Antimycobacterials Flashcards
Challenges to kill TB
- Difficult to kill
- vulnerable to cidal drugs only when metabolically active
- small populations are dormant
- Slow growth
- hampers identification/susceptibility test
- Lengthy therapy: compliance and toxicity
- intracellular forms
- chronic disease
- debilitating may go systemic
- becomes well established before symptoms occur
spontaneous resistance to TB requires
multi-drug therapy
-requires cidal drugs to complete the cure
describe the structure of mycobacterium tuberculosis
- cytoplasmic membrane
- cell wall
- outer membrane made up of mycolic acid
-it is able to survive on surfaces for months!!!
List the first line drugs to TB
-Isoniazid
-Rifampin
-Ethambutol
Pyrazinamide
-Sreptomycin
Isoniazid MOA
- cidal for actively growing bacilli
- inhibits synthesis of mycolic acid
- activated by catalse peroxidas (KatG protein)
- targets the enoyl-acyl carrier protein reductase (InhA protein)
resistance to isoniazid
- mutations in KatG prevent drug activation
- mutations in InhA prevent activated drug from binding its target
Isoniazid use
-all patients infected with INH-sensitive strains should receive INH if possible
for treatment of active TB always given in combination (but for latent can be given alone for 9 months)
Explain acetylation polymorphism in INH
there are slow acetlyators and fast acetylators based on N-acetyltransferase genetic polymorphism that impact the half life of INh
adverse effects of Isoniazid
- neurotoxicity esp peripheral neuritis
- significantly improved with pyridoxine (vitamin B6) administration
- hepatotoxicity
Rifampin MOA
- inhibits bacterial RNA synthesis by binding RNA polymerase B
- cidal
Rifampin adverse effects
- hepatotoxicity (short term it doesn’t matter but this is used for months so it is a concern)
- potent inducer of multiple CYPs causing increase metabolism of other drugs
- orange-red color
Ethambutol MOA
- interferes with arabinosyl transferase, blocking cell wall synthesis
- tuberculostatsic (but it doesn’t interfere with the cidal effects of other drugs in fact it weakens the cell barrier enhancing drug entry )
Ethambutol distribution
-Well absorbed and distributed including adequate levels in CSF
Ethambutol adverse effects
- optic neuritis (5-15%)
- not hepatotoxic
Pyrazinamide
- blocks mycolic acid synthesis by inhibiting fatty acid synthase I
- cidal
- used in combination therapy: important component of short-term therapy
- well absorbed, widely distributed: particularly useful for CNS involvement
Pyrazinamide adverse effects
- Hepatic damage
* especially when combined with rifampin
Streptomycin MOA
- aminoglycoside
- binds to several ribosomal sites at the 30S/50S interface. restricts polysome formation (ie stops initiation) and causes mRNA misreading
Streptomycin use
-usually reserved for the most serious forms of TB
Streptomycin adverse effects
- ototoxicity: affects balance and hearing
- nephrotoxicity
explain the multi drug regimines
we use the more toxic drugs for shorter periods of time than the longer drugs
why do we use four or more drugs for a TB infection
known exposure to drug resistant strains
which TB drugs are bactericidal
isoniazid
rifampin
pyrazinamide
List an Atypical mycobacterial infections
MAC=M.avium- intracellulare complex
MAC
M. avium intracellulare complex
-MAC is less fatal than TB, so if you find acid fast bacillus institute an anti- TB regimen until the gaent is identified
Rifabutin
- single agent prophylaxis of M avium intracellulare (MAC) in AIDS patients
- alternate to rifampin for multi drug resistant treatment of MAC or other mycobacteria
RIfabutin adverse effects
- similar to rifampin but less frequent (esp at prohylactic doses)
- drug interactions similar to rifampin, but to a lesser extent
Clarithromycin
- part of a multi-drug regimen for treatment of M. avium-intracellulare in AIDS patients
- also for MAC prophylaxis
- cidal
Leprosy (Hansen’s Disease)
-only specialists should treat leprosy consult National Hansen’s Disease Program, Baton Rouge Lousiana
Dapsone
- structural analog of para-aminobenzoic acid (PABA); inhibits folic acid synthesis
- bacteriostatic
- used in combination with other drugs
- alternative for prophylaxis (and treatment) of Pneumocystis jiroveci (carinii) in AIDSs patients
- metabolism similar to isoniazid, slow and fast acetylators
Dapsone adverse effects
- hemolytic anemia
- methemoglobinemia
Clofazimine
- phenazine dye that binds to DNA, interfering with reproduction and growth
- only used in combination therapy
- adverse: red brown pigmentation of the skin (sputum, urine sweat sclera)
RIfampin
-widely used in combination therapy (eg with dapsone) for leprosy
