Antibacterial pharmacology: Aminoglycosides Flashcards
Bacterial ribosomes: selective targets for antibiotics
- while the general process of translation from mRNA to protein is similar in prokaryotes and eukaryotes, bacterial ribosomes are fundamentally different in composition
- bacterial ribosomes have a smaller overall “sedimentation rate” (S) and are comprised of a 50S subunit and a 30S subunit
- rRNAs are responsible for the important activities of the ribosome and are targets of antibiotic drugs
Antibiotics that inhibit or disrupt normal bacterial protein synthesis come with some considerations …
- selectivity: some antibiotic drugs that interfere with ribosomal function can also inhibit host ribosomes → can lead to serious advere effects (e.g. chloramphenicol)
- complete inhibition of protein synthesis is not sufficient to kill a bacterium; therefore, most inhibitors of protein synthesis are bacteriostatic
- aminoglycosides are an exception to this rule: they are bactericidal
Attributes of aminoglycosides
- used mainly to treat infections caused by gram negative bacteria
- bind to the 16S rRNA of the 30S ribsosomal subunit
- induces misreading of mRNA - aminoglycoside (AG) resistance: bacterial expression of transferase enzymes can alter AG structure; mutation to 16S rRNA
- highly ionized → limited ability to cross membrane
- can be used synergistically with b-lactams but b-lactams can not be used with other inhibitors of protein synthesis
- All generic names end in “-mycin”, “-micin”, “-cin” but Vancomycin is not an AG
Aminoglycosides (AGs) tend to work best agaisnt what bacteria?
- AGs tend to work best against gram negative bacteria; since they are hydrophilic, they can access the cytoplasm through porins
what are the three subclasses of aminoglycosides?
- Gentamicin
- Tobramycin
- Amikacin
What are the two main clinical uses of aminoglycosides?
- systemic, empirical administration for dangerous, life-threatening gram negative aerobic infections
- e.g. septicemia, infective endocarditis, sepsis, complicated intraabdominal infections, and complicated genitourinary infections
- can also be used directly (after C&S) to manage hard-to-treat infections
- e.g. combined therapy for brucellosis, listeriosis, CNS nocardiosis, and Pseudomonas aeruginosa infection, or monotherapy for tularemia or the plague - topical administration (e.g. for staph, e.coli, etc)
- all follow the concentration-dependent model of killing bacteria
attributes of aminoglycoside Gentamicin
- bactericidal
- broadest spectrum of activity
- excellent against gram negative aerobes, some gram positive aerobes (inc. staph), and some atypical bacteria (mycoplasma) - administered IV due to limited absorption, but for skin staph infections or some eye infections, topical or ophthalmic formulations are available
- resistance: usually through plasmid-acquired enzymes that alter AG structure through adenylation, acetylation, or phosphorylation
attributes of aminoglycoside Tobramycin
Attributes:
- clinically interchangable with gentamicin
- used as a second-line treatment for bacteria that are resistant to gentamicin (resistance is less common with tobramycin
- inhaled tobramycin is approved to manage cystic fibrosis (CF) in patients aged six or older with Pseudomonas aeruginosa
- Tobramycin for opthalmic use is approved to treat external ocular infections
Aminoglycosides distribution and elimination
Distribution:
- while AGs absorb poorly, once in the bloodstream , they do distribute to most tissues (minus the CNS)
- Preferentially accumulate in the renal cortex and inner ear (perilymph and endolymph)
Elimination:
- mainly excreted unchanged in urine
- short elimination half-life (2-3h)
attributes of aminoglycoside amikacin
Attributes:
- clinically interchangable with gentamicin
- used as a second-line treatment for bacteria that are resistant to gentamicin (resistance is less common with amikacin)
what are the main adverse effects of aminoglycosides?
- Nephrotoxicity
- Ototoxicity
Main adverse effect of aminoglycosides: nephrotoxicity
- Ags accumulate in renal tubular cells and enchance free radical formation → damage some renal tubular epithelial cells in every patient
- proximal renal tubular epithelium regenerates well → usually not a problem (i.e. as long as cell loss is not extensive)
- Ordinary doses can be very damaging to kidneys of dehydrated patients and patients with renal disease (half-life of most AGs doubles in old age)
- AGs enter renal cells via saturable transporter → amount entering cells depends on duration of exposure rather than peak concentration
- damage is minimized by allowing a washout period each day → give single daily dose and allow concentrations to fall for remainder of the day
Main adverse effect of aminoglycosides: oxytoxicity
- AGs damage CN VII and hair cells in cochlea and vestibular apparatus
- can cause permanent, severe, high-frequency hearing loss
- hair cells in vestibular apparatus appear to have some regenerative ability → permanent vestibular damage possible but less common than hearing loss
nephrotoxicity and ototoxicity occur independently - some individuals develop hearing loss within 1 day (sometimes within 4 h) of treatment; others my experience no hearing loss even after several months of treatment
- it appears susceptible individuals metabolize aminoglycosides to produce a cytotoxin; this ability appears to be inherited
- Nephro- & ototoxicity dramatically limit the systemic use of AGs
what are the 4 mechanisms of bacterial resistance?
- keep the antibiotic out
- pump the antibiotic out
- modify the target
- destroy the antibiotic
Mechanism of bacterial resistance - keep the antibiotic out
Mechanism of bacterial resistance - pump the antibiotic out
- All bacteria possess chromosomally encoded genes for efflux pumps
- Some are expressed constitutively, others are overexpressed under certain environmental stimuli
- Mutations in chromosomal DNA or horizontal gene transfer through plasmid DNA can confer resistance in previously sensitive bacteria
