Exam 5 Lecture 5 Flashcards
What does acid fast bacteria (AFB) mean?
Mycobacterium tuberculosis is acid fast.
Is neither gram positive nor gram negative. After staining with a dye (ziehl-neelsen stain) cannot be decolorized by acid wash
WHat type of bacteria is mycobacterium tuberculosis
Obligate aerobes
What is most common tx of active Tb infection? Alternative tx
RIPE- Combination of rifampin, isoniazid (INH), pyrazinamide, and ethambutol
Alternative- Rifapentine, INH, pyrazinamide and moxifloxacin
Why do we treat TB using combination of drugs
Different drugs are needed to combat dividing and dormant forms
Tb rapidly develops resistance to individual drugs
Describe the composition of the mycobacterial cell wall, how it differs from the cell walls
of Gram-negative and Gram-positive bacteria, and how it influences mycobacterial
susceptibility to antibiotics
mycobacterium lipid rich cell wall contains mycolic acids and is impermeable to many drugs
What is isoniazid activated by? static/cidal? What is it specific for
Pro drug that is activated by M. tb KatG protein
bactericidal
Specific for M. tb
Isoniazid MOA
It is activated by KatG
Forms adducts with NAD+ and NADP+
Inhibits enzymes that use NAD+ and NADP+
When isoniazid adducts with NAD and NADP, what enzymes do they inhibit
NAD adduct inhibits INhA and KasA
NADP adduct inhibits
- DHFR
What are InHA and KasA used for
mycolic acid synthesis
What is InhA a component of? WHat does it do?
FAS II (fatty acid synthase II)
It catalyzes the NADH dependent reduction of fatty acids bound to acyl carrier protein (synthesis of mycolic acid)
Summarize MOA of isoniazid? How does resistance to isoniazid occur
Isoniazid activated by KatG, forms adducts with NAD/P, which inhibit InhA, which blocks mycolic acid synthesis. Leads to a defective cell wall.
Resistance can emerge if we overexpress InhA (low level resistance)
Mutation of KatG (high level resiistance)
How is isoniazid metabolized?
acetylation by liver N-acetyltransferase (NAT2)
WHat is the major concern of toxicity for isoniazid
Hepatitis
Peripheral neuropathy is also common
how is peripheral neuropathy caused by isoniazid reversed?
Pyridoxine
How does pyridoxine reverse isoniazid peripheral neuropathy
Isoniazid resembles pyridoxine, so isoniazid competitively inhibits pyridoxine phosphokinase.
(pyridoxine phosphokinase converts pyridoxine to pyridoxal phosphate (active form)
What is the MOA of pyrazinamide? (what is it actuvated by? PH?? What is it converted to?) What does it treat?
It is a prodrug that requires conversion to pyrazinoic acid by pncA. It is inactive at neutral PH and is activated by low PH (<5.5).
It is a sterilizing agent against residual intracellular bacteria (non replicating perisistent bacteria (NRPB)
What does panD do?
Involved in making coenzyme A
pyrazinamide inhibits panD
How is panD inhibited?
pyrazinoic acid (POA) binds o panD, precursor pyrazinamide does not
How does resistance to pyrazinamide happen
Pyrazinoic acid does not bind to mutant panD
toxicity of pyrazinamide (most common and most dangerous)
Joint pain (arthralgia) is most common side effect
Hepatitis is most dangerous side effects
How does pyrazinamide treatment work
Pyrazinamide reduces accumulation of coA precursors after panD step
Increases level of free fatty acid
How does resistance to pyrazinamide occur
Generated easily, but suppressed when used in combo
Primarlly due to mutations in pncA
What is the cause of toxicity of pyrazinamide
Hydroxylated POA
Is ethambutol bacteriostatic or cidal? MOA?
Bacteriostatic
MOA- inhibits mycobacterial arabinosyl transferase
What is arabinosyl transferase involved in? WHat inhibits it? WHat does this inhibition lead to?
It is involved in polymerization of arabinogalactan
Ethambutol is the inhibitor
Results in build up of arabinan
What parts of mycobacteroium do isoniazid and ethambutol inhibit
Ethambutol inhibits arabinogalactan
Isoniazid inhibits mycolic acid
What is ethambutol synergistic with
rifampin
How does resistance occur in ethambutol
is due to over expression of mutations in arabinosyl transferase. Not used alone bc of resistance
What is the most important toxicity in ethambutol
Optic neuritis. Can be irreversible if tx not dx
What is the most effective drug in RIPE? Why?
Rifampin.
Can kill M tb inaccessible to many other drugs (highly sterilizing and rapidly renders pts non infectious)
active against growing and stationary (non dividing cells) with low metabolic activity
Is rifampin cidal or static? WHen is it the most effective
Bactericidal
Most effective when cell division is occuing
Rifampin MOA
binds to RNA polymerase deep within the DNA/RNA channel
(blocks path of elongating RNA (Not chain terminator)
rifampin adverse effects
Colors urine, tears and sweat orange
(can permanently stain contact lenses)
Use of fluoroquinolones in TB
Can be used instead of ethambutol
MOA of fluoroquinolones (moxifloxacin)? Cidal or static?
Traps gyrase on DNA as ternary complex and prevents resolution of supercoiled DNA. Disrupts DNA replication
Bactericidal
preferred fluoroquinolone for tb
Mox- better PK (better penetration from plasma to tissue)
WHat TB drugs have hepatitis toxicity? Eye damage? Orange discoloration of urine? How often to monitor for adverse effects
Hepatitis- isoniazid, pyrazinamide, rifampin
Eye damage- Ethambutol
Orange discoloration- Rifampin
Monitor patients monthly
What do we use to treat extensively drug resistant tb and treatment intolerant or non responsive multi drug resistant tb
BPaL
Bedaquiline
Pretomanid
Linezolid
linezolid MOA
inhibits protein synthesis
Bedaquiline MOA? Cidal or static? ROA?
Oral bactericidal drug
MOA- inhibits ATP synthase
How does resistance occur in bedaquiline
Mutations in atpE
pretomanid MOA
prodrug activated by m.tb deazaflavin dependent nitroreductase (Ddn)
How does pretomanid differ in aerobic and anaerobic conditions
Aerobic- forms reactive intermediate metabolite that inhibits mycolic acid production
Anaerobic (non replicating, persistent bacilli)
- generates reactive nitrogen species such as NO
-Direct poisoning of the respiratory complex (ATP depletion)
- increases killing by innate immune system
When are second line agents for TB considered
-Resistance to first line agent
- Failure of clinical response to 1st line agent
- intolerance to 1st line agent
name second line agents against TB
Streptomycin
Ethionamide
Para aminosalicylic acid
Cycloserine
Capreomycin
What TB drug is especially useful in cerebral meningitis due to strong penetration into the CSF
PZA
What TB drug is avoided in kids
EThambutol
Addition of what drug reduces mortality of TB meningitis
Dexamethasone
Describe the hepatitis isoniazid, pyrazinamide and rifampin cause
Isoniazid causes a slower and less acute hepatotos that progressively gets worse, but PZA and RIF cause a more acute and fulminant hepatotoxicity
What are different tests for TB? describe them (check slide)
- PPD- delayed skin test (within days)
- IGRA (Quantiferon)- Interferon test that is fast working (within hours)
Culture- slow test
sputum smear- we do 3 different tests to discharge patients
which LTBI medication would we typically avoid or be cautious of in pts living with HIV? How soon do we see this interaction?
rifampin (IMPORTANT) and other rifamycin derivatives
Takes a couple of days to a few weeks.
What are the 5 different TB types
Drug susceptible TB
Monoresistant TB
Polyresistant TB
MDR TB
extensively drug resistant TB (XDR)
describe each different type of TB (exam)
Drug susceptible TB- TB strains that are sensitive to the standard 1st line agents
Monoresistant- TB strains that are sensitive to just one anti-TB drug
Polyresistant- TB strains that are resistant to more than one anti TB drug but not INH and RIF
MDR TB- TB strains that are resistant to RIF and INH
Extensively drug resistant TB- TB strains that are resistant to RIF and INH + At least one injectable agent (amikacin, kanamycin or capreomycin) + any of the fluoroquinolones
how is resistance in TB different than other bacteria (exam)
TB has a spontaneous rate of mutation. (They do not transmit mutation to each other the way other bacteria do)
Every 10^-8 will be resistant to rifampin spontaneously. If we have a large enough load, we can calculate this rate
For drug susceptible TB, what are the intensive phase and continous phase? How did guidelines change?
The first two months are the intensive phase where we take 4 drugs (rifapentine+ Isoniazid+ Moxifloxacin+ pyrazinamide) and rifapentine + Isoniazid + Moxifloxacin for 4 2 months (4 month total)
Guideline used to be rifampin + Isoniazid+ethambutol and pyrazinamide as intensive 2 month and rifampin + isoniazid as contionious phase for 4 months
(6 month total)
