Tuberculosis Flashcards
what is tb
Tuberculosis (TB) is an contagious and airborne infectious disease caused by bacteria
TB is curable and preventable
Only a small proportion of those infected will become sick with TB
what bacteria causes TB?
TB is caused by bacteria belonging to the Mycobacterium tuberculosis complex.
Different from Gram-positive and Gram-negative bacteria
Synthesise mycolic acids (exterior wall)
Obligate aerobes
Slow growing with incubation period about 2-10 weeks
Life cycle have different microenvironments that can affect drug susceptibility
explain mycobacterium tuberculosis life cycle
1) Initial infection: a carrier exposes MTB to the air via coughing
2) Host macrophages in the lung phagocytize the pathogen Inflammatory response triggered
3) Bacterial burden is contained inside foamy macrophages
4) Macrophages form the encapsulated vascularised granuloma- Other immune cells are present
5) Granuloma matures
Cells die and caseum develops at the core of the necrotic granuloma (tubercles)
Extracellular bacilli enter their dormant state
6) Granulomas can fuse to the airways of the lungs and burst, releasing the pathogen to spread to new tissue and new hosts
A) host macrophages in the lung attempt to phagocytize the pathogen and transport it across the alveolar epithelium and into the lung. This triggers a proinflammatory response that will recruit other immune cells to form an encapsulated granuloma, which is a typical immune response to a pathogen.
B)At this point, most of the bacterial burden is contained inside what are now considered foamy macrophages which begin to line the outside of the granuloma.
C) When the granuloma is first formed, it is well vascularized and a lot of immune cells are present which bolsters the ability of drugs to reach the infection and the host’s immune system to combat the pathogen.
D) As the granuloma continues to mature against the relentless immune response, the outer wall begins to harden with a thick fibrous capsule, and the inner core is walled-off from the immune cells. Foamy macrophages line the outside of this lesion, cells die and caseum (necrotic zone, calledcaseumdue to its milky appearance) develops at the core, which cuts off the remaining vasculature. At this point, the granuloma is considered necrotic, and the bacilli exist extracellularly in this caseum and can enter their largely dormant state. Necrotic granuloma lesions (also known as tubercles) make drug penetration difficult
E)After years or in cases of immune system compromise, the granulomas will fuse to the airways of the lungs and burst, releasing the pathogen to spread to new tissue and new hosts
Each of these points in the Mtb life cycle have different microenvironments that can affect drug susceptibility. For example, various degrees of vasculature result in lower blood flow, decreased oxygen levels, and pH differences in the intra/extracellular fluids that can affect ionization or activation of drugs, drug targets in Mtb may be turned off, depending on the replication stage (latent vs. actively replicating), and the ability of the drug to penetrate tissues and membranes required to reach the mycobacteria.
who are in the risk group for TB
Healthcare workers or in close contacts of TB patient (especially those with sputum smear-positive disease)
People from countries with a high prevalence of TB
Immunosuppressed (e.g. high-dose steroids)
HIV positive
Immunosuppressed (e.g. high-dose steroids)
People with chronic renal failure or in haemodialysis
Haematological malignancy
Injecting drug users/Alcoholics
what is the sign and symptoms of active pulmonary TB
Cough: >3 weeks; productive
Purulent sputum
Haemoptysis
Weight loss
Malaise
Fever
Night sweats
Symptoms of non-pulmonary TB vary depending on affected organ(s).
what are the clinical signs of active pulmonary TB
- Sputum microscopy/culture
Acid-fast staining of sputum smears (at least 3 samples) - Chest radiography
Non specific
Advanced TB
White/shadowing: bronchopneumonia, lung infiltrations
Primary infection
Transmission
Infection requires inhalation of particles small enough to traverse the upper respiratory defenses and deposit deep in the lung, usually in the subpleural airspaces of the middle or lower lobes. Larger droplets tend to lodge in the more proximal airways and typically do not result in infection. Infection usually begins from a single droplet nucleus, which typically carries few organisms. Perhaps only a single organism may suffice to cause infection in susceptible people, but less susceptible people may require repeated exposure to develop infection.
