Flashcards in aminoglycosides Deck (48):
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
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
-serious nosocomial infections caused by gram G- aerobic bacilli in hospitals (where there is resistance to Gentamicin and Tobramycin)
-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*
-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!!*
inhibit bacterial protein synthesis by irreversibly binding to the bacterial 30 S bacterial ribosomal subunit
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
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)
aminoglycosides risk of ototoxicity increases with ??
other drugs that cause ototoxicity:
Loop Diuretics: furosemide, ethacrynic acid
pts who are elderly, dehydrated, or receiving high doses for long periods
most common offenders??
tinnitus (ringing in the ear) and loss of hearing
Amikacin, Kanamycin, Netilmicin and Neomycin
vertigo, ataxia, and loss of balance
Gentamicin, Streptomycin, and Tobramycin
Nephrotoxicity – Acute tubular necrosis
most common offenders?
in the proximal tubule cells
-can be reversible
-rise in serum creatinine levels (measure every 2 – 3 days to monitor)
-cell or casts in urine, dec. sp. gravity, oliguria, proteinuria, inc. BUN
Gentamicin, Tobramycin and Neomycin
Increased risk of aminoglycoside-induced nephrotoxicity:
-higher doses, tx lasting longer than 5 days
-co-admin w. another nephrotoxic agent like vanco or a ceph
-pre-existing renal failure
-elderly and dehydrated patients
most potent offenders?
w. high doses
-muscle weakness and respiratory paralysis
-can inhibit the release of ACh at the NM junction, and also inhibit postsynaptic sensitivity to ACh
Neomycin and Netilmicin
how to tx NM blockage from aminoglycoside
IV calcium salt and a Cholinesterase inhibitor
(e.g. edrophonium and neostigmine)
mechanically assisted respiration
Increased risk of aminoglycoside-induced neuromuscular blockade:
-Intrapleural injection or peritoneal instillation
-pt w. myasthenia gravis
-with general anesthetics, or neuromuscualr blocking drugs (Succinylcholine, Tubocurarine)
Because the aminoglycosides are highly toxic ?? are routinely determined in patients
blood levels of drug
-Peak concentration: 30 - 60 minutes after an IV infusion or IM admin, shows if achieving therapeutic levels
-Trough concentration: 30 minutes prior to the next dose : *above 2 μg/ml for gentamicin are indicative of a potential for toxicity* (use hemodialysis)
Frequency of determining blood levels of aminoglycosides
-within 48 hours after starting therapy, and every 3-4 days thereafter in patients with stable renal function
-several times/wk if life threatening systemic infections
-If dosage increased in a pt (e.g. 24 hours after changing the dose)
-also in pts with rapidly changing renal function
when to check blood levels with a once a day dosing regimen
don’t need to check the peak concentrations because they will be high and will be in the therapeutic range
-do need to monitor the trough concentration to avoid toxicity
-goal with Gentamicin: obtain a trough of less than 1 μg/ml 18 to 24 hours after dosing.
most important mechanism of bacterial resistance to the aminoglycosides ??
bacterial enzymes that can phosphorylate, adenylate, or acetylate the drug
-metabolites formed from these enzymatic reactions are can't bind 30 S ribosome-->can't inhibit bacterial protein synthesis
most important form of resistance is mediated by ??that are spread by ??
what aminoglycosides are more resistant to these inactivating enzymes??
mediated by plasmids that are spread by conjugation (cross-resistance to other abx may be transferred: SMX, tetra, chloramphenicol)
-wide spread and are especially problematic in hospital settings
-Amikacin and Netilmicin: more useful against hospital-acquired infections, Gentamicin-resistant G- bacteria are usually susceptible
Plasmid mediated resistance by bacterial production of aminoglycoside inactivating enzymes is of concern with ??
enterococcal infections (e.g. *E. faecium* and E. faecalis)
-concern with treating endocarditis
-Strains of E. faceium resistant to all known antibiotics are a serious concern in hospitals in the US
other mechs of bac resistance to aminoglycosides
-Inability of the abx to penetrate the bac: genotypic: decreased porins/porin mutations in G-bac
phenotypic: low O2/acidic-->can't get in via O2 dependent transport
-Mutations in the 30 S ribosome that alter ribosomal structure and decrease binding of the aminoglycoside (occurs w. Streptomycin)
aminoglycoside spectrum of activity: G+ bacteria??
limited, used in combo w. an abx that inhibits bacterial cell wall synthesis to get a synergistic bactericidal effect and to get better coverage against G+ bac
-Gentamicin and Tobramicin: in vitro effect against 90% S. aureus, 75% S. epidermidis (but don't use alone for serious staph infections)
-*S. pneumo and S. progenies are highly resistant*
Gentamicin and Streptomicin are used with a ?? to get a synergistic effect with sensitive strains of ??
bacterial cell wall synthesis inhibitor (e.g. Penicillin G or Ampicillin)
-enterococci and S. viridans
aminoglycoside spectrum of activity: G- bacteria??
best activity against AEROBIC G- enteric bacteria
Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis
what amino glycosides have activity against Psueudomonas??
Gentamicin, Tobramycin, Netilmicin and Amikacin
aminoglycoside spectrum of activity: anaerobic bacteria??
NOT ACTIVE AGAINST, aminoglycosides get transported into bacteria by an oxygen-dependent transport process
-ALSO not effective against Fungi or Viruses
clinical uses of the Aminoglycosides
-severe systemic infections caused by G- enteric bacteria (e.g. sepsis)
-combo with a bac cell wall sysnthesis inhibitor (e.g. PCN) to treat bac endocarditis
Streptomycin adverse effects
-allergic skin rashes
-Pain at injection site
-Ototoxicity: disturbance of vestibular function of the ear, typ. irreversible, associated with vertigo and loss of balance
(Vestibular toxicity is seen more often in patients taking drug for > 2 weeks)
-use by pregnant women can cause deafness in the child
Tobramycin and Amikacin are less active against ?? than Gentamicin, and these two aminoglycosides should not be used for ??
(The enterococcal enzyme that inactivates Gentamicin also can inactivate Amikacin, Netilmicin, and Tobramycin)
Gentamicin adverse effects
-Nephrotoxicity – Can be reversible and occurs in 5 – 25% or patients who receive the drug for more than 3-5 days
-Ototxicity: *more vestibular toxicity* (e.g. Loss of balance, vertigo, ataxia), but loss of hearing may also occur (1 - 5 % in pts tx more than 5 days)
-A trough concentration of >2 μg/ml for longer than 10 days has been associated with toxicity.
nephrotox and ototox (big surprise)
nephro and oto (auditory defects more common)
Neomycin and Kanamycin (FYI?)
not significantly absorbed from the GI tract, and use is limited to topical and oral admin
Spectinomycin (Trobicin) (FYI?)
alternative agent for treating gonorrhea for patients who are allergic or resistant to other drugs (the drug of choice for gonorrhea is a third generation cephalosporin e.g. Cefixime or Ceftriaxone)