Antimycotic agents Flashcards
What is the different protein that makes up part of the cell wall in mycobacteria?
Mycolic acid
What is the classic culture result for mycobacterium?
Acid-fast
What does mycobacterium avium complex cause?
Pulmonary and disseminated infections
What does mycobacterium lepra cause?
leprosy
What is mycolic acid?
Lipid in the cell wall of TB
What is the gram stain of mycobacterium? Why?
gram stain poorly or not at all due to mycolic acid structure
Where does TB like to replicate?
macrophages
How fast does TB grow?
Slowly
What is the morphology of TB?
Rod
What infection is closely correlated with TB infection?
HIV
How is TB transmitted?
Respiratory droplets
True or false: most patient infected with TB show some type of symptoms
false-90% are asymptomatic
What are the classic symptoms for TB infection?
Night sweats
Weight loss
Hemoptysis
Fever/chills
In latent TB infection, what are the ssx? CXR results? Sputum smears/cultures? Are they infectious?
Nothing will show positive, except for blood tests (IFN-gamma release)
They are not infectious
What are the diagnostic criteria for active TB?
Positive blood tests
CXR abnormal
sputum
What is the IFN-gamma test for TB?
Expose WBCs of a pt to TB antigen, and see if they produce IFN-gamma. If they do, then positive for infection
What are the obstacles of treating TB?
Slow growing
Toxicity of TB drugs
Resistance
Why are patient not compliant with TB drugs?
Really toxic
Why do you always treat TB with 3-4 different drugs?
Resistance
What is the MOA of rifamycin? Is it bactericidal or bacteriostatic? Why is this drug particularly useful for treating TB?
Inhibits RNA synthesis by targeting bacterial RNA polymerase
Bactericidal
Goes into macrophages
What is the MOA of streptomycin?
Inhibits protein synthesis by targeting the 30s subunit
What is the MOA of isoniazid? Is this bactericidal or bacteriostatic? Why is this drug particularly useful for treating TB?
Inhibit mycolic acid synthesis by forming covalent bond with two proteins
Bactericidal
Can go into macrophages
What is the MOA of Ethambutol?
Inhibit arabinosyl which inhibits cell wall synthesis
What is the MOA of pyrazinamide? This is a synthetic analog to what compound?
Inhibits cell membrane synthesis (somehow?)
Synthetic analog to nicotinamide
What are the bacteria that are a part of the mycobacterium avium complex?
M. Avium
M. intracellulare
What are the ssx of MAC infection? In whom does each type of infection occur?
Pulmonary disease in immunocompetent individuals and disseminated disease in AIDS pts
How are the MAC bacteria acquired?
ingestion of contaminated food and water
What is the preferred regimen for active TB infection? (4 drugs, how long?)
Daily INH, Rifampin, pyrazinamide, and ethionamide x8 weeks
What is involved in the continuation phase of TB infection?
Daily INH and rifampin x18 weeks
What is the treatment for latent TB? What is the alternative
Isoniazid x9 months
Rifampin is alternative
Is isoniazid useful for MAC?
less effective than for TB
What vitamin supplement should pts on isoniazid treatment be placed on? Why?
B6 since isoniazid resembles B6, and will inhibit heme synthesis pathway at AIP synthase
Isoniazid is a prodrug. What converts it to the active form?
Mycobacterial catalase-peroxidase enzyme (Kat G)
True or false: INH is one of the safest and most effective TB treatment we have
True
What are the two ways in which TB develops resistance to INH?
Mutation in the Kat G gene
Overexpression of the inh A protein
Why is a combination drug therapy used in the treatment of TB?
Reduce resistance
Who has more toxic side effects with INH? What are the two chief toxicities associated with INH? Does this affect the efficacy of the drug?
Slow acetylators
Peripheral neuropathy and hepatitis
Does not affect efficacy
True or false: INH, Rifampin, Ethambutol, and pyrazinamide are all readily absorbed from the GI tract
True
What are the two factors that increase the probability that hepatitis will occur with INH treatment?
Age
EtOH dependence
What is the MOA of INH causing peripheral neuropathy?
B6 inhibition
In whom is peripheral neuropathy more likely?
Immunosuppressed
Slow Acetylators
What is are the side effects of rifampin?
n/v
HA, dizziness
Hepatitis
What is the benign side effect of rifampin that pts will worry about?
red-orange color of urine, feces, sweat, tears, and salive
What is the major concern for rifampin, and why should AIDS patients not take it? What is the alternative for them (hint: not INH)?
induces p450 enzymes, which will interfere with HIV drugs
Rifabutin
True or false: pyrazinamide is an alternative drug for INH or rifampin
False-always used in combination with one of these
Pyrazinamide is administered as a prodrug. What activates it?
pyrazinamide enzyme of bacteria and low pH of macrophage lysosome
Why is the fact that pyrazinamide needs a low pH useful for therapy?
Good at killing macrophage engulfed TB
How does resistance to pyrazinamide develop?
Mutation in the pyrazinamide enzyme
What are the two major adverse effects of pyrazinamide? Which is seen in a small percent of pts, and which is seen in nearly all patients?
Hepatotoxic (5% of pts)
Hyperuricemia (nearly all)
Do you ever use pyrazinamide or ethambutol alone? Why or why not?
Nope
resistance
Is ethambutol useful for MAC?
Yep
How is resistance to ethambutol brought about?
Point mutations in the genes encoding arabinosyl transferase
What are the two major adverse effects of ethambutol?
Retrobulbar neuritis (color blindness) Hyperuricemia
When is streptomycin used for TB treatment?
Strains that are resistant to other first-line drugs
What is the major issue with streptomycin as compared to other TB treatments?
Does not penetrate into macrophages
What are the two major side effects with streptomycin?
Ototoxic
Nephrotoxic
What is the MOA of Rifabutin?
inhibits bacterial RNA polymerase (just like Rifampin)
True or false: Rifabutin has lesser activity against MAC organisms than Rifampin
False–much greater activity
When is Rifabutin used instead of Rifampin? Why?
In HIV pts to prevent the induction of p450 enzymes that may interfere with the antiretrovirals
What are the three drugs that are used for a MAC infection
- macrolide
- Rifampin
- Ethambutol
When do you start to prophylax HIV pts for MAC? What drug(s) do you use?
CD4
What are the two forms of Mycobacterium leprae infection? What is the cellular response in each?
- Lepromatous form (Th2 response)
2. Tuberculoid form (Th1 response–they chose wisely)
What are the ssx of the tuberculoid form of M. Leprae infection?
hypopigmented plaque or macules
What are the ssx of the lepromatous form of M. Leprae infection?
Modules and disfiguring skin lesions that develop very slowly
A biopsy of a lesion of the tuberculoid form of M. Leprae infection will show what? Lepromatous form?
Tuberculoid = few, if any bacteria Lepromatous = tons o' bacteria
What is the three drug regimen for leprosy?
Dapsone
Clofazimine
Rifampin
What is the MOA of dapsone?
Structural analog of PABA, that competes for folic acid synthesis in bacteria
What are the major side effects of dapsone?
non-hemolytic anemia if have G6PD
What is the MOA of Clofazimine?
DNA intercalator (maybe)
What are the major side effects of Clofazimine?
Red-brown to black skin discoloration