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Infectious Disease Unit 2 > Antimicrobials III > Flashcards

Antimicrobials III Flashcards

1
Q

Antitubercular agents

A

Isoniazid, Rifampin, Ethambutol, Pyrazinamide, Streptomyin

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2
Q

For active TB, what is drug regimen

A

4 drug therapy: Isoniazid, Rifampin, Ethambutol, and Pyrazinamide
-administered via directly observed therapy (DOT)

  • if showing susceptibility, can get rid of pyrazinamide/ethambutol after 2 months and continue with isoniazid and rifampin for 6 months treatment
  • sometimes can require other drugs if treatment resistant TB present
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3
Q

Why do we treat TB with multiple drugs for a long time

A
  • Can evade host mechanisms/survive in macrophages, so many drugs don’t work
  • treat with 4 to decrease development of more resistant strains
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4
Q

Isoniazid MOA

A
  • most potent agent for treating TB
  • Prodrug converted into active metabolite in bacterial cell to inhibit mycolic acid synthesis. Interats with catalase peroxidase enzyme, binds covalently to adenine nucleotide of nicotinamide in enoyl-acyl carrier protein reductase-InhA
    (action analogous to penicillins)
  • tuberculoCIDAL for growing cells but tuberculoSTATIC for resting cells
  • This is selectively toxic since other bacteria, fungi, humans don’t make mycolic acids
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5
Q

Isoniazid mechanism of resistance

A
  • develops rapidly through alterations in drug uptake, mutations in KatG, and mutations in InhA target
  • INH resistant strains seem to be less pathogenic
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6
Q

Isoniazid pharmacokinetics

A
  • readily absorbed from GI, distributed through body water,
  • penetrates brain & cells
  • metabolized via acetylation to N-acetyl INH
  • toxicity influenced by how fast it is acetylated (fast vs slow inactivators)
  • Fast acetylators have poor therapeutic response; 50% of US are slow acetylators
  • Most drug recovered in urine as metabolized drug
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7
Q

Isoniazid toxicity/adverse effects of isoniazid

A
  • Peripheral neuritis, optic neuritis, convulsions, mental disturbances
  • associated with increased excretion of pyridoxine, so prevent by administering pyridoxine
  • Neuropathy more common in slow acetylators
  • Sensitization reactions (fever, rash, blood dyscrasia)
  • Hepatic damage (more common in rapid acetylators, older pts, Asian descent); worse with EtOH use
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8
Q

Isoniazid Spectrum/use

A

First line TB therapy for treatment and prophylaxis after exposure and testing

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9
Q

Rifampin MOA

A
  • inhibit RNA synthesis initiation by binding beta subunit of DNA dependent RNA polymerase
  • Bactericidal and synergistic with isoniazid/streptomycin
  • selective for mycobacteria due to differences in mammalian vs bacterial RNA polymerase but can interact with human RNA polymerase and penetrate bacterial and mammalian cells
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10
Q

Rifampin mechanism of resistance

A

point mutations in RNA polymerase (rpoB)

  • frequency of 10^(-7) - 10^(-8)
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11
Q

Rifampin pharmacokinetics

A
  • orally active, widely distributed
  • metabolized via deacetylation resulting in active product
  • enterohepatic circulation and excreted mostly in feces (30% in urine)
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12
Q

Rifampin toxicity

A
  • Immunologic reactions – flu-like syndrome maybe associated with renal/bone marrow toxicity
  • rare hepatotoxicity
  • Red-orange colored urine/feces and other secretions
  • Induce microsomal enzyme oxidizing system (MEOS) –DDI. Decreases half life of other drugs (esp AIDS drugs, corticosteroids, theophylline)
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13
Q

Rifampin Spectrum/uses

A
  • 1st line agent for TB and other mycobacteria (MAC and leprosy)
  • Against Gram (+) and Gram (-) Cocci, Legionella for serious infections
  • Prophylaxis against meningococcal infections in exposed individuals
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14
Q

Pyrazinamide MOA

A

unknown, possibly fatty acid synthesis but recent report suggests not

  • prodrug hydrolyzed to pyrazinoic acid via pyrazinamidase (pncA)
  • Active at low pH - effective tuberculocidal activity in caseous lesions at low pH
  • Enters macrophages (controversial)
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15
Q

