Tuberculosis Flashcards
What are the risk factors of tuberculosis?
Poverty and overcrowding which increases inter patient spread, resulting in the inhalation of aerosolised droplets by coughing, sneezing or talking
Medical risk factors like diabetes, conditions requiring long term high dose CS, immunosuppressant patents,
Homelessness, IV drug users, alcohol misusers
Malnutrition (deficiency of vitamin A and D)
HIV- the single most important factor determining the increased incidence of TB in the last 10 years
HIV weakens the immune system and increases likelihood of infection with TB bascilli
TB is the Leading cause of death among people who are HIV positive (13% of AIDS death worldwide)
What is the epidemiology of tuberculosis?
Kills more people than any other single infectious agent
~1/3 if the worlds population is infected
1/3 of 40million people living with HIV are co infected with TB
Infection rates and risk of TB differ markedly between affluent and poorer areas of the world
Asia has the largest burden of disease
India and china are responsible for 35% of all cases worldwide
3million people die each year from the disease
There are 400 cases per year in NZ
2/3 of cases are pulmonary and 1/3 of cases are extrapulmonary
There is a 16x increased rate in maori than in Europeans
What are the microbiological characteristics of TB?
Aerobic bacilli.
Complexes include M. Tuberculosis, M. Bovis, M. Microti, M africanum.
Predominant pathogen in humans is M. Tuberculosis.
Produces β lactamase enzymes: intrinsic resistance to penicillin.
Acid fastness: resistance to decolourisation by acid. Hence, acid fast bacilli
What is the Pathogenesis of TB?
Primary infection initiated by alveolar implantation of organisms in droplet nuclei which are small enough to reach the alveolar surface (~1-5mm)
Ingestion and inoculation are rarer ways of getting TB infection.
What are the main causative organisms of primary TB infection?
M. Tuberculosis M. Bovis M. Micro tri M. Canetti M. Africanum
What are the main disease stages of TB?
Immediate clearance of organisms
Latent infection
Primary disease
Re activation of disease
What does the progression of TB disease depend on?
The number of bacteria inhaled or ingested
The virulence of bacteria
The cell mediated immune response of the host
What is primary TB infection?
Occurs within first 2-3 years after infection
Accounts for half of TB cases
Caused by inhaled TB bacilli reaching alveoli and infecting alveolar macrophages to induce n immune response with attraction of other inflammatory cells
What is the immune response to primary TB infection?
CD4+ lymphocytes activate macrophages to engulf and kill mycobacteria. This forms a tubercle.
T lymphocytes destroy macrophages which are unable to kill invaders.
Depletion of T lymphocytes in HIV = inadequate defences against M. TB
If macrophages can kill the bacterial the infection is aborted.
If macrophages cannot kill bacteria, the bacteria multiplies within the macrophages.
If the bacteria cannot be contained, the macrophages rupture and release it which is then taken up by other macrophages to continue the process.
What are the two mechanisms of immune evasion exhibited by M. TB?
Inhibition of lysosomes to phagosome fusion
Lopoarabinomamnan
What is inhibition of lysosomes to phagosome fusion?
This prevents the destructive enzymes found in lysosomes from getting to the bacilli captured in hit he phagosomes.
This allows the M. TB to escape into the cytoplasm where it is able to multiple in the macrophage cytoplasm
What is lipoarabinomanan?
This induces immunosuppressive cytokines, blocks macrophage activation, scavenges oxygen and therefore prevents attacks by superoxide anions, hydrogen peroxide and hydroxyl radicals
What are the two ways which describe how is TB eradicated?
cell mediated immunity
delayed type hypersensitivity
What is cell mediated immunity?
Where CD4+ T lymphocytes are presented with M. TB antigen
This stimulates macrophages to become bactericidal via interferonγ to target the mycobacterium and control the infection
What is delayed type hypersensitivity?
This also develops through activation and multiplication of T lymphocytes.
This kills the infected macrophages and release the mycobacterium which is then killed by activated macrophages.
Which hypersensitivity produces a positive TB test?
The delayed type hypersensitivity where T lymphocyte activation and multiplication kills infected macrophages to release the bacterium which can then be eradicated by active macrophages
What are the the possible implications for people who have had primary TB ?
90% have no further clinical manisfestation
5% get progressive primary disease at site of infection leading to meningitis and often to involvement of upper lobes of the lung.
