Agents for VRE: Oxazolidinones, Stretogramins, Cyclic

Report
Agents for VRE:
Oxazolidinones, Stretogramins,
Cyclic Lipopeptides
Mark S. Johnson, Pharm.D., BCPS
Associate Professor and
Director of Postgraduate Education
Linezolid (Zyvox®)
• Oxazolidinone class
www.onlinepharmacycatalog.com
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
www.microblog.me.uk
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
www.rxlist.com
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
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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 714 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

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