Protein Syn Inhibitors ABX PART 1 - 30s Flashcards
Mechanisms for inhibition of protein synthesis
- Bind to 30S ribosome
- Bind to 30S ribosome
a) Aminoglycosides (Streptomycin,Gentamicin, Tobramycin, Amikacin, Neomycin)
MOA: Block proofreading & ribosomal translocation
b) Tetracyclines (Tetracycline, Doxycycline, Minocycline)
MOA :prevents binding of incoming tRNA
Mechanisms for inhibition of protein synthesis
- Bind to 50s ribosome
- Bind to 50S ribosome
a) Macrolides (Clarithromycin, Azithromycin)
MOA: Blocks polypeptide exit tunnel
b) Lincosamides (Clindamycin)
MOA: Binding site overlaps with Macrolides
c) Streptogramins (Quinupristin/Dalfopristin)
MOA: Binding site overlaps with Macrolides
d) Oxazolidinones (Linezolid, Tedizolid)
MOA: Binds 23S rRNA, prevents ribosome assembly
Aminoglycosides
MOA/ where it acts
- Primarily bind the aminoacyl (A) site of 16S rRNA in the 30S subunit, this results in the genetic code being misread and translocation inhibited.
- Pass Gram neg outer membrane through porins.
- Pass inner membrane by oxygen & energy dependent transport….NO activity against anaerobes (C.diff or B. Fragilis)
- IRREVERSIBLE inhibitors of protein synthesis. Bind to 30S ribosome, Block proofreading & ribosomal translocation.
- BACTERICIDAL (unlike most protein synthesis inhibitors!)
Aminoglycosides
Drug names only
Streptomycin, Neomycin, Gentamicin, Tobramycin, Amikacin
Aminoglycosides
Effects, PK, administration?
• IV administration
• Concentration-dependent killing: Dosing goal=Plasma Concentration 10-12 Times the MIC (Single daily dose!)
• Post-antibiotic effect (PAE)-Gram neg
• Synergistic with Beta-lactam antibiotics or vancomycin due to the disruption of
cell wall synthesis, which enhances diffusion of the aminoglycosides into the bacterium
Aminoglycoside used in combination with . . .
o in combination with a β-lactam antibiotic in serious infections with
aerobic Gram-negative bacteria (improves survival in sepsis!)
o Gentamicin in combination with vancomycin or a β-lactam antibiotic
for Gram-positive endocarditis (Enterococcus)
Resistance to Aminoglycosides
- Ribosome mutations prevent binding
- Aminoglycoside modifying enzymes (AME) – acetylation, phosphorylation
- Impaired entry (porin deletion/mutation, loss of active transport)
- Efflux pumps
BOXED WARNINGS (Aminoglycosides) 1-3
- ) Neurotoxicity, manifested as both bilateral auditory and vestibular ototoxicity can occur. The risk of aminoglycoside induced ototoxicity is greater in patients with renal damage. High frequency deafness usually occurs first and can be detected only by audiometric testing. Vertigo may occur and may be evidence of vestibular injury. Other manifestations of neurotoxicity: numbness, skin tingling, muscle twitching and convulsions. Patients who develop cochlear damage may not have symptoms during therapy to warn them of eighth‐nerve toxicity, and partial or total irreversible bilateral deafness may continue to develop after drug is stopped. IRREVERSIBLE!!!!!!
- ) Nephrotoxicity, Risk is greater in patients with impaired renal function and in those who receive high doses or prolonged therapy. Rarely, nephrotoxicity may not become apparent until the first few days after cessation of therapy. Aminoglycoside nephrotoxicity usually is reversible.
- Embryofetal toxicity: May can cause fetal harm when administered during pregnancy.
Aminoglycosides
Significant Toxicity:
Nephrotoxic (reversible) . . . how does kidney tox happen??
Dosage adjustment required in renal dysfunction!!
- Aminoglycosides bind to cytoplasmic membrane of proximal tubular cells and are internalized and trapped in lysosomes.
- Lysosomes also accumulate myeloid bodies. These cause damaged and leaky membranes.
Monitor: Serum creatinine concentration is best
measure of renal toxicity
Aminoglycosides
Significant Toxicity:
Ototoxic (hearing loss, vestibular damage-loss of balance) how does it happen? what to monitor ??
Destroys hair cells in cochlea
Auditory impairment irreversible!
Exposure dependent – can occur with single dose
MONITOR: Renal fxn 8th nerve fxn Serum drug conc (periodic) Urine specific gravity/protein Serum BUN, creatinine & creatine clearance Serial audiograms
Aminoglycosides . . . the different drugs and their key points!
- Gentamicin: IV, also topical and ophthalmic forms . . . can be use in combo with cell wall syn inhibitors!
- Amikacin: Can be used to treat severe, HA-infections with
MDR Gram neg bacteria (P. aeruginosa, Acinetobacter, Enterobacter)
administered IV, IM or nebulization - Neomycin: Topical or Oral (oral before bowel surgery nor absorbed!)
- Streptomycin: Widespread resistance, Use generally limited to susceptible tuberculosis, plague, tularemia
Tetracyclines/Glycylcyclines
Drugs and MOA ?
DRUGS: Tetracycline (short acting)
Doxycycline (Vibramycin®, Doryx®), Minocycline (Minocin®) –> long acting
MOA: Binds reversibly to the 30S ribosome and prevents binding of the incoming charged tRNA unit
Generally bacteriostatic
Can inhibit protein synthesis in mammalian cells (partially), but an
active efflux mechanism prevents intracellular accumulation. so not bad for humans . . .
Tetracyclines . . . MOA of entry inside bacteria? (2 ways)
- Enter Gram (+) bacteria by an energy-dependent transport protein carrier mechanism
- Enter Gram (-) bacteria by passive diffusion and/or through porins in the
outer membrane followed by the energy-dependent transport in the cytoplasmic membrane.
Concentrated intracellularly in susceptible organisms
Tetracyclines resistance? (3 ways)
- Resistance due to active efflux through an energy dependent system
- Acquisition of genes that encode ribosomal protection proteins that block binding of tetracyclines
- Antibiotic modification (enzymatic inactivation)
Tetracyclines coverage
KNOWN FOR: Strength in activity against ATYPICAL bacteria, including rickettsiae (Rocky Mountain spotted fever, Lyme disease), chlamydiae and mycoplasms
KNOW THIS - Doxycycline – CAP (s. pneumonia) and MRSA and MSSA
Minocycline – P. acnes, bacterial meningitis, STIs
(gonorrhea and Chlamydial infections), also covers
MRSA
