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

Agents for VRE:Oxazolidinones, Stretogramins, Cyclic

Lipopeptides

Mark S. Johnson, Pharm.D., BCPSAssociate Professor and

Director of Postgraduate Education

Linezolid (Zyvox®)• Oxazolidinone class

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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

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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

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

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.

Linezolid (Zyvox®)PKS

• Absorption: BA 100%• Distribution: Vdss: Adults: 40-50 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%

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

Linezolid (Zyvox®)Drug Interactions

• Weak, reversible monoamine oxidase inhibitor– Tyramine containing foods (HTN)– SSRI’s (serotonin syndrome)– Decongestants (HTN)– MAOI inhibitors

Linezolid (Zyvox®)Dosage Forms/Dosing

• Oral: – 600mg tablets– 100mg powder per 5ml suspension– Most uses: 600mg PO Q12h– Uncomplicated skin and skin structure

infections: 400 mg every 12 hours– Cost: 600 mg (#20) = $1724.51

• Parenteral:– 200 mg (100 mL); 600 mg (300 mL)– 600mg IV Q12h

Quinupristin/Dalfopristin (Synercid®) Streptogramins

• Streptogramin class http://www.rxlist.com/synercid-drug.htm

Quinupristin (a streptogramin B) Dalfopristin (a streptogramin A)

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

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

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

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%)

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%)

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

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.

Daptomycin (Cubicin®)

• A cyclic lipopeptide – Fermentation product of Streptomyces

roseosporus

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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

Daptomycin (Cubicin®)

• MOA: disruption of bacterial membrane function

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

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)

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%)

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

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

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