Mycobacteria Drugs

Question 1

Second line drugs charactersitics

Answer 1

MDR TB
1st line too
less effective, more toxic, expensive

Question 2

Treatment of Tb

Answer 2

3-8 weeks to ID strains so start with all4 first line drugs

Question 3

Mechs for difficulty in treatment Tb Infections

Answer 3

Thick/tough/waxy.lipid rich CW
Dormant/slow growing/hides in macrophages
Rapidly accumulates mutations via chormasomal mutato (not gene transfer)
6-9 moth regimen-compliance is issue

Question 4

General therapy

Answer 4

Give INH/RIF to kill Tb

Give PYR to decrease time to kill to 6 months vs 9

Give ETM/STP together to cover INH/RIF resistant strains

Question 5

INH

• special
• use
• mech
• metabolism
• resistance
• side fx

Answer 5

Isoniazid-Resembles B6

BacteriCIDAL vs Growing extracellular myco, can enter macrophage to kill intracellular bacteria

Prodrug-activated by KatG, binds to NAD+, binds to Fab1 subunit of InhA enzyme in FASII (second carbon addition) that results in mycelia acid

Oral, metabolized by N-acetyltrasnferase in liver (genetic)

KatG mutation results in INH-NAD not form, NADH binding pocket of InhA mutant so INH-NAD can’t bind, increased InHA (Fab1) (need more drug), Increased NADH-outcompetes INH-NAD binding to InhA pocket

Hepatitis (worse at elderly), peripheral neuropathy due to B6 deficiency

Question 6

PYR

• special
• use
• mech
• metabolism
• resistance
• side fx

Answer 6

Pyrazinamide (PZA)

Bactericidal against DORMANT bacteria (called persistent killer)

inhibits trans-translation (can’t start stalled ribosome in times of stress=no recycling of DNA), prodrug activated by bak PcnA enzyme

Synergistic with INF (similar structure) and RIF, oral, inexpensive

PcnA mutations energy rapidly

hepatotoxicity, hyperuricemia, NV

Question 7

ETM

• use
• mech
• metabolism
• resistance
• side fx

Answer 7

Ethambutol

Inhibits fast growing extracellular TB

Bacteristatic-inhibitis arabinogalactan synthesis by inhibiting EmbA and B arabinosyl transferase-makes CW weak

oral and well absorbed, 50% excreted in urine, drug accumulates in renal failure, crosses BBB if meninges inflamed

resistance energyes easily

optic neuritis and R/G color blindness (young kids)

Question 8

RIF

• special
• use
• mech
• metabolism
• resistance
• side fx

Answer 8

Rifampin/Rifampicin-rifamycin

Rifabutin/Rifapentsomething-more potent, longer half life, decreased affects of CYP450

Bactericidal for Gm+/- mycobac and clap

• active against GROWING EXTRACELLULAR Tb in lungs (and slow growing intracellular tyco)
• used for leporoy when used with sulfone
• used with ceftraixone/vancomycin for meningitis

Inhibits bacterial RNA polymerase

Strong cross resistance with other RIF, oral, penetrates CSF is meningitis

Mutation in bacterial RNA poly

OJ sweet/urinetears/ flu like Sx if give longer than 2 weeks, increases elimination of other drugs by increasing P450 activity, hepatitis

Question 9

STP

-special

Answer 9

Streptomycin

Second line to PYR cuz expensive?

Bactericidal-life threatening TB (meningitis) and MDR Tb-does not penetrate CW, CNS,macrophages

Amino glycoside protein synthesis inhibitor

resistance emerge fast in gene incoming the ribosomal submit it effects

otoxic/nerhotoxic (like other ahminoglycosides