Antibiotics: Inhibitors of Protein Synthesis Flashcards
Protein Synthesis
- Step 1: aminoacyl tRNA binds to a vacant ribosomal A-site by forming base pairs with the mRNA codon
- Step 2: Peptide joined to amino acid at A-site by peptidyl transferase
- Step 3: New peptidyl tRNA is translocated to the P-site as the ribosome moves along the mRNA molecule
Inhibitors of Protein Synthesis
- Aminoglycosides (gentamicin, tobramycin, amikacin)
- Macrolides (azithromycin, clarithromycin)
- Lincosamides (clindamycin)
- Tetracyclines (doxycycline)
Aminoglycosides
- Gentamicin, tobramycin, amikacin
- Mechanism of action:
- Enters bacterium via electron transport chain
- Cannot penetrate gram positive cell wall
- Binds of 30S ribosomal subunit
- Spectrum of activity/clinical use:
- Aerobic gram negative rods, including Pseudomonas
- Combination therapy with beta lactam for gram positives
- Inhaled form to prevent cystic fibrosis exacerbations
Aminoglycosides Pharmacokinetics
- Poorly absorbed from the GI tract; must be given parenterally
- Concentrated in renal tubules
- Penetration into bacterium requires active electron transport chain
- Do not enter CSF in therapeutic concentrations (unless meninges are inflamed)
- Excreted through the kidney predominantly by glomerular filtration; thus directly proportional to creatinine clearance
- Must adjust in renal insufficiency
Aminoglycoside Toxicity
- Nephrotoxicity (common: 5%-25%; usually reversible)
- Ototoxicity
– Auditory (3%-14%; often permanent)
– Vestibular (4%-6%)
- Risk is dose and duration dependent
- Increased with other nephrotoxic drugs
- Serum concentrations monitored
Once Daily Aminoglycoside Dosing
- Originally used in multiple daily doses (q8h) to maintain serum levels above MIC for most of day
- Long post-antibiotic effect
- Concentration-dependent killing; Peak/MIC ratio best predictor
- Toxicity is both concentration AND time-dependent
- Single daily dosing may be more effective against gram negative bacteria and less toxic
Macrolides
- Erythromycin is the prototypic drug
- Structural changes in clarithromycin and azithromycin improve absorption, increase T1/2, and increase spectrum of activity
- Mechanism: bind to 50S ribosomal subunit
- Resistance
– Decreased permeabililty; active efflux
– Esterases (by Enterobacteriaceae) hydrolyze the drug
– Modification of ribosomal binding site
Macrolides Pharmacokinetics
• Erythromycin
– High incidence of nausea/diarrhea; binds motilin receptors
– Poor penetration of CSF - all macrolides
• Azithromycin
– Unique pharmacokinetic properties
– Large VD
– tissue/intracellular concentrations 10-100 X serum
– Eliminated slowly (half-life 2-4 days) in urine and feces as unchanged drug
– Once daily dosing; relatively short course of therapy
• Clarithromycin
– Similar to Pk/Pd and spectrum of activity as azithromycin
– More hepatotoxicity and drug-drug interactions
Macrolides Clinical Use
- Community acquired pneumonia (which organisms?)
- Pertussis
- Infectious diarrhea (Campylobacter, S. typhi, etc)
- Non-gonococcal urethritis (e.g. Chlamydia)
- Alternative to penicillin for Group A strep pharyngitis (resistance significant)
- Clarithromycin/azithromycin active against Mycobacterium avium complex
- Helicobacter pylori - Clarithromycin
Clindamycin
- Binds 50S ribosome; resistance due to change in ribosomal binding site
- Cross resistance with macrolides (D-test)
- Active against streptococci, staphylococci (some MRSA), anaerobic gram positive bacteria
- No activity against enterococci, aerobic gram negative bacteria
- Oral / IV administration
- Metabolized in the liver
Clindamycin Clinical Use
- Skin/soft tissue infections (MSSA, MRSA, group A strep)
- Osteomyelitis (MSSA, MRSA)
- Strep pharyngitis if penicillin-allergic
- Aspiration pneumonia (to cover anaerobes)
- To limit toxin production in toxic shock syndrome
- Acne (topical formulation)
Clindamycin Adverse Effects
- Highest risk of C. difficile colitis
- Tastes terrible
Tetracyclines
- Binds 30S ribosome
- Widespread use for minor illnesses has produced resistance. Extensive use in animal feeds has also contributed.
- Clinical use: doxycycline
– Acne, Chlamydia, Rickettsia species, Borrelia burgdorferi
Tetracycline Pharmacokinetics/Adverse Effects
- Doxycycline and minocycline have longer half-lives • Chelated by cations - reduced GI absorption
- Concentrations in CSF not therapeutic
- Strong affinity for bones and teeth (yellow-brown color) - not used in pregnancy or children <8y
- GI effects common
- Photosensitization
Chloramphenicol
- Once an important antibiotic but rarely used in U.S. because of toxicity
- Reaches CSF and effective against bacterial pathogens for meningitis
- Dose dependent myelosuppression - common and reversible
- Aplastic anemia – rare and irreversible
- Gray baby syndrome
- Clinical Use – very rare unless you care for koalas
