 hours. Very little of the antibiotic is metabolized. The drug may accumulate to toxic concentrations in patients with renal insufficiency; it may be removed from the circulation by dialysis.

Therapeutic Uses

Cycloserine should be used only when retreatment is necessary or when microorganisms are resistant to other drugs. When cycloserine is employed to treat tuberculosis, it must be given together with other effective agents. Cycloserine is available for oral administration. The usual dose for adults is 250 to 500 mg twice daily.

Untoward Effects

Reactions to cycloserine most commonly involve the central nervous system. Symptoms tend to appear within the first 2 weeks of therapy and usually disappear when the drug is withdrawn. Among the central manifestations are somnolence, headache, tremor, dysarthria, vertigo, confusion, nervousness, irritability, psychotic states with suicidal tendencies, paranoid reactions,

catatonic and depressed reactions, twitching, ankle clonus, hyperreflexia, visual disturbances, paresis, and tonic-clonic or absence seizures. Large doses of cycloserine or the concomitant ingestion of alcohol increases the risk of seizures. Cycloserine is contraindicated in individuals with a history of epilepsy and should be used with caution in individuals with a history of depression, as suicide is a risk.

(7.1-7.8 → Goodman and Gilman’s The Pharmacological Basis of Therapeutics 11th Edition)

7.9 Kanamycin

Kanamycin and amikacin are bactericidal agents of the aminoglycoside class, obtained from Streptomyces. Their bactericidal effect in vitro and in vivo against M. tuberculosis is very similar and their adverse reactions are those of other aminoglycosides. Their bactericidal effect may be valuable in patients with bacilli resistant to streptomycin. Cross-resistance between kanamycin and amikacin is usual.

PRESENTATION AND DOSAGE

The drugs are presented as sterile white powder for intramuscular injection in sealed vials containing the equivalent of 250 mg, 500 mg or 1 g of drug. The drug should be dissolved in 2 ml of 0.9% sodium chloride injection or water for injection. The optimal dose is 15 mg/kg body weight, usually 750 mg to 1 g, given daily or 5 days per week by deep intramuscular injection. Rotation of injection sites avoids local discomfort. The duration of daily therapy is usually 3-4 months. When necessary, the drug may be given at the same dosage 2 or 3 times weekly during the continuation phase, under close monitoring for adverse reactions.

ADVERSE REACTIONS

Side-effects are similar to those associated with streptomycin and capreomycin. Ototoxicity, deafness, vertigo or reversible nephrotoxicity may occur.

PRECAUTIONS

In patients with impaired renal function, the daily dosage should be reduced and/or the intervals between dosages increased, to avoid accumulation of the drug. In these patients, renal function should be monitored regularly during use. This drug should not be used in pregnant women except as a last resort.

7.10 Capreomycin

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Capreomycin is a bactericidal agent from the polypeptide class, obtained from Streptomyces capreolus. Its bactericidal effect may be valuable in patients with bacilli resistant to streptomycin, kanamycin and amikacin: there is no cross-resistance with the other aminoglycosides.

PREPARATION AND DOSAGE

Capreomycin sulfate is supplied as a sterile white powder for intramuscular injection in sealed vials each containing 1000 units, approximately equivalent to 1 g capreomycin base. This should be dissolved in 2 ml of 0.9% sodium chloride; 2- 3 minutes should be allowed for complete solution. The usual dosage is 1g in a single daily dose, not exceeding 20 mg/kg, for 40-120 days after which dosage must be reduced to 2 or 3 times weekly, as the risk of important side-effects rises

sharply at that time.

ADVERSE REACTIONS

Side-effects are similar to those of streptomycin, mainly tinnitus and vertigo with a lesser risk of deafness. Kidney damage may occur with elevation of serum and urine creatinine. Hypokalaemia, hypocalcaemia and hypomagnesaemia have also been reported. General cutaneous reactions and hepatitis may occur rarely. There may be pain and swelling at injection sites if it is not given by deep intramuscular injection.

PRECAUTIONS

Capreomycin should be avoided, if possible, in patients with impaired hearing or renal function. Serum urea and electrolytes should be monitored during treatment. It is contraindicated in pregnancy and best avoided in children.

(7.9-7.10 → Guidelines for National Programmes)

RESERVE ANTITUBERCULOSIS DRUGS (2nd line)

AMINOGLYCOSIDESo Kanamycin and amikacino Capreomycin (polypeptide)

THIOAMIDESo Ethionamideo Protionamide

FLUOROQUINOLONESo Ofloxacino Ciprofloxacin

CYCLOSERINE (AND TERIZIDONE) P-AMINOSALICYCLIC ACID (PAS)

(Guidelines for National Programmes)

8. Write a prescription naming an antituberculous agent and label them properly.

For AdultsRx: - superscriptionEthambutol HCl 275 mg, Rifampicin 150 mg, INH 75 mg, Pyrazinamide 400 mg (Myrin-P Forte) - subscriptionSig: Take 3 tabs before meals. - transcription

