Glycopeptides, Oxazolidinones, Streptogramins and Aminoglycosides

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Glycopeptides, Oxazolidinones, Streptogramins and
Aminoglycosides

• Hail M. Al-Abdely, MD
• Consultant, Adult Infectious Diseases
• King Faisal Specialist Hospital and Research
  Center

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AIM OF THIS PRESENTATION

• Practical use of these antibiotics

No sophisticated stuff!!
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Driving forces behind Drug development

• Good market
• Common NOT rare (pseudomonas versus Burkhelderia)
• Common in the rich (HIV versus leishmania)
• Difficult to treat
• Emerging new organisms (Fungi in immune
  suppressed patients)
• Resistance in old organisms (several bacteria)
• Better kinetics and safety (Ampho B versus
  Azoles)
• Basic Human need

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Glycopeptides
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Glycopeptides

• Vancomycin
• Licensed throughout the world
• Teicoplanin
• Not FDA approved

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Vancomycin

• Vancomycin is obtained from Nocardia orientalis
• Vancomycin has been used clinically since 1956
• Recent improvements in manufacturing have
  increased its purity and reduced its toxicity
• Pure gram positive spectrum

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Vancomycin

• Vancomycin is bactericidal (except enterococcus)
• binds to the precursor units of bacterial cell
  walls (peptidoglycans), inhibiting their
  synthesis.
• In addition, RNA synthesis is inhibited
• Work systemically, topically and locally
• Systemic gram-positive infections
• C. difficile colitis
• Shunt infections/ventriculitis

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When do you need Vancomycin
Nafcillin
Vancomycin
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When do you need Vancomycin

• Resistance to better drugs
• MRSA, Coagulase-negative Staphylococi
• Amp-resistant enterococcus,
• Some corynebacteria and bacillus
• Allergy to better drugs
• Toxicity of better drugs
• Empiric therapy for suspected resistance
• Special situations
• Dosing intervals in OPD setting
• Dialysis

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Disadvantages of Vancomycin

• Parentral
• Poor penetration to CSF
• Lower efficacy than penicillins
• Mild to moderate toxicity
• Resistance
• VRSA
• VRE

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Nosocomial Enterococci Reported as Resistant to
Vancomycin, by Year
National Nosocomial Infections Surveillance
(NNIS) System Data, 1989-1999.
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Vancomycin-resistant enterococci
Non-Intensive Care Unit Patients Intensive Care
Unit Patients
Source National Nosocomial Infections
Surveillance (NNIS) System
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Due you need to measure levels

• No except
• Pre-existing renal impairment
• Rising creatinine
• Co-administered nephrotoxic drugs
• Assure therapeutic levels (serious infections)
• Measure only trough levels (pre-dose)
• Dialysis patients pre-dialysis level
• STOP weekly vancomycin dosing in HD patients

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Teicoplanin

• Similar to vancomycin in spectrum
• Once daily and I.M dosing
• May retain activity against vancomycin-resistant
  Staphylococcus aureus
• More active against enterococcus than vancomycin

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When you may need Teicoplanin

• Dosing advantages for out-patient treatment
• VRSA
• Some strains of VRE

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Lipopepetides
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Daptomycin
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Lipopepetides

• Daptomycin
• Approval by FDA September 2003 for treatment of
  complicated skin and soft tissue infections
• Mechanism of action disruption of the plasma
  membrane function.
• Bacteriocidal against multidrug-resistant,
  gram-positive bacteria
• Methicillin-resistant Staphylococcus aureus
• Vancomycin-resistant enterococci
• Glycopeptide-intermediate and -resistant S.
  aureus.
• Penicillin-resistant Streptococcus pneumoniae

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Daptomycin

• Fast bacteriocidal action
• Concentration-dependent killing
• Post antibiotic effect
• Once daily dosing
• Excreted mainly through kidneys

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Streptogramins
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quinupristin
dalfopristin
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Streptogramins

• Isolated from Streptomyces pristinaespiralis
• Used as oral agents in France since the 1960s
• Dalfopristin and quinupristin are the only
  parentral agents
• The combination product (Synercid) has up to 16
  times the activity of each agent alone
• Streptogramins inhibit bacterial protein
  synthesis by irreversibly blocking ribosome
  functioning
• Each component is bacteriostatic but the
  combination is bacteriocidal
• The main reason for development and approval is
  VRE

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Synercid

• Combination of dalfopristin and quinupristin
• administered by intravenous infusion
• Metabolism is not dependent on cytochrome P450.
  But a major inhibitor of the activity of
  cytochrome P450 3A4 isoenzyme
• Elimination through fecal excretion

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When you may ask for Synercid

• Serious VRE infection
• MRSA infection for which you can not use
  vancomycin /- linezolid

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Safety of Synercid

• Safe with no major toxicities
• Thrombophlebitis, GI
• Mostly given through a CVL

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Oxazolidinones
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Oxazolidinones

• Synthetic antibiotics
• One approved (Linezolid), some are still
  investigational (Eperezolid, furazolidone)

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Linezolid
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Linezolid

• Approved for use in adults April 2000 and for
  pediatrics December 2002
• Works against aerobic gram-positive organisms
• Linezolid inhibits bacterial protein synthesis by
  interfering with translation
• binds to a site on the bacterial 23S ribosomal
  RNA of the 50S subunit this action prevents the
  formation of a functional 70S initiation complex,
  an essential step in the bacterial translation
  process

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Linezolid

• Linezolid is administered by intravenous infusion
  or orally
• oral bioavailability for linezolid is 100.
• have significant penetration into bone, fat,
  muscle, and hematoma fluid
• metabolism is non-enzymatic and does not involve
  CYP450
• does not inhibit or induce CYP450 isoenzymes.
• Non-renal clearance accounts for 65 of an
  administered linezolid dosage (no adjustment in
  renal failure)

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Indications of Linezolid

• Mainly developed because of VRE
• first new antibiotic approved to target
  methicillin-resistant staphylococci in 35 years

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Resistance to Linezolid

• linezolid-resistant VRE organisms were being
  discovered in various institutions
• Also some MRSA

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Safety of Linezolid

• linezolid is a non-selective inhibitor of
  monoamine oxidase (MAO)

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AMINOGLYCOSIDES
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AMINOGLYCOSIDES

• Members of the Group
• Streptomycin Dibekacin
• Neomycin Netilmicin
• Kanamycin Sisomycin
• Gentamycin Aminosidine
• Tobramycin Paromomycin
• Amikacin Spectinomycin
• Arbikacin

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AMINOGLYCOSIDES

• Mechanism of Action
• interfere with protein synthesis
• active transport mechanism
• Mode of Action
• bactericidal

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AMINOGLYCOSIDES

• Antibacterial activity
• Spectrum
• aerobic gram (-) bacteria
• mycobacteria
• Brucella
• gram () bacteria
• Characteristics
• Highly polar cations ?? limited distribution
• Low activity in low PH

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AMINOGLYCOSIDES

• Pharmacodynamics
• Concentration dependent killing
• Postantibiotic effect
• Once daily dosing
• Similar efficacy
• Low nephrotoxicity

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AMINOGLYCOSIDES

• Pharmacokinetics
• Absorption very poorly absorbed
• ?parenteral
• Distribution negligible binding to plasma
  proteins
• excluded from most cells
• VD ECF
• in renal cortex / inner ear
• Excretion GF

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AMINOGLYCOSIDES

• Mechanisms of Resistance
• inactivation by microbial enzymes
• Plasmid-mediated
• Acetylases, adnylases, phosphorylases
• Amikacin is the most stable
• impaired intracellular transport / failure of
  permeation
• altered ribosomal binding site / low affinity of
  the drug
• Enterococcus In cases of high level resistance
  to gentamicin, you can only use streptomycin

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PROBLEMS OF AMINOGLYCOSIDES

• Adverse Effects
• Ototoxicity
• Nephrotoxicity ? Monitoring
• Neurotoxicity
• Distribution ? Combined with other agents
• Resistance ? Alternatives

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Monitoring levels of Aminoglycosides

• Trough levels correlate with nephrotoxicity and a
  lesser extent ototoxicity
• High peak levels in elderly can be associated
  with nephrotoxicity and ototoxicity
• If dosing once daily, check trough levels. They
  should be non-detectable
• Close monitoring is essential in renal impairment

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Final Statement

• Microbes are going to stay with us no mater what
  we do to them
• Those who are going to stay with us are those
  that are most resilient (i.e. resistant) ones
  that can adapt to all of our weapons
• So, lets try to keep facing the less resilient
  ones those that we can treat effectively
• We do that by a wise management of the battle
  with microbes through judicious use of
  antimicrobials.

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• Thank you