Protein Synthesis Inhibitors

Question 1

What are the drugs that inhibit 30 S? 50 S?

Answer 1

30S inhibitors include aminoglycosides and tetracycline

50S inhibitors include linezolid, macrolides, chloramphenicol, clindamycin,
quinupristin/dalfopristin

Question 2

Oxazolidinones - Linezolid

Answer 2

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 (antidepressants elevate serotonin too)

Important Facts: Excellent bioavailability

Question 3

Aminoglycosides- gentamicin, amikacin, tobramycin , neomycin, streptomycin

Answer 3

Mechanism: Bactericidal- Prevents formation of initiation complex, causes misreading of mRNA, and induces early termination. Concentration dependent (>10 times above MIC)

Spectrum: Gram negative aerobic (unless combined with penicillin then you can hit Gram positive)

Resistance:
Intrinsic resistance- failure of antibiotic to enter bacterial cell (anaerobic)
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

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

Question 4

Tetracyclines- tetracycline, doxycycline, minocycline

Answer 4

Mechanism: Bacteriostatic-bind 30S preventing attachment of aminoacyl-tRNA

Spectrum: Broad initially but due to resistance
B. burgdorferi, H. pylori (ulcers), Mycoplasma pneumoniae.

Resistance:  
Intrinsic:  decreased uptake 
Acquired:
Increased efflux* (most common)
Alteration of ribosomal target
Rarely enzymatic inactivation of drug (acetyl)

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 5

Chloramphenicol

Answer 5

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 6

Macrolides- erythromycin, azithromycin, clarithromycin

Answer 6

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

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

Resistance:
methylation of 23S rRNA binding site- also associated with clindamycin and quinupristin/dalfopristin resistance
increased efflux
hydrolysis of the the macrolide by esterases

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
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Question 7

Which drugs can you use on Mycoplasma pneumonia?

Answer 7

Doxycycline, Azithromycin, Levofloxacin

Question 8

Lincosamide: Clindamycin�

Answer 8

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 9

Streptogramins: Quinupristin/Dalfopristin

Answer 9

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.