Post on 26-Dec-2015
Glycopeptides, Glycopeptides, Oxazolidinones, Oxazolidinones,
Streptogramins and Streptogramins and AminoglycosidesAminoglycosidesHail M. Al-Abdely, MDHail M. Al-Abdely, MD
Consultant, Adult Infectious Consultant, Adult Infectious DiseasesDiseases
King Faisal Specialist Hospital and King Faisal Specialist Hospital and Research CenterResearch Center
AIM OF THIS PRESENTATIONAIM OF THIS PRESENTATION
Practical use of these antibioticsPractical use of these antibiotics
No sophisticated stuff!!No sophisticated stuff!!
Driving forces behind Drug Driving forces behind Drug developmentdevelopment
Good marketGood marketCommon Common NOTNOT rare (pseudomonas versus rare (pseudomonas versus
Burkhelderia)Burkhelderia)Common in the rich (HIV versus leishmania)Common in the rich (HIV versus leishmania)Difficult to treatDifficult to treat
Emerging new organisms (Fungi in immune Emerging new organisms (Fungi in immune suppressed patients)suppressed patients)
Resistance in old organisms (several bacteria)Resistance in old organisms (several bacteria)Better kinetics and safety (Ampho B versus Better kinetics and safety (Ampho B versus
Azoles)Azoles)Basic Human needBasic Human need
GlycopeptidesGlycopeptides
VancomycinVancomycinLicensed throughout the worldLicensed throughout the world
TeicoplaninTeicoplaninNot FDA approvedNot FDA approved
VancomycinVancomycin
Vancomycin is obtained from Vancomycin is obtained from Nocardia orientalisNocardia orientalis
Vancomycin has been used clinically Vancomycin has been used clinically since 1956 since 1956
Recent improvements in Recent improvements in manufacturing have increased its manufacturing have increased its purity and reduced its toxicity purity and reduced its toxicity
Pure gram positive spectrumPure gram positive spectrum
VancomycinVancomycin
Vancomycin is bactericidal (except Vancomycin is bactericidal (except enterococcus)enterococcus) binds to the precursor units of bacterial cell binds to the precursor units of bacterial cell
walls (peptidoglycans), inhibiting their walls (peptidoglycans), inhibiting their synthesis. synthesis.
In addition, RNA synthesis is inhibited In addition, RNA synthesis is inhibited Work systemically, topically and locallyWork systemically, topically and locally
Systemic gram-positive infectionsSystemic gram-positive infections C. difficile colitisC. difficile colitis Shunt infections/ventriculitisShunt infections/ventriculitis
When do you need When do you need VancomycinVancomycin
Resistance to better drugs Resistance to better drugs MRSA, Coagulase-negative StaphylocociMRSA, Coagulase-negative StaphylocociAmp-resistant enterococcus, Amp-resistant enterococcus, Some corynebacteria and bacillusSome corynebacteria and bacillus
Allergy to better drugsAllergy to better drugs Toxicity of better drugsToxicity of better drugs Empiric therapy for suspected resistanceEmpiric therapy for suspected resistance Special situationsSpecial situations
Dosing intervals in OPD settingDosing intervals in OPD setting DialysisDialysis
Disadvantages of Disadvantages of VancomycinVancomycin
ParentralParentralPoor penetration to CSFPoor penetration to CSFLower efficacy than penicillinsLower efficacy than penicillinsMild to moderate toxicityMild to moderate toxicityResistanceResistance
VRSAVRSAVREVRE
0
5
10
15
20
25
30
89 90 91 92 93 94 95 96 97 98 99
Year
% V
an
co
mycin
-Resis
tan
t E
nte
roco
cci
Nosocomial Enterococci Reported Nosocomial Enterococci Reported as Resistant to Vancomycin, by as Resistant to Vancomycin, by
YearYear
*National Nosocomial Infections Surveillance (NNIS) System Data, 1989-1999.
0
5
10
15
20
25
30
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
Per
cen
t R
esis
tan
ce
Vancomycin-resistant enterococci
Non-Intensive Care Unit Patients
Intensive Care Unit Patients