Exam 1- Cushman Lec 3- Aminoglycosides Flashcards
What are the core structures of an aminoglycoside?
*Streptidine and *2-deoxystreptamine
1,3-diaminocyclitol structures
-usually linked to one or more aminoglycoside rings
What are the clinically important aminoglycosides?
Tobramycin
Plazomicin
Amikacin A
Gentamicin C2
Neomycin B
Streptomycin
What is the MOA of aminoglycosides?
Multifaceted
-Inhibit protein biosynthesis by binding the 30S ribosomal subunit and causing a frame shift mutation
-Bind the 16S rRNA forming the A site which interferes with initiation complex formation, blocks translation, and elicits premature termination
-Causes impairment of the proofreading function of the ribosome and formation of “nonsense proteins” -resulting from selection of the wrong amino acids during translation
–nonsense proteins impair bacterial cell wall function which then allows transport of more aminoglycoside inside
-protein synthesis ceases
-Leakage of ions occurs and disruption of cytoplasmic membrane, causing cell death
What are the aminoglycoside uptake mechanisms?
Initial entry of positively charged aminoglycosides through the outer bacterial membrane involves displacement of Mg and Ca ions that form salt bridges with phosphates of phospholipids in the membrane
-makes the membrane more permeable to aminoglycosides
Passage through the cytoplasmic membrane is an active transport process
What are the 3 mechanisms of resistance against aminoglycosides?
Metabolism
Altered Ribosomes
Altered Aminoglycoside Uptake
What are the 3 mechanisms of aminoglycoside metabolism?
Bacteria inactivate aminoglycosides by:
-Acetylation
-Adenylation
-Phosphorylation
What toxicities are seen with aminoglycosides?
-Ototoxic (irreversible)
-Nephrotoxicity (reversible)
-Curare-like effects (large doses)
-Respiratory paralysis (reversible with medication)
What are the symptoms of ototoxicity?
-Tinnitus
-High-frequency hearing loss
Vestibular damage (vertigo, loss of balance, ataxia)
What drugs used concurrently with aminoglycosides can increase the risk of nephrotoxicity?
-Loop diuretics (ethacrynic acid + furosemide)
-Nephrotoxic antimicrobials (vancomycin + amphotericin)
If ototoxicity or nephrotoxicity occur with an aminoglycoside, what should be done?
Discontinue the drug or dose adjust
What medications can be given to reverse respiratory paralysis caused by aminoglycosides?
Neostigmine
Calcium gluconate
What are the risk factors for aminoglycoside toxicity?
More likely to occur if:
-treatment is extended more than 5 days
-elderly
-impaired renal function
-higher doses
How can aminoglycoside toxicity be minimized?
There are typically more effective and less toxic alternatives available
-aminoglycosides should be used sparingly and only for specific indications
-duration should be minimized and serum concentrations monitored
What are the main clinical uses of the aminoglycosides?
-Almost always reserved for Gram -
-Often used in combination with penicillins due to synergism
-Penicillin/ Amino combo: Bacterial endocarditis
-Streptomycin: Tuberculosis
*Gentamycin: UTI, burns, pneumonias, joint and bone infections caused by susceptible Gram - infections
Amikacin: hospital-acquired resistant infections
Why should aminoglycosides and penicillins be administered in different solutions/injection sites?
A chemical reaction can occur between the two classes
-chemical reaction leaves both drugs inactivated
Penicillin/Aminoglycoside combinations are used to treat what?
Bacterial endocarditis
Streptomycin is used to treat what?
Tuberculosis
Gentamicin is used to treat what?
UTI
Burns
Pneumonias
Eye infections
Joint and bone infections
Amikacin is used to treat what?
Hospital-acquired (nosocomial) resistant infections
Used competitively with gentamicin to treat:
-Mycobacterium tuberculosis
-Francisella tularensis
-Pseudomonas aeruginosa
why is amikacin less susceptible to bacterial metabolism than kanamycin?
Amikacin is synthesized from kanamycin A
-the presence of the L-hydroxyaminobuteryl amide moiety inhibits bacterial metabolism by R factors
-this makes amikacin more potent and resistant
How does bacterial metabolism of tobramycin occur?
-It lacks a 3’-hydroxyl group and cannot be phosphorylated here
-But, it is adenylated at C-2 and acetylated at C-3
Tobramycin is used to treat what?
Pseudomonas aeruginosa
-same indications as gentamycin
Why is gentamycin the most important aminoglycoside in use?
-Low cost
-Reliable activity against all but the most resistant Gram - aerobes
Which aminoglycosides are used orally?
Neomycin
Paromomycin
*note that aminoglycosides are not absorbed from the digestive tract, these work locally
What are the oral aminoglycosides used for?
Suppression of gut flora in travelers diarrhea
Prophylactic prior to GI surgery
-decrease incidence of peritonitis
Paromomycin: tapeworms + amoebic dysentery
How is streptomycin administered?
Deep IM injections
-painful
What is Plazomicin used for?
Complicated UTI’s