For ChildrenRx:Rifampicin 200 mg/5ml (Refam susp)INH 200 mg, pyridoxine HCl 20 mg/5ml (Terozid Forte syr)Pyrazinamide 250 mg/5ml (Pyramin susp)Sig: Refam susp TB Childn 10-20 mg/kg body wt. Max: 600 mg/day. For prophylaxis give ½ the dose for active therapy for 6-12 months. Terozid Forte syr Childn 10-12 yr 2-3 tsp (10-15 mL), 7-9 yr 1½-2 tsp (7.5-10 mL), 3-6 yr 1-1½ tsp (5-7.5 mL), 1-2 yr 1 tsp (5 mL). Pyramin susp Adult & childn Continuous therapy (7 times/wk) 15-30 mg/kg body wt. Max: 2 g/day. Intermittent therapy 50-70 mg/kg body wt 2-3 times weekly.Take on empty stomach 1 hour before meals.

1) Patients’ Name: Chuck Galon Date: 11-28-08 Address: Capitol, Cebu CityRx2) Rifampicin 150mg, Isoniazid 75mg, Pyrazinamide 400mg, Ethambutol 275 mg (Fixcom 4) 3) #90 tabs4) Sig: take 1 tablet 3x daily

5) Dr. Dan Tan M.D. PTR TIN

LIC

18

1. Superinscription2. Inscription3. Subscripton4. Sigma/transcription5. Name of prescriber

9. How is TB DOTS treatment outcomes classified?

In order to facilitate monitoring, reporting, and cohort analyses, the recommended NTP treatment outcome classification and their definitions are as follows:

CURE = refers to a sputum positive smear positive patient who has completed treatment and is sputum negative in the last month of treatment and on at least one previous occasion. TREATMENT COMPLETED = is the term used for a patient who has completed treatment but does not meet the criteria to be classified as cure or failure. This group includes: (1) a sputum smear-

positive patient initially who has completed treatment without follow-up sputum examinations during the treatment, or with only one negative smear during the treatment, or without sputum in the last month of treatment; and (2) a sputum smear-negative patient who has completed treatment.

DIED = a patient who dies for any reason during the course of treatment FAILURE = refers to a patient who is smear-positive at five months or later during treatment or a sputum smear-negative patient initially before starting treatment and becomes smear-positive during

the treatment. DEFAULTER = is one whose treatment was interrupted for 2 consecutive months or more. TRANSFERRED OUT/IN = a patient who has been transferred to another facility with proper referral/transfer slips for continuation of treatment.

Treatment outcomes for MDRTB are classified as follows:

CURED = patients who completed treatment and are culture negative for the last 12 months of treatment. TREATMENT COMPLETERS = clinically cured but not meeting bacteriological requirement for cure DEFAULTER = patients with 2 or more consecutive months of treatment interruption FAILURE = those with more than 1 positive culture during the past 12 months of treatment, those with 1 of their last culture positives, or those remaining persistently culture positive with treatment

being stopped by the physician. DIED = those who died from any cause at any point during treatment.


Treatment Outcome

Cure Smear (+) becomes smear (-) on the last 2 sputum follow-up exams towards the end of treatment

Treatment completed

Patient has completed treatment but has no proof of cure

Treatment failure Patient remains or becomes smear (+) at > 5 months during treatment

Treatment interrupted (lost)

Treatment interrupted for > 2 months

Treatment stopped & patient is unretrieved

Transfer-out Patients transfers to another reporting unit & treatment outcome is unknown

Died Patient dies for any reason during treatment

(Dr. Faith D. Villanueva’s Lecture)

10. What is MDRTB? How does MDRTB develop? How is it diagnosed? Give the WHO recommendation for the management of MDRTB.

MDRTB is defined by WHO as in vitro resistance to both Isoniazid and Rifampicin.


Multi-drug resistant TB (MDRTB) is defined as the presence of at least 1% of Mycobacterium strains in a bacterial population or culture that are resistant to at least INH and RIF. The practices associated with the occurrence of MDRTB are: failure to predict, identify or adequately address non-adherence to therapy, use of an inadequate initial regimen, use of INH monotherapy

when the patient actually has active disease (not LTBI), and the addition of a single drug to a failing regimen. The most important demographic clues for drug resistance are: being a resident of a large urban, coastal or border community area (in the USA), or from areas of high MDRTB (outside the USA, eg,

Russia), or being HIV-infected (probably reflecting higher proportion of disease resulting from recent transmission). The most important historical clues are prior therapy for TB, and (less so) cavitary lesions. MDRTB is treated with 4 drugs as in usual therapeutic regimens, plus at least additional 2 drugs to which the patient's organism is thought to be susceptible. In patients with culture-confirmed MDRTB, treatment with at least 3 drugs the organism is susceptible to, for at least 12 months after the sputum conversion. Most experts recommend 18 to 24 months total duration of therapy. INH-resistant cases can be treated with RIF, PZA and ETB for 6-9 months, while patients with RIF-resistant TB are treated with INH, PZA and ETB for 9-12 months after sputum cultures become

negative. Consultation with a TB expert and Public Health Department's assistance are mandatory in managing a MDRTB case.

