anti-mycobacterial therapies Flashcards
how are mycobacteria different from bacteria?
in cell wall structure :
• enclosed by inner cytoplasmic membrane and a murein cell wall layer
• the outer membrane is thick, asymmetric and highly impermeable due to the presence of mycolic acids
• cell wall of 3 linked macromolecules: 70-90C branched FAs (the mycolic acids) forming the outer lipid layer; linked to carbohydrate middle arabinogalactan; which is linked to the peptidoglycan inner layer.
why is mycobacterial treatment hard?
- infections tend to be chronic ( long treatment)
- bacteria are often intracellular
- bacteria tend to develop resistance to any one drug (must use combination therapy)
first line agents used in combination for TB treatment
isoniazid (INH) rifampin ethambutol pyrazinamide (IREP)
isoniazid
part of IREP to treat TB
o Mechanism: Inhibits mycolic acid synthesis
o bacteriostatic for resting and bactericidal for dividing organisms
o extra- and intracellular levels are similar, therefore it is effective against intracellular mycobacteria
o enters CNS
INH resistance
INH has to be activated by catalase peroxidase enzyme encoded by the KatG gene. A mutation in this gene can easily lead to resistance.
rifampin
part of IREP to treat TB o Mechanism: inhibits the bacterial DNA dependent RNA polymerase o Bactericidal o kills intracellular bacteria as well. o turns body fluids orange-red color
Other uses: prophylaxis of h. infleunzae meningitis and staph infections (endocarditis, osteo-myelitis, nasopharyngeal)
o Induces CYP450 enzymes
why is rifampin significant with HIV patients?
o Drug Interactions: Induces many hepatic CYP450 enzymes reduces the half-life of many drugs
Particularly important with HIV patients, as concentration of protease inhibitors is significantly affected by rifampin
dosing of rifampin
flu like symptoms when given less than 2x/wk so administer more often!
ethambutol
part of ‘irep to treat TB
o Mechanism: Inhibits the synthesis of arabinogalactan. Bacteriostatic.
o Side effects: optic neuritis resulting in decreased visual acuity and loss of differentiating red/green;
which drug of irep causes optic neuritis/loss of visual acuit?
ethambutol
pyrazinamide
o Mechanism: Inhibits mycobacterial FA synthase I gene involved in mycolic acid biosynthesis
o Activated by pyrazinamidase
o Side effects: Hepatotoxicity. Contra indicated in patients with severe liver disease or gout.
mutation that will cause resistance to pyrazinamide?
mutation in pyrazinamidase
MDR-TB
TB that is resistant to isoniazid and rifampin
XDR-TB
TB that is resistant to atleast 2 first line drugs and at least 3 second line drus
second line agents for resistant TB
FACES fluoroquinolones aminosalycilic acid (PAS) cycloserine ethionamide streptomycin
fluoroquinolones that are 2nd line for TB
levofloacin
moxifloxacin
ofloxacin
–antibiotics
streptomycin
2nd line for TB, combine w other drugs
aminoglycoside; does NOT enter cells and kill intracellularly
side effect- ototoxicity and nephrotoxicity
ethionamide
similar to INH, inhibits mycolic acid synthesis
poorly tolerated due to GI issues, metallic taste, and vision/smell issues
aminosalycilic acid
PAS
2nd line for TB; similar to sulfonamide; bacteriostatic
high levels are reached in the urine –> keep urine alkaline to prevent crystalluria
what drug can reach high [] in urine?
how to prevent bad consequence?
PAS (aminosalycilic acid) - 2nd line for TB
keep urine alkaline to prevent crystalluria
cycloserine
2nd Line drug for TB
o Mechanism: Irreversible inhibitor of alanine racemase and D-Ala-D-Ala synthetase which are involved in bacterial cell wall synthesis.
Also a partial agonist at NMDA receptors, leading to significant CNS side-effects.
CNS dysfunctions =(somnolence, headache, tremor, etc.) and psychotic reactions (suicidal tendencies, paranoid reactions, etc.).
cycloserine side effects
a 2nd line for TB
CNS dysfunctions =(somnolence, headache, tremor, etc.) and psychotic reactions (suicidal tendencies, paranoid reactions, etc.).
standard chemo treatment for TB lasts ______________;
_____ for ____months followed by ________ for ____months
6 months
IREP for 2 months
followed by
combo of rifampin and INH for 4 months
using more drugs shortens treatment of TB length
true or false
true
in TB treatment, HIV patients sometimes have issues with which IREP drug?
replacement?
rifampin
rifabutin is the replacement
treatment of TB in kids
Kids not given ethambutol due to side effects – so INH/ RIF/ PZA for 2 months followed by INH/RIF for 4 months.
a single agent is never added to a failed regimen
true or false
true
how to treat MAC (mycobacterium avium complex)
standard anti-microbials have little efficiency over M. avium complex
Clarithromycin or azithromycin (macrolide antibiotics) with ethambutol
hansens disease
• a chronic, infectious disease caused by Mycobacterium leprae.
M. Leprae is intracellular - lives in the cytoplasm of the macrophage.
• Require multi-drug treatment
2 types
o Paucibacillary (PB) leprosy
characterized by 5 or less lesions with absence of organisms on smear.
includes the tuberculoid and borderline lepromatous categories
treatment of PB leprosy
Dapsone + Rifampin
o Multibacillary (MB) leprosy
6 + lesions with visualization of bacilli on smear.
Lepromatous, borderline lepromatous, and midborderline are included in the multibacillary category
treatment of MB leprosy
Dapsone + Rifampin + Clofazimine
dapsone
to treat hansens disease
Mechanism: Same as sulfonamides (inhibits folate synthesis), bacteriostatic
Side effects: Hemolysis, methemoglobinemia, and erythema nodosum leprosum
clofazimine
slow acting, accumulates in tissues (half life 2 months)
o side effects: GI intolerance; red discoloration of the skin (it is a phenazine dye).
what drug causes red coloring of the skin?
clofazimine (for hansens disease)
