aminoglycosides Flashcards
Gentamicin (generic, Garamycin, Jenamicin)
1st choice due to low cost!
-Pseudomonas, enterobacter, Klebsiella, Serratia and others
-UTIs (+ B-lactam abx for complicated) (uncomp: TMP-SMX; less toxic)
-pneumonia from G- bac (+ B-lactam): NOT recommended for CAP (not effective against S. pneumo, anaerobes) DON’T use as sole agent (low penetration, low O2, low pH: dec. activity)
-meningitis: (1st line is Ceftriaxone, etc)
-G+ infections: + PCN for enterococcal ENDOCARDITIS
-sepsis from G- bacteria (including Pseudomonas: + antips. PCN)
-topical, for burns
-peritonitis
Tobramycin, Amikacin, Netilmicin can also be used in these ways
Tobramycin (generic, Nebcin)
- better activity against Pseudomonas aeruginosa than Gentamicin, used to tx bacteremia, osteomyelitis, and pneumonia (combo w. antiPs-PCN, aztreonam, or ceftizidime)
- inhalation dosage form of Tobramycin (TOBI): tx of bronchopulmonary Pseudomonal inf. in CF pts
- NOT effective aging E. faecium
Amikacin (generic, Amikin)
broadest spectrum: resistant to many of the bac enzymes that inactivate others (Gentamicin and Tobramycin)
-Kleb, Pseudomonas, Proteus, Enterobacter, Serratia
-not good against G+, less active against enterococci (not used for ent. endocarditis)
-activity against Mtb, including streptomycin-resistant strains
USED FOR:
-serious nosocomial infections caused by gram G- aerobic bacilli in hospitals (where there is resistance to Gentamicin and Tobramycin)
Streptomycin
- less activity against G- enteric bacteria, resistance limits the use of this drug to only a few clinical applications:
- bac endocarditis (enterococci, Strep viridans) in combination with PCN (Gentamicin typ. preferred but may show resistance)
- 2nd line for MDR-Mtb (combo)
- Yersinia pestis (Plague) and tularemia (IM w. oral tetra)
-inactivated by a different enzyme than the other aminoglycosides.
most frequently used aminoglycosides
Gentamicin, Tobramycin, Amikacin
aminoglycoside structure and properties
hexose nucleus attatched by glycosidic linkages to amino sugars
- polar drugs, poor oral absorption (almost entire dose may be eliminated in feces!) give IV or IM
- water soluble, stable in solution, and are more active at an alkaline pH than at an acidic pH.
Aminoglycosides administered simultaneously with with beta-lactam antibiotics should not be mixed in the same solution, why?
can form a chemical complex
typical route of aminoglycoside administration
traditional administration frequency?
30 – 60 minute IV infusion
2-3x/day. However, a once a day dosing regimen may be preferred
aminoglycosides: enter cells readily??
what tissues do they not penetrate well?
NO, polar drugs that do not readily enter cells (They are relatively lipid insoluble)
eye and CNS
although do not penetrate CNS well, with inflammation of the meninges you can get approximately 20% of the serum levels into the brain, tx of choice for meningitis??
not a high enough concentration of drug to be effective for treating meningitis
-BUT can be administered by intrathecal or intraventricular injection to treat brain infections, BUT ceftriaxone is tx of choice
Concentrations in most tissues after IV or IM administration: high or low?
where can it be found high?
not extremely high
-renal cortex and inner ear (nephrotoxicity and ototoxicity)
how aminoglycosides get into cells?
diffuse through the porin channels in the OM of G- bac
-then cross plasma membrane by O2-dependent active transport
active transport process across the plasma membrane is inhibited by ??
low pH and anaerobic conditions
-not effective against anaerobic bacteria and they won’t be effective in the acidic environment of an abscess
Antibiotics that inhibit ?? enhance the transport of aminoglycosides into the bacterial cell
bacteria cell wall synthesis (e.g. Penicillins, cepahlosporins, vancomycin)
synergistic killing effect
aminoglycoside elimination
- not metabolized and are cleared by the kidney (via glomerular filtration) in direct proportion to creatinine clearance
- w. normal renal function: half-life: 2-3 hrs
- renal failure: 24-48 hrs! need to adjust dose!!
aminoglycoside MOA
inhibit bacterial protein synthesis by irreversibly binding to the bacterial 30 S bacterial ribosomal subunit
-bactericidal (dose-dependent)
aminoglycoside MOA in detail
- block initiation of protein synthesis
- block the movement of the ribosome, causing the 70 S ribosome to break up into 50S and 30 S subunits (polysomes become nonfunctional monosomes)
- misreading of the mRNA code leading to the production of mutant proteins that kill the bacteria (effect continues after drop below MIC, once daily doses effective)
aminoglycoside adverse effects
Ototoxicity Auditory toxicity Vestibular toxicity Nephrotoxicity Neuromuscular block hypersensitivity skin reactions (rare, streptomycin)
Ototoxicity (8th cranial nerve damage)
Potentially irreversible Auditory and Vestibular damage
Streptomycin = kanomycin > Amikacin = Gentamicin = Tobramycin > Netilmicin
-accumulate in endolymph and perilymph of the inner ear and can cause irreversible destruction of vestibular and cochlear sensory cells (hair cells)