TB & TB Therapy Flashcards
facultative intracellular bacillus, acid-fast pathogen that can cause chronic pneumonia and tuberculosis
Mycobacterium tuberculosis
- transmitted through aerosols
Mycobacterium tuberculosis is facultative in what cell?
macrophages
Examples of facultative intracellular pathogens
- Mycobacterium tuberculosis
2. Legionella
Examples of obligate intracellular pathogen
Chlamydia
Why are antibodies not very helpful for intracellular pathogens?
Drugs must penetrate into cells to be effective; most antibodies can prevent infections though.
What plays a major role in the clearance of intracellular pathogens?
cell-mediated adaptive immune responses
Special characteristics of mycobacterium membranes
- Has peptidoglycan but has mycolic acid in outer membrane (neither gram - or +)
- No LPS
What stain is used for mycobacterium?
acid fast stains
- Ziehl-Neelsen
- Fluorescent Auramine-Rhodamin
Why is TB often undiagnosed in primary TB phase?
It takes about 6-8 weeks after exposure to mycobacterium for the PPD skin test to be positive; PPD skin test will be false negative if tested too early.
Studies suggest that some people can clear M.tuberculosis even after exposure because of
the clearance by their innate immune mechanism (still unclear why)
People with _______ have the highest risk for developing active TB
HIV
*TB-HIV Syndemic”
Why is HIV the strongest risk factor developing active TB?
Hastens progression from primary/latent TB infection to disease
*(TB accelerates the progression of HIV as well)
TB can be harder to diagnose in HIV infected individuals (True or False)
True (if you already have a depressed immune system, you won’t respond to the skin test as well)
People with HIV and latent TB have a 10% chance of reactivation EVERY year (True or False)
True
Long-lasting bad cough, Hemoptysis, Chest pain, Weight loss, Fever, and Night sweats are symptoms of
active TB
What causes the symptoms of active TB
the immune response (cytokines such as IL-1 and TNF-a, macrophages and T cells)
What can spontaneously occur in 6 months of TB?
spontaneous healing
How does TB survive in macrophages?
Arrest phagosome maturation (doesn’t get acidic enough to kill it)
TB-infected macrophages have what histological appearance?
foamy appearance due to lipid accumulation
Protection against TB is highly dependent on
TH1 mediated (CD4 and CD8) response
TB-infected macrophages induce TH1 response via
IL-12
CD4 and CD8 cells make what cytokine to activate infected macrophages, leading to oxygen/nitrogen radicals being produced and lysosome fusion
IFN-gamma
The end-product of TH1 immune response to TB
Formation of a multi-cellular granuloma that walls off the infection (making it not infectious)
What structure denotes latent TB infection?
granuloma (mycobacterium adopt a non-replication persistent states to survive in granulomas)
Reactivation of latent TB means
Granulomas has deteriorated and M. tuberculosis is reactivated, triggering overly robust T-cell response leading to lung damage.
Reactivation TB disease is highly
infectious
How does TB react in HIV patients?
primary infection is not controlled, so dissemination occurs throughout lungs (milliary TB)
miliary TB appears like _____ on CXR
millet seeds
Diagnostic tests for ACTIVE TB
- Acid fast bacillus (AFB) staining of sputum
- Culture bacilli from sputum on lowenstein-jensen agar
- Xpert MTB/RIF (allows detection of mycobacterium & rifampicin resistance)
- 3 consecutive sputum samples are needed
- culture takes weeks to grow in vitro
Which test is suggested by the WHO for initial diagnostic for people suggested of having MDR TB or HIV co-infection
Xpert MTB/RIF test (2 hour PCR test)
Diagnostic tests for TB exposure & complications
- PPD (aka TST) skin test
- delayed-type hypersensitivity response
- false + in ppl with BCG vaccine (M. bovis)
- doesn’t work in HIV patients - IGRA
- measures IFN-gamma produced by T-cells
- no BCG cross-reaction
- doesn’t work in HIV patients
MDR vs. XDR vs. TDR TB (what do they mean)
MDR: Multi-drug resistance
XDR: Extensive drug resistance
TDR: Total drug resistance
Best method to ensure patient compliance with TB medication
DOTS (Directly Observed Treatment Short Course)
Challenges of TB drugs are
- Access to M.tuberculosis in granulomas
2. efficacy on non-replicating M.tuberculosis that are in limited environments (nutrient-limited, hypoxic, acidic)
Airborne precautions of TB
- Clean hands & wear PPE to protect against small droplets that remain airborne for hours
- Rooms with negative pressure (one way air; no recirculation)
What is the vaccine against m.tuberculosis?
BCG (live attenuated M. bovis)
- not used in the US
Examples of Acid-Fast mycobacterium besides TB
M.bovis
M. avium complex
M.leprae (causes leprosy)
other NTMs (aka atypical mycobacteria)
What are NTMs/atypical mycobacteria?
