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Pharm > aminoglycosides > Flashcards

aminoglycosides Flashcards

1
Q

Gentamicin (generic, Garamycin, Jenamicin)

A

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

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2
Q

Tobramycin (generic, Nebcin)

A
  • 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
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3
Q

Amikacin (generic, Amikin)

A

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)

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4
Q

Streptomycin

A
  • 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.

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5
Q

most frequently used aminoglycosides

A

Gentamicin, Tobramycin, Amikacin

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6
Q

aminoglycoside structure and properties

A

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.
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7
Q

Aminoglycosides administered simultaneously with with beta-lactam antibiotics should not be mixed in the same solution, why?

A

can form a chemical complex

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8
Q

typical route of aminoglycoside administration

traditional administration frequency?

A

30 – 60 minute IV infusion

2-3x/day. However, a once a day dosing regimen may be preferred

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9
Q

aminoglycosides: enter cells readily??

what tissues do they not penetrate well?

A

NO, polar drugs that do not readily enter cells (They are relatively lipid insoluble)

eye and CNS

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10
Q

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??

A

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

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11
Q

Concentrations in most tissues after IV or IM administration: high or low?
where can it be found high?

A

not extremely high

-renal cortex and inner ear (nephrotoxicity and ototoxicity)

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12
Q

how aminoglycosides get into cells?

A

diffuse through the porin channels in the OM of G- bac

-then cross plasma membrane by O2-dependent active transport

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13
Q

active transport process across the plasma membrane is inhibited by ??

A

low pH and anaerobic conditions

-not effective against anaerobic bacteria and they won’t be effective in the acidic environment of an abscess

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14
Q

Antibiotics that inhibit ?? enhance the transport of aminoglycosides into the bacterial cell

A

bacteria cell wall synthesis (e.g. Penicillins, cepahlosporins, vancomycin)
synergistic killing effect

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15
Q

aminoglycoside elimination

A
  • 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!!
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16
Q

aminoglycoside MOA

A

inhibit bacterial protein synthesis by irreversibly binding to the bacterial 30 S bacterial ribosomal subunit
-bactericidal (dose-dependent)

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17
Q

aminoglycoside MOA in detail

A
  • 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)
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18
Q

aminoglycoside adverse effects

A 
Ototoxicity 
Auditory toxicity
Vestibular toxicity
Nephrotoxicity
Neuromuscular block
hypersensitivity skin reactions (rare, streptomycin)
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19
Q

Ototoxicity (8th cranial nerve damage)

A

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)

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20
Q

aminoglycosides risk of ototoxicity increases with ??

A

other drugs that cause ototoxicity:
Loop Diuretics: furosemide, ethacrynic acid
Vancomycin
Cisplatin

pts who are elderly, dehydrated, or receiving high doses for long periods

21
Q

Auditory toxicity

most common offenders??

A

tinnitus (ringing in the ear) and loss of hearing

Amikacin, Kanamycin, Netilmicin and Neomycin

22
Q

Vestibular toxicity

common offenders??

A

vertigo, ataxia, and loss of balance

Gentamicin, Streptomycin, and Tobramycin

23
Q

Nephrotoxicity – Acute tubular necrosis

most common offenders?

A

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

24
Q

Increased risk of aminoglycoside-induced nephrotoxicity:

A
  • 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
25
Q

Neuromuscular block

most potent offenders?

A

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

26
Q

how to tx NM blockage from aminoglycoside

A

IV calcium salt and a Cholinesterase inhibitor
(e.g. edrophonium and neostigmine)
-may require
mechanically assisted respiration

27
Q

Increased risk of aminoglycoside-induced neuromuscular blockade:

A
  • Intrapleural injection or peritoneal instillation
  • pt w. myasthenia gravis
  • with general anesthetics, or neuromuscualr blocking drugs (Succinylcholine, Tubocurarine)
28
Q

Because the aminoglycosides are highly toxic ?? are routinely determined in patients

A

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)
29
Q

Frequency of determining blood levels of aminoglycosides

A
  • 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
30
Q

when to check blood levels with a once a day dosing regimen

A

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.
31
Q

most important mechanism of bacterial resistance to the aminoglycosides ??

A

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

32
Q

most important form of resistance is mediated by ??that are spread by ??

what aminoglycosides are more resistant to these inactivating enzymes??

A

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
33
Q

Plasmid mediated resistance by bacterial production of aminoglycoside inactivating enzymes is of concern with ??

A

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
34
Q

other mechs of bac resistance to aminoglycosides

A
  • 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)
35
Q

aminoglycoside spectrum of activity: G+ bacteria??

A

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
36
Q

Gentamicin and Streptomicin are used with a ?? to get a synergistic effect with sensitive strains of ??

A

bacterial cell wall synthesis inhibitor (e.g. Penicillin G or Ampicillin)
-enterococci and S. viridans

37
Q

aminoglycoside spectrum of activity: G- bacteria??

A

best activity against AEROBIC G- enteric bacteria

Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis

38
Q

what amino glycosides have activity against Psueudomonas??

A

Gentamicin, Tobramycin, Netilmicin and Amikacin

39
Q

aminoglycoside spectrum of activity: anaerobic bacteria??

A

NOT ACTIVE AGAINST, aminoglycosides get transported into bacteria by an oxygen-dependent transport process
-ALSO not effective against Fungi or Viruses

40
Q

clinical uses of the Aminoglycosides

A
  • 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
41
Q

Streptomycin adverse effects

A

-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

42
Q

Tobramycin and Amikacin are less active against ?? than Gentamicin, and these two aminoglycosides should not be used for ??

A

enterococci
enterococcal endocarditis

(The enterococcal enzyme that inactivates Gentamicin also can inactivate Amikacin, Netilmicin, and Tobramycin)

43
Q

Gentamicin adverse effects

A
  • 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.
44
Q

Tobramycin toxicity

A

nephrotox and ototox (big surprise)

45
Q

Amikacin toxicity

A

nephro and oto (auditory defects more common)

46
Q

Neomycin and Kanamycin (FYI?)

A

not significantly absorbed from the GI tract, and use is limited to topical and oral admin

47
Q

Spectinomycin (Trobicin) (FYI?)

A

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)

48
Q

FA: “Mean” (aminoglycoside) GNATS caNNOT kill anaerobes.

A

Gentamicin, Neomycin, Amikacin, Tobramycin, Streptomycin

Nephrotoxicity, Neuromuscular blockade, Ototoxicity (especially when used with loop diuretics). Teratogen

Pharm (45 decks)

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