Tuberculosis Flashcards
What is TB
a contagious, debilitating (consuming) bacterial disease
spread by airborne droplets from an infected person
Caused by a bacterium
Mycobacterium tuberculosis
slow growing, difficult to kill, waxy coat
coughing speaking sneezing
Left untreated, one person with tuberculosis
will infect 10-15 people per year
TB has tissue destruction producing holes/cavitiies
Symptoms of pulmonary TB
Early in disease, non-specific and insidious
A cough that will not go away Feeling tired all the time Weight loss Loss of appetite Fever Night sweats
Cough - initially non-productive
later is productive
haemoptysis
~ 35% 5-year mortality pre-antibiotics
Clinical illness directly following infection called
Primary tuberculosis
starts as dry cough, as disease progresses you get haemoptysis- blood comes out
Ghon complex
Initial infection with Mycobacterium tuberculosis in an immunocompetent individual usually occurs in an
upper region of lower lobe of the lung producing a lesion called
a Ghon focus.
Granulomatous involvement of peribronchial and/or hilar lymph nodes is frequent in primary tuberculosis due to lymphangitic spread from the Ghon focus.
The early Ghon focus together with the lymph node lesion constitute the Ghon complex.
These lesions undergo healing and over time usually evolve to fibro-calcific nodules.
Caseous necrotic tissue - constitutes the granulomas in this
gross appearance of a Ghon complex of primary TB.
Most patients with primary tuberculosis are asymptomatic
creamy white are is nectrotic damage- Grohn focus
the lymph node has a cheesy constituency
Why is TB the ‘great imitator’
‘The great imitator’
TB can infect any part of the body, mimicking other diseases
Extra-pulmonary TB
TB is the great imitiator so can not only affect lungs but any part of body- extrapulmnary TB
extrapulmonary TB
only 30% of people exposed get infected w TB
of 30% of those who get affected, only 5% get the active disease
otherwise you become latent infected- you have microscopic lesions in lower lobes of lung/bone marrow/lymph tissue
we know that from mantoux skin test- inject TB antigens and look for T cell reaction- you get a hypersensitivity reaction if person has bee exposed to TB
latent TB can become active TB if you become HIV positive/diabetic/ cancer
Cellular pathology of TB
Cell-mediated delayed type hypersensitivity response (Type IV)
healthy lung: mono layer of cells, alveolar cells, surveillance macrophages etc
right side: someone w pulmonary TB- alveoli obstructed by granuloma .
TB granuloma spherical collection of lymphocytes, macrophages and epithelioid cells with a small area of central caseation necrosis
Epitheliod like cells (activated macrophages)
The centre of the granuloma undergoes a combination of
liquefaction and coagulative necrosis producing caseous necrosis,
which is unique to TB and causes considerable tissue destruction to the host.
tissue necrosis- all the cells recrutied to the granuloma can become necrotic and lysed
Diagnosis of pulmonary TB
Chest X ray
CT
Sputum- - cough or induced
- smear, culture, PCR
Bronchoscopy, lavage, biopsy
make smear of TB ousing ZN stain and take PCR of dna from sputum
look for acid fast bacilli
some sort of mycobacterium
set up in culture
TB treatment overview and history
Started off with just needing 'fresh air' New way – antibiotics 1943 - Selman Waxman - Streptomycin TB rapidly became resistant to 1 drug 10,000,000,000 bacteria mutating DNA
Post- 1973 - 4 drug combination trials – Prof Denny Mitchison
Standard short !! Course - 6 months
Isoniazid (H)
rifampicin (R)
pyrazinamide (Z)
ethambutol (E)
- >95% effective – relapse rates
- prevented resistance
TB is unusual in the fact that it has many more bacteria in your body
can exist in HIGH numbers
driving chronic inflammatory immunopathology
so a single antibiotic drives drug resistance
Intensive vs continuous phase
Intensive phase RHZE for 2 months
Continuation phase RH for 4 months
in some cases, treatment lasts longer
e.g.
- patients with cavities on chest x-ray and positive sputum cultures at 2 months
should have treatment extended to 9 months
- Meningeal TB
intensive phase is with all the 4 drugs for 2 months
then in continuation phase you go with R and H for 4 months
9%% effective treatment
might need to treat people longer for sometimes because bacterial load is higher or tissue penetration not good
eg for bone TB
but general pulmonary TB treatment is 6 month therapy
Treatment rules for TB
Treatment must contain multiple drugs to which organisms are susceptible
Treatment with a single drug or adding a single drug to failing regimen can lead to the development of drug-resistant TB
High bacterial load in TB (unique)
Selection of pre-existing resistant mutants
dropping one drug and adding another just adds to resistance
bacterial load is so high so there will naturally be pre exisiting mutants
TB antibiotics
Isoniazid (INH) – inhibits synthesis of mycolic acid, required for mycobacterial cell wall
Rifampicin (RIF) – inhibits bacterial RNA polymerase
Pyrazinamide (PZA) – binds to the ribosomal protein S1 (RpsA) and inhibitstranslation + other possible mechanisms
Ethambutol (EMB) – inhibits arabinosyl transferases involved in cell wall biosynthesis of arabinogalactans
RIF prevents mRNA
all 4 drugs have dif sites of action- they have a synergistic effect
Cell wall inhibition in TB
and how does isoniazid work
INH acts on mycolic acids on the membrane
EMB acts on arabinogalactan
Isoniazid is a pro drug needs to be activated in bacteria Activated by catalase peroxidase activates enzyme cascade go through pathway eventually inhibits InhA gene blocking synthesis of myocolic acids
how does pyraminazidase work
Conversion of pyrazinamide to its active acid form
pyrazinoic acid by PncA - pryazinamidase (PZase)
enzyme
Pz’ase only active at acid pH
POA - multiple targets – membrane e- potential;
fatty acid synthesis for cell walls
trans-translation
pro drug is only made into its active form as a result of the enzyme pryazinamidase, encoded by PncA
if PcNA gene muates, this pro drug can’t be activated and you become resistant
Why does TB therapy take 6 months
M.tuberculosis drug tolerant persisters
tolerant persisters are not generally antibiotic resistant- they are metabollically tolerant
they are longer turning over cell walls or producing certain enzymes
if the bacteria is not expressing the enzyme
the antibitoic is going to have no effect
In vitro bactericidal activities of Isoniazid vs M.tuberculosis
Log phase Rapid killing followed by: Stationary phase Slow killing, stasis
if the bacteria don’t go down and stay stationary
you need other drugs
LTBI Treatment RegimensIsoniazid or Rifampicin
Purpose : to prevent people with latent TB or exposed to TB
from developing disease
Preferred regimen - isoniazid (INH) daily for 9 months (min. 6 mo)
Rifampicin (RIF) – alternative, if: Cannot tolerate INH Have been exposed to INH-resistant TB RIF should be given daily for 4 months RIF should not be used with certain combinations of anti-retroviral (ARV) therapy
12-dose once-weekly regimen of INH and RPT(long lasting rif)
not if on ARVs or < 12 years old
rifampicin and isoniazid daily for 3-4 months
Why a single drug?
low bacterial load,
low chance of pre-existing mutants
how can we treat latent TB (its non infectious)
isoniazid is good for rapidly killing but not so good at killing resistors