M. marinum
M. fortuitum
M. abscessus
Describe M. avium complex
- found in water supplies
- form biofilms
- causes pulmonary/disseminated diseases
- more common in HIV patients
What 2 forms of leprosy can be caused by M. leprae?
- Tuberculoid (Th1 response)
- deformity due to nerve damage - Lepromatous (Th2 response)
- Active, nodulous
What leprosy form is infectious?
Lepromatous (Th2 response)
What is another name for leprosy?
Hansen disease
Both forms of leprosy are treatable with multidrug therapy (True or False)
True
acid-fast bacilli; normal inhabitants of soil and water; more common in southern and midwestern US; associated with Lady windermere syndrome (slender, older women); difficult to treat
NTM
Why are NTMs difficult to treat?
TB drugs don’t work
Describe M. abscessus?
- Frequent in bronchiectasis, COPD, CF patients
- Forms biofilms
- causes chronic lung infection or skin/soft tissue infections
- intrinsically resistant to drugs (poor outcome)
NTM that is fast growing and recently associated with nail salons; causes bright red skin lesions
M. fortuitum
First line drugs for TB (5 total)
Isoniazid
Ethambutol
Rifampicin/Rifampin, Rifabutin
Pyrazinamide
What is WHO-approved TB therapy?
8 weeks of intensive phase (4 drug-combination) followed by 18 weeks of continuation phase (2 drug-combination) = total of 26 weeks
MDR TB is defined as being resistant to what drugs?
Isoniazid
Rifampicin
XDR TB is defined as being resistant to what drugs?
Isoniazid
Rifampicin
2 classes of 2nd-line
TDR TB is defined as being resistant to what drugs?
Isoniazid
Rifampicin
2 classes of 2nd-line
Others
Second line drugs for TB (10 total)
- -Manids
- Cycloserine
- -Mycins (+Amikacin)
- Linezolid
- -Floxacins
- Bedaquiline
Drugs that blocks the synthesis of mycolic acid
1st line: Isoniazid
2nd line: -Manids
MoA of Isoniazid
Isoniazid gets converted into its active form by bacterial KatG enzyme. The active form inhibits bacterial InhA enzyme that produces mycolic acid.
MoR (Mechanism of resistance) against Isoniazid
Mutations in KatG and InhA enzymes confer resistance
Toxicities of Isoniazid
- Hepatotoxicity (inc. w/age but 3% overall)
- associated with NAT 2 acetylation
- associated with CYP2E1 enzyme - Peripheral Neuropathy
- associated with Vitamin B6 deficiency
Explain association between NAT2 acetylation and hepatotoxicity
More NAT 2 acetylation = fast acetylators (less prone to toxicity)
Lower NAT 2 acetylation = slow acetylators (more toxic metabolites)
- NAT 2 polymporphisms differ among races
- 50% of Americans are slow acetylators
With Isoniazid, ethanol can promote what enzyme, causing more toxic metabolites and worse hepatotoxicity
CYP2E1
Since _____ is similar to Isoniazid in structure, its production decreases.
Vitamin B6
- vitamin B6 supplements are taken with Isoniazid
What drug has advantages over older drugs because it has no significant CYP-associated drug interactions?
Delamanid
Drugs that blocks the synthesis of galactan portion of the cell wall
1st line: Ethambutol
2nd line: Cycloserine
MoA of Ethambutol and Cycloserine
The drugs inhibit arabinosyl-transferase enzyme necessary to make galactan in cell wall
MoR of Ethambutol and Cycloserine
Mutations in arabinosyl-transferase confer resistance
Toxicities of Ethambutol
Optic neuritis (inflammation of optic nerve) that can cause R-G color blindness
- reversible
Toxicities of Cycloserine
Various neurologic symptoms
- Don’t Memorize (headache, vertigo, drowsiness, etc)
Drug that is a RNA Polymerase inhibitor
Rifampin, Rifabutin (both 1st line)
MoR of Rifampin and Rifabutin
Mutations in RNA polymerase confer resistance
Toxicities of Rifampin/Rifabutin
- Orange coloration of skin, urine, feces, saliva, tears
- Nephrotoxicity (inflammation of nephron tubules)
- Drug Interactions
- Induces CYP enzyme therefore decreases HIV drug effects
Drug that converts into its negative form by PZase enzyme and uses pH trapping to disrupt cell energetics
Pyrazinamide (1st line)
MoR of Pyrazinamide
Mutations in PZase
Toxicities of Pyrazinamide
- Hepatotoxicity
2. Pregnancy risk category C (still can be used)
Drugs that are protein synthesis inhibitors
- Aminoglycosides
- Mycins (+Amikacin) - Oxazolidenone
- Linezolid
*they are 2nd lines
Drugs that are DNA synthesis inhibitors
Fluoroquinolones (-floxacins)
- 2nd line
Drug that inhibits ATP synthase
Bedaquiline (2nd line)
Toxicity of Bedaquiline
Drug interactions
- co-administration with rifampin reduces HIV drug effects by inducing CYP enzyme