Streptogramin antibiotics and oxazolidinone antimicrobial agents Flashcards
streptogramin structure
They are semisynthetic
derivatives of a natural mixture of pristinamycin I and pristinamycin II isolated from Streptomyces pristinaspiralis. Synercid® is a mixture containing 30% quinupristin and 70% dalfopristin (weight ratio)
The parent natural product mixture of pristinamycins lacks suitable solubility* for reliable dosages. The derivatives quinupristin and dalfopristin have amino side chains that allow salt formation and enhance the water solubility needed to make a useful formulation.
***Each of these compounds is bacteriostatic alone, but in combination they provide a bactericidal mixture.
Streptogramin is administered parenterally, but there are other pristinamycin combinations under development that have useful oral activity.
dalfopristin MOA
During peptide synthesis, when the second tRNA base pairs with the appropriate codon in the mRNA, peptidyl transferase (ribosomal RNA) catalyzes the formation of a peptide bond between the two amino acids present (while breaking the bond between fmet and its tRNA). Dalfopristin directly *interferes with the peptidyl transferase-catalyzed step.
quinupristin MOA
Quinupristin binds in the ribosomal tunnel and causes blockage of the tunnel
therapeutic use of synercid
Synercid® is used IV for treatment of:
- Vancomycin-resistant Enteroccus faecium bacteremia (it is not effective against Enterococcus faecalis infections). Certain Enteroccus faecium strains are resistant to all other antibiotics.
- Skin infections caused by MRSA.
- Vancomycin-resistant Enteroccus faecium urinary tract infections.
resistance to synercid
The most common resistance to quinupristin is due to adenine methylation of A2058 in the 23S rRNA** as in the case of erythromycin and clindamycin. Susceptibility of the organism to dalfopristin is not affected by this rRNA modification, but renders synercid a bacteriostatic* agent at the normal dose. Extension of the dosing to 3X a day is well tolerated and allows for more sustained tissue drug levels.
Resistance can also be due to efflux and enzymatic inactivation (metabolism) by resistant bacteria.
Streptogramin treatment of vancomycin-resistant E. faecium is currently resulting in a 70% cure rate. This drug will most likely be reserved for serious life-threatening* infections caused by Gram-(+) organisms.
The continued use of streptogramins (virginiamycin) in animal feeds will continue to result in more resistant bacterial strains.
There is a report of patients treated with a 14 day course of synercid selecting resistant forms of E. faecialis, E. faecium, and S. aureus. To avoid this selection, a careful approach to dosage regimen and combination therapy will be required.
synercid AEs
There is no known significant toxicity presented by synercid.
Several mild side effects have been reported and include inflammation and pain at the site of injection, nausea, diarrhea, muscle weakness and rash.
synercid PKs
The pharmacokinetics are complicated because of the different elimination rates for each component and their metabolites.
The average T1/2 is 1.5 hours in serum with a linear relationship between the dose and the AUC.
Most tissues of importance to Gram-(+) infections achieve up to 85% of the serum concentrations of Synercid®. The blood/brain or placental barriers are not penetrated. Macrophages concentrate the drug up to 50X the extracellular fluid concentration.
Clearance is 75% through biliary excretion (fecal matter) and the remainder appears in the urine.
inhibit CYP 3A4
oxazolidinones MOA
linezolid, eperezolid
While most of the widely known antibiotics (macrolides, chloramphenicol) inhibit bacterial protein synthesis at the peptide chain elongation stage, linezolid acts early by potent interaction with 50S ribosomal subunit. In the initiation step of bacterial translation, the 50S subunit associates with fMet-tRNA and a complex composed of the 30S ribosomal subunit and mRNA to form the functional 70S initiation complex. Linezolid interacts with the 50S subunit with micromolar affinity (and it has no affinity to the 30S subunit). This interaction prevents the formation of the 70S initiation complex. Linezolid interacts specifically with 23S rRNA.
therapeutic use of oxazolidinones
Linezolid is used to treat:
-Vancomycin-resistant Enterococcus faecium
-Nosocomial pneumonia caused by methacillin-–resistant strains of Staphylococcus aureus
-Skin infections caused by methicillin–resistant strains of Staphylococcus aureus
Linezolid has excellent oral bioavailability, and it is also available for I.V. administration.
***To reduce the development of drug-resistant bacteria and maintain the effectiveness of linezolid, it should be used only to treat or prevent infections that are proven or strongly suspected to be caused by multiply drug-resistant Gram-(+) bacteria
oxazolidinones resistance
Linezolid has been used to treat a number of resistant strains of bacteria (e.g., methicillin resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium). However, the emergence of linezolid resistance has been reported, initially in Enterococcus species. More recently, resistant strains of MRSA, E. coli and other bacteria have also been identified. Target site modification* is virtually the only mechanism of resistance that has thus far been proven. Resistance mutations identified in various species are **associated with G to U substitution in the peptidyl transferase center of 23S rRNA at position 2576* and result in reduced affinity of linezolid to the 50S subunit. This and other sites of mutations (e.g. T2500A in S. aureus) lie in the proximity of the P site, which confirms the mechanism of action of oxazolidinones.
oxazolidinones AEs
In clinical studies on 828 patients, 314 adverse effects were recorded in 223 (27%) of them. The most frequently reported side effects (10%) were GI nausea, vomiting and diarrhea. Other adverse effects included headache, tongue discoloration and oral Candidiasis (“thrush”)**. More serious side effects included thrombocytopenia, GI bleeding and anemia. Long-term treatment resulted in fully reversible myelosuppression. Complete blood counts should be monitored weekly in patients receiving linezolid. Linezolid-induced neuropathy was also reported among patients receiving linezolid for more than 6 months.
oxazolidinones metabolism
Linezolid is metabolized via morpholine ring oxidation. In humans, approximately 30% of a linezolid dose is excreted in the urine as the parent drug. The two major metabolites do not appear to have significant toxicity or antimicrobial activity.
oxazolidinones PKs
Linezolid is 100% bioavailable after oral administration and has a half-life to 4-6 hours. It is administered either orally or intravenously.
oxazolidinones drug interactions
Linezolid is a moderately potent, reversible, nonselective inhibitor of monoamine oxidase. Therefore, it has the potential for interaction with adrenergic and serotonergic agents. A reversible potentiation of pressor response to pseudoephedrine has been observed when linezolid is administered to normotensive subjects. Linezolid should therefore be used with caution in patients who are sensitive to increases in BP due to preexisting conditions. Also, patients taking linezolid should not consume large quantities of foods or beverages that are rich in tyramine in order to avoid a significant pressor response.
tedizolid
1) Tedizolid phosphate (FDA approved June 20, 2014) is a second-generation oxazolidinone used for treatment of acute bacterial skin and skin structure infections.
2) It is more potent than linezolid vs. MRSA.
3) The mechanism of action is the same as linezolid.
4) Administration can be oral or IV.
5) Tedizolid phosphate is a prodrug of tedizolid that is activated by plasma phosphatases to tedizolid. It can be administered orally or parenterally.
