Antibacterial Agents 3 - Protein Synthesis Inhibitors

Question 1

Blank

Answer 1

Blank

Question 2

Macrolides

Answer 2

~ Erythromycin, Clarithromycin, Azithromycin
~ Mechanism: binds to 50S ribosomal subunit blocking translocation of peptidyl tRNA from acceptor site to donor site on ribosome and peptide bond formation
~ bacteriostatic, enters bacteria via passive diffusion
~ Resistance: methylation of 50S ribosome prevents binding
~ Absorption: GI tract
~ Distribution: most tissues except brain and CSF
- cross placenta to fetus
~ Excretion:
- Erythro: metabolized liver, excreted in bile
- Clarithro: metabolized, renally excreted
- Azithro: not metabolized
- breast milk
~ Spectrum: Streptococci, pneumococci, H. influenzae, Chlamydia (Azithromycin), Mycoplasma pneumoniae

Question 3

Tetracyclines

Answer 3

~ Tetracycline, Doxycycline, Minocycline
~ bacteriostatic
~ Mechanism: binding to 30S ribosome (reversible) prevents access of aminoacyl tRNA to site on mRNAribosome complex blocking addition of amino acids to peptide chain
~ Some selective toxicity: mammalian cells have an active efflux mechanism preventing intracellular accumulation of drugs and lack an active transport for moving drug into cell
~ Absorption: empty stomach, retention in GI alters intestinal flora & contributes to superinfection
- impaired by milk products
~ Distribution: most tissues/fluids, placenta
~ Excretion: concentrated in liver, excreted in bile
- most excreted into urine
~ Spectrum: broad (has led to widespread resistance)
- Staphylococcus aureus (methicillin-resistant-MRSA), H. influenzae, Chlamydia, Mycoplasma pneumoniae
~ Interactions: Antacids / Iron Supplements (metal ions): ↓ bioavailability by forming insoluble salts

Question 4

Clindamycin

Answer 4

~ Mechanism: binding to 50S ribosome and preventing translocation of peptidyl tRNA and peptide bond formation
~ Bacteriostatic
~ Absorption: high oral
~ Distribution: most tissues, especially bone, not CSF
~ Excretion: metabolized by liver, excreted bile; breast milk
~ Spectrum: Treatment of severe anaerobic infections
- Streptococci, Staphylococcus aureus (MSSA), Staphylococcus aureus (MRSA), Clostridium perfringens, Bacteroides fragilis
~ Adverse Effects: Pseudomembranous colitis (do not use for Clostridium difficile)

Question 5

Aminoglycosides

Answer 5

~ Streptomycin, Tobramycin, Gentamicin, Amikacin, Kanamycin, Neomycin
~ bacteriostatic low conc.; cidal high conc.
~ Mechanism: combines with 30S ribosome, altering the
interaction of mRNA with the subunit, producing inhibition of protein synthesis initiation, breakup
of polysomes, and misreading the code
~ Resistance: chemical modifications of the antibiotic that impair ribosomal binding and further drug
uptake (plasmid mediated resistance)
~ Absorption: BAD oral, IM
~ Distribution: NO nervous system; accumulates renal cortex and inner ear
~ Excretion: kidneys; postantibiotic effect
~ Spectrum: declining use due to toxicity
- Not effective against anaerobic organisms (requires O2)
- Pseudomonas aeruginosa, E. coli, Klebsiella, Mycobacterium tuberculosis, Enterococci
~ Adverse Rxn: VERY TOXIC
- 8th nerve damage, renal toxicity

Question 6

Chloramphenicol

Answer 6

~ Mechanism: reversible binding to 50S ribosome resulting in block of peptidyl transferase action and
incorporation of amino acids into newly formed peptides
~ Bacteriostatic
~ also inhibits mammalian mitochondrial protein synthesis (lowered selective toxicity)
~ Absorption: GI tract
~ Distribution: all tissues/fluids, incl. CNS & CSF
~ Excretion: metabolized by glucuronidation
- toxic in fetus and neonate
- breast milk
~ Spectrum: broad
- meningitis: N. meningitides, H. influenza, Bacteroides
~ Adverse Rxns: bone marrow toxicity, gray baby syndrome

Question 7

Novel Class: Linezolid

Answer 7

~ First member of oxazolidinone class of antibiotics
~ bacteriostatic
~ Mechanism: binds to 50S ribosome (23S portion) at different site than other agents, thus no cross resistance observed with other protein synthesis inhibitors
- inhibits formation of 70S ribosome
~ Absorption: 100% via oral
~ Spectrum: Should be held in reserve for life-threatening infections
- Enterococci (including VRE), Staphylococci (including MRSA), Streptococci
~ Adverse: inhibits MAO

Question 8

Novel Class: Quinupristin / Dalfopristin

Answer 8

~ First member of streptogramin class of antibiotics
~ Mechanism: Quinupristin binds to 50S ribosome and inhibits peptide elongation, leading to early termination. Dalfopristin binds at nearby site on 50s ribosome, inducing conformational change that both enhances quinupristin binding and directly interferes with peptide
chain formation.
~ Absorption: IV only
~ Spectrum: Should be held in reserve for life-threatening infections
- Enterococci (including VRE), Staphylococci (including MRSA), Streptococci
~ Adverse Rxns: Inhibits cytochrome 3A4 and may lead to increased plasma levels of 3A4 substrates