aminoglycosides Flashcards
what are aminoglycosides?
Neomycin Streptomycin Spectinomycin Gentamicin* Tobramycin* Amikacin
Entry into Bacterial Cell
amino considered bactericidal
Cationic aminoglycosides (due to amino groups) bind to negatively charged anionic outer membrane protein,
lipopolysaccharides, polar heads of phospholipids in Gramnegative organisms
Competitively displace cell wall Mg++ andCa++
Causes rearrangement of lipopolysaccharide & formation of
transient holes
Then enter cell through energy dependent processes
EDP-1 (slow to cytosol), EDP-II (fast to ribosome, bacterial killing)
entry into cell pH dependent (reduced at low pH or anaerobic
environment)
Exhibit concentration-dependent killing effect
Mechanism of Action
Binds to 30S ribosomal binding sites in the mRNA decoding region of the 30S subunit
Interferes with mRNA binding sites & tRNA acceptor sites
“Infidelity in reading genetic code”
Production of “Fraudulent” Proteins
Elusive Effects
Lethal effects on bacterial cell
Mechanisms of Acquired
Resistance
Enzymatic Modification ofAminoglycoside
most common mechanism of resistance
enzymes catalyse addition of acetyl, adenyl,
or phosphoryl grp inactivating aminoglycoside
enzymes have overlapping affinities for
various aminoglycosides → may lead to cross-resistance
enzyme production often plasmid mediated
Ribosomal Resistance Rare → loss of binding to streptomycin Ineffective Transport Into Cell Rare (S. aureus) Efflux MexXY efflux pump appears to explain adaptive resistance
Adaptive Resistance
A transient resistance to aminoglycosides that follows the rapid, early, concentration-dependent killing of susceptible bacteria
Lasts only a few hours but lasts beyond the post-antibiotic effect (PAE) into time of regrowth
Due to the activation of the MexXY efflux pump that pumps out the aminoglycoside in the presence of aminoglycosides
Resistance (and function of MexXY efflux pump) disappears as aminoglycoside concentrations approach 0
Once daily dosing (Extended Interval Dosing (EID))
beneficial in reversing adaptive resistance
Spectrum of Activity
facultative Gram-negative bacteria including Pseudomonas
synergistic effects with cell wall activeagents
synergistic with β-lactams and Vancomycinagainst:
MSSAStaphylococci, MRSA
Streptococci, (Viridans grp in endocarditis)
Group B Streptococci
Enterococcus faecalis (Gentamicin synergy 78% 2019)
Enterococcus faecium (Gentamicin synergy 87% 2019)
Listeria
P. aeruginosa UAH 2019 All T 95%, G 90%
CF T 82%, G 63%
Added Spectrum
Amikacin
Mycobacteriumtuberculosis
Mycobacterium avium
Streptomycin
Mycobacterium tuberculosis
tularemia, Yersinia pestis
Spectinomycin
N. gonorrheae
Absorption
very poorly absorbed orally
Caution in renal failure – even small amounts absorbed may accumulate
poor absorption topically unless severe skin damage
(e.g. major burns)
very good absorption IM (equal to 20-30 min IV) unless
shock, edema etc.
rapid absorption from peritoneum, pleura
little absorption from bladder irrigations and intratracheal administration
Distribution
Freely distributed to most interstitialspaces
Distributes to extracellular fluid
Crosses biological membranes poorly unless active transport system,
as in renal tubular cell where transport leads to toxicity
Crosses poorly into CSF except in neonate
eye
• distributes to cornea and aqueous
humour and slowly to vitreous humour
• subconjunctival and intravitreal
injections used in endopthalmitis
Urinary concentration 25 -100 times serum levels and remains therapeutic for days
Poor levels in prostate
Metabolism/Elimination
> 90% eliminated unchanged renally
t1/2 2-3 hours (normal renal function adults)
Toxicity
Three major toxicities
Nephrotoxicity Ototoxicity Cochlear (hearing loss) Vesitibular (vertigo) Neuromuscular blockage(rare)
Nephrotoxicity
5 - 25% of patients - usually mild and reversible
Rarely - progression to dialysis-dependent renal failure
↑ SCr a good indicator (may be lag time inappearance)
↑ trough levels of aminoglycoside can be an early indicator with traditional dosing
aminoglycosides transported across the renal tubular brush border cells through endocytosis and concentrated in proximal renal tubular cells (5-50x serum concentration), contributing to nephrotoxicity
onset - usually after severaldays
Accidental overdose of ≤ 1 day has not resulted in acute tubular necrosis
Uptake of aminoglycosides by renal tubular cells, and possibly toxicity, is mediated by an endocytotic receptor megalin
Through a complex mechanism the apoptotic pathway is activated, causing necrosis of cells in the renal proximal tubule
Ototoxicity
Damage may be cumulative with further doses of
aminoglycosides due to further damage to the hair cells
(cochlear or vestibular)
May be potentiated by other ototoxic drugs such as cisplatin
or the loop diuretics (ethacrynic acid, furosemide)
Recognized in 1940s withstreptomycin Aminoglycosides may cause Cochlear damage – hearing loss Vestibular damage – vertigo HearingLoss Damage to hair cells of organ of Corti in the cochlea Vestibulardysfunction Damage to hair cells of summit of ampullar cristae in the vestibular complex
may occur during therapy
may occur weeks after therapy discontinued
incidence of hearing loss has been reported to be as high as 62%
overall incidence is quoted as 3 -14%
Cochlear Toxicity
Drug accumulates in the endolymph and perilymph in the inner ear, resulting in damage to the sensory hair cells of the organ of Corti in the cochlea
Limited regenerative capacity of sensory cells and
supporting cells
Damage is oftenpermanent
Future treatment with aminoglycosides may result
in additive cochlear toxicity
Progression of Hearing Loss
Tinnitus and feeling of fullness in ears may be the first signs of ototoxicity
Tones of higher frequency lost first
unnoticed by the patient
Ideal to test by audiometry (pre and post administration)
Hearing loss progresses and lower frequency tones
(regular, speaking tones) affected
Hair cells do not usually regenerate, however some
damaged hair cells may develop improved function
Future doses of aminoglycosides may result in cumulative hearing loss
Ototoxicity likely a function of
Ototoxicity likely a function of total exposure (AUC) concentrationsachieved In the rat, the hair cell uptake rapid, dose dependent demonstrates early saturation increasing tissue t1/2 with prolonged exposure
Vestibular Toxicity - Vertigo
Drug accumulates in the endolymph and perilymph in the inner ear
resulting in damage to the hair cells of the summit of the ampullar
cristae in the vestibular complex
manifested as imbalance, dizziness, and visual problems
Imbalance is worse in the dark or if footing is uncertain
Spinning vertigo is uncommon
Visual symptoms, oscillopsia, results in transient
blurring of vision with head movements
Age is a risk factor since normally vestibular ganglion cell
counts decrease with age so that by 80 years of age, only
about 50% of vestibular neurons remain
long term vest toxicity
Initially dizziness, loss of balance, visual disturbances
Long-term
Patients may compensate with visual and proprioceptive
mechanisms
May have problems with eyes closed, in thedark
May have problems compensating in patients with
poor vision or proprioceptive difficulties
hearing loss and vertigo usually consideredirreversible
clinical reports & laboratory studies – may be some potential
for regeneration
Toxicity – Risk Factors
Nephrotoxicity unadjusted dosages > 3 days treatment Pre-existing renal failure/hepatic dysfunction Hypotension/volume depletion Frequent dosing interval Concomitant nephrotoxic drugs (e.g. vancomycin, amphotericin B, etc.) Previous aminoglycoside
Ototoxicity duration oftreatment dose hypovolemia(BUN/Cr) renal failure/hepatic dysfunction loopdiuretics Hypotension previousaminoglycoside
Strategies to Reduce
Aminoglycoside Oto/Nephrotoxicity
Limit use ofaminoglycosides Monitoring of serumlevels Avoiding other ototoxic/nephrotoxic drugs Automatic stoporders ? Once daily dosing ofaminoglyosides
Neuromuscular Paralysis
Rare
Associated with high concentrations at
the neuromuscular junction
Ensure dose given slowly over 20 - 30 minutes
Enhanced by curare-like drugs,
succinylcholine, magnesium, and myasthenia gravis
Can be treated with prompt administration of Ca
(experimentally has inhibited myocardial and
vascular smooth muscle as well ?? clinical relevance)
Gentamicin/Tobramycin
treatment of serious Gram-negative infections
Gentamicin > activity against Gram positives (including
Enterococci) and Serratia
(gentamycin synergistic with penicillins/ampicillin against
Enterococci)
Tobramycin > activity against Pseudomonas
May be cross-resistance
Tobramycin ??? less nephrotoxic and ototoxic than
Gentamicin
Amikacin
lower in vitro potency – must give higher doses
Potential Advantage
May be stable to plasmid-mediatedenzymes
Streptomycin
primarily an antituberculardrug
• also treats tularensis, Yersina pestis, Brucella
synergistic with penicillin or vancomycin
for S. viridans or Enterococcus
endocarditis (gentamicin usually preferred)
often not used if patient > 50 yrs due to risk ofototoxicity
least nephrotoxic, most ototoxic of aminoglycosides
Spectinomycin
only use - resistant N. gonorrheae
not effective for pharyngeal gonorrhea
Neomycin
too toxic to be used systemically
has been used topically (may cause skin sensitisation)
e.g., Neosporin cream or ointment
has been used as oral tablets 500 mg to sterilize GIT
(1g q4h x 2-3 days)
hepatic encephalopathy
(250 mg tid-qid - 4 g/day orally)
caution in renal failure (small amount absorbed
but not excreted in renal failure )
Aminoglycoside Interactions
AdditiveNephrotoxicity
Amphotericin B, Cisplatin, Cyclosporin, ? Vancomycin
AdditiveOtotoxicity
Loop diuretics (e.g., furosemide, ethacrynic acid)
?Vancomycin
Enhanced neuromuscular blockade with muscle
relaxants (e.g., succinylcholine)
Penicillins (high dose) or in same IV bag may inactivate
aminoglycosides
Give IV drugs separately (one hour apart)
May also occur in vivo in severe renal failure
May interfere with blood levels taken for PK
(Oral Neomycin inhibits the oral absorption of penicillin
by as much as 50%)
Plazomicin
New aminoglycoside recently approved in USA
Treatment of serious bacterial infections due to multidrugresistant Enterobacterales, including carbapenem-resistant
Enterobacterales
