Aminoglycoside Flashcards
Be able to recognize the structural features that are common to aminoglycoside antibiotics.
a) They have 1,3-diaminocyclitol “core structure” that are usually linked to one or more aminoglycoside rings. Core structures are streptidine and 2-deoxystreptamine.
Be able to describe the mechanism of action of the aminoglycosides.
a) Inhibit protein biosynthesis by binding to the 30S ribosomal subunit. Bind to the 16S rRNA in the 30S subunit forming the A site. This interferes with formation of the initiation complex, blocks further translation, and elicits premature termination.
Binds to RNA through ionic bonding
c) Can also affect the 30S ribosomal subunit to cause a frame shift. This results in the formation of altered proteins
Be able to characterize aminoglycoside uptake mechanisms.
involves the displacement of Mg++ and Ca++ ions that form salt bridges with phosphate of the phospholipids in the membrane. This makes the membrane more permeable to the aminoglycosides. This passage through the cytoplasmic membrane is energy dependent – an active transport process.
Be able to describe the mechanisms that bacteria use to become resistant to aminoglycosides.
a) 3 mechanisms involved:
i) Metabolism: bacteria inactivate aminoglycosides by acetylation, adenylation, and phosphorylation. Makes biologically inactive metabolites. The genes responsible for metabolism can be transferred to other bacteria.
ii) Altered ribosomes: 16S rRNA binding site can be altered through point mutations.
iii) Altered aminoglycoside uptake: don’t get into bacterial cell; rate of emergence is far less than resistance due to metabolism, and the phenotype reverts after the drug is removed.
Be able to describe the toxicity of aminoglycosides.
a) Toxicity is low incidence. All are ototoxic (irreversible) and nephrotoxic (reversible).
Be able to describe the symptoms of aminoglycoside ototoxicity.
a) Ototoxicity can result in tinnitus and high-frequency hearing loss, or in vestibular damage resulting in vertigo, loss of balance, and ataxia.
Be able to state which aminoglycoside toxicities are reversible and which are not.
a) Ototoxic: irreversible; nephrotoxic: reversible
Be able to specify which drugs can potentiate the nephrotoxicity of the aminoglycosides.
a) Concurrent use with loop diuretics (ethacrynic acid and furosemide) or other nephrotoxic antimicrobial drugs (vancomycin or amphotericin) can potentiate ototoxicity and nephrotoxicity.
Be able to describe the potential toxic effect that aminoglycosides can have on respiration, and how it can be reversed or treated.
a) Respiratory paralysis can usually be reversed by neostigmine (acetylcholinesterase inhibitor) or calcium gluconate, but mechanical respiratory assistance may be necessary. Calcium increases the degree of depolarization at the neuromuscular junction caused by acetylcholine.
Be able to describe the risk factors for manifestation of aminoglycoside toxicity.
a) Ototoxicity: risk factors include concurrent use of other ototoxic drugs (loop diuretics or vancomycin), compromised renal function, or genetic vulnerability.
b) Nephrotoxicity: concurrent use with loop diuretics (ethacrynic acid and furosemide) or other nephrotoxic antimicrobial drugs (vancomycin or amphotericin) can potentiate nephrotoxicity and should be avoided.
Be able to describe how aminoglycoside toxicity can be minimized.
duration of therapy should be minimized, and serum concentrations should be monitored to minimize toxicity.
Be able to specify the main clinical uses of the aminoglycosides.
a) Have broad spectrum antibiotic activity against both gram-(+) and gram-(-) bacteria, in practice, their use is almost always reserved for treatment of gram-(-) bacteria.
Often used in combo with penicillins in order to take advantage of the synergism between these 2 classes of antibiotics (their activities potentiate each other).
b) Penicillin/aminoglycoside combo treats bacterial endocarditis.
c) Streptomycin treats tuberculosis.
d) Gentamicin is used for UTIs, burns, some pneumonias, and joint and bone infections caused by susceptible gram-(-) infections.
e) Amikacin has retained antibacterial activity against aminoglycoside-resistant strains and is useful to treat nosocomial infections.
Be able to explain why aminoglycosides and penicillins should not be administered together in the same solution, or even at the same injection site.
a) Should be administered in different compartments, one in each arm, to avoid a chemical reaction between the 2 classes. The beta lactam ring of penicillins and chemically reactive and interact with the amino groups (acylation of amino groups) present in aminoglycosides forms an inactive complex. They neutralize each other’s antibacterial activity.
Be able to describe an aminoglycoside-induced frame shift, and its consequences.
This means, for example, that instead of a codon CCG, a codon CGU is read by aminoacyl tRNA, which carries a different amino acid, because the anticodon on the aa-tRNA is different. This results in the formation of altered proteins. Misreading of codons or shifting of the reading frame during translation.
b) Get disruption of accurate synthesis of proteins.
Main clinical use of amikacin
: used competitively with gentamicin for treatment of mycobacterium tuberculosis, francisella tularensis, and severe pseudomonas aeruginosa infections resistant to other agents. Also used to treat aminoglycoside-resistant nosocomial infections in hospitals.
