Exam 1- Cushman Lec 2- Streptogramin Antibiotics + Oxazolidinone Antimicrobials Flashcards
Synercid is a streptogramin antibiotic that contains what two parts?
30% Quinupristin
70% Dalfopristin
What part of the quinupristin and daltopristin structures allow for salt formation and why is this important?
Amino side chains
-allow salt formation which enhances water solubility needed to make a formulation
How does the activity against bacteria compare between quinupristin, dalfopristin, and streptogramin (synercid)?
Quinupristin and Dalfopristin are bacteriostatic when on their own
Synercid is bacteriostatic against Enterococcus faecium, but bacteriocidal against methicillin-susceptible and resistant staphylococci
How is Syncercid administered?
Parenterally
What is the moa of Dalfopristin?
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
What is the moa of Quinupristin?
It binds in the ribosomal tunnel and causes blockage of the tunnel
What are the therapeutic uses of Synercid?
IV treatment of:
-Vancomycin-resistant Enterococcus faecium bacteremia and UTI
(note: not effective against Enterococcus faecalis)
-MRSA
How does resistance to quinupristin occur?
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
- Efflux and enzymatic inactivation (metabolism) by resistant bacteria
- Use of virginiamycin in animal feed
What are the major CLINICAL uses of synercid?
Treatment of vancomycin-resistant E. faecium
-reserve streptogramins for serious life-threatening infections by Gram + organisms
What are the side effects of synercid?
NO KNOWN SIGNIFICANT TOXICITY
Mild SE: inflammation, injection site pain, nausea, diarrhea, muscle weakness, rash
What are important pharmacokinetic points for synercid?
Half-life: 1.5h
No blood/brain barrier or placenta penetration
Clearance: 75% biliary, rest appears in urine
What are the possible drug interactions with Synercid and how do they occur?
Streptogramins inhibit CYP 3A4
-drugs metabolized by this will have interactions
What drug is an oxizolidinone?
Linezolid
What is the moa of the oxazolidinones (linezolid)?
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
What rRNA does linezolid interact with?
23S
What is linezolid used to treat?
1) Vancomycin-resistant Enterococcus faecium
2) Nosocomial pneumonia caused by methacillin-resistant Staph aureus
3) Skin infections caused by methicillin-resistant Staph aureus
To reduce the development of drug-resistant bacteria and maintain linezolid effectiveness, what should be done?
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
How does linezolid resistance occur?
-Initially in Enterococcus species
*Target site modification is the only mechanism so far that has been proven
What target modification has been seen in linezolid resistance, and where does it occur?
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
What are the main side effects of linezolid?
GI: nausea, vomiting diarrhea
Headache
*Tongue discoloration
*Oral Candidiasis (thrush)
Thrombocytopenia,GI bleeding, anemia
Reversible myelosuppression
Neuropathy when given for 6 mo
What should be monitored in patients receiving linezolid?
Complete blood counts
How is linezolid metabolized?
Morpholine ring oxidation
-30% is excreted in urine as parent drug
-The rest becomes two metabolites with no toxicity or activity
What are the pharmacokinetics of linezolid?
100% bioavailable after oral administration
Half-life: 4-6h
How is linezolid administered?
PO or IV
Linezolid is an inhibitor of what?
Monoamine oxidase
Inhibition of monoamine oxidase by linezolid results in what?
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
What is Tedizolid Phosphate?
Second-generation oxazolidinone used for acute skin infections
How does Tedizolid compare to Linezolid?
Tedizolid is more potent vs MRSA
Same MOA
IV or PO administration
-Tedizolid phostphate is a prodrug of tedizolid activated by plasma phosphatases
