19: Protein Synthesis Inhibitors

Question 1

Name the classes of protein synthesis inhibitors.

Answer 1

1. Macrolides
2. Aminoglycosides
3. Tetracyclines
4. Chloramphenicol
5. Oxazolidinones
6. Streptogramins

Question 2

For macrolides:

1. Mechanism
2. Types
3. Resistance
4. Spectrum
5. Pharmacology
6. Indications
7. Toxicity

Answer 2

1. Inhibit formation of 50S ribosome, blocking trans-peptidation or translocation
2. Erythromycin, clarithromycin, azithromycin
3. Decreased permeability (enterobac), altered binding site, efflux pumps
4. GP (s. pneu, viridans, GA/BS, s. aureus); GN (Bordatella, Neisseria, Campylobacter, Legionella, Haemophilus); Misc. (Myco/Ureaplasma, chlamydia, treponema); azithro has enhanced GN, clarithro has enhanced GP
5. Orally or parenterally; well-distr, but limited CNS penetration
6. CAP, otitis media, pertussis, campy gastroenteritis, MAC; alt for strep, rheumatic fever, CT urethrits, anthrax
7. GI, prolonged QT, drug intx

Question 3

For clindamycin:

1. Mechanism
2. Types
3. Resistance
4. Spectrum
5. Pharmacology
6. Indications
7. Toxicity

Answer 3

1. Same as macrolides; bacteriostatic
2. Just clindamycin (a lincosamide)
3. Inducible
4. GP, anarobes, Toxoplasma
5. High bone concentrations (tx of osteomylitis), no CSF penetration
6. PCN-resistant anaerobic infx, MSSA/MRSA
7. Diarrhea (classic predisposing drug for C. difficile colitis), allergy

Question 4

For aminoglycosides:

1. Mechanism
2. Types
3. Resistance
4. Spectrum
5. Pharmacology
6. Indications
7. Toxicity

Answer 4

1. Diffuse through proin channel on GN, bind and alter membrane causing leakage and disruption; interfere with mRNA translational accuracy at 30S ribosome
2. Gentamicin, streptomycin, amikacin; IV
3. Enzymatic modification of drug via adenylation, phosphorylation, acetylation
4. Aerobic GN (never use alone), some strep, staph (synergy)
5. Given PO, not extensively metabolized (good for UTIs)
6. Empiric therapy with cell wall abx, synergistic for enterococcal endocarditis, pseudomonas infx, inhalation for CF pts
7. Nephrotoxicity, ototoxicity

Question 5

For tetracyclines:

1. Mechanism
2. Types
3. Resistance
4. Spectrum
5. Pharmacology
6. Indications
7. Toxicity

Answer 5

1. Binds 30S and prevents access of aminoacyl tRNA molecules to mRNA ribosome-peptide complex
2. Tigecylcine, Doxycycline, Minocycline
3. Decreased uptake and increased excretion of drug (efflux pumps)
4. GPs (S. pneu, GA/BS, entero), GNs (E. coli, Neisseria spp., Haemophilus spp., Shigella spp.), Misc (Borrelia, Rickettsiae, Chlamydiae, Mycoplasma, Legionella, Pasteurella, Ehrlichia); Tigecycline has activity against resistant GP/N, but very limited use
5. PO, IV in severe; dairy products (cations) interfere w/ absorption; excellent distribution, some in CSF
6. Chlamydia, Mycoplasma, Brucella, Vibrio, Rickettsia, Borrelia, Ehrlichia, Acne, MRSA, tick-borne illness
7. GI, photosensitivity, discoloration of teeth (not used under 8yo), anaphylaxis (rare), hepatotoxicity

Question 6

For Chloramphenicol:

1. Mechanism
2. Types
3. Resistance
4. Spectrum
5. Pharmacology
6. Indications
7. Toxicity

Answer 6

1. Binds peptidyl transferase, component of 50S
2. Just chloramphenicol
3. Via chloramphenicol transacetylase
4. Broad; bacteriostatic; aerobic GPs, most GNs, most anaerobes, Rickettsia; bactericidal against pneumococcus, Neisseria
5. Higher levels, prolonged t.5 following PO vs. IV; well-distr (including CSF); metabolized in liver
6. Typhoid fever, meningitis in specific situations, rickettsial infx
7. Gray baby syndrome, irreversible bone marrow aplasia

Question 7

For Oxazolidinones:

1. Mechanism
2. Types
3. Resistance
4. Spectrum
5. Pharmacology
6. Indications
7. Toxicity

Answer 7

1. Bind 50S, inhibit formation of initiation complex.
2. Linezolid
3. Mutation of 23S RNA (50S)
4. Bacteriostatic; GPC, even VRE/MRSA
5. Parenterally or orally; excellent distribition, metabolized by liver, excreted in urine
6. Drug-resistant enterococcal/staphylococcal infx (last resort to prevent resistance)
7. Myelosuppression, peripheral and optic neuropathy

Question 8

For Streptogramins:

1. Mechanism
2. Types
3. Resistance
4. Spectrum
5. Pharmacology
6. Indications
7. Toxicity

Answer 8

1. Interfere w/ 50S: Q inhibits peptide chain elongation, D interferes w/ peptidyl transferase.
2. Pristinamycin (Quinupristin + Dalfopristin)
3. Methylation of MLS binding site, drug modification, efflux
4. Limited; GPC (not E faecalis)
5. Only parenteral, well distr., metabolized in liver
6. VRE/MRSA/VRSA
7. Phlebitis, myalgias, arthralgias