Lecture 19: Antitubercular therapies Flashcards
How is TB acquired?
by person-to-person transmission of airborne droplets of organisms from an active case to a susceptible host
Evidence of TB
tiny, fibrocalcific nodule at the site of the infection
Latent vs active TB
Latent tuberculosis: positive tuberculin skin test, no disease (body has antibodies that are keeping infection under control)
Active tuberculosis: clinical signs and symptoms, radiographic evidence, bacteriological evidence
Symptoms of tuberculosis
Pulmonary cavitation (areas of the lung in the centre of a nodule that are gas filled)
Myobacteria dissemination
Presence of bacteria in sputum
Malaise, anorexia, weight loss, fever
Increased sputum, at first mucoid and later purulent (pus)
Extrapulmonary effects (liver, bone marrow, spleen, adrenals, meninges, kidneys, fallopian tubes, epididymis)
Characteristics of M. tuberculosis
Acid fast bacillus
High lipid content of cell wall (stains gram negative)
Slow growing (divides every 16-20 hours)
Resistant to drying
Resistant to most antibiotics (due to high lipid)
Resistant to host killing
Intracellular survival
Components of the M. tuberculosis cell envelope
Capsule-like
Lipids, glycans, peptides, proteins
Mycolic acid (unique to TB)
Arabinogalactan
Peptidoglycans
Cell membrane
How do people become infected with tuberculosis?
TB is spread by inhaled droplet nuclei.
Approximately 10% of inhaled droplet nuclei reach the terminal airways where they can cause infection
Once a droplet lands on something it is no longer infectious
Number of droplet nuclei produced per cough: 3 000, per Sneeze: 1 000 000
Progression of TB
Infected macrophages die and release more TB
TB is carried to lymphatics and beyond, continues to replicate(bacteremia)
8 weeks after initial infection, cell-mediated immunity and delayed hypersensitive test is developed. With cellular immunity, infection can be controlled (latent)
However, if immune defences are lowered, TB can cause re-infection (occurs in 5% of infections)
Latent infection is reactivated and becomes communicable and life threatening
How does reactivation of TB occur? Where does it occur?
Loss of balance between immune system and bacilli
Reactivation most often occurs in the lungs but can occur in lymph nodes, pleural space, kidneys, gut, CNS
The patient is now symptomatic (cough, weight loss, fever, night sweats)
Certain groups of patients are more likely to reactivate than others
Examples of groups that are more likely to experience reactivation of TB
Patients with HIV/AIDS
Patients with transplantations (immunosuppression)
Spending time in hospital
Underweight
Chronic disease
Undeveloped immune system
How is TB treated?
Based on stage: latent or active
Primarily antibiotics
What can lead to treatment failure and drug resistance?
Long duration of drug treatment
Poor adherence
First line drugs for TB therapy
Isoniazid (5mg/kg)
Rifampin (10mg/kg)
Pyrazinamide (25mg/kg)
Ethambutol (15mg/kg)
Mycolic acid - importance, structure
Unique/essential mycobacteria cell wall components
Beta-hydroxy fatty acids with a long -alkyl side chain
Each molecule contains between 60 and 90 carbon atoms
Multi-step synthesis
What is the standard treatment regime for active TB?
Intensive phase (0-8 weeks): Goal is to quickly kill the rapidly dividing organism to control disease and render patient non-infectious and prevent emergence of drug resistance
Continuation phase (2 months to 6): Sterilize the lungs by killing dormant and semi-dormant organisms to prevent relapse, directly observed therapy allows for intermittent therapy
