Aminoglycosides Flashcards
Major toxicities associated with aminoglycosides
- Nephrotoxicity (Kidney)
- REVERSIBLE
- Gent > trob > amk > strep
- risk factors: age, prolong use + hi [trough], underlying RI, HYPOvolemia, conconimant neprhopathies - Ototoxicity (ear)
- idiopathic
- very dangerous because NOT reversible
- damage to CN 8
- symptoms can occur after damage
cochelar: amikan> gent > trop
vestibular: strep > gen > am > trop
Aminoglycosides - name the drugs
GNATS: gentamycin N- Amikacin Trobamycin Streptomycin
Order of discovery: S > G > T > A
Aminoglycosides: MOA
Inhibition of Protein Synthesis
IRREVERSIBLY binds the 30S subunit of the ribosome, disrupting initiation of protein synthesis, leading to decrease synthesis and misreading mRNA
Concentration-dependent bacteriCIDAL activity
Aminoglycosides - does it work against anaerobes?
is NOT effective against anaerobes, because AG require oxygen to enter the cell, thus in environments without oxygen, the AG won’t be able to come in.
Aminoglycosides: Mxn of Resistance (3)
- Synthesis of AG modifying enzymes:
- plasma -mediated resistance)
- bacteria enz modifies the AG (acetylation, adenyation etc), to cause poor AG-ribosome binding
- cross resistance btw gent and trob - Lack of cellular concentration of AG, via decrease porin channels and/or increase efflux pumps
- Poor binding by changing the binding site or target
overall, by changing any part of the bidnign or the electrochemical gradient, could lead to decrease in AG penetration
Also, alteration of ribo binding site (more rare)
Aminoglycosides: Spectrum of Activity Streptomycin
Gram +, esp. Enteroccocus
Mycobacteria T. (less than amikacin)
Aminoglycosides: Spectrum of Activity
Gentamycin
Gram +
(ENTEROCCOCUS, S. aureus, S. penumo, S. pyogenes), viridians group
Gram -
(PEK, citrobact, enterobac, morganella, serration and PSEUDOMONAS)
Aminoglycosides: Spectrum of Activity
Trobomycin
Gram -
Similar to gent (PEK, citrobact, enterobac, morganella, serration and PSEUDOMONAS)
but a bit less gram neg activity with MORE ACTIVITY AGAINST PSEUDOMONAS
Aminoglycosides: Spectrum of Activity
Amikacin
Gram -
more activity against gram - nosocomial infections! (EXCEPT pseudomonas)
Broad activity against mycobaterial infections
Nocardia
Aminoglycosides: Clinical Uses
Gram -
- gent, trob, amikacin*
- (use combine with B-lactams)
- Pseudomonas (Trob > gent)
- Pneumonia (high dose of amikacin)
- UTIs (probably only monotherapy)
- Bacteremia
- Intra-abdominal infections
- *EMPIRIC for SEPSIS esp. urinary source**
- SSTI
Gram + *Gent and Strep* - in combo with (naf or vanco) for severe inf. - ENTERROCOCCUS infection - staph endocarditis (low doses okay)
Other: Mycobacterial infections (amikacin, strepto) in combo + high doses
Aminoglycosides: AEs
- Nephrotoxicity [9-15%]
- Reversible (if dose is lower or DC)
- occurs probably due to accumulation of AGs in the renal tubules; AGs can saturate _ at therapeutic levels
- INC in BUN, INC in Creatinine
- GENT>Trob>AM >Strepto
- Risk Factors: age, dose, how long it is used for, concentration at trough level, hypovolumic state, RI, underlying nephrotoxicity, concominant nephrotoxicies (vanco, cisplatin, CT contrasts) - Ototoxicity [3-14%]
- IRREVESIBLE, damage to CN VIII
- toxicity can occur prior to symptoms
Cochlear damage: Amik > gent > trop
Vestibular damage: Strepto > gent > am
- sx range from tinnitus, hearing loss to vestibular sx of dizziness, vertigo, ataxia, nystagmus
- Risk Factors: prolong therapy >2 wks, RI, ??:age, [trough], genetics - RARE - neuromuscular blockage preventing presynaptic internalization of calcium required for ACH release
Aminoglycosides: Pharmocology
Absorption:
- poor oral absorption
- IV preferred
Distribution:
- good urine distribution
- high H2O solubility
- low CNS, increase with inflammation
- pleural, pericardial, ascites and synovial fluids
Elimination:
-Renal
(reabsorption into proximal tubule may lead to accumulation in renal cortex - renal tox??)
- 30-40% removed by HD
Pharmacodynamics:
- Concentration-dependent killing
- Peak/Mic goal > 8-10
-exhibits post-antibiotic effects
depends on: organism, [drug], duration of
drug exposure, antimicrobial activity
Rational for using extended release (6):
- Concentration-dependent bacteriCIDAL activity
gents minimized with extended intervals - Post-antibiotic effects
increases with extended, because higher
[peak] - Adaptive resistance
less risk for bug to develop resistance,
because with extended interval at higher
dose - Decrease risk for toxicity
allows for AG to clear out, not accumulate - Cost savings
- Efficacy