Pathophysiology
Natural defenses= immune system, usually control or destroy the germs once they are inhaled leaving them inactive. While one-third of the world’s population is infected withMycobacterium tuberculosis, only 5 to 10% of those infected will develop active disease.
To initiate infection,M. tuberculosisbacilli must be ingested by alveolar macrophages. Bacilli that are not killed by the macrophages actually replicate inside them, ultimately killing the host macrophage (with the help of CD8 lymphocytes); inflammatory cells are attracted to the area, causing a focal pneumonitis that coalesces into the characteristic tubercles seen histologically.
Latent TB may become active if body is weakened by other medical problems/damaged immuno system/treatment that reduce immuno defeneces (cancer treatment/ rheumatoid arthritis)
Extra-pulmonary disease
In the early weeks of infection, some infected macrophages migrate to regional lymph nodes (eg, hilar, mediastinal), where they access the bloodstream. Organisms may then spread hematogenously to any part of the body, particularly the apical-posterior portion of the lungs, epiphyses of the long bones, kidneys, vertebral bodies, and meninges. Hematogenous dissemination is less likely in patients with partial immunity due to vaccination or to prior natural infection withM. tuberculosisor environmental mycobacteria.
Extra-pulmonary disease
Infected macrophages access the bloodstream.
Infection is not primarily located in the lungs but in other organs e.g., lymph nodes, pleura, abdomen, genitourinary tract, skin, joints and bones, or meninges
More common in children <4 yr, patients with immunosuppression or HIV and the elderly
what is the first line management of tb
Initial phase, 2 months treatment with:
Isoniazid (H)
Rifampicin (R)
Pyrazinamide (Z)
Ethambutol (E)
Continuation phase, further 4 months treatment with:
Rifampicin
Isoniazid
what is the mechanism of action of isonazid
effects
pharmokenetics
adverse effects
- Inhibition of Biosynthesis of mycolic acids
- Synthesis of cell wall
Mechanism of action:
Inhibits biosynthesis of mycolic acids constituents of mycobacterial cell wall
Prodrug: activated by bacterial catalase
Effects:
Bacteriostatic for resting bacilli
Bactericidal for extracellular dividing microorganisms
Pharmacokinetic
Orally active
Metabolism: by acetylation
Slower acetylators respond well!!
Adverse effects: 5% of patients
Peripheral neuropathy
Autoimmune phenomena and blood disorders: agranulocytosis, anaemia
Hepatotoxicity
what is the mechanism of action of Ethambutol
Inhibition of Arabinoyl Transferase
Synthesis of cell wall
Uncertain
Impairs biosynthesis of bacterial cell wall
Orally active
what is the mechanism of action of Rifampicin
Inhibition of RNA polymerase
Inhibits DNA-dependent RNA polymerase of mycobacteria
Orally active
what is the mechanism of action of Pyrazinamide
Intracellular acidification
Plasma Membrane disruption
Uncertain
M ay involve metabolism of drug within bacteria to produce toxic product
Pro-drug converted to its active form (pyrazinoic acid) by pyrazinamidase
what are the effects of Rifampicin
Bactericidal effect on the three MTB population
MTB populations and environments
1) Open pulmonary cavities: plenty of oxygen, rapid growth, drug resistance develops!
2) Closed lesions in the lung: oxygen starved, slow growing/dormant bacilli, poor blood supply, limited penetration of drug
3) Intracellular: low pH, drugs may be inactive, lack of oxygen, slow/ intermittent growing bacilli
what are the side effects of rifampicin
adverse effect
drug interactions
Side effects:
Causes orange-red coloration of urine and other body fluids (important for soft contact lenses users!)
Adverse effect: rare BUT serious:
Hepatotoxicity
Toxic syndrome
Drug interactions: many!
It induces hepatic metabolising enzymes increasing degradation of warfarin, glucocorticoids, analgesic, oestrogen!
NOTE: in patient using oral contraceptives, alternative family planning advice should be offered
Rapid development of resistance!
what is the effects/ adverse effects and pharmokenetics of ethambutol
Pharmacokinetic
Orally active
Effects: bacteriostatic (selective for mycobacteria)
Adverse effects:
Uncommon
Optic neuritis: changes in colour vision or visual field – usually reversible (check visual acuity before treatment and repeat regularly)
In children use it with care! Why?
