1. Agents for VRE: Oxazolidinones, Stretogramins, Cyclic Lipopeptides
Mark S. Johnson, Pharm.D., BCPS
Associate Professor and Director of Postgraduate Education

2. Linezolid (Zyvox®)
Oxazolidinone class

3. Linezolid (Zyvox®) MOA
Inhibits bacterial protein synthesis by preventing formation of the ribosome complex that initiates protein synthesis by binding to 23S ribosomal RNA of the 50S subunit, preventing formation of 70S initation complex

4. Linezolid (Zyvox®) Spectrum of Activity
Gram Positives:
Gram Positive Aerobic Cocci: MSSA, MRSA, streptococci species (including multi-drug resistant Streptococcus pneumoniae), Enterococcus faecalis, Enterococcus faecium (including VRE)
Linezolid is bacteriostatic against enterococci and staphylococci and bactericidal against most strains of streptococci
Gram Positive Anaerobic cocci: Peptostreptococcus
Gram Positive Aerobic bacilli: Corynebacteria, Listeria monocytogenes

5. Linezolid (Zyvox®) FDA-Approved Indications
Treatment of vancomycin-resistant Enterococcus faecium (VRE) infections
Nosocomial pneumonia caused by Staphylococcus aureus (including MRSA) or Streptococcus pneumoniae (including multidrug-resistant strains [MDRSP])
Complicated and uncomplicated skin and skin structure infections (including diabetic foot infections without concomitant osteomyelitis)
Community-acquired pneumonia caused by susceptible gram-positive organisms

6. Linezolid (Zyvox®) Bacteremia
Trial Showing Increased Rate of Death in Catheter-Related Bacteremias- March, 2007
The FDA issued an alert to healthcare professionals regarding an increased rate of death among patients treated with linezolid for catheter-related bacteremia and catheter-site infections.
Linezolid is not approved for the treatment of catheter-related bloodstream, catheter-site, or gram-negative infections.

7. Linezolid (Zyvox®) PKS
Absorption: BA 100%
Distribution: Vdss: Adults: L
Protein binding: Adults: 31%
Metabolism: Hepatic via oxidation of the morpholine ring, resulting in two inactive metabolites (aminoethoxyacetic acid, hydroxyethyl glycine); minimally metabolized, may be mediated by cytochrome P450
Severe hepatic impairment: use not evaluated
Half-life elimination: 4-5 hours
Excretion: Urine (~30% of total dose as parent drug, ~50% of total dose as metabolites); feces (~9% of total dose as metabolites)
Renal failure: no dose adjustment
Nonrenal clearance: Adults: ~65%

8. Linezolid (Zyvox®) ADR’s
Hematologic
Reversible myelosuppression: thrombocytopenia (3%), neutropenia, anemia
Most often after >2 weeks of therapy
Neuro
Peripheral neuropathy, optic neuropathy
Most often after 4 weeks of therapy
Due to inhibition of intramitochondrial protein synthesis
Other: Lactic acidosis, acute interstitial nephritis, black hairy tongue, headache, diarrhea

9. Linezolid (Zyvox®) Drug Interactions
Weak, reversible monoamine oxidase inhibitor
Tyramine containing foods (HTN)
SSRI’s (serotonin syndrome)
Decongestants (HTN)
MAOI inhibitors

10. Linezolid (Zyvox®) Dosage Forms/Dosing
Oral:
600mg tablets
100mg powder per 5ml suspension
Most uses: 600mg PO Q12h
Uncomplicated skin and skin structure infections: mg every 12 hours
Cost: 600 mg (#20) = $
Parenteral:
200 mg (100 mL); 600 mg (300 mL)
600mg IV Q12h

11. Quinupristin/Dalfopristin (Synercid®) Streptogramins
Streptogramin class
Quinupristin (a streptogramin B) Dalfopristin (a streptogramin A)

12. Quinupristin/Dalfopristin (Synercid®) Streptogramins
Mechanism of action
Quinupristin/dalfopristin synergistically inhibits bacterial protein synthesis by binding to different sites on the 50S bacterial ribosomal subunit thereby inhibiting protein synthesis
30:70 ratio of quinupristin to dalfopristin

13. Quinupristin/Dalfopristin (Synercid®) Spectrum of Activity
Gram Positive Aerobic Cocci
Streptococci species (including multi-drug resistant Streptococcus pneumoniae), MSSA, MRSA, ), Enterococcus faecium (including VRE)
NOT Enterococcus faecalis
Gram Positive Aerobic bacilli:
Corynebacteria, Listeria monocytogenes
Gram (–):
generally NOT susceptible (except for Moraxella catarrhalis and Neisseria spp.)
Atypical organisms
Mycoplasma pneumoniae, Chlamydophilia pneumoniae

14. Quinupristin/Dalfopristin (Synercid®) FDA-Approved Indications
Treatment of serious or life-threatening infections associated with vancomycin-resistant Enterococcus faecium bacteremia
Treatment of complicated skin and skin structure infections caused by methicillin-susceptible Staphylococcus aureus or Streptococcus pyogenes

15. Quinupristin/Dalfopristin (Synercid®) PKS
Distribution: Quinupristin: 0.45 L/kg; Dalfopristin: 0.24 L/kg
Protein binding: Moderate
Metabolism: To active metabolites via nonenzymatic reactions
Half-life elimination: Quinupristin: 0.85 hour; Dalfopristin: 0.7 hour (mean elimination half-lives, including metabolites: 3 and 1 hours, respectively)
Excretion: Feces (75% to 77% as unchanged drug and metabolites); urine (15% to 19%)

16. Quinupristin/Dalfopristin (Synercid®) ADR’s
Local
Local pain (40% to 44%), inflammation at infusion site (38% to 42%), local edema (17% to 18%), infusion site reaction (12% to 13%)
Neuromuscular & skeletal
Arthralgia (up to 47%), myalgia (up to 47%)
Hepatic
Hyperbilirubinema (3-35%)

17. Quinupristin/Dalfopristin (Synercid®) Drug Interactions
CYP3A4 inhibitor—many DI’s possible
HIV meds: NNRTI’s and PI’s
Vincristine, paclitaxel, docetaxil
Cyclosporine, tacrolimus
Calcium channel blockers
Midazolam, diazepam
Statins
Others

18. Quinupristin/Dalfopristin (Synercid®) Dosage Forms/Dosing
Injection, powder for reconstitution:
Synercid®500 mg = Quinupristin 150 mg and dalfopristin 350 mg
Reconstituted solution should be added to at least 250ml of D5W for peripheral administration (increase to 500ml or 750ml if necessary to limit venous irritation). An infusion volume of 100ml may be used for central line infusions. Must use D5W
Dosing
Vancomycin-resistant Enterococcus faecium: I.V.: 7.5 mg/kg every 8 hours
Complicated skin and skin structure infection: I.V.: 7.5 mg/kg every 12 hours
CNS shunt infection due to vancomycin-resistant Enterococcus faecium: I.V.: 7.5 mg/kg/dose every 8 hours.

19. Daptomycin (Cubicin®)
A cyclic lipopeptide
Fermentation product of Streptomyces roseosporus

20. Daptomycin (Cubicin®)
MOA:
Binds to components of the cell membrane of susceptible organisms via calcium-dependent insertion of its lipid tail.
Causes rapid depolarization with potassium efflux and rapid cell death
Thus, inhibits intracellular synthesis of DNA, RNA, and protein.
Bactericidal in a concentration-dependent manner

21. Daptomycin (Cubicin®)
MOA: disruption of bacterial membrane function

22. Daptomycin (Cubicin®) Spectrum of Activity
Gram positive Aerobic cocci:
MSSA, MRSA, streptococci species, Enterococcus faecalis, Enterococcus faecium (including VRE)
Resistance to Staphylococcus aureus has been reported
Similar spectrum, but more rapidly bactericidal than vancomycin, linezolid, and quinupristin/dalfopristin
Gram Positive Aerobic bacilli:
Corynebacteria

23. Daptomycin (Cubicin®) FDA-Approved Indications
Treatment of complicated skin and skin structure infections caused by susceptible aerobic gram-positive organisms
Staphylococcus aureus bacteremia, including right-sided infective endocarditis caused by MSSA or MRSA
Not for respiratory tract infections (penetrates lungs well, but human pulmonary surfactant binds to daptomycin and inactivates)

24. Daptomycin (Cubicin®) PKS
Distribution: 0.1 L/kg
Protein binding: 90% to 93%; 84% to 88% in patients with Clcr<30 mL/minute
Half-life elimination: 8-9 hours (up to 28 hours in renal impairment)
Excretion: Urine (78%; primarily as unchanged drug); feces (6%)

25. Daptomycin (Cubicin®) ADR’s
CPK elevation (3-9%)—monitor weekly CPK
HA (5-7%), dizziness (2-6%)
Rash (4-7%)
GI (3-12%): constipation, nausea, diarrhea
Injection site reaction (3-6%)
Eosinophilic Pneumonia Associated with Daptomycin Use - July 2010
Some reagents can falsely prolong PT and INR

26. Daptomycin (Cubicin®) Drug Interactions
HMG-CoA Reductase Inhibitors
May enhance the adverse effect of daptomycin
Risk of skeletal muscle toxicity may be increased
Consider temporarily stopping HMG-CoA reductase inhibitor

27. Daptomycin (Cubicin®) Dosage Forms/Dosing
Injection, powder for reconstitution:
Cubicin®: 500 mg
Skin and/or skin structure infections (complicated): I.V.: 4 mg/kg once daily for 7-14 days
Bacteremia, right-sided endocarditis caused by MSSA or MRSA: I.V.: 6 mg/kg once daily for 2-6 weeks
Dose modify for CrCl<30ml/min; not studied in severe hepatic impairment