Protein Synthesis Inhibitors Flashcards
In general, what are the possible ways antibiotics can interfere with protein synthesis?
Interact with ribosomes
Block initiation
Inhibit tRNA synthesis
Affect multiple mechanisms leading to RNA processing disruption
Which protein synthesis inhibitors affect the 50S subunit and which affect the 30S subunit?
50S subunit = Chloramphenicol, Ketolides (blocks aminoacyl tRNA to acceptor site)… Macrolides, Clindamycin, Streptogramins (blocks peptidyl tRNA translocation from acceptor to donor site)
30S Subunit = Tetracyclines (blocks amino acid tRNA to acceptor site) and Aminoglycosides (block initiation complex formation, misread mRNA, translocation of mRNA)
Can antibiotics move from -static to -cidal?
Yes
Can increase concentration, also depends on site of infection and infecting organism i.e. Linezolid is -static for enterococci and staph…but cidal for strep
How do Aminoglycosides work?
All have an aminocyclitol ring
Mechanism: displaces cations that link phospholipids together which causes membrane leak, irreversibly disprupts protein synthesis (blocking initiation or translocation, misreading mRNA), access membrane through porin channels via active oxygen dependent process (decreased activity with in acidic/anaerobic conditions like in abscesses, synergistic with cell-wall antibiotics like PCN and cephalosporins)
How do bacteria develop resistance against Aminoglycosides? How is this dealt with?
Resistance: modify the aminoglycoside so it can’t bind ribosome, alter binding of aminoglycosides on rRNA, reduce aminoglycoside uptake
To combat this, combine cell-wall inhibitors with aminoglycosides
What is the spectrum of Aminoglycosides?
Aerobic gram-negative bacilli (but not really anaerobes and gram-positive)
i.e. Klebsiella, Enterobacter, Pseudamonas aeruginosa and treating things like UTI, respiratory tract, skin and soft-tissue infections
Usually used in combination to broaden ability to cover serious illness like bacteriemia/sepsis, pseudomonal infection, and endocarditis (synergizing with Vancomycin or PCN)
What are the ADRs of Aminoglycosides and how should dosing be monitored?
Aminoglycosides have concentration-dependent killing (so need to monitor peaks AND troughs to keep in therapeutic range but avoid toxicity)… also have pronounced post-antibiotic effect
ADR: ototoxicity (possibly irreversible) and nephrotoxicity (usually reversible), risk is increased with increased therapy duration, other oto/nephrotoxic drugs, elderly and elevated serum levels… may also have NMJ blockade with curare-like effect in patients with myasthenia gravis or Parkinson’s (respiratory paralysis)
- Streptomycin most ototoxic (not reported with Gentamycin), and also should not use with sulfite-allergic because contains metabisulfite
- Tobramycin inhaled form can cause bronchospasm and hoarseness
- Rare Reactions: Hypersensitivity, optic nerve dysfunction, peripheral neuritis, encephalopathy, pancytopenia, exfoliative dermatitis, amblyopia
What are the most widely used Aminoglycosides? What are some other ones and their limitations?
Most widely used = Gentamycin, Tobramycin, Amikacin (these have cross-resistance)
Streptomycin for enterococcal infections
Neomycin and Kanamycin oral or topical use only due to toxicity
*Spectinomycin has structural similarities to aminoglycosides (used for treating gonorrhea in PCN-allergic patients
What are the pharmacokinetics of Aminoglycosides?
Not orally absorbed (but although Neomycin is too toxic for IV, can use to clean bowel)
Distributes widely in extracellular fluid, insoluble in lipid so volume of distribution is lower in obese… also poor distribution in bile, aqueous humor, bronchial secretions, sputum and CSF
Clearance is proportional to CrCl so need to adjust for renal insufficiency to avoid accumulation
What is the two dosing options/strategies for Gentamycin?
“Once daily”: recommended for most clinical situations since allows for very high concentration-dose killing and can monitor for toxicity…but NOT recommended for gram-positive, if CrCl is less than 30, CF, spinal cord infection or burn patients
Multiple daily: use synergy load then maintenance
What are the potential drug interactions from using Aminoglycosides?
Loop diuretics (increased nephrotoxicity)
Non-depolarizing muscle relaxants (respiratory depression)
Digoxin levels altered by Neomycin (which alters GI flora responsible for metabolism)
What should be known about giving Aminoglycosides to pregnant women?
Amikacin, Streptomycin, Tobramycin, Kanamycin = Category D and 8th Cranial Nerve toxicity in fetus
Gentamycin, Neomycin (minimal absorption of PO dose) = Category C
Breastfeeding = AAP (american academy of pediatrics?) compatible
What is the spectrum of Tetracyclines and what are some conditions they can treat?
Broad spectrum: Gram-positive, gram-negative, aerobic and anaerobic
- Mycoplasma pneumoniae
- Chlamydia pneumoniae/trachomatis (for cervicitis, urethritis, PID, prostatitis if under 35, partners)
- Rickettsia for RMSF
- Borrelia burgdorferi for Lyme’s
- Inhalation Anthrax for when combined with doxycyline in multidrug regimen
- Inflammatory acne
- Sinusitis
- Malabsorption syndrome from overgrowth
- Rickettsia and Borrelia burgdorferi harder targets for tetracyclines
What is the mechanism of Tetracyclines and the 3 groups based on pharmacokinetics?
Mechanism: Reversible protein synthesis inhibition via 30S RNA subunit binding, blocks addition of amino acids to the growing polypeptide
(Bacteriostatic)
3 Groups:
Short-acting i.e. Tetracycline, Oxytetracycline
Intermediate-acting i.e. Democlocycline for SIADH (no longer used as antibiotic)
Long-acting i.e. Doxycycline, Minocycline
*If short-acting would need frequent dosing QID, if longer-acting can use BID)
What is the most important mechanism of resistance against Tetracyclines? Which tetracycline has the most resistance against this resistance?
Bacterial efflux pump (encoded in multi-drug resistence gene shared via plasmids)
*Minocycline is the most resistant against this
Also resistance via prevention of TCN entering the cell
