Aminoglycoside Antibiotics

Question 1

Core structure of aminoglycoside antibiotics

Answer 1

1,3-diaminocyclitol

sually linked to one or more aminoglycoside rings

Question 2

Three core structures of…

Answer 2

Streptidine
2-Doxystreptamine
Spectinamine

Question 3

Seven clinically important aminoglycosides…

Answer 3

Tobramycin
Kanamycin A
Amikacin A
Gentamycin C2
Neomycin B
Streptomycin
Spectinomycin

Question 4

How do aminoglycosides work?

Answer 4

Inhibit protein biosynthesis by binding the 30S ribo. subunit

Question 5

Where on the ribosome to aminoglycosides bind?

Answer 5

16S rRNA forming the A site.

Question 6

Specifically, what cellular activities go awry with Aminoglycoside binding

Answer 6

Formation of initiation complex
Blockes further translation
Elicits premature termination
Impaired proofreading fxn – nonsense protein formation

Question 7

Effect of Aminoglycoside caused nonsence proteins

Answer 7

Impaired bacterial cell wall function

Damaged membranes let in more aminoglycosides until a full stop is reached

Question 8

Ultimate long term kill move of aminoglycosides

Answer 8

Leakage of ions and disruption of the cytoplasmic membrane

Cell death

Question 9

Initial entry of positively charged aminoglycosides through the outer membrane

Answer 9

Displacement of Mg, Ca ions that form salt bridges with phosphates of the phospholipids in the membrane
This increases permeability

Question 10

Type of process passage of aminoglycosides through the cytoplasmic membrane is…

Answer 10

Active Transport

Question 11

Three bacterial resistance mechanisms to aminoglycosides

Answer 11

1. Metabolism by acetylation, adenylation, and p-ation
2. Altered Ribosomes
3. Altered Aminoglycoside uptake

Question 12

When bacterial resistance is altered by changes in ribosomes, what happens? Example?

Answer 12

16s rRNA binding site altered through point mutations

TB

Question 13

Main form of reversible and irreversible toxicity associated with aminoglycosides?

Answer 13

Irrev – Ototoxicity

Rev – Nephrotoxicity

Question 14

Consequences of Ototoxicity from aminoglycosides

Answer 14

Tinnitus, High Freq hearing loss

Vertigo, Balance Loss, Ataxia

Question 15

Risk factors for ototoxicity with aminoglycosides?

Answer 15

Concurrent use with other ototoxics
Compromised renal fxn
Compromised renal fxn
Genetic vulnerability

Question 16

Nephrotoxicity with aminoglycosides is precipitated by

Answer 16

Use of loop diuretics
Nephrotoxic antimicrobials (vancomycin, amhotericin)

Question 17

What to do with appearance of nephrotoxicity or ototoxicity?

Answer 17

Stop the drug/Adjust the dose

Question 18

Very large doses of aminoglycosides can cause what less common side effect?

Answer 18

Curare-like effects
Respiratoy Paralysis (reversed by neostigmine, calcium gluconate)

Question 19

Why are aminoglycosides often spared as a treatment option?

Answer 19

More effective and less toxic alternatives are usually available.

Question 20

How are aminoglycosides typically provided therapeutically?

Answer 20

G-

Given w/ penicillin

Question 21

Special rules for aminoglycoside penicillin administration

Answer 21

Chemical reaction between the two classes of drugs prevent mixture into one solution
Put them in their respective arms

Question 22

Aminoglycosides/Penicillins combinations treat…

Answer 22

Bacterial Endocarditis

Question 23

Streptomycin is most often used to treat…

Answer 23

TB

Question 24

The most important of the aminoglycosides?

Answer 24

Gentamicin

Question 25

Gentamicin is used to treat...

Answer 25

UTI Burns Pneumonias Joint and Bone Infections caused by G-

Question 26

Aminoglycoside-resistant strains are a big deal. | Who is nobody resistant to...

Answer 26

Amikacin | yay Amikacin...

Question 27

What is Streptogramins?

Answer 27

Semisynthetic derivatives of Pristinamycin I and pristinamycin II isotlated from Strep. pristinaspiralis

Question 28

What is Synercid?

