Inhibitors of Protein Synthesis

Question 1

30S inhibitors include:

Answer 1

aminoglycosides and tetracycline

Question 2

50S inhibitors include:

Answer 2

linezolid, macrolides, chloramphenicol, clindamycin, quinupristin/dalfopristin

Question 3

Linezolid

Answer 3

Mechanism: 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, Vancomycin Resistant Enterococci

Resistance: alterations or modifications in 23S ribosomal RNA unique binding site does not result in cross-resistance with other drug classes.

Adverse Effects: Bone marrow suppression, Inhibits monoamine oxidase which can lead to Serotonin Syndrome if taken with SSRI hallucinations, increase heart beat, agitation, nausea

Question 4

Aminoglycosides- gentamicin, amikacin, tobramycin, — neomycin, streptomycin

Answer 4

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

Spectrum: Gram negative aerobic (usually used in combination)

Resistance: Intrinsic resistance- failure of antibiotic to enter bacterial cell (anaerobic) Cotreat with cell wall inhibitor

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

Amikacin- less susceptible to enzyme inactivation and broader spectrum including Pseudomonas

Question 5

Concentration-dependent killing

Answer 5

Achieve more killing at a higher concentration
Peak concentration >10 times over MIC, 1 or 2 high daily doses
Ex: Aminoglycosides, fluoroquinolones

Question 6

Time-dependent killing

Answer 6

t>MIC depending on the half life of the antibiotic may need to dose multiple times/day may not
Beta-lactams and vancomycin

Question 7

What are some adverse effects of aminoglycosides?

Answer 7

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

Important Facts:
Poor gut absorption usually administered by IV
Drugs are polar and excluded from CSF

Question 8

Tetracyclines- tetracycline, doxycycline, minocycline

Answer 8

Mechanism: Bacteriostatic-bind 30S preventing attachment of aminoacyl-tRNA
Spectrum: Broad initially but due to resistance
B. burgdorferi, H. pylori, Mycoplasma pneumoniae.
Resistance:
Intrinsic: decreased uptake
Acquired: Increased efflux*, Alteration of ribosomal target
Rarely enzymatic inactivation of drug (acetyl)

Question 9

Adverse effects of tetracyclines are:

Answer 9

Adverse effects: 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)

Question 10

Chloramphenicol

Answer 10

Mechanism: Bacteriostatic- binds 50S preventing peptide bond formation- peptidyltransferase
can’t associate with amino acid substrate

Spectrum: Extended but use is limited due to severe side effects

Resistance: acetyltransferase modifies drug to prevent binding to the ribosome

Adverse effects: 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

Question 11

Macrolides- erythromycin, azithromycin, clarithromycin

Answer 11

Mechanism: Bacteriostatic
Inhibits translocation by binding 23S rRNA of the 50S subunit

Spectrum: Broad coverage of respiratory pathogens, Chlamydia (single dose)

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

Question 12

Lincosamide: Clindamycin

Answer 12

Mechanism: Bacteriostatic- blocks translocation at 50S ribosomal subunit

Spectrum: Gram positive including anaerobic. Treat acne.

Resistance: mutation of ribosome, methylation of ribosomal RNA (D-test),
Cross resistance with macrolides and streptogramins
inactivation of drug by adenylation

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

Question 13

Streptogramins: Quinupristin/Dalfopristin

Answer 13

Mechanism:
Combined action is bactericidal for some organisms.
Binds 50S to inhibit translocation.

Spectrum:Quinupristin/dalfopristin should be reserved for
infections caused by multiple drug-resistant G+ bacteria.

Resistance: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.

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

Question 14

What are some drawbacks to using drugs in combination?

Answer 14

1. Risk of toxicity from two agents: Vancomycin or Aminoglycosides each alone have some nephrotoxicity. If given together you get marked renal impairment.
2. Antagonism Pneumococcal meningitis
   Penicillin - 21% mortality
   Penicillin + Tetracycline - 79% mortality
3. Selection of microorganisms resistant to antibiotics
4. Superinfection
5. Extra cost

Question 15

Cite some important guidelines when administering antibiotics.

Answer 15

Avoid using antibiotics to treat colonization or contamination
Goal to use narrow-spectrum agent that is effective
Use the proper dose if exposed to low concentrations that don’t kill more likely to develop resistance
Use the shortest effective duration of therapy