10% develope activation disease which occurs years later
What sorts of patients typically make up the 5% who get progressive primary disease after the initial infection?
Children, elderly or the immunocompromised
What is the usual site of primary TB infection?
The lower lobes
What is progressive primary TB?
This occurs in 5-10% of cases and arises due to an inadequate immune system,
Patient develops both pulmonary and constitutional symptoms
May occur in 50% of HIV patients
What is miliary TB?
Chronic TB infection where original primary infection is spread via lymphatic system.
Immunocompromised patients are more at risk
Treat with INH, rifampacin, ethambutol and other antibiotics
What is latent TB infection?
Patient has TB but infection is not clinically apparent.
No active disease due to presence of live, dormant and non-reproducing M. TB
Disease may occur if host’s immune defences are impaired.
Chest X-ray either normal or trivial/stable evidence of past TB
5% of individuals with latent TB develop active disease within 2 years
Another 5% develop after 2 years
What is post primary infection?
This occurs if the individual becomes reinfected or the primary disease is reactivated
What is inactive TB?
Chest X-rat is not trivial
Patients have annual risk of developing active disease at least 2.5x greater than patients with latent TB
Patient is likely to have more dominant TB organisms than a patient with Mantoux conversion and a normal chest X-ray
How is pulmonary TB clinically presented?
Persistent productive cough (>2 weeks)
Pleuritic chest pain
Shortness of breath
Haemoptysis (coughing up blood)
X-ray shows apical (upper lobe) consolidation + cavity formation
Pulmonary cavity favours bacterial multiplication to very high levels
Patients usually sputum smear positive and highly infectious
How is CNS clinically presented?
Most serious clinical manisfestation
Results in meningitis or space occupying lesions of the brain.
Meningitis usually presents as headache, neck stiffness + fever
Alteration in mental status is common.
Cranial nerve palsies may occur
Severe form of sudden onset of meningitis may occur with rapid progression to coma
What is different about clinical presentations of TB in HIV patients?
Usually prevents atypically.
HIV patients:
Less likely to have Positive skin tests, cavitary lesions or fever
Higher incidence of extrapulmonary TB
More likely to present with progressive primary disease
What is different about the clinical presentations of TB in elderly patients?
TB in elderly is easily confused with other respiratory diseases
TB in elderly is less likely to present in skin tests, fevers, night sweats, sputum production or haemoptysis
Whatis the preliminary diagnosis of TB based on?
Patient symptoms and signs
Tuberculin reaction
Radiographic appearance
What are the clinical tests for TB?
Mantoux test
Interferon γ release assay test
What is the Mantoux test?
Individuals in whom TB is suspected are given 0.1mL of 100units/ml interdermal tuberculin purified protein derivative injection.
This causes a hypersensitivity reaction in patients exposed to TB, BCG and other mycobacteria as they will have the antibody against it.
After 48-72 hours, result is measured based on the size of the welt formed on the skin.
How is latent TB interpreted using the Mantoux test?
Size of the welt is correlated with future risk of developing TB
How is recent TB infection interpreted using the Mantoux test?
Shown by the conversion of the Mantoux from negative to positive due to infection non with TB or non TB mycobacteria which includes the BCG vaccination
What are the limitations of the Mantoux test?
Time consuming
Requires great skill to administer
Has poor positive predictive value for current active disease as there is no correlation between size of welt and likelihood of active disease.
Diagnosis of disease depends on isolation of organism
HIV/aids, and other immunosuppressive illnesses can give false negative Mantoux results
What is considered a positive result for the Mantoux test?
If the size of the welt is >/=10mm for normal patient
Or >/=5 mm for immunosuppressed patients e.g. On prednisone etc
What is the interferon γ release assay test?
3 test tubes are used
One is a nil tube which acts as the control
One is the nitogen tube and contains phytothemagglutinin which acts as the positive control
One is the TB antigen coated tube which is the test tube.
Blood from the infected patient is added to each tube.
An immune response is triggered if patient is infected, releasing interferon γ from the T cells indicating tuberculosis
What is the advantage of the interferon γ release assay test?
It is moire specific than the Mantoux test
What are the desired outcomes of TB?
TB is a Notifiable disease. As stated by the TB act 1948 a medical officer needs to be notified to identify the source case and educated contacts about TB in order to rapidly identify new cases of TB.
