Aminoglycosides and Colistin Flashcards
Describe the MOA of Aminoglycosides
Electrostatic binding to bacterial outer membrane, weakening lipopolysaccharide links and causing formation of temporary holes in the outer membrane, which allow the antibiotic to enter the bacterial cytoplasm.
* Once an aminoglycoside has entered the cell, it binds to specific 30S-subunit ribosomal proteins.
* Protein synthesis is inhibited by aminoglycosides in at least three ways:
o They interfere with the initiation complex of peptide formation;
o They induce misreading of mRNA, which causes incorporation of incorrect amino acids into the peptide, resulting in a nonfunctional or toxic protein; and
o They cause a breakup of polysomes into nonfunctional monosomes. These activities occur more or less simultaneously, and the overall effect is irreversible and lethal for the cell.
List the aminoglycosides
Gentamycin, tobramycin and amikacin
What are mechanisms of resistance for aminoglycosides?
- Plasmid-encoded enzyme productionthat results in reduction of the AB activity (principal resistance mechanism)
- Altered target: Ribosomal 30S subunit
- Altered AG transport mech, which reduce AG concentrations inside the bacteria
Describe aminoglycoside chemical structure
Aminoglycosides have a hexose ring, either streptidine (in streptomycin) or 2deoxystreptamine (other aminoglycosides), to which various amino sugars are attached by glycosidic linkages.
What other AB do aminoglycosides work synergistically with?
- Aminoglycosides frequently exhibit synergism with β-lactams or vancomycin in vitro. In combination they eradicate organisms more rapidly than would be predicted from the activity of either single agent. However, at high concentrations aminoglycosides may complex with β-lactam drugs, resulting in loss of activity, and they should not be mixed together for administration.
List the 5 different types of toxicities associated with aminoglycosides?
- Nephrotoxicity
- Ototoxicity
- Cochlear damage: auditory toxicity
- Vestibular toxicity due to damaged hair cells
- Neuromuscular Blockade
Describe the Nephrotoxicity that can result from AG use?
Injury to the proximal tubule leads to a decrease in CrCl
o Affects 5-10% patients; usually reversible upon d/c AG
o May manifest as increasing SCr and BUN, proteinuria, oligouria or non-oligouric renal failure
o SCr should be monitored every 4 days in patients on AG
What are risk factors to experiencing nephrotoxicity?
- Length of therapy (>10 days)
- Older age
- Pre-existing renal dysfunction or hepatic dysfunction
- Volume depletion or hypotension
- Concomitant use of nephrotoxic agents, including vancomycin, amphotericin B, cyclosporine, furosemide, NSAIDS and foscarnet
- Previous courses of AG therapy or other nephrotoxins within 1 year
- Renal transplant
What type of dosing may help reduce nephrotoxicity with aminoglycosides?
Once daily dosing!
Describe ototoxicity that can occur with AG use?
Often reversible, may occur during or up to weeks after AG therapy in d/c; repeated exposure increases risk. If detected, AG must be stopped.
How does vestibular toxicity manifest with AG?
- nausea, vomiting, vertigo, dizziness, unsteady gait with nystagmus.
Describe the potential neuromuscular blockade side effect of aminoglycosides?
Rare, but potentially fatal complication of therapy o Has occurred after intraperitoneal lavage or rapid IV bolus therapy, especially in patients with myasthenia gravis or concurrent use of succinylcholine
o Mech: AG interferes with presynaptic release of ACh and post-synaptic receptors, causing weakness of respiratory muscles, flaccid paralysis and dilated pupils
o Potentiated by hypocalcemia or hypomagnesemia
o Paralysis may be reversed by administering calcium gluconate, and can be prevented by infusing AG’s slowly over 20-30 min
Describe the PK of Aminoglycosides
Only available for parenteral administration
- Renally eliminated; dosage adjustment necessary in renal impairment
- Limited penetration into CSF and poor penetration into bronchial secretions
- May be dosed in two ways: conventional dosing or extended interval dosing
What describe how conventional dosing works for aminoglycosides:
- How is it dosed based on wt?
- Who is it reserved for?
- When are troughs used? Peaks?
Conventional dosing:
- based on IBW; may be initiated with a loading dose followed by regular dosing at q 8-12 hr intervals
- usually reserved for patients who are not candidates for extended interval dosing (e.g. moderate to severe renal insufficiency, dialysis, endocarditis, burns, pregnancy, ascites, single prophylactic doses before surgery) or when AG is being used for synergy (e.g. vs. Enterococcus species)
- trough levels useful for monitoring against toxicity in prolonged therapy; peak levels only performed if efficacy is questionable
Why can extended interval dosing be used with AGs?
due to concentration-dependent killing and prolonged post-antibiotic effect vs. gram negative bacteria
