Lecture 20 Aminoglycosides Flashcards
What are examples of aminoglycosides?
neomycin, streptomycin, spectinomycin, gentamicin, tobramycin, amikacin
How do aminoglycosides enter bacterial cells?
they are cationic and bind (-) charged outer membrane proteins (lipopolysaccharides) polar heads of phospholipids in Gram (-) organisms
competitively displaces cell wall Mg2+ and Ca2+ ⇒ causes rearrangement of lipopolysaccharide and formation of transient holes
enters cell through energy dependent processes ⇒ EDP-I, EDP-II, entry into cell is pH dependent
What is the MOA of aminoglycosides?
binds to 30S ribosomal subunit binding sites in mRNA decoding region ⇒ interferes with mRNA binding sites and tRNA acceptor sites ⇒ infidelity in reading genetic code ⇒ production of fraudulent proteins
What are mechanisms of acquired resistance for bacteria against aminoglycosides?
enzymatic mod of drug ⇒ most common mech of resistance, enzymes catalyze addition of acetyl, adenyl, or phosphoryl group inactivating drug, enzymes have overlapping affinities for different types of this drug (cross-resistance possibility), often plasmid mediated
Ribosomal resistance ⇒ rare, loss of binding to streptomycin
Ineffective transport into cell ⇒ rare (S. aureus)
Efflux ⇒ MexXY pump appears to explain adaptive resistance
What is adaptive resistance to aminoglycosides?
transient resistance that follows rapid, early, conc-dependent killing of susceptible bacteria
lasts only few hours but lasts beyond PAE into time of regrowth
due to activation of MexXY efflux
resistance disappears as aminoglycosides conc approach 0
once daily dosing (extended interval dosing) beneficial in reversing
What is the spectrum of activity of aminoglycosides, and which drugs have additional spectrum?
synergistic with beta-lactams and vancomycin against ⇒ Gram +: S. aureus (MRSA, MSSA), streptococci (viridans in endocarditis) + GBS, enterococcus, Listeria
Gram -: Pseudomonas, facultative bacteria
Amikacin: M. tuberculosis and avium, other mycobacteria
Streptomycin: M. tuberculosis, Tularemia, Y. pestis
Spectinomycin: N. gonorrhoeae
What is the absorption of aminoglycosides?
very poorly absorbed orally (caution in renal failure)
poor absorption topically unless severe skin damage,, very good absorption IM (= to 20-30 min IV) unless shock, edema
rapid absorption from peritoneum, pleura
little absorption from bladder irrigations and intratracheal admin
How do aminoglycosides distribute, and eliminated?
freely to most interstitial spaces
distributes to ECF
crosses biological membranes poorly unless active transport (as in renal tubular cell)
cross poorly into CSF except in neonate
for the eye distributes to cornea and aqueous humor and slowly to vitreous
poor levels in prostate
they are eliminated >90% unchanged renally, t1/2 2-3 hours
What are the major toxicities of aminoglycosides?
nephro, oto - cochlear, vestibular
neuromuscular blockage
How do aminoglycosides cause nephrotoxicity, how prevalent is it?
5-25% of pt (usually mild and reversible)
increased SCr good indicator, and increased trough levels can be early indicator
they are transported across renal tubular brush border cells through endocytosis and conc in proximal tubular cells (5-50x serum conc) and through a complex mech the apoptotic pathway is activated causing necrosis in renal proximal tubule
happens usually after several days
What is aminoglycoside ototoxicity, prevalence, progression, and what may be the fxn causing it?
may cause cochlear damage = hearing loss, vestibular damage = vertigo
for hearing loss it causes damage to hair cells of organ of Corti in cochlear ⇒ damage often permanent but some damaged hair cells may develop improved fxn, with future tx possibly causing additional toxicity
in vertigo it causes damage to hair cells of summit of ampullar cristae ⇒ long-term, usually considered permanent
may occur during tx or weeks after tx discontinued
has been reported as high as 62%, but overall quoted as 3-14%
Progression: tinnitus and fullness may be first S&S for hearing loss, tones of high frequency lost first (unnoticed by pt) ⇒ progresses to lower tones
imbalance (may be worse in dark), dizziness, visual problems, oscillopsia, blurred vision with head movement, and age risk factor since vestibular ganglion cells decrease with age may be first S&S for vertigo
Cause: likely fxn of total exposure (AUC) and conc achieved, in rats the hair cell uptake is rapid and dose dependent, demonstrates early saturation, increasing tissue t1/2 with prolonged exposure
What are toxicity risk factors for nephrotoxicity and aminoglycosides?
unadjusted dosage, >3 days tx, pre-existing renal failure/hepatic dysfxn, hypotension, frequent dosing interval, concomitant nephrotoxic drugs, previous aminoglycoside
What are toxicity risk factors for ototoxicity and aminoglycosides?
duration of tx, dose, hypovolemia, renal failure/hepatic dysfxn, concurrent loop diuretics and cisplatin, hypotension, previous aminoglycoside
What is aminoglycoside neuromuscular paralysis?
rare, associated with high conc at neuromuscular jxn,, ensure dose given slowly over at least 20-30 min
enhanced by curare/like drugs like succinylcholine, Mg2+, and myasthenia gravis
can be tx with prompt admin of Ca2+
What are common uses of gentamicin and tobramycin, amikacin, streptomycin, spectinomycin, and neomycin (when are they used, when aren’t they used, for example)?
Gentamicin/Tobramycin: tx of serious Gram (-) infections, gentamicin > against Gram (+) (including enterococci) and serratia, tobramycin > against Pseudomonas,, may be cross-resistance
Amikacin: lower in vitro potency - must give higher doses, has higher therapeutic range, potential advantage of it maybe being stable to plasmid-mediated enzymes
Streptomycin: primary antitubercular drug, also treats tularensis, Y. pestis, Brucella
synergistic with penicillin or vancomycin for S. viridans or enterococcus in endocarditis (gentamycin usually preferred)
often not used if pt > 50 yrs due to ototoxicity, is least nephrotoxic but most ototoxic
Spectinomycin: only use - resistant N. gonorrhoeae, not effective for pharyngeal gonorrhea
Neomycin: too toxic for systemic use, has been used topically, and orally as 500 mg to sterilize GIT (1 g Q4H F2-3D), hepatic encephalopathy (250 mg TID-QID - 4 g/day orally), caution in renal failure
What are drug interactions that aminoglycosides can have?
additive nephrotoxicity ⇒ amphotericin B, cisplatin, cyclosporine, vancomycin
additive ototoxicity ⇒ loop diuretics, vancomycin
enhanced neuromuscular blockage ⇒ with muscle relaxants (ex. succinylcholine)
with penicillins (high dose) or in same IV bag ⇒ may inactivate drug, give IV separately (1 hour apart), may occur in vivo in severe renal failure, may interfere with blood levels taken for PK, (oral neomycin inhibits oral absorption of penicillin by as much as 50%)
What is plazomicin?
new aminoglycoside recently approved in USA
used for tx of serious bacterial infections due to multidrug-resistance enterobacterales including carbapenem-resistant enterobacterales
