2: Aminoglycosides, Streptogramins, and Oxazolidinones Flashcards Preview

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Flashcards in 2: Aminoglycosides, Streptogramins, and Oxazolidinones Deck (52):
1

core structure of aminoglycosides

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

2

name 7 clinically important aminoglycosides

-tobramycin
-kanamycin A
-amikacin A
-gentamicin C2
-neomycin B
-streptomycin
-spectinomycin

3

aminoglycoside MOA

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

4

what do aminoglycosides ultimately lead to?

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

5

describe bacterial aminoglycoside uptake

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

6

passage of aminoglycosides through membrane: active or passive

active transport process

7

three mechanisms of resistance to aminoglycosides

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

8

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

adenylation and phosphorylation on -OH groups
acetylation on amino groups

9

what are the toxicities of aminoglycosides

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

10

describe aminoglycoside ototoxicity

-tinnitus, high-frequency hearing loss
-vertigo, loss of balance, ataxia

11

how can you monitor ototoxicity during aminoglycoside use

serial audiograms

12

risk factors for ototoxicity with aminoglycosides

-concurrent use of other ototoxic compounds (loop diuretics, vancomycin)
-compromised renal function
-genetic vulnerability

13

name two loop diuretics that can potentiate nephrotoxicity in aminoglycosides

-ethacrynic acid
-furosamide

14

name two nephrotoxic antimicrobial drugs that can potentiate nephrotoxicity in aminoglycosides

-vancomycin
-amphotericin

15

how can you monitor nephrotoxicity during aminoglycoside use

creatinine clearance and dosage decrease

16

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

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

17

what increases likelihood of aminoglycoside toxicity

length of treatment period

18

use of aminoglycosides

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

19

what are aminoglycosides often paired with

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

20

what are penicillin/aminoglycoside combos used to treat

bacterial endocarditis

21

what is streptomycin most often used to treat

TB

22

what is gentamicin usually used for

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

23

which aminoglycoside has retained antibacterial activity against resistant strains

amikacin

24

what are the streptogramins

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

25

what is synercid a combination of

30% quinupristin
70% dalfopristin

26

why do we not use the parent combination of streptogramins

less suitable solubility for reliable solubility
-the amino side chains of quinupristin and dalfopristin allow salt formation and enhance water solubility

27

synercid: bacteriostatic or bacteriocidal

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

28

how is streptogramin administered

parenterally

29

dalfopristin MOA

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

30

quinupristin MOA

binds in the ribosomal tunnel and causes blockage of the tunnel
"constipation of the ribosome"

31

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

mutation of A2062

32

IV synercid used to treat what

-VRE bacteremia
-MRSA skin infections
-VRE UTIs

33

resistance mechanisms for synercid

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

34

what is streptogramin often reserved for

serious life-threatening G(+) infections

35

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

continued use of virginiamycin in animal feeds

36

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

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

37

streptogramin side effects

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

38

why are the PK of streptogramins complicated?

different elimination rates for each component and their metabolites

39

half life of streptogramins

1.5h - linear relationship b/w dose and AUC

40

does synercid cross any barriers?

nope - not BBB or placental barriers

41

what do macrophages do to synercid?

concentrate it up to 50x the extracellular fluid concentrations

42

describe elimination of synercid

75% via biliary excretion (fecal matter)
25% via urine

43

DDI with streptogramins

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

44

what are two oxazolidinones

linezolid and eperezolid

45

linezolid MOA

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

46

what is linezolid used to treat

-VRE
-nosocomial pneumonia (MRSA)
-MRSA skin infections

47

why is linezolid a magic bullet

-excellent oral bioavailability
-can be given oral or IV
-half life 4-6h

48

linezolid resistance in what species

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

49

linezolid mechanism of resistance

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

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

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

more severe:
-thrombocytopenia
-GI bleeding
-anemia

long-term:
-fully reversible myelosuppression
-neuropathy

51

what should be monitored in linezolid therapy and how often

CBC weekly

52

DDI with linezolid

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)