(http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/pulmonary/tb/tb.htm)

Multi-drug Resistant Tuberculosis (MDR–TB)

Although MDR-TB varies widely across regions, it occurs in all geographical settings able to produce data and is therefore a world-wide problem. WHO estimates a global prevalence of one million MDR-TB cases, and some 300,000 -600,000 new cases emerging every year. China, India and the Russian Federation account for 68% of the annual incidence of MDR-TB cases. Of the estimated 300,000-600,000 new cases of MDR-TB, about half of them are new TB patients (primary drug resistance) and the other half have been previously treated (acquired drug

resistance). It is estimated that the average MDR-TB patient infects up to 20 other people in her/his lifetime. A multi-drug resistant organism requires treatment with second-line drugs and falls under WHO diagnostic category IV treatment. While treatment of MDR-TB is more complicated and longer than treatment with first-line drugs, it has been

http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/pulmonary/tb/tb.htm

19

proven cost-effective and very efficacious. Patients who are identified early with MDR-TB can have greater than an 85% chance of cure. The treatment is also feasible in low resource areas. It is extremely important to treat MDR-TB patients both to prevent their deaths and to prevent those who remain infectious from spreading drug-

resistant TB in the community. Good history taking is essential when people present with TB symptoms to determine previous TB treatment, its length and the drugs used. In addition, during history taking the patient may reveal contact with someone who suffered from drug-resistant disease. This patient’s sputum should be cultured for drug sensitivity when risk factors for MDR-TB are detected. In some areas there are no resources for culture and sensitivity testing, but in those settings, a history of inadequate treatment, or past treatment with only one drug, or a past default on treatment,

followed by a return of symptoms, may be considered as reasonable suspicion that one is dealing with MDR-TB. When MDR-TB is confirmed by culture and sensitivity testing, or is suspected based on the patient’s history, the first phase of treatment should include at least four drugs susceptible to the infecting

strain. Often, since susceptibility cannot be guaranteed, five or six drugs are recommended initially (category IV treatment). The first phase, which uses an injectable agent, should be a minimum of 6 months and many programmes extend treatment if the patient has not converted both smear and culture. The entire treatment period is 18-24 months past smear and culture conversion. Patients with MDR-TB take more tablets for a longer period of time, may experience more adverse effects and require increased support to continue treatment and/or to monitor adverse effects. Detecting and controlling adverse effects in a timely manner prevents adherence problems and defaults.

(TB GUIDELINES 2nd Edition → http://www.icn.ch/tb/TB_MDRTB_Guideline.pdf)

11. What is XDRTB? How is XDRTB diagnosed? What is the WHO recommendation for XDRTB management?

Extensively drug-resistant tuberculosis (XDR-TB)

Extensively Drug-Resistant TB (XDR-TB) is a rare type of MDR-TB. XDR-TB is defined as resistance to rifampicin and isoniazid (which is the definition of MDR-TB), in addition to any fluoroquinolone, and at least one of the three following injectable drugs used in anti-TB treatment: capreomycin, kanamycin and amikacin.

Because XDR-TB is resistant to first- and second-line drugs, patients are left with treatment options that are less effective. However, it can be identified early, can be treated and cured in some cases under proper TB control conditions. Successful treatment outcomes depend on the extent of the drug resistance, the severity of the disease and the immune response of the patient. XDR-TB strains have been found in all regions of the world. XDR-TB is rare, but in some places 19% of MDR-TB cases were XDR-TB cases17. Drug-resistant TB occurs as a result of poorly managed TB control programmes and underlines the need for the development of new TB diagnostics, treatments and vaccines, since the current tools

are outdated and insufficient. XDR-TB poses a grave global public health threat, especially in populations with high rates of HIV. The international response to the XDR-TB emergency began with the establishment of a WHO Global Task Force on XDR-TB. The recommendations of this Task Force include18:

Immediate strengthening of TB control in countries along with scaling up universal access to HIV treatment and care. Improved management of XDR-TB suspects in settings of high and low HIV prevalence. Implementation of programmatic management of XDR-TB and treatment design in HIV-negative and positive individuals. Dissemination of revised laboratory XDR-TB definition and laboratory strengthening. Implementation of appropriate infection control measures and protection of health-care workers, with emphasis on settings with high HIV prevalence. Embedding surveillance of XDR-TB in existing drug resistance surveillance systems to increase access to second-line DST. Establishment of an XDR-TB task force on advocacy, communication and social mobilization within existing structures. Resource mobilization: development of a fully budgeted plan for raising the resources and funding required addressing XDR-TB. Research and development related to XDR-TB.

(TB GUIDELINES 2nd Edition → http://www.icn.ch/tb/TB_MDRTB_Guideline.pdf)

http://www.icn.ch/tb/TB_MDRTB_Guideline.pdf

http://www.icn.ch/tb/TB_MDRTB_Guideline.pdf

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