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Pharm > 2: Aminoglycosides, Streptogramins, and Oxazolidinones > Flashcards

2: Aminoglycosides, Streptogramins, and Oxazolidinones Flashcards

1
Q

core structure of aminoglycosides

A

1,3-diaminocyclitol linked to one or more aminoglycoside rings

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2
Q

name 7 clinically important aminoglycosides

A
  • tobramycin
  • kanamycin A
  • amikacin A
  • gentamicin C2
  • neomycin B
  • streptomycin
  • spectinomycin
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3
Q

aminoglycoside MOA

A

bind 16S rRNA of 30S:

  • interferes with formation of initiation complex
  • blocks further translation
  • elicits premature termination
  • impairment of proofreading
  • formation of nonsense proteins that impair bacterial cell wall function
  • damage membranes, allowing increased transport of drug into cell -> stops protein synthesis completely
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4
Q

what do aminoglycosides ultimately lead to?

A

leakage of ions and disruption of the cytoplasmic membrane, resulting in cell death

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5
Q

describe bacterial aminoglycoside uptake

A

drugs displace Mg2+ and Ca2+ ions that form salt bridges with phosphates of the phospholipids of the membrane
-makes the membrane more permeable

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6
Q

passage of aminoglycosides through membrane: active or passive

A

active transport process

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7
Q

three mechanisms of resistance to aminoglycosides

A
  1. metabolism via acetylation, adenylation, phosphorylation
  2. 16S rRNA binding site altered via point mutations
  3. reduced uptake of drug
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8
Q

metabolic resistance to aminoglycosides: describe where each of the processes occurs (on what functional groups)

A

adenylation and phosphorylation on -OH groups

acetylation on amino groups

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9
Q

what are the toxicities of aminoglycosides

A

irreversible ototoxicity
reversible nephrotoxicity
in large doses- curare-like effects

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10
Q

describe aminoglycoside ototoxicity

A
  • tinnitus, high-frequency hearing loss

- vertigo, loss of balance, ataxia

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11
Q

how can you monitor ototoxicity during aminoglycoside use

A

serial audiograms

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12
Q

risk factors for ototoxicity with aminoglycosides

A
  • concurrent use of other ototoxic compounds (loop diuretics, vancomycin)
  • compromised renal function
  • genetic vulnerability
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13
Q

name two loop diuretics that can potentiate nephrotoxicity in aminoglycosides

A
  • ethacrynic acid

- furosamide

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14
Q

name two nephrotoxic antimicrobial drugs that can potentiate nephrotoxicity in aminoglycosides

A
  • vancomycin

- amphotericin

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15
Q

how can you monitor nephrotoxicity during aminoglycoside use

A

creatinine clearance and dosage decrease

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16
Q

what are the curare-like effects you can get with aminoglycosides and how do you reverse them?

A

respiratory paralysis - can usually be reversed by neostigmine or calcium gluconate (AChEi)

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17
Q

what increases likelihood of aminoglycoside toxicity

A

length of treatment period

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18
Q

use of aminoglycosides

A 
both G(+) and G(-) 
but almost always reserved for G(-)
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19
Q

what are aminoglycosides often paired with

A

penicillins due to synergism, but they are administered in different compartments to avoid a chemical rxn between the two drugs

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20
Q

what are penicillin/aminoglycoside combos used to treat

A

bacterial endocarditis

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21
Q

what is streptomycin most often used to treat

A

TB

22
Q

what is gentamicin usually used for

A

UTIs
burns
some pneumonias
joint and bone infections caused by susceptible G(-)’s

23
Q

which aminoglycoside has retained antibacterial activity against resistant strains

A

amikacin

24
Q

what are the streptogramins

A

semisynthetic derivatives of a natural mixture of pristinamycin I and pristinamycin II

25
Q

what is synercid a combination of

A

30% quinupristin

70% dalfopristin

26
Q

why do we not use the parent combination of streptogramins

A

less suitable solubility for reliable solubility

-the amino side chains of quinupristin and dalfopristin allow salt formation and enhance water solubility

27
Q

synercid: bacteriostatic or bacteriocidal

A

each component is bacteriostatic on its own, but combination is bacteriocidal

28
Q

how is streptogramin administered

A

parenterally

29
Q

dalfopristin MOA

A

directly interferes with peptidyl transferase-catalyzed step of peptide bond formation

30
Q

quinupristin MOA

A

binds in the ribosomal tunnel and causes blockage of the tunnel
“constipation of the ribosome”

31
Q

what is another way you can get resistance to streptograim that involves gating the exit tunnel

A

mutation of A2062

32
Q

IV synercid used to treat what

A
  • VRE bacteremia
  • MRSA skin infections
  • VRE UTIs
33
Q

resistance mechanisms for synercid

A
  • adenine methylation of A2058 = blocks quinupristin, but no effect on dalfopristin (makes it bacteriostatic)
  • efflux and enzymatic inactivation (metabolism)
34
Q

what is streptogramin often reserved for

A

serious life-threatening G(+) infections

35
Q

what will continue to result in more resistant bacterial strains to streptogramins

A

continued use of virginiamycin in animal feeds

36
Q

in some patients, what has a 14d course of synercid selected for?

A

resistant forms of E. faecialis, E. faecium, and S. aureus

37
Q

streptogramin side effects

A 
no known significant toxicity 
several mild side effects: 
-inflammation/pain at injection site 
-nausea
-diarrhea
-muscle weakness
-rash
38
Q

why are the PK of streptogramins complicated?

A

different elimination rates for each component and their metabolites

39
Q

half life of streptogramins

A

1.5h - linear relationship b/w dose and AUC

40
Q

does synercid cross any barriers?

A

nope - not BBB or placental barriers

41
Q

what do macrophages do to synercid?

A

concentrate it up to 50x the extracellular fluid concentrations

42
Q

describe elimination of synercid

A

75% via biliary excretion (fecal matter)

25% via urine

43
Q

DDI with streptogramins

A

inhibit CYP3A4
-potential DDI w/ warfarin, diazepam, astemizole, terfenadine, cisapride, non-nucleoside reverse transcriptase inhibitors, and cyclosporine

44
Q

what are two oxazolidinones

A

linezolid and eperezolid

45
Q

linezolid MOA

A

interacts with 23S rRNA of 50S with uM affinity - prevents the formation of the 70S initiation complex

46
Q

what is linezolid used to treat

A
  • VRE
  • nosocomial pneumonia (MRSA)
  • MRSA skin infections
47
Q

why is linezolid a magic bullet

A
  • excellent oral bioavailability
  • can be given oral or IV
  • half life 4-6h
48
Q

linezolid resistance in what species

A

initially Enterococcus

now resistant strains of MRSA, E. coli, and others

49
Q

linezolid mechanism of resistance

A

target site modification

  • G2576U in peptidyl transferase center of 23S rRNA: reduced affinity of linezolid to 50S
  • other sites of mutation (T2500A) in S. aureus are close to P site
50
Q

linezolid side effects: mild, more severe, and long term

A
  • GI: nausea/vomit/diarrhea
  • headache
  • tongue discoloration
  • oral Candida infection (thrush)

more severe:

  • thrombocytopenia
  • GI bleeding
  • anemia

long-term:

  • fully reversible myelosuppression
  • neuropathy
51
Q

what should be monitored in linezolid therapy and how often

A

CBC weekly

52
Q

DDI with linezolid

A

neither inhibits nor induces cyt p450

reversible, nonselective MAOi -potential to interact w/ adrenergic/serotonergic agents (should not consume large amounts of food/drinks rich in tyramine to avoid significant pressor response)

Pharm (19 decks)

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