Answer 28

30% quinupristin | 70% dalfopristin

Question 29

Why make the synthetic forms of pristinamycins?

Answer 29

``` Pristinamycins lack suitable solubility for reliably dosages The derivatives (quinu and dalfo) have amino side chains that allow salt formation and enhance water solubility. ```

Question 30

Quinupristin and Dalfopristin. Isolated Effect? Synnergistic effects?

Answer 30

Bacteriostatic Together | Bactericidal as a mixture

Question 31

How are streptogramins administered?

Answer 31

Parenterally

Question 32

How does Dalfopristin work?

Answer 32

Blocks Peptidyl transferase (which would normally catalyze formation of a peptide bond between the two AAs present)

Question 33

How does Quinupristin work?

Answer 33

Binds in the ribosomal tunnel and causes blockage of the tunnel "Ribosomal Constipation"

Question 34

Therapeutic use of Synercid

Answer 34

VR-Enterococcus faecium bacteremia or UTI (70% success) | Skin infections from MRSA

Question 35

Types of Resistance to Synercid (2)

Answer 35

1. Quin resistance from methylation of A2058 in 23SRNA | 2. Efflux and Enzymatic Activation by resistant bacteria

Question 36

What does the prof say has to stop to deal with all the resistance

Answer 36

Use of streptogrammins (Virginiamycin) in animal feeeds

Question 37

Side effects of Synercid?

Answer 37

No known toxicity | Some SEs --> inflamm/pain at injection site, nausea, diarrhea, muscle weakness, rash

Question 38

Average half life of Synercid/streptogramins?

Answer 38

1.5 hours in serum | Linear relationship between the dose and AUC

Question 39

Effects of Synercid/streptogramins on BBB, placental barrier?

Answer 39

None | These barriers aren't penetrated

Question 40

Clearance of Synercid/streptogramins is __% biliary excretion. The remainder leaves through _____

Answer 40

75% | Urine

Question 41

Drug interactions of Synercid/streptogramins?

Answer 41

They inhibit Cytochrome CYP3A4 | Less metab. of warfarin, diazepam, astemizole, terfenadine, cisapride, non-nucleosie RTIs, cyclosporine

Question 42

What do Oxazolidinones do?

Answer 42

Inhibit bacterial protein synthesis

Question 43

COmmon Oxazolidinone?

Answer 43

Linezolid (Zyvox)

Question 44

Oxazolidinone Mechanism of Action

Answer 44

Potent interaction with the 50S ribosomal subunit | Normally, 50S would assocaited with fMet-tRNA to form the 70S. Can't form 70S with Linezolid.

Question 45

Linezolid interacts specific with...

Answer 45

23S rRNA

Question 46

Linezolid is used to treat

Answer 46

VR enterococcus faecium Nosocomial pneumonia caused by MRSA Skin Infections from MRSA

Question 47

How's the bioavailabiltiy for Linezolid

Answer 47

Excellent oral bioavailability | IV administration

Question 48

Why don't we treat everything with Linezolid

Answer 48

Save the magic bullet

Question 49

Linezolid resistance occurs where/how?

Answer 49

Enterococcus Target site modification G to U substitution in the peptidyl transferase center of 23S rRNA at position 2576

Question 50

Less serious Side effects of Linezolid?

Answer 50

NBD GI Upset, Vomiting, Diarrhea Headache, Tongue Discoloration, Candida

Question 51

More serious side effects of linezolid

Answer 51

Thrombocytopenia Gi Bleeding Anemia Neuropathy (treatment over 6months)

Question 52

Bioavailability of Linezolid?

Answer 52

100% after oral administration

Question 53

Half life of Linezolid?

Answer 53

Half-life of 4-6 hours

Question 54

Drug interactions of Linezolid

Answer 54

Reversible, nonselective inhibitor of monamine oxidase Interaction with adrenergic and serotonergic agents

Question 55

Linezolid taking patinets should avoid eating lots of food or beverages that are rich in _______. It will.....

Answer 55

Tyramine | cause a significant pressor response