Also requires isolation of patient to prevent spread
Collection of appropriate samples for sears and cultures
Prompt resolution of signs and symptoms of disease after initiation of treatment
Achievement of non infectious state in order to stop the isolation
Promote adherence to treatment
Cure patient ASAP usually with at least 6 months treatment
What is the aim of pharmacological treatment of TB?
Reduce bacterial population as rapidly as possible and prevent the emergence of drug resistant bacteria.
What is the fundamental treatment principle with TB?
A single drug should never be attempted
A single drug should never be added to a failing regimen
What are the first line drugs for TB treatment?
Rifampicin Isoniazid Pyrazinamide Ethambutol Streptomycin
What are the second line drugs for TB treatment?
Aminoglycosides (amikacin, streptomycin)
Quinolones (ciprofloxacin)
Macrolides (clarithromycin, azithromycin)
Rifabutin (structurally related to rifampicin)
What is rifampicin?
Bactericidal drug that should be given on an empty stomach
What is the mechanisms of rifampicin?
Inhibits DNA dependent RNA polymerase in bacterial cells by binding to its β subunit to prevent transcription to RNA and subsequent translation to protein
What is a benefit of the lipophilic nature of rifampacin?
Makes it a good candidate to treat meningitis forms of TB as this requires distribution of the drug to the CNS and penetration through the bbb.
A lipophilic drug gains access to the bbb easier
When would rifabutin be used?
It is a less potent enzyme inhibitor, it is better tolerated by HIV patients and their multi drug therapy.
What are the adverse effects of rifabutin?
Hepatitis Cutaneous reactions like flushing, rash, redness GI reactions Flu like symptoms Staining of secretions Thrombocytopenia
What is isoniazid?
Highly specific, readily absorbed drug and should be taken on an empty stomach
Why is acetylator status important in TB?
Isoniazid is metabolised by n acetyl transferase, so patients known to be fast acetylators may require a higher dose
Patients known to be slow acetylators require close monitoring
What is a significant side effect with isoniazid?
LFTs will rise within the first weeks, isoniazid can cause peripheral neuropathy (often dose related) need to co administer pyridoxine (vitamin B6)
Other side effects include Hepatitis, cutaneous reactions, Hypersensitivity Peripheral neuropathy
What is the mechanism of isoniazid?
Inhibits synthesis of my colic acid required for mycobacterial cell wall synthesis
Why is isoniazid co administered with pyroxidine?
The main adverse effect from isoniazid use is peripheral neuropathy
This mechanisms involves inhibition of pyridoxine activity which causes a decreased production of several neurotransmitters including dopamine, noradrenaline, serotonin and GABA
However this can be prevented by adding pyridoxine (vitamin B6) to the regimen.
Avoid high doses of pyridoxine as this may interfere with antibacterial action
What is pyrazinamide?
Largely bacteriostatic drug but can be bactericidal on actively TB bacteria
How does pyrazinamide work?
Acts as a substrate for the pyrazinamidase enzyme in M. TB.
This gets converted into pyrazinoic acid in acidic conditions.
Accumulation of pyrazinoic acid disrupts the membrane potential, interfering with energy production which is necessary for the survival of M. TB at an acidic site of action
What are the adverse effects of pyrazinamide?
Anorexia Nausea Vomiting Hepatitis Arthralgia (pain in a joint) Hyperuricaemia Cutaneous hypersensitivity
What is ethambutol?
Drug which is bacteriostatic against actively growing TB bacilli
When is ethambutol used?
If isoniazid resistance is suspected or if patient has been in a high risk TB country
How does ethambutol work?
Obstructing the formation of the cell wall by inhibiting the arabinosyl transferase enzyme and hence, the production of arabinogalactan. This prevents my colic acids from attaching onto the arabinogalactan residues to form the mycolyl-arabinogalactan peptidoglycan complex in the cell wall.
The result is increased permeability of the cell wall.
What are the adverse effects of ethambutol?
Retrobulbar neuritis (changes in eye vision, see green) Arthralgia
What is streptomycin?
Bactericidal antibiotic.
This is given as IM to reduce drug resistance
How does streptomycin work?
Binds to 30S ribosome subunit and interferes with binding of formyl-methionyl-tRNA to the 30S subunit
Leads to inhibition of protein synthesis and death of microbial cells
What are the adverse effects of streptomycin?
