2: Aminoglycosides, Streptogramins, and Oxazolidinones

Question 1

core structure of aminoglycosides

Answer 1

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

Question 2

name 7 clinically important aminoglycosides

Answer 2

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

Question 3

aminoglycoside MOA

Answer 3

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

Question 4

what do aminoglycosides ultimately lead to?

Answer 4

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

Question 5

describe bacterial aminoglycoside uptake

Answer 5

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

Question 6

passage of aminoglycosides through membrane: active or passive

Answer 6

active transport process

Question 7

three mechanisms of resistance to aminoglycosides

Answer 7

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

Question 8

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

Answer 8

adenylation and phosphorylation on -OH groups

acetylation on amino groups

Question 9

what are the toxicities of aminoglycosides

Answer 9

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

Question 10

describe aminoglycoside ototoxicity

Answer 10

• tinnitus, high-frequency hearing loss

- vertigo, loss of balance, ataxia

Question 11

how can you monitor ototoxicity during aminoglycoside use

Answer 11

serial audiograms

Question 12

risk factors for ototoxicity with aminoglycosides

Answer 12

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

Question 13

name two loop diuretics that can potentiate nephrotoxicity in aminoglycosides

Answer 13

• ethacrynic acid

- furosamide

Question 14

name two nephrotoxic antimicrobial drugs that can potentiate nephrotoxicity in aminoglycosides

Answer 14

• vancomycin

- amphotericin

Question 15

how can you monitor nephrotoxicity during aminoglycoside use

Answer 15

creatinine clearance and dosage decrease

Question 16

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

Answer 16

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

Question 17

what increases likelihood of aminoglycoside toxicity

Answer 17

length of treatment period

Question 18

use of aminoglycosides

Answer 18

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

Question 19

what are aminoglycosides often paired with

Answer 19

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

Question 20

what are penicillin/aminoglycoside combos used to treat

Answer 20

bacterial endocarditis

Question 21

what is streptomycin most often used to treat

Answer 21

TB

Question 22

what is gentamicin usually used for

Answer 22

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

Question 23

which aminoglycoside has retained antibacterial activity against resistant strains

Answer 23

amikacin

Question 24

what are the streptogramins

Answer 24

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

Question 25

what is synercid a combination of

Answer 25

30% quinupristin | 70% dalfopristin

Question 26

why do we not use the parent combination of streptogramins

Answer 26

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

Question 27

synercid: bacteriostatic or bacteriocidal

Answer 27

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

Question 28

how is streptogramin administered

Answer 28

parenterally

Question 29

dalfopristin MOA

Answer 29

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

Question 30

quinupristin MOA

Answer 30

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

Question 31

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

Answer 31

mutation of A2062

Question 32

IV synercid used to treat what

Answer 32

- VRE bacteremia - MRSA skin infections - VRE UTIs

Question 33

resistance mechanisms for synercid

Answer 33

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

Question 34

what is streptogramin often reserved for

Answer 34

serious life-threatening G(+) infections

Question 35

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

Answer 35

continued use of virginiamycin in animal feeds

Question 36

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

Answer 36

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

Question 37

streptogramin side effects

Answer 37

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

Question 38

why are the PK of streptogramins complicated?

Answer 38

different elimination rates for each component and their metabolites

Question 39

half life of streptogramins

Answer 39

1.5h - linear relationship b/w dose and AUC

Question 40

does synercid cross any barriers?

Answer 40

nope - not BBB or placental barriers

Question 41

what do macrophages do to synercid?

Answer 41

concentrate it up to 50x the extracellular fluid concentrations

Question 42

describe elimination of synercid

Answer 42

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

Question 43

DDI with streptogramins

Answer 43

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

Question 44

what are two oxazolidinones

Answer 44

linezolid and eperezolid

Question 45

linezolid MOA

Answer 45

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

Question 46

what is linezolid used to treat

Answer 46

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

Question 47

why is linezolid a magic bullet

Answer 47

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

Question 48

linezolid resistance in what species

Answer 48

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

Question 49

linezolid mechanism of resistance

Answer 49

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

Question 50

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

Answer 50

- GI: nausea/vomit/diarrhea - headache - tongue discoloration - oral Candida infection (thrush) more severe: - thrombocytopenia - GI bleeding - anemia long-term: - fully reversible myelosuppression - neuropathy

Question 51

what should be monitored in linezolid therapy and how often

Answer 51

CBC weekly

Question 52

DDI with linezolid

Answer 52

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)