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Flashcards in mycobacterial dz Deck (45)
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1. Describe the unique properties of mycobacteria and how they create special problems for the isolation and identification of these organisms.

Aerobic rod shaped. Slow growing (require 3-6 weeks for primary isolation). Resistant to desiccation (M. tuberculosis is viable after 6-8months in dried sputum) and resistant to disinfectants, but can be killed by UV.


Why is mycobacteria resistant to disinfectants

high lipid content of their cell wall. Clinical samples containing M. tuberculosis are often treated with alkali, which kills most normal flora but not the mycobacteria, prior to culturing.


mycobacterial cell wall

Attached to the peptidoglycan matrix is a polysaccharide (arabinogalactan) that anchors the long chain mycolic acids. Also associated with this basic structure are lipoproteins and glycoproteins. Cell wall is rich in lipids (made of mycolic acids)


What does the tuberculin skin test test for

lipoproteins and glycoproteins attached to the cell wall of TB


What is acid fastness

Hallmark of mycobacteria- The mycolic acids of mycobacteria are long chain lipids of 60-90 carbons, that make the bacteria hardy and very difficult to stain, but once stained resist de-staining with acidified alcohol. Ziehl-Neelson stain stains mycobacteria red and others do not retain the stain.


Which mycobacterial strains can cause human TB

M. tuberculosis, M. africanum, M. bovis, M. pinnipedii, M. microti, and M. canettii. They are all from a common ancestor


What proportion of the world population is infected with TB

1/3 of the world. Most persons infected with M. tuberculosis become tuberculin skin test positive and harbor viable bacteria but show no signs of active disease and are considered latently infected


2. Describe how M. tuberculosis is transmitted and the odds of developing disease.

airborne droplet nuclei (size 1-5 mm) expelled when a person coughs, sneezes, or speaks who has infectious (not latent) TB. Rarely from ingestion. Infected contacts develop a positive delayed-type hypersensitivity reaction to the tuberculin test between 2-10 weeks after initial infection. 5-10% progress to active TB within the first 2 years of infection, another 5% develop active TB within their lifetime.


Who is at increased risk of developing active TB

HIV infected persons with a latent TB infection have a 7-10% chance of developing active TB disease each year. Persons with other medical conditions such as diabetes, end-stage renal disease, and immunosuppressive therapy are also at an increased chance for developing active TB.


forms of TB

Pulmonary, lymphatic, pleural, miliary (disseminated). Infants, HIV positive and immunosuppressed are more likely to get extrapulmonary and miliary forms


3. Describe the development of immunity to M. tuberculosis.

Cell mediated immunity develops at 2-6weeks (TH1). Cell mediated immunity controls infection. Th cells activate macrophages which kill intracellular bacteria. When the macrophages die, bacilli are released and spread to lymph nodes and other tissues/organs. Also IFNgamma and alpha control TB infection.


TB symptoms/ signs

During the initial infection symptoms are absent or produce a mild influenza-like disease. In healthy people, TB lesions will heal and become fibrotic or calcified (visible on CXR). Some mycobacteria may persist within granulomas for decades causing continued antigenic stimulation and possible reactivation later in life. Latent TB can not be spread


4. List the immune factors known to control M. tuberculosis.

Th1 cells (and macrophages), IFNg and IFNa.


TB histology

The bacteria are confined in “tubercles”, granulomas (see figure) consisting of epithelioid cells, giant cells, and lymphocytes. With time the tubercles grow and their centers may become necrotic (caseous necrosis).


Ghon complex

The combination of a (usually single)TB lesion in the lung and in the draining bronchial lymph node


5. Differentiate between primary, latent, and reactivation tuberculosis.

Primary: 5-10% chance in first 2 years post infection. In immunocompromised often spreads to all organs leading to potentially fatal miliary TB. Secondary: aka reactivation. Often associated with impaired immune function (AIDs, measles, corticosteroids, chemo, anti-TNFalpha therapy). Disease manifestations are in large part the result of hypersensitivity to tubercular antigens and are not the result of a specific bacterial toxin


Most common site of TB reactivation and pathogenesis

Apex of the lung (most highly oxygenated), ), but can occur in any tissue harboring latent bacteria from a primary infection. Lesions slowly become necrotic, caseous, and eventually liquefy. Adjacent lesions may coalesce to form larger lesions and eventually break through to the bronchi. Organisms actively grow both intra- and extracellularly, and may reach very high densities in these lesions. The bacteria-laden material is discharged into the bronchi resulting coughing and transmission the bacilli to other susceptible individuals.


6. Describe M. tuberculosis pathogenesis

Intracellular survival- inhaled bacilli are phagocytosed and multiply in alveolar macrophages. M. tuberculosis interferes with membrane controlled trafficking and arrests phagosome maturation at a stage when no harm can be done to the pathogen (marked by prevention of phagosome acidification), while delivery of nutrients by membrane bound vesicles is unimpeded.


How does M. tuberculosis arrest phagosome maturation

PIM: Stimulates fusion between phagosomes and early endosomes ensuring continual nutrient supply to the phagosomal compartment. Man-LAM: Inhibits phagosomal maturation. SapM: protein that cleaves the late endosomal vesicular marker PI3P in the phagosome membrane, which in turn prevents fusion of the M. tuberculosis phagosome with lysosomes


Antimycobacterial mechanisms of activated macrophages

The antimicrobial peptide cathelicidin, that requires vitamin D for its expression in macrophages, kills intracellular M. tuberculosis in human macrophages. The production of NO by activated macrophages is critical for control of M. tuberculosis infection in animal models. Its role in human infection is less clear. Superoxide production does not appear to be important for control.


7. Discuss the primary goal of tuberculosis control.

The primary goal of tuberculosis control is to identify active infectious cases and treat them in order to save the individual and stop transmission to others. Next step is treat latent infections to prevent progression. Finally, vaccination with BCG prevents disseminated forms in children


8. Describe the symptoms of active tuberculosis and two methods for detecting latent infection.

Symptoms of pulmonary TB include cough, chest pain, and hemoptysis. Systemic symptoms of TB include fever, chills, night sweats, appetite loss, weight loss, and fatigue.


8. Describe methods for detecting latent TB infection.

1. Mantoux tuberculin skin test: The primary method for testing but is not used to diagnosis TB because up to 20% of pulmonary TB cases will have a negative skin test and up to 50% of disseminated cases will have a negative test result. 2. Interferon gamma release assays (IGRAs): measure the release of interferon-gamma (IFN-γ) in whole blood in response to stimulation by various antigens.


describe the PPD test and what is considered positive results

A preparation of tubercular protein is injected intradermally under skin. A positive rxn is due to cell mediated immune response to the protein. Positive results after 2-3 days. Low risk: >15mm induration. Intermediate risk: >10mm induration. High risk: >5mm induration


describe the IFN gamma release assay and its advantages over PPD

Incubate pts lymphocytes O/N with M. tuberculosis antigens and measure IGN gamma release. Advantages: less cross-reactivity from vaccination with BCG and non-tuberculosis mycobacteria. They are less susceptible to reader variability. They require only one patient visit to obtain results, and may be more specific


9. Describe a typical antimicrobial regimen for treatment of active M. tuberculosis (drug sensitive).

Isoniazid, rifampin, ethambutol, and pyrazinamide are given for 2 months. Then pyrazinamide is stopped and ethambutol is stopped (when isolate is shown to be drug susceptible). INH and rifampin are continued for an additional 4 months for a total of 6 months. For cases slow to respond, 9 months


describe treatment of latent TB

INH alone for 9 months. Rifampin for 4 months. OR INH plus rifapentine for 3 months (given once weekly)


isoniazid MOA and adverse rxns

Inhibits mycolic acid cell-wall synthesis; specific for mycobacteria and activated by catalase; bactericidal; can cause drug-induced hepatitis.


rifampin MOA and adverse rxns

Inhibits RNA synthesis by binding RNA polymerase; turns body fluids red-orange (which is effective in determining patient compliance); bactericidal; can cause drug-induced hepatitis and hypersensitivity reactions


Pyrazinamide MOA and adverse rxns

Derivative of nicotinic acid, target unknown, requires acidic pH for activity, and is highly specific for M. tuberculosis; slowly bactericidal; can cause arthralgias and drug-induced hepatitis.


ethambutol MOA and adverse rxns

Inhibits arabinogalactan cell wall synthesis and is specific for mycobacteria; bacteriostatic; can cause optic neuritis


TB drug resistance

Due to chromosomal mutations, not by acquiring foreign DNA. Multi drug resistant TB is resistant to at least isoniazid and rifampin. Extensively drug resistant TB is resistant to isoniazid, rifampin, fluoroquinolones and at least one of three injectable ssecond line anti-TB drugs


10. Describe the pros and cons of BCG vaccination.

Cons: Little protection against adult TB. Become tuberculin positive. Pros: prevents or minimizes severity of meningeal and disseminated TB in young children.



HIV-infected are 26-31 times more likely to develop active TB than people without HIV. Disease in HIV-infected and AIDS patients is more likely to be extrapulmonary, involving the lymph nodes, bone marrow, GI tract and CNS and advances rapidly and is often fatal


11. Compare and contrast M. tuberculosis and non-tuberculosis mycobacterial (NTM) infections.

In non-TB mycobacterial infections, Patients exhibit lower respiratory disease similar to tuberculosis (M. kansasii, M. avium-intracellulare, M. abscessus), cervical lymphadenitis (M. avium-intracellulare, M. scrofulaceum), skin and soft tissue infections (M. ulcerans, M. marinum and rapid growers), or disseminated disease in persons infected with HIV. It does not become latent.


Non-tuberculosis mycobacterial transmission

The infection is not transmissible between humans, but is acquired from environmental sources (e.g., soil and water)


non-tuberculosis mycobacterial diagnosis

sx: cough, fatigue, weight loss. Radiograph: nodular or cavitary opacities on CXR or multifocal bronchiectasis with multiple small nodules on CT. Bacteriology: positive culture from 2 separate sputum samples, one bronchial wash/lavage or lung biopsy


12. Describe disease caused by MAC.

Mycobacterium avium complex- comprised of M. avium, M. intracellulare and M. chimaera. Disseminated infection in HIV or immunosuppressed. Pulmonary dz in non-immunocompromised. Cervical lymphadenitis in children. Initial transmission is often GI. Not contagious to general population


13. Describe the definitive treatment for Buruli ulcer in early disease.

Buruli ulcer is caused by M. ulcerans, linked to contaminated water. This bacteria produces a toxin, mycolactone, which induces tissue necrosis leading to ulceration. Treated with surgery early in disease. Rifampin and streptomycin for 8 weeks.


14. Describe how M. leprae is transmitted.

Leprosy is spread from person to person, but the rate of transmission is very low, 1%-2% exposed population develop clinical disease. In lepromatous leprosy, organisms are shed from the nasal septa resulting in transmission. 240 million leprosy germs can be shed in 24 hours through the nose if untreated. Incubation period: 3-5 years.


Which cells does M. leprae infect



15. Compare and contrast the two extreme forms of leprosy in terms of their bacteriological and immunological characteristics.

Lepromatous leprosy: malignant form. Strong Ab response but defect in cell mediated immune response and low/no delayed hypersensitivity to lepromin due to active suppression by bacteria. Results in loss of eyebrows, thickened nares, ears and cheeks. Loss of nasal bone and septa, loss of local sensation. Tuberculoid leprosy: better prognosis, may be self limiting. Active cell mediated response to lepromin and few bacteria in tuberculoid lesion. Blotchy red lesions on face, trunk and extremities with loss of local sensation (more than lepromatous)


diagnosis of leprosy

At least one of following: (1) one or more hypopigmented, anaesthetic skin patches, (2) one or more thickened peripheral nerves, and (3) a positive skin smear. The most accurate way to diagnose leprosy is a tissue biopsy.


leprosy treatment

dapsone, rifampin and clofazimine for multibacillary. Rifampin and dapsone for paucibacillary. However, as is the case for tuberculosis, drug resistance is becoming a serious problem.


What is Potts

TB of spine