Anti-Mycobacterial Therapies - Fan 5/3/16 Flashcards
major mycobacterial disease
tuberculosis
- latent (LTBI) : treated with isoniazid, rifampin, or combo
- active TB : always treated with combo
leprosy
M. avium Complex (MAC) infection
- M. avium, M. intracellulare, M. paratuberculosis
- complication of late stage AIDS and chronic lung disease
anti-TB drugs (US guidelines)
1st line: RIPE
- rifampin (plus derivatives: rifabutin, rifapentin)
- isoniazid
- pyrazinamide
- ethambutol
2nd line
- ethionamide
- p-aminosalicylic acid
- cycloserine
- streptomycin, amikacin/kanamycin, capreomycin
- levofloxalin, moxifloxalin, gatifloxalin
- bedaquilline
2nd line TB drugs
- guidelines
- characteristics
guidelines
- MDR (resistant to rifampin and isoniazid)
- XDR (MDR + resistance to a fluoroquinollone and injectable aminoglycoside)
- cases where first line drugs are effective but toxic
characteristics
- less effective than 1st line
- significant toxic side effects
- expensive
mycobacterial wall features/targets
acyl lipids : targeted by
mycolate : targeted by isoniazid, ethionamide p-aminosalicylic acid (INH, ETA, PAS)
arabinogalactan : targeted by ethambutol (EBM)
lipoarabinomannan : targeted by
drugs targeting macromolecule synthesis
fluoroquinolones: inhibit DNA synth
rifampin: inhibit RNA synth
streptomycin: inhibit protein synth (via 23S)
macrolides: inhibit protein synth (via 30S)
challenges in TB treatment
- dormant or slow-growing intracellular infection
* chronic, asymptomatic infections with slow growing bacteria that can be dormant - Mtb is good at picking up genetic mechs for resistance
- patient and doctor compliance
- issues with lengthy tx regimen, especially if there are side effects
- potential solution: direct observed treatment
- strong, lipid-rich cell wall
* potential solution: drugs targeting cell wall components - coincidence of TB and HIV/AIDS
* need to treat both; be watchful for drug interactions
Mtb mechanisms of resistance
genetic mechanisms
- natural resistance due to chromosomal mutation (not horizontal gene transfer)
biochemical mechanisms
- overexpression of drug target, decreased drug binding, increased drug removal
- deficiency in pro-drug activation (IHN, PZA, PSA)
difference between tx regimen for culture positive and culture negative TB
why multiple drug therapy?
why RIPE?
culture positive: aggressive tx
- RIPE start, potentially taper down
- long period of tx (9mo)
culture negative: less aggressive tx
- RIPE start for 2 months
- RI for 2 months
why use multiple drugs?
much lower chance of bacteria being resistant to BOTH drugs than to one or the other
why RIPE?
no cross resistance indicated!
de facto monotherapy
responsible for the devpt of resistance in patients treated with multiple drugs
can occur due to
- preexisting resistance
- poor distribution of drugs due to fibrotic tissues
- differential targeting of bacterial forms (active vs dormant forms)
INH
isoniazid
- small, water soluble molecule
- bactericidal against intra- and extra-cellular mycobacteria
mechanism
- prodrug, activated by KatG (catalase peroxidase) to IHN-NAD (active) → inhibits mycolic acid synthesis
admin, PK, combo use
- oral: absorbed from GI tract and distributed
- high probability of resistance → always used in combo with others (except prophylaxis or LTBI)
mycolic acid biosynth
role of INH
synthesized in two stages
FAS-I : single polypeptide that synthesize chains from C16-C26 using CoA as carrier
FAS-II : multienzyme system that lengthens FA chains to >C52
INH targets the Fab1 (InhA) unit of FAS-II
- Fab1 carries out last step in FAS-II cycle
- NADH-dependent enoyl ACP reductase
- binds INH-NAD tightly in NADH binding region
INH
adverse rxn
elimination
resistance
adverse rxn
- hepatitis risk
-
peripheral neuropathy (10-20%)
- mild form: sensory abnormality, muscle weakness
- severe form: burning pain, muscle paralysis/wasting, organ/gland dysfx (maldigestion, difficulty breathing, low bp, etc)
WHY?
INH resembles pyridoxine, so subs in for some of those rxns → causes issues
- tx: boost vitB6 in the diet
elimination
metabolism initiated by acetylation by liver-specific N-acetyltransferase
- genetically, there are slow acetylators and fast acetylators → might influence
resistance
- KatG mutations (precludes INH-NAD formation)
- mutation of Fab1 NADH binding pocket
- mutation increasing expression of Fab1
- mutation increasing levels of NADH (outcompetes INH-NAD)
RIF
rifampin
- semi-synthetic antibiotic based on rifamycin (from Streptomyces)
- inhibits RNA synth by messing with bacterial transcription elongation
- bactericidal for Gram+, Gram-, chlamydia, mycobacteria
RIF mechanism of action, resistance
interacts with large beta subunit of bacterial RNA poly → blocks path of growing RNA strand → RNA poly is effectly stuck at promoter region
*doesnt bind human RNA poly! selective for bacteria
resistance occurs via mutation of beta subunit of RNApoly
- also see cross-resistance with other rifamycin derivatives
RIF
use
administration
adverse effects
uses
- bactericidal against fast-growing extracellular, slow-growing intracellular mycobacteria
- effective for leprosy, atypical mycobacterial infection when used with sulfone
admin and PK
- oral admin: well absorbed and distributed
- penetrates CSF if meninges inflamed
- mainly excreted in feces
adverse rxn
- if administered under 2x weekly, flu like symptoms
- induces cytochrome P450s (incl CYP3A) to increase elimination of other drugs
- might need to change the dose of RIF or sub it with other drugs
- harmless purple or red color to urine/tears
