Anti-TB Flashcards
innate resistance TB
- highly complex
- impermeable mycobacterium wall
- efflux transporters
- intracellular location of infection
- slow proliferation, dormancy
Acquired resistance TB
- spontaneous mutations (therapy long term)
- each mutation confers resistance to one drug
mutation frequency in TB
1 in 10^6
The chance of one bacterium developing resistance to 2 drugs is
1 in 10^12
What reduces incidence of relapse in TB?
multi drug therapy
- some drugs are effective against active bacilli other against dormant
Why dose multi drug anti-TB therapy not lead to superinfection?
- standard drugs highly selective for TB
MDR to TB due to what? and what drugs?
Isoniazid + rifampin
- inadequate drug therapy
- lack of compliance
Extensive drug resistance (XDR)
MDR + fluoroquinolone and aminoglycosides
INH MOA
- inhibit synthesis of mycolic acid
- prodrug activated by KatG
INH bactericidal or bacteriostatic?
bactericidal –> active
bacteriostatic –> quiescent
INH active against extracellular or intracellular?
both!
INH resistance
mutation or deletion of katG gene
INH in host liver
NAT2 –> inactive
INH in bacillus
KatG –> INH radical –> active form
INH metabolism
- inactivated by liver by acetylation
- N-acetyl-INH excreted by kidneys
Which drug has slow or rapid acetylators?
INH
T/F acetylator status effects dosing and therapeutic outcomes?
false!
dose not
INH use
Latent: alone
Active: combo
Adverse reaction INH
- peripheral neuropathy
- hepatotoxicity
- hepatitis
peripheral neuropathy in INH
- caused by drug induced deficiency in pyridoxine
peripheral neuropathy in INH can be reduced by
taking B6
BBW INH
hepatitis: fatal hepatic necrosis
Rifampin MOA
inhibit DNA dependent RNA polymerase
Rifampin bacteriostatic or bactericidal?
bactericidal
Rifampin for intracellular or extracellular organisms?
intracellular
Rifampin resistance
- mutation in rpoB gene for B subunit
- not used for mono therapy!
Rifampin use
active: combo with INH
MAC: combo with macrolide
serious deep seated staph infection: combo with other antibiotics
Rifampin adverse reactions
- hepatotoxicity: cholestatic jaundice
- discoloration of body fluids (red/orange)
- strong induction of CYP
Which drug can increase elimination of contraceptives, warfarin and hIV drugs?
rifampin
Ethambutol MOA
inhibit mycobacterial arabinosyl transferase
Ethambutol bacteriostatic or bactericidal
bacteriostatic
Ethambutol intracellular or extracellular organisms
both!!!
ethambutol resistance
mutation of embAB
Ethambutol use
active: combo
MAC
ethambutol adverse effect
optic neuritis (loss of visual acuity, red/green blindness)
Pyrazinamide MOA
- prodrug converted to POA (active in acidic conditions)
- molecular target unknown
Pyrazinamide bacteriostatic or bactericidal
bactericidal
pyrazinamide intracellular or extracellular oganisms
intracellular organisms
Pyrazinamide use
combo
Pyrazinamide adverse effects
- hepatotoxicity
- hyperuricemia
2nd line antimycobacterial agents
streptomycin
Streptomycin use
severe life threatening TB
streptomycin intracellular or extracellular organisms
extracellular
TB prophylaxis use
- high risk patients with latent infections to prevent emergence of active
TB prophylaxis therapy
- daily mono therapy 9 months: INH
- daily mono therapy 4months: rifampin alternative
TB combination therapy use
confirmed active infection
2 phases of TB combo therapy
induction phase (first 2 months) continuation phase (next 4 months)
Induction phase TB
Rifampin, INH, pyrazinamide, ethambutol
Goal of induction phase TB
- eliminate actively dividing extracellular organisms
- render non-infectious
- prevent development of resistance
Most common cause of treatment failure in induction phase TB
non-adherence
- Directly observed therapy (DOT) is standard of care
Continuation phase TB
intermittent therapy (2 weekly): INH + rifampin - may prolong to 7 months if more severe
In continuation phase TP what should you monitor for?
hepatotoxicity
