Streptogramin and Oxazolidinone

Question 1

Be able to identify the antibiotics that are present in streptogramin.

Answer 1

a) Quinupristin and dalfopristin = synercid

Question 2

How do quinupristin and dalfopristin ehance water solubility?

Answer 2

a) They have amino side chains that allow salt formation and enhance the water solubility needed to make a useful formulation.
b) Quinupristin has carboxyl groups (negatively charged) and can form salts with positively charged ions. Amine groups can accept a proton and become positively charged and form salts with anionic counterions.
c) Dalfopristin: sulfonate groups (negatively charged) can form salts with positively charged counterions. Carboxyl groups that can ionize and contribute to salt formation.

Question 3

Be able to describe how streptogramin, quinupristin, and dolfopristin compare with regard to being bacteriostatic vs. bactericidal.

Answer 3

a) Quinupristin and Dalfopristin are bacteriostatic alone.
b) Synercid is bacteriostatic against enterococcus faecium and bactericidal against strains of methicillin-susceptible and methicillin-resistant staphylococci.

Question 4

Be able to specify the route of administration of streptogramin.

Answer 4

Parenterally

Question 5

Be able to describe the mechanism of action of dalfopristin.

Answer 5

a) Inhibits peptidyl transferase. During peptide synthesis, peptidyl transferase catalyzes the formation of a peptide bond between the 2 amino acids present. Dalfopristin directly interferes with the peptidyl transferase catalyzed step. This inhibits bacterial protein synthesis.
b) It binds to the 50S subunit of the bacterial ribosome.

Question 6

Be able to describe the mechanism of action of quinupristin.

Answer 6

a) Binds in the ribosomal tunnel and causes blockage of the tunnel. Binds to a specific region of the 50S ribosomal subunit, overlapping the peptidyl transferase center and the exit tunnel where the growing peptide chain exits the ribosome.

Question 7

Be able to list the therapeutic uses of synercid.

Answer 7

a) Used IV for vancomycin resistant enteroccus faecium bacteremia, skin infections caused by MRSA, vancomycin-resistant enteroccus faecium urinary tract infections.
b) Streptogramin treatment of vancomycin-resistant E. faecium reserved for serious life-threatening infections caused by grm-(+) organisms.

Question 8

Be able to describe the quinupristin resistance mechanisms.

Answer 8

a) Most common resistance to quinupristin is due to adenine methylation of A2058 in the 23S rRNA.
b) Can also be due to efflux and enzymatic inactivation by resistant bacteria.

Question 9

Be able to recognize the main Synercid side effects.

Answer 9

a) No known significant toxicity.
b) Mild side effects include inflammation and pain at the site of injection, nausea, diarrhea, muscle weakness, and rash.

Question 10

Be able to characterize the pharmacokinetics of synercid.

Answer 10

a) Pharmacokinetics are complicated because of the different elimination rates for each component and their metabolites. Avg T1/2 is 1.5 hours in serum with a linera relationship between the dose and the AUC. 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, remainder in urine.

Question 11

Be able to characterize the metabolism of quinupristin and dalfopristin.

Answer 11

b) Quinupristin and dalfopristin metabolized primarily in the liver.
i) Quinupristin metabolized via enzymatic hydrolysis to form quinupristin glutathione conjugate and quinupristin cysteine conjugate.
ii) Dalfopristin metabolized via enzymatic hydrolysis to form hydrolysis product or pristinamycin IIA  prinstinamycin IIA reduction product.

Question 12

Be able to describe the potential that synercid has for drug interactions, and the mechanism involved.

Answer 12

a) Streptogramins inhibit cytochrome CYP3A4, which metabolizes many drugs, so there are many drug interactions.

Question 13

Example of an oxazolidinone

Answer 13

linezolid

Question 14

Be able to describe the mechanism of action of the oxazolidinones.

Answer 14

a) They act by inhibiting protein synthesis. Acts early by potent interaction with 50S ribosomal subunit with micromolar affinity (has no affinity to the 30S subunit). This interaction prevents the formation of the 70S initiation complex. Interacts specifically with 23S rRNA.

Question 15

Be able to list the main therapeutic uses of linezolid.

Answer 15

a) Vancomycin-resistant enterococcus faecium, nosocomial pneumonia caused by methicillin, skin infections caused by methicillin.
b) Has excellent oral bioavailability but also available IV.

Question 16

Be able to explain why linezolid should be used only to treat or prevent infections that are proven or strongly suspected to be caused by multiply drug-resistant Gram-(+) bacteria.

Answer 16

a) 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, or when pts are allergic to otherwise effective alternatives.

Question 17

Be able to describe the mechanism by which bacteria become resistant to linezolid.

Answer 17

a) Target site modification is virtually the only mechanism of resistance that has thus far been proven. Resistance mutations are associated with G  U substitution in the peptidyl transferase center of 23S rRNA at position 2576 and result in reduced affinity of linezolid to the 50S subunit.

Question 18

Be able to describe the main side effects of linezolid.

Answer 18

a) Most frequent were: GI nausea, vomiting, and diarrhea. Others included headache, tongue discoloration, and oral candidiasis. Serious side effects included thrombocytopenia, GI bleeding, and anemia. Long-term tx resulted in fully reversible myelosuppression. Neuropathy when pts received for more than 6 mo.

Question 19

Be able to describe the main metabolic pathways of linezolid.

Answer 19

a) Metabolized via morpholine ring oxidation. 2 major metabolites produced do not appear to have significant toxicity or antimicrobial activity.

Question 20

Be able to characterize the pharmacokinetics and routes of administration linezolid.

Answer 20

a) Administered orally or intravenously. 100% bioavailable after oral administration. T1/2 4-6 h.

Question 21

Be able to describe the potential that linezolid has for drug interactions, and the mechanism involved.

Answer 21

inhibitor of monoamine oxidase: Potential for interaction with adrenergic and serotonergic agents. Use with caution in pts who are sensitive to increases in BP due to preexisting conditions.
c) Do not consume large quantities of foods/beverages rich in tyramine (cheese + red wine) to avoid pressor response (increased BP).

Question 22

Be able to compare tedizolid phosphate with linezolid with respect to potency and mechanism of action.

Answer 22

a) Tedizolid phosphate is a 2nd gen oxazolidinone for acute bacterial skin and skin structure infections. More potent than linezolid vs MRSA.
b) Same MOA as linezolid. Tedizolid phosphate is a prodrug of tedizolid that is activated by plasma phosphatases to tedizolid.