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Week 4 Foundations of Medicine > Inhibitors of Protein Synthesis Lecture Sep 16 > Flashcards

Inhibitors of Protein Synthesis Lecture Sep 16 Flashcards

1
Q

What allows protein synthesis inhibitors to display selective toxicity against bacteria?

A

They bind and inhibit prokaryotic ribosomes without blocking the eukaryote ribosome

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2
Q

What are the 2 30S inhibitors?

A

aminoglycosides and tetracycline

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3
Q

What are the 5 50S inhibitors?

A

linezolid

macrolides

chloramphenicol

clindamycin

quinupristin/dalfrpristin

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4
Q

What ABx block the initiation step of protein synthesis?

elongation?

termination?

A
  1. Initiation- linezolid, aminoglycosides
  2. Elongation- aminoglycoside, tetracycline, macrolide,
    chloramphenicol, clindamycin,
    quinupristin/dalfoprisitin
  3. Termination- aminoglycoside
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5
Q

Are most ribosome inhibitors bacteriostatic or bacteriocidal? what’s one exception?

A

Most are bacteriostatic except for aminoglycosides

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6
Q

What are 3 abx that interfere with mitochondrial ribosomes as well? What does this lead to?

A

Linezolid

Tetracycline

chloramphenicol

This causes bone marrow suppression

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7
Q

What are the 3 steps of initiaion in prokaryotes?

A
  1. Initiation factors associate with the 30S ribosomal subunit.
  2. Formylmethionine initiator tRNA and mRNA bind to 30S subunit.
  3. 50S ribosome then binds and you have the complete initiation complex.
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8
Q

How does linezolid block initiation?

How do aminoglycosides block initiation?

A

Linezolid binds to the P-site on the 50S so that the formylmethionin tRNA can’t bind

Aminoglycosides bind to the 30S ribosome and freeze the initiation complex. (you get the development of monosomes)

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9
Q

What is the mechanism and spectrum of linezolid?

A

Bacteriostatic-inhibits protein synthesis by binding to the 23S ribosomal RNA on the 50S subunit and preventing formation of the initiation complex.

Spectrum: gram +, including MRSA and VRE

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10
Q

How does resistance to linezolid develop?

A

alterations or modifications in 23S ribosomal RNA

this is unique binding site, so it does not result in cross-resistance with other drug classes.

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11
Q

What are the adverse effects of linezolid?

A

Bone marrow suppression

Inhibits monoamine oxidase which can lead to Serotonin Syndrome

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12
Q

What are the 5 aminoglycosides we need to remember?

A

gentamicin

amikacin

tobramycin

neomycin

streptomycin

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13
Q

What is the mecanism and spectrum of the aminoglycosides?

A

Mechanism: Bactericidal- Prevents formation of initiation complex, causes misreading of mRNA, and induces early termination.

Spectrum: Gram negative aerobic

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14
Q

Why do anaerobic bacteria have intrinsic resistance to the aminoglycosides?

How can acquired resistance develop?

A

Intrinsic resistance- the drug is polar, so it has to be transported into the cell, which requires energy. Because anaerobic bacteria don’t produce as much energy as aerobic bacteria, the drug doesn’t reach high enough concentrations in anaerobic bacteria to be effective.

Acquired resistance-Acquisition of enzymes which inactivate the drug through acetylation, phosphorylation, or adenylation

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15
Q

Which aminoglycosides is less susceptible to enzyme inactivation?

It also has a broader spectrum which includes pseudomonas

A

amikacin

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16
Q

How are aminoglycosides administered?

A

One single large dose via IV (poor gut absoprtion from oral)

in a concentration that is over 10 times the MIC most effective at killing the organism

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17
Q

What does cumulative dose mean?

A

the area under the curve of a concentration by time plot.

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18
Q

What are the adverse effects of aminoglycosides?

THe use is limited due to side effects.

A 
Tubular necrosis:  nephrotoxicity- drug retained in renal cortex (reversible)
      ototoxicity- vestibular and auditory dysfunction (irreversible)
      pregnancy class D- hearing loss in fetus
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19
Q

Can aminoglycosides be used for CNS infections?

A

No–they are polar and thus excluded from the CSF

20
Q

Which aminoglycoside is synergetic with penicillin and used to treat some gram positive organisms?

A

gentamycin

21
Q

What are the three tetracyclines we need to remember?

A

tetracycline

doxycycline

minocycline

22
Q

What is the mechanism of tetracyclines?

Spectrum?

A

Bacteriostatic–bind to 30S preventing attachment of aminoacyl-tRNA

Spectrum was broad initially, but not anymore due to resistance. Still used for B burgdorferi, H pylori, and Mycoplasma pneumonia

23
Q

What are the intrinsic and acquired resistance mechanisms for tetracycline?

A

Intrinsic: decreased uptake

Acquired: Increased efflux*
Alteration of ribosomal target
Rarely enzymatic inactivation of drug (acetyl)

24
Q

What are the adverse effects of tetracyclines?

A

form stable chelates with a number of metal ions such as calcium, magnesium, iron and aluminum decreasing gut absorption of the drug.

Gastrointestinal irritation and photosensitivity (abnormal sunburn reaction)

Discoloration of teeth and inhibits bone growth in children.

Pregnancy class D (should not be used)

25
Q

What is the mechanism and spectrum for chloramphenicol?

A

Bacteriostatic–binds 50S preventing peptide bond formation

peptidyltransferase can’t associate with the amino acid susbstrate

Spectrum: extended, but use is limited due to severe side effects

26
Q

HOw does resistance develop to chloramphenicol?

A

acetyltransferase
modifies drug to prevent binding to
the ribosome

27
Q

What are the adverse effects of chloramphenicol?

A

TOXIC: bone marrow depression and aplastic anemia

Gray baby syndrome- premature infants
lack the enzyme UDP-glucuronyl transferase and have decreased renal function so high levels of the drug accumulate, which can lead to cardiovascular and respiratory collapse

28
Q

What are the 3 macrolides we need to remember?

A

erythromycin

azithromycin

clarithromycin

29
Q

What is the mechanism and spectrum for the macrolides?

A

bacteriostatic–inhibit translocation by binding the 23S rRNA of the 50S subunit

Spectrum is broad coverage of respiratory pathogens and chlamydia (in a single dose)

30
Q

What are the three ABx that can be used against mycoplasma pneumonia?

A

doxycycline

azithromycin

levofloxacin

(beta lactams not effective)

31
Q

What are the mechanisms of resistance for the macrolides?

A

methylation of 23S rRNA binding site- also associated with clindamycin and quinupristin/dalfopristin resistance

increased efflux

hydrolysis of the the macrolide by esterases

32
Q

What are the adverse effects of the macrolides?

Which one can’t you use during pregnancy?

A

GI discomfort, Hepatic failure, and Prolonged QT interval
Inhibitors of cytochrome P450 enzymes (check with other medications)
Clarithromycin is not safe during pregnancy

33
Q

What is the mechanism and spectrum of clindamycin?

A

It’s a bacteriostatic abx that blocks translocation at the 50S ribosomal subunit.

Spectrum gram positive including anarobes.

Treats acne

34
Q

How does resistance develop for clindamycin?

A

mutation of ribosome, methylation of ribosomal RNA (D-test),

Cross resistance with macrolides and streptogramins

inactivation of drug by adenylation

35
Q

What are the adverse effects of clindamycin?

A

Hypersensitivity: rash and fever
Diarrhea, abdominal pain, mucus and blood in stool
Superinfection with C. difficile

36
Q

What is the streptogramin combo we need to remember?

A

quinupristin/dalfopristin

37
Q

What is the mechanism and spectrum of quinupristin/dalfopristin?

A

combined action is bactericidal for some organisms

they bind the 50S to inhibit translocation

They should be reserved for infections caused by multiple drug-resistant G+ bacteria

38
Q

How does resistance develop to streptogramins?

A

Ribosomal methylase prevents binding of drug to its target.
Enzymes inactivate the drugs.
Efflux proteins that pump them out of the cell.

Cross resistance with macrolides and clindamycin.

39
Q

What are the adverse effects of streptpgramins?

A

High incidence including arthralgias and myalgias are common.
Inhibits a cytochrome P450 enzyme and is likely to have significant drug interactions.

40
Q

What are the two ABx you shouldn’t use with newborns? why?

A

chloramphenicol

sulfonamides

they can’t glucoronidate

41
Q

What 2 ABx should you not use in children?

A

tetracyclines

fluoroquinolones

42
Q

Which ABx shouldn’t you use in pregnancy?

A

tetracycline

aminoglycosides

clarithromycin

fluoroquinolones

chloramphenicol

sulfonamides

43
Q

What three classes of drugs need to be adjusted in the elderly with reduced renal function?

A

beta-lactams

aminoglycosides

fluoroquinolones

44
Q

What are the 5 instances when combination drug therapy is appropriate?

A
  1. Enhancement of antibacterial activity in the treatment of specific infections (synergism)
    Trimethoprim – Sulfamethoxazole
    Inhibits multiple steps in folate synthesis

Aminoglycoside + Penicillin Penicillin increases permeability of cell membranes increasing the ability of aminoglycosides to enter the cell

  1. Treatment of mixed bacterial infections caused by two or more microbes.

Therapy of severe infections in which a specific etiology is unknown.
Not to be used as a shortcut but used until clinical and lab data allow the selection of a specific antimicrobial

  1. Prevention of the emergence of resistant organisms.
    Treatment of Tuberculosis
  2. Addition of inhibitors to prevent degradation or excretion of the enzyme
    Ampicillin-sulbactam, Amoxicillin-clavulanate, Piperacillin-tazobactam, Ticarcillin-clavulanate
    Imipenem-cilastatin (blocks renal dehydropeptidase) Penicillin- probenecid (decrease renal excretion
45
Q

What are the 5 drawbacks of combination drug therapy?

A
  1. Risk of toxicity from two agents
    Vancomycin or Aminoglycosides each alone have some nephrotoxicity. If given together you get marked renal impairment.

  1. Antagonism
    Pneumococcal meningitis
    Penicillin - 21% mortality
    Penicillin + Tetracycline - 79% mortality
  2. Selection of microorganisms resistant to antibiotics
  3. Superinfection
  4. Extra cost
46
Q

Are aminoglycosides concentration or time dependent for dosing?

How about beta lactams?

How about linezolid?

A

Aminoglycosides are CONCENTRATION dependent, so you administer 1 huge IV dose

Beta lactams are TIME dependent, so you have to dose them multiple times–their effectiveness depends on the amount of time being over the MIC in the body

Most drugs, including linezolid are more dependent on a comination of the two - the cumulative dose (AUC)

Week 4 Foundations of Medicine (13 decks)

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