Tuberculosis Flashcards
What is mycobacterium tuberculosis?
slow-growing aerobic bacterium, relatively resistant to most antibiotics
can be dormant (granulomas)
an acid fast bacteria - after staining with dye, cannot be decolorized by acid wash
made up of lipid rich cell wall containing mycolic acids and is impermeable to many drug
causes both latent and active infections
What is the mycobacterium composed of?
mycolic acid rich, arabinogalactan, peptidoglycan, lipid bilayer
What is the treatment of active Tb infections?
RIPE - combo of rifampin, isoniazid (INH), pyrazinamide, and ethambutol
alternative: rifapentine, INH, pyrazinamide, and moxifloxacin
use a combo of drugs because different ones are needed to combat dividing and dormant forms and to help with resistance
Isoniazid
specific for M. tb
bactericidal
only active against growing M. tb
pro-drug: activated by M. tb KatG protein
What is the MOA of isoniazid?
activation by KatG –> forms adducts with NAD+ and NADP+ –> inhibits enzymes that use NAD+ and NADP+
activated isoniazid inhibits InhA (component of FAS II) and KasA, inhibiting mycolic acid synthesis –> defective cell wall
What is InhA?
a component of FAS II that catalyzes the NADH-dependent reduction of fatty acids bound to acyl carrier protein
isoniazid inhibits this
What is the synthesis of mycolic acid?
FAS I makes 20 carbon precursors (linked to CoA) –> FAS II makes 56 carbon chains (linked to CoA) –> addition of side chain and cyclopropyl groups –> transport out of cell –> linkage to arabinogalactan
Isoniazid resistance
over-expression of InhA (low level of resistance)
mutations in KatG (higher levels of resistance)
What is the metabolism of isoniazid?
acetylation by liver N-acetyltransferase (NAT2)
rate determined genetically - slow or rapid metabolizers
What is the toxicity of isoniazid?
hepatitis is major concern - loss of appetite, N/V, jaundice
peripheral neuropathy
What is the mechanism of isoniazid toxicity?
acetylisoniazid can be converted to acetylhydrazine: CYP2E1 converts acetylhydrazine to hepatotoxic metabolites
NAT2 can acetylate acetylhyrazine to nontoxic diacetylhydrazine
rapid acetylators will rapidly remove acetylhyrazine; slow acetylators or induction of CYP2E1 will lead to more toxic metabolites
Which drug induces CYP2E1?
rifampin induces CYP2E1 –> potentiates isoniazid hepatotoxicity
How do you reverse peripheral neuropathy caused by isoniazid toxicity?
reversed by administering pyridoxine (vitamin B6)
isoniazid resembles pridoxine: isoniazid competitively inhibits pyridoxine phosphokinase (prevents conversion to its active form); INH metabolites directly inactivate pyridoxine species
Pyrazinamide
sterilizing agent against residual intracellular bacteria
structurally similar to nicotinamide
pro-drug: requires conversion to pyrazinoic acid by pncA
What is the activity of pyrazinamide dependent on?
pH!
inactive at neutral pH
activated by low pH - pH<5.5
What is the MOA of pyrazinamide?
inhibition of panD leading to inhibition of coenzyme A synthesis (CoA used for a lot of different processes)
reduces accumulation of CoA precursors after panD step, increases levels of free fatty acids
What does panD do?
panD converts L-aspartate to alanine
pyrazinoic acid (POA) binds to panD, but pyrazinamide (PZA) does not
POA does not bind to mutant panD
What is the binding affinity of panD?
panD binding affinity is low
binding leads to degradation of panD (doesn’t completely inhibit panD, leads to loss of panD)
accumulation in granuloma offsets low binding affinity
Pyrazinamide resistance
primarily due to mutations in pncA
What is the toxicity of pyrazinamide?
joint pain (arthralgia) most common
hepatitis most dangerous - from hydroxylated POA
pyrazinamide most common cause of hepatitis in 4 drug treatment
Ethambutol
bacteriostatic inhibitor of M. tb (doesn’t kill bacterium)
resistance due to over-expression of or mutations in arabinosyl transferase
What is the MOA of ethambutol?
inhibits mycobacterial arabinosyl transferases, which are involved in the polymerization of arabinogalactan –> results in build up of arabinan
inhibits formation of arabinogalactan and liparabinomannan (LAM)
What is ethambutol synergistic with?
rifampin - increases penetration into cell
What is the toxicity of ethambutol?
optic neuritis
Rifampin
reduced length of therapy from 18 to 9 mo
most effective 1st line agent! - high sterilizing activity, rapidly renders patients non-infectious
penetrates most tissues and phagocytic cells
active against growing and stationary cells with low metabolic activity
can kill M. tb inaccessible to many other drugs
What is the MOA of rifampin?
bactericidal; most effective when cell division is occurring
binds to RNA polymerase deep within the DNA/RNA channel - binds far from active site –> blocks the path of the elongating RNA
What is rifapentine?
derivative of rifampin
contains a cyclopentyl ring that makes it more lipophilic –> longer half life
What are the adverse effects of rifampin?
colors urine, tears, and sweat orange
potent inducer of CYP450s
increase in CYP enzymes increases elimination of other drugs metabolized by these enzymes
Fluoroquinolones can replace what?
ethambutol - shorter treatment period of 4 months
moxifloxacin, gatifloxacin, and levofloxacin
What is the MOA of fluoroquinolones?
traps gyrase on DNA as ternary complex –> prevents resolution of supercoiled DNA –> disrupts DNA replication
bactericidal
Which FQ is preferred?
moxifloxacin - better PK
better penetration from plasma to tissues
better at reducing and/or killing M. tb in lesions
What drugs are associated with hepatitis?
isoniazid, pyrazinamide, and rifampin
What drugs are associated with eye damage?
ethambutol - loss of visual acuity and red-green color blindness
What drug is associated with discolored urine?
rifampin
What is the BPaL regimen?
combo therapy: bedaquiline, pretomanid, and linezolid (inhibits protein synthesis)
treats drug-resistant tuberculosis (XDR-TB) and treatment-intolerant or non-responsive multidrug-resistant TB (MDR-TB)
Bedaquiline
oral administration
bactericidal against actively growing and dormant bacilli - has sterilizing activity
What is the MOA of bedaquiline?
inhibits ATP synthase
resistance: mutations in atpE (target enzyme)
What is bedaquiline metabolized by?
CYP3A4 - metabolite is less active
What are the nitroimidazoles?
pretomanid and delamanid
N-O2 group important for activity of the compound
What is the MOA of pretomanid?
prodrug activated by M. tb deazaflavin-dependent nitroreductase (Ddn); inhibition of mycolic acid synthesis
What happens with pretomanid in aerobic conditions?
forms reactive intermediate metabolite that inhibits mycolic acid production
What happens with pretomanid in anaerobic conditions?
generates reactive nitrogen species such as NO; direct poisoning of the respiratory complex –> ATP depletion
increases killing by innate immune system
What are second line agents?
streptomycin - protein synthesis inhibitor
ethionamide
para-aminosalicyclic acid - folate synthesis antagonist
cycloserine - cell wall synthesis inhibitor, analog of D-alanine
capreomycin - peptide protein synthesis inhibitor
