Exam 1- Cushman Lec 2- Streptogramin Antibiotics + Oxazolidinone Antimicrobials

Question 1

Synercid is a streptogramin antibiotic that contains what two parts?

Answer 1

30% Quinupristin

70% Dalfopristin

Question 2

What part of the quinupristin and daltopristin structures allow for salt formation and why is this important?

Answer 2

Amino side chains

-allow salt formation which enhances water solubility needed to make a formulation

Question 3

How does the activity against bacteria compare between quinupristin, dalfopristin, and streptogramin (synercid)?

Answer 3

Quinupristin and Dalfopristin are bacteriostatic when on their own

Synercid is bacteriostatic against Enterococcus faecium, but bacteriocidal against methicillin-susceptible and resistant staphylococci

Question 4

How is Syncercid administered?

Answer 4

Parenterally

Question 5

What is the moa of Dalfopristin?

Answer 5

1st function: When peptides are synthesized, when the second tRNA base pairs with the appropriate codon in the mRNA, the peptidyl transferase (ribosomal RNA) catalyzes peptide bond formation between the two amino acids present (while breaking the bond between met and its tRNA)

*Dalfopristin interferes with the peptidyl transferase-catalyzed step

2nd function: Binds and changes the conformation of the ribosome to facilitate strong binding of quinupristin

Question 6

What is the moa of Quinupristin?

Answer 6

It binds in the ribosomal tunnel and causes blockage of the tunnel

Question 7

What are the therapeutic uses of Synercid?

Answer 7

IV treatment of:

-Vancomycin-resistant Enterococcus faecium bacteremia and UTI
(note: not effective against Enterococcus faecalis)

-MRSA

Question 8

How does resistance to quinupristin occur?

Answer 8

1.Due to adenine methylation of A2058 in the 23S rRNA
-addition of two methyl groups causes steric hindrance and blocks binding of quinupristin to the ribosome
**this does not affect dalfopristin susceptibility
**this renders synercid bacteriostatic

2. Efflux and enzymatic inactivation (metabolism) by resistant bacteria
3. Use of virginiamycin in animal feed

Question 9

What are the major CLINICAL uses of synercid?

Answer 9

Treatment of vancomycin-resistant E. faecium
-reserve streptogramins for serious life-threatening infections by Gram + organisms

Question 10

What are the side effects of synercid?

Answer 10

NO KNOWN SIGNIFICANT TOXICITY

Mild SE: inflammation, injection site pain, nausea, diarrhea, muscle weakness, rash

Question 11

What are important pharmacokinetic points for synercid?

Answer 11

Half-life: 1.5h

No blood/brain barrier or placenta penetration

Clearance: 75% biliary, rest appears in urine

Question 12

What are the possible drug interactions with Synercid and how do they occur?

Answer 12

Streptogramins inhibit CYP 3A4
-drugs metabolized by this will have interactions

Question 13

What drug is an oxizolidinone?

Answer 13

Linezolid

Question 14

What is the moa of the oxazolidinones (linezolid)?

Answer 14

Inhibit protein synthesis

-Acts early by potent interaction with the 50S ribosomal subunit
-In the initiation step of bacterial translocation, the 50S subunit associates with fMet-tRNA and the 30S ribosomal subunit to form the 70S initiation complex
*Linezolid interacts with the 50S subunit which prevents formation of 70S

Question 15

What rRNA does linezolid interact with?

Answer 15

23S

Question 16

What is linezolid used to treat?

Answer 16

1) Vancomycin-resistant Enterococcus faecium
2) Nosocomial pneumonia caused by methacillin-resistant Staph aureus
3) Skin infections caused by methicillin-resistant Staph aureus

Question 17

To reduce the development of drug-resistant bacteria and maintain linezolid effectiveness, what should be done?

Answer 17

Linezolid should only be used to treat or prevent infections that are proven or strongly suspected to be caused by multiply drug-resistant Gram + bacteria, or when patients are allergic to effective alternatives

Question 18

How does linezolid resistance occur?

Answer 18

-Initially in Enterococcus species

*Target site modification is the only mechanism so far that has been proven

Question 19

What target modification has been seen in linezolid resistance, and where does it occur?

Answer 19

G to U substitution
-in the peptidyl transferase center of the 23S rRNA at position 2576

*results in reduced affinity of linezolid for the 50S subunit

Question 20

What are the main side effects of linezolid?

Answer 20

GI: nausea, vomiting diarrhea
Headache
*Tongue discoloration
*Oral Candidiasis (thrush)
Thrombocytopenia,GI bleeding, anemia
Reversible myelosuppression
Neuropathy when given for 6 mo

Question 21

What should be monitored in patients receiving linezolid?

Answer 21

Complete blood counts

Question 22

How is linezolid metabolized?

Answer 22

Morpholine ring oxidation

-30% is excreted in urine as parent drug
-The rest becomes two metabolites with no toxicity or activity

Question 23

What are the pharmacokinetics of linezolid?

Answer 23

100% bioavailable after oral administration

Half-life: 4-6h

Question 24

How is linezolid administered?

Answer 24

PO or IV

Question 25

Linezolid is an inhibitor of what?

Answer 25

Monoamine oxidase

Question 26

Inhibition of monoamine oxidase by linezolid results in what?

Answer 26

Drug interactions with adrenergic and serotonergic agents

A reversible potentiation of pressor response to pseudoephedrine has also been seen, so linezolid should be used with caution in patients who are sensitive to BP increases due to preexisting conditions

Avoid foods high in tyramine (cheese, red wine, good foods) to avoid significant pressor response

Question 27

What is Tedizolid Phosphate?

Answer 27

Second-generation oxazolidinone used for acute skin infections

Question 28

How does Tedizolid compare to Linezolid?

Answer 28

Tedizolid is more potent vs MRSA
Same MOA
IV or PO administration

-Tedizolid phostphate is a prodrug of tedizolid activated by plasma phosphatases