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Aminoglycosides
bactericidal inhibitors of protein synthesis
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Aminoglycoside drugs
- streptomycin
- neomycin
- kanamycin
- amikacin
- gentamicin
- tobramycin
- sisomicin
- netilmicin
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Aminoglycosides are used most widely against
- gram-negative enteric bacteria
- bacteremia
- sepsis
- endocarditis
- tuberculosis
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Stability of aminoglycosides
- water soluble
- stable in solution
- more active at alkaline pH
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Mechanism of action of aminoglycosides
- irreversible inhibition of protein synthesis
- passive diffusion across the outter membrane
- active transport across the cell membrane
- transport may be enhanced by PCN or vanc
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Aminoglycosides bind _____ inside the cell
- 30s ribosomal subunit
- some bind 50s
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3 ways protein synthesis is inhibited by aminoglycosides
- block initiation complex formation
- interfere with the proofreading process, causing increased rate of errors in synthesis
- inhibition of ribosomal translocation where the peptidyl-tRNA moves from the A site to the P site
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Initial site of aminoglycoside action
- outer bacterial membrane
- aminoglycoside creates fissures in the cell membrane
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3 mechanisms of resistance to aminoglycosides
- enzymes that inactivate the aminoglycoside
- impaired entry of aminoglycosides into the cell
- absence or alteration of the receptor on the 30s subunit
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Most common mechanism of resistance encountered by aminoglycosides
enzymatic inactivation
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Oral absorption of aminoglycosides
- very poor
- only good if ulcerations are present
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Aminoglycoside bactericidal effects are based on
- drug concentrations
- increasing concentrations kill increasing proportions of bacteria
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Postantibiotic effect
- antibacterial activity persists beyond the time which measureable drug concentrations are present
- can last several hours with aminoglycosides
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Aminoglycosides in anaerobes
- energy is needed for aminoglycoside uptake
- less energy available in anaerobes
- aminoglycoside = less effective in anaerobes
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Single daily doses are ______ when compared to multiple smaller doses through out the day.
just as effective and no more toxic
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it is recommended that aminoglycosides be given
once daily
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aminoglycosides must be dosed based on
renal function
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aminoglycosides are cleared by the _____ and excretion is directly proportional to _______.
- kidney
- creatinine clearance
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Aminoglycoside distribution
- highly polar compounds that do not enter cells readily
- excluded from CNS and the eye
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Aminoglycoside dosing is based on
renal function
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Manditory during aminoglycoside therapy
monitoring of serum levels
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Aminoglycosides are used mostly against
gram-negative enteric bacteria
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Aminoglycosides are almost always used in combination with
- b-lactam antibiotics
- extends coverage to gram + organisms
- utilizes synergism
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PCN-aminoglycoside combo therapy is used in the treatment of
- enterococcal endocarditis
- shortens the duration of therapy for staph. endocarditis
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the lowest concentration of a drug in the blood between doses
trough
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Adverse effects of aminoglycosides are ____ and ____ dependant
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Toxicity is unlikely to occur with aminoglycosides until
- a certain threshold concentration is met
- 2 mcg/ml trough = toxicity
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All aminoglycosides exhibit this toxicity
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Aminoglycoside oto/nephrotoxicity are more likely to be encountered when
- therapy is more than 5 days
- high dosage is used
- elderly pt
- pt has renal insufficiency
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Use of aminoglycosides with ______ can potentiate nephrotoxicity.
- loop diuretics
- other nephrotoxic antimicrobials
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The most ototoxic aminoglycosides
- neomycin
- kanamycin
- amikacin
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The most vestibulotoxic aminoglycosides
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the most nephrotoxic aminoglycosides
- neomycin
- tobramycin
- gentamicin
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Streptomycin
- similar activity as the aminoglycosides
- same mechanisms of resistance
- resistance limits the use of this drug
- ribosomal resistance develops readily
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Streptomycin is mainly used as
- a second line agent for treatment of tuberculosis
- only in combo with other agents to prevent resistance
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Use of streptomycin in non-tuberculosis infections
- plague, tularemia, brucellosis
- in combo with oral TCN
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Streptomycin is useful in combo with PCN for the treatment of
- enterococcal endocarditis
- 2 week therapy for viridans strep. endocarditis
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Streptomycin alone may be used to treat
enterococcal infections
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Adverse reactions of Streptomycin
- hypersensitivity (rash, fever...)
- usually in patients on long therapy
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the most serious toxic effect with streptomycin
- disturbance of vestibular function (irreversible)
- vertigo, loss of balance
- porportional to age, blood levels and duration of therapy
- can cause deafness in a newborn if given to mom
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Gentamycin spectrum
gram - and gram +
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All aminoglycosides, including gentamicin have no activity against
anaerobes
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Streptococci and enterococci are relatively resistant to gentamicin because
gentamicin fails to penetrate into the cell
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Gentamicin uptake into the cells is greatly increased when administered with
vancomycin
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Among gram-negative bacteria, resistance to gentamicin is most commonly due to
aminoglycoside modifying enzymes
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Gentamicin is mainly used IV or IM for
severe infections caused by gram - bacteria
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Gentamicin is used in combo with a second agent because
an aminoglycoside alone my not be effective for infections outside the urinary tract
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Aminoglycosides are not used as single-agent therapy for pneumonia because
- penetration of lung tissue is poor
- local condition of low pH and low oxygen = poor activity
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Topical gentamicin is used for
- infected burns, wounds or skin lesions
- prevention of IV catheter infections
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Gentamicin ADRs
- reversible mild nephrotoxicity (5-25% of pt receiving for 3-5 days)
- irreversible ototoxicity (vestibular dysfunction)
- loss of hearing could be possible
- hypersensitivity is uncommon
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