Vestibular ototoxicity (nausea, vomiting, vertigo),
paraesthesia (numbness) of face
Rash
What is rifinah?
Combination pill of isoniazid and rifampicin (2 tablets/day)
Reduces risk of patients inadvertently receiving monotherapy for TB with assoc. risks of resistances
Aids compliance
Evidence suggests incidence of side effects are lower
Why are 6 month regimens of rifampacin, isoniazid, pyrazinamide and sometimes, ethambutol necessary?
TB bacteria grow relatively slowly and dormant bacteria only divide when threatened by antibiotic therapy so 6 month treatment regimens are necessary to ensure all active and dormant organisms are killed
What are the two main phases of TB treatment?
Initial phase- bacterialcidal phase
Continuous phase- sterilisation phase
What is require in the initial or bactericidal phase?
At least 3 drugs used concurrently for 2 months (usually Rifampacin, isoniazid and pyrazinamide) or rifampacin, ethambutol and pyrazinamide if isoniazid resistance is suspected
Or all 4 if patient has been suspected to have been in a high risk country
Treatment should be continued until two consecutive smear results come back negative even if this exceeds 2 months
What happens in the continuous or sterilisation phase of TB treatment?
The treatment is continued for a further 4 months, usually with isoniazid and rifampacin
Longer treatment is necessary with meningitis and resistant organisms
When should a smear test be done in the TB treatment regime?
Once every week or twice weekly.
If patient has 2 negatives in a row, then the treatment is good.
If the smear test comes back as positive, drug susceptibility tests need to be conducted.
When is streptomycin used?
It may be used in the initial phase of treatment if resistance to isoniazid has been established before therapy has been commenced
What is the recommended dosage for standard 6 month treatment of TB?
Rifampacin for 6 months:
Adult 50kg: 600mg daily
Child 15mg/kg daily (max 450mg if under 50kg, max 600mg if over 50kg)
Isoniazid for 6 months
Adult 300mg daily, child 10mg/kg daily (300mg max)
Pyrazinamide for 2 months initial phase
Adult. 50kg: 2g daily
Child. 35mg/kg daily (max 1.5g daily if under 50kg, max 2g daily if over 50kg)
Ethambutol for 2 months initial phase
Adult 15mg/kg daily
Child 20mg/kg daily
Which TB drug cannot be used in pregnancy?
Streptomycin
Can the standard TB treatment regimen be used in breastfeeding?
Yes
What is dot?
Direct observational therapy Where health care workers watch patients swallow the medication for all doses during the course of TB treatment to ensure that patient optimises therapy via checking they are taking: -the correct drug -the correct dose - at the correct time. This prevents resistance.
When should dot therapy be used?
When there is resistance to rifampicin, Multi drug resistance Relapse/reactivation Clear inability to self medicate Poor adherence despite close monitoring
What is the largest cause of treatment failure in TB?
Non adherence by the patient
What are the main reasons for non adherence by the patient?
They feel better and do not appreciate the need to continue with medication
They have received a lack of clarity of instructions
Adverse effects of the drugs
Increased number of tablets to take
What is primary drug resistance and secondary drug resistance ?
Primary: organisms transmitted have existing resistance and continue to develop mutations spontaneous
Secondary: resistance develops on medication
Can TB be cured?
Yes, provided that an adequate treatment regimen is prescribed and the patient complies to it.
How can patient adherence be improved?
Dispense OD using as few tablets as possible.
Advise rifampacin and isoniazid to be taken on an empty stomach, 1 hour before food generally before breakfast (absorbed better)
Cue the tablet taking to regular activity such as brushing teeth
Use of combination preparations
What factors should be considered regarding patient education of TB?
Offer written instruction to support verbal counselling
Emphasise disease is curable but requires months of treatment and compliance
Warn and explain the side effects and when to refer to health professionals
Offer instructions in other languages, pictorial material and dosage sheets
What are the main counselling points for patients with TB?
Rifampacin causes harmless discolourisarion or urine and other bodily fluids like sweat and tears
The staining of soft contacts by tears is permanent- warn patient
Should use other non hormonal type contraception for the duration of rifampacin treatment and for 8 weeks afterwards
Stop medication and report to doctor if there are any changes in vision e.g. Reduction in visual activity or changes to colour vision. This may be reversible upon discontinuation, but may also be permanent if the medication is not stopped.