Pyrazinamide - resistance

A
  • via mutations to pncA and alterations in drug uptake

- rapid development if used alone

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16
Q

Pyrazinamide Pharkacokinetics

A
  • orally active, wide distribution (CNS, lungs, organs), quickly absorbed
  • excrete in urine as hydrolyzed forms
17
Q

Pyrazinamide toxicity/adverse effects

A
  • hepatitoxic in 15%, some with jaundice, death rare–check hepatic function
  • hyperuricemia since drug inhibits urate excretion
  • arthralgias, anorexia, nausea, vomiting, dysuria, fever
18
Q

Pyrizinamide spectrum/uses

A

1st line anti-TB agent. more potent than PAS or cycloserine but can be toxic. Used mainly in initial weeks of therapy

19
Q

Ethambutol MOA

A
  • inhibits mycobacterial cell wall biosynthesis via binding and inhibiting arabinosyltransferase (emb genes)
  • Arabinosyltransferase polymerizes arabinan in arabino-galactan and lipoarabinomannan layers of cell wall
  • Bactericida/static depending on environment of bacilli
  • selective toxicity related to fact that other bacteria/fungi/human cells don’t make arabino-galactan
  • CONCENTRATES IN LUNG-TB LESIONS. CONTROVERSY ON HOW WELL IT CAN ENTER MAMMALIAN CELLS
20
Q

Ethambutol Resistance

A
  • mutaiton in emb genes if used alone

- active against most isoniazid- and streptomycin-resistant strains

21
Q

Ethambutol pharmacokinetics

A
  • orally active, quickly absorbed, widely distributed to tissues/CSF
  • Excreted in urine (10% metabolized)
22
Q

Ethambutol toxicity/adverse events

A
  • optic neuritis– reversible; rare with recommended doses and no impaired renal function
  • Hyperuricemia
  • Nausea/vomiting/dysuria/fever
23
Q

Ethambutol Spectrum/use

A

active only against mycobacteria; 1st line TB agent

24
Q

Route of TB drugs

A

all are oral except streptomycin (IV)

25
Q

2nd Line Anti-TB drugs

A

1) cycloserine- inhibit alanine racemase and D-alanyl-D-alanine synthetase in cell wall synthesis. More toxic than isoniazid/PAS. Don’t combine with isoniazid

2) Aminosalicylic acid (PAS)
- slight tuberculostatic action but synergistic with other anti-TB drugs. GI toxicity common and not used much today due to poor pt acceptance

3) Capreomycin - similar to streptomycin but more toxic
4) Ethionamide
5) protein synthesis inhibitors (Amikacin, kanamycin)
5) fluoroquinolones (ofloxacin, cipro-, levo-, spar-)
6) Rifabutin - similar to rifampin

26
Q

Treat mycobacterium avium complex (MAC)

A 
Rifabutin
Macrolides (calrithromycin/azithromycin)
Fluoroquinolones 
Clofazamine (also in leprosy)
Amikacin
27
Q

Treat Leprosy

A
  • use multidrug therapy
    1) Sulfones (i.e. Dapsone)
  • bacteriostatic and thought to competitively antagonize PABA utilization
  • relatively nontoxic but perhaps hemolytic anemia in G6PD deficiency.
  • Have to give long time (1-5 years)
  • Amithiozone = alternative agent

2) Rifampin- bactericidal for M. leprae. Used in multidrug therapy
3) Clofazimine - phenazine dye binding DNA.
- bactericidal and used for dapsone-resistant leprosy and skin ulcers.
- Orally available but slow activity (50 days)

28
Q

TB drugs with good intracellular activity

A

INH, RIF, Pyrazinamide is variable

29
Q

TB drugs with poor intracellular activity

A

Ethambutol, Streptomycin, Pyrazinamide is variable

30
Q

Streptomycin

A

Protein synthesis inhibition at 30 S subunit (CIDAL)
- alternative 1st line treatment
- give IV/IM;
-accumulates in kidney, ear– high toxicity
- renal excretion
USE: Med. Spectrum Gram -ve aerobes, limited +

31
Q

Use of TB drugs in pregnancy

A
  • relatively safe
  • Ethambutol/Rifampin = Pregnancy category C
  • Benefits may outweigh risks with Rifampin

Infectious Disease Unit 2 (22 decks)

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