Mycobacteria theory 23.gslides

Mycobacteria Dr. Shnyar Hamid Mycobacteria Mycobacteria are aerobic, acid-fast bacilli (rods) (Figure 1). They are neither gram-positive nor gram-negative. Mycobacteria Acid-fast term Retain the carbol fuchsin stain after treatment with an ethanol–hydrochloric acid mixture. The high lipid content (a...

Mycobacteria Dr. Shnyar Hamid Mycobacteria Mycobacteria are aerobic, acid-fast bacilli (rods) (Figure 1). They are neither gram-positive nor gram-negative. Mycobacteria Acid-fast term Retain the carbol fuchsin stain after treatment with an ethanol–hydrochloric acid mixture. The high lipid content (approximately 60%) of their cell wall. The major pathogens are: 1- Mycobacterium tuberculosis, the cause of tuberculosis. Figure 1 Mycobacterium tuberculosis—acid-fast stain. Long red rods of M. tuberculosis are seen on a blue background. 2- Mycobacterium leprae, the cause of leprosy. 3- Atypical mycobacteria, such as Mycobacterium avium-intracellulare complex and Mycobacterium kansasii TABLE 1 Medically Important Mycobacteria Species Growth on Bacteriologic Media Preferred Temperature Source or Mode of In Vivo (°C) Transmission M. tuberculosis Slow (weeks) 37 Respiratory droplets M. bovis Slow (weeks) 37 Milk from infected animals M. leprae None 32 Prolonged close contact Slow (weeks) Slow (weeks) 37 32 Soil and water Water M. avium-intracellulare Slow (weeks) complex 37 Soil and water Atypical mycobacteria1 M. kansasii M. marinum TABLE 2 Clinical Features of Important Mycobacteria Skin Test in Common Use Multiple-Drug Therapy Used Vaccine Available M. tuberculosis Lungs Yes Yes Yes M. avium-intracellul Lungs are No Yes No No Yes No Organism M. leprae Main Site of Infection Skin, nerves Mycobacterium Tuberculosis Disease This organism causes tuberculosis. M. tuberculosis causes more deaths than any other single microbial agent. Each year, it is estimated that 1.7 million people die of tuberculosis and that 9 million new cases occur. Important Properties 1- Mycobacterium tuberculosis grows slowly (i.e., it has a doubling time of 18 hours, in contrast to most bacteria, which can double in number in 1 hour or less). Because growth is so slow, cultures of clinical specimens must be held for 6 to 8 weeks. Mycobacterium tuberculosis can be cultured on bacteriologic media, whereas M. leprae cannot. Media used for its growth: Löwenstein-Jensen medium Important Properties 2- Mycobacterium tuberculosis is an obligate aerobe; it causes disease in highly oxygenated tissues such as: the upper lobe of the lung. 3- The acid-fast property of M. tuberculosis (and other mycobacteria) is attributed to long-chain fatty acids called mycolic acids in the cell wall. Mycobacterial cell wall. LAM, lipoarabinomannan. Important Properties 4- Cord factor is correlated with virulence of the organism. antigenic makeup includes Proteins are the antigens in the tuberculin skin test. A lipid located in the bacterial cell wall is required for pathogenesis in the lung. Important Properties 5- Because of its hydrophobic lipid surface, MTB is unusually resistant to drying, to most common disinfectants, to acids and alkalis. Tubercle bacilli are sensitive to heat. 6- Resistant to dehydration, therefore survives in dried expectorated sputum; this property may be important in its transmission by aerosol. Important Properties 7- Strains of M. tuberculosis resistant to the main antimycobacterial drug, isoniazid, as well as strains resistant to multiple antibiotics called multidrug- resistant (MDR strains), have become a worldwide problem. This resistance is attributed to one or more chromosomal mutations. Transmission & Epidemiology Mycobacterium tuberculosis is transmitted from person to person by respiratory aerosols produced by coughing. The portal of entry: is the respiratory tract, and the initial site of infection is the lung. In tissue, it resides chiefly within reticuloendothelial cells (e.g., macrophages). Transmission & Epidemiology Macrophages kill most of the infecting organisms. Can disseminate to other organs. Primary Reservoir: Humans (main). Some animals, such as cattle, can be infected Transmission & Epidemiology Tuberculosis is almost exclusively a human disease. Mycobacterium bovis also causes tuberculosis in humans. Mycobacterium bovis is found in cow’s milk, which, unless pasteurized, can cause gastrointestinal tuberculosis in humans. Transmission & Epidemiology Most cases of tuberculosis are associated with reactivation in elderly, malnourished men. The risk of infection and disease is highest among people, who have poor housing and poor nutrition. These factors, rather than genetic ones, probably account for the high rate of infection. Pathogenesis Primary tuberculosis, which typically results in a primary lesion (Ghon focus) in the lower lung. Primary tuberculosis can: Heal by fibrosis Lead to progressive lung disease, Cause bacteremia and miliary tuberculosis Or can cause hematogenous dissemination resulting in no immediate disease but with the risk of reactivation in later life. FIGURE 2 Pathogenesis by Mycobacterium tuberculosis. CNS, central nervous system; GI, gastrointestinal. Pathogenesis If the primary infection heals without causing disease, it is called a latent infection. Those who have latent infection, approximately 10% progress to active disease (reactivation) at a later time, whereas 90% remain latent. Pathogenesis Secondary tuberculosis with a cavity in the upper lobes. This can cause disease directly or result in reactivation disease in later life with central nervous system lesions, vertebral osteomyelitis (Pott’s disease), or involvement of other organs. Pathogenesis Mycobacterium tuberculosis produces no exotoxins and does not contain endotoxin in its cell wall. M. tuberculosis produces two proteins that appear to play a role in pathogenesis: 1- One is tuberculosis necrotizing toxin (TNT); resulting in death of the infected macrophage. 2- The other is early secreted antigen-6 (ESAT-6), a protein that reduces the innate immune response by reducing gamma interferon production, thereby enhancing the virulence of the organism. Pathogenesis Lesions are dependent on the presence of the organism and the host response. There are two types of lesions: (1) Exudative lesions, which consist of an acute inflammatory response and occur chiefly in the lungs at the initial site of infection. (2) Granulomatous lesions, which consist of a central area of giant cells containing tubercle bacilli surrounded by a zone of epithelioid cells. These giant cells, called Langhans’ giant cells. Pathogenesis Spread of the organism within the body occurs by two mechanisms: (1) A tubercle can erode into a bronchus, and thereby spread the organism to other parts of the lungs, to the gastrointestinal tract if swallowed, and to other persons if expectorated. (2) It can disseminate via the bloodstream to many internal organs. Immunity & Hypersensitivity After recovery from the primary infection, resistance to the organism is mediated by cellular immunity (i.e., by CD4- positive T cells and macrophages). Circulating antibodies also form, but they play no role in resistance and are not used for diagnostic purposes. Patients deficient in cellular immunity, such as patients with (AIDS), are at much higher risk for disseminated, life-threatening tuberculosis. Clinical Findings The clinical findings are varied Many organs can be involved The lungs are the main site of infection. Symptoms: such as fever, fatigue, night sweats, and weight loss are common. Clinical Findings Note that most (approximately 90%) infections with M. tuberculosis are asymptomatic. Asymptomatic infections, also known as latent infections, can reactivate and cause symptomatic tuberculosis. For example, AIDS patients have a very high rate of reactivation of prior asymptomatic infection and of rapid progression of the disease. Clinical Findings 1- pulmonary tuberculosis, the main findings are cough and hemoptysis. 2- Scrofula is mycobacterial cervical lymphadenitis that presents as swollen, nontender lymph nodes, usually unilaterally. Clinical Findings 3- Erythema nodosum, characterized by tender nodules along the extensor surfaces of the tibia and ulna. Clinical Findings 4- Miliary tuberculosis is characterized by multiple disseminated lesions that resemble millet seeds. Tuberculous meningitis and tuberculous osteomyelitis, especially vertebral osteomyelitis (Pott’s disease), are important disseminated forms. Clinical Findings 5- Gastrointestinal tuberculosis is characterized by abdominal pain and diarrhea accompanied by more generalized symptoms of fever and weight loss. Intestinal obstruction or hemorrhage may occur. 6- Oropharyngeal tuberculosis typically presents as a painless ulcer accompanied by local adenopathy. Clinical Findings 7- Renal tuberculosis, dysuria, hematuria, and pain. The urine contains white blood cells. Laboratory Diagnosis Laboratory Diagnosis 1- Acid-fast staining of sputum or other specimens is the usual initial test For rapid screening purposes. 2- In addition to performing an acid-fast stain, the specimen should be cultured on special media, such as Löwenstein-Jensen agar or Middlebrook agar, for up to 8 weeks. It will not grow on a blood agar plate. Laboratory Diagnosis 3- If growth in the culture occurs, the organism can be identified by biochemical tests. For example, M. tuberculosis produces niacin, whereas almost no other mycobacteria do. It also produces catalase. Laboratory Diagnosis 4- Nucleic acid amplification tests (NAATs) can be used to detect the presence of M. tuberculosis directly in clinical specimens such as sputum. NAATs are available that detect either the ribosomal RNA or the DNA of the organism. These tests are highly specific. Laboratory Diagnosis 5- There are two approaches to the diagnosis of latent infections. A- One is the PPD skin. B- Second test is an interferon-γ release assay (IGRA) A positive skin test result indicates previous infection by the organism but not necessarily active disease. The tuberculin test becomes positive 4 to 6 weeks after infection. Immunization with bacillus Calmette-Guérin (BCG) vaccine can cause a positive test, but the reactions are usually only 5 to 10 mm and tend to decrease with time. People with PPD reactions of 15 mm or more are assumed to be infected with M. tuberculosis even if they have received the BCG vaccine. Laboratory Diagnosis IGRA assay, blood cells from the patient are exposed to antigens from M. tuberculosis, and the amount of interferon-γ released from the cells is measured. The sensitivity and specificity of the IGRA are as good as those of the PPD skin test. Because the antigens used in the test are specific for M. tuberculosis and are not present in BCG, the test is not influenced by whether a person has been previously immunized with the BCG vaccine. 6- chest X-ray Note that the IGRA and PPD tests are positive in both latent disease and in active tuberculosis, so any person with a positive test must be evaluated for the presence of active disease by obtaining a chest X-ray and a sputum sample. Treatment & Resistance Isoniazid (INH), a bactericidal drug Multidrug therapy is used to prevent the emergence of drug- resistant mutants during the long (6- to 9-months) duration of treatment. (Organisms that become resistant to one drug will be inhibited by the other.) Treatment & Resistance Treatment for most patients with pulmonary tuberculosis is with three drugs: INH, rifampin, and pyrazinamide. INH and rifampin are given for 6 months, but pyrazinamide treatment is stopped after 2 months. Treatment & Resistance a fourth drug, ethambutol, is added: 1- In patients who are immunocompromised (e.g., AIDS patients), who have disseminated disease. 2- Or who are likely to have INH-resistant organisms. and all four drugs are given for 9 to 12 months. Treatment & Resistance Although therapy is usually given for months, the patient’s sputum becomes noninfectious within 2 to 3 weeks. Treatment of latent (asymptomatic) infections consists of INH taken for 6 to 9 months or INH plus rifapentine for 3 months. INH is also used in children exposed to patients with symptomatic tuberculosis. Treatment & Resistance Strains of M. tuberculosis resistant to multiple drugs (MDR strains) have emerged, primarily in AIDS patients. The treatment of MDR organisms usually involves the use of four or five drugs, including ciprofloxacin, amikacin, ethionamide, and cycloserine. Treatment & Resistance Bedaquiline was approved for the treatment of MDR strains. It should be used in combination with other drugs, not as monotherapy. Prevention 1- This is attributed to better housing and nutrition, which have improved host resistance. 2- The use of masks and other respiratory isolation procedures to prevent spread to medical personnel is also important. 3- Contact tracing of individuals exposed to patients with active pulmonary disease who are coughing should be done. Prevention 4- Pasteurization of milk and destruction of infected cattle are important in preventing intestinal tuberculosis. 5- BCG vaccine can be used to induce partial resistance to tuberculosis. The vaccine contains a strain of live, attenuated M. bovis called bacillus Calmette-Guérin. Book: -Review of Medical Microbiology & Immunology -Sherris Medical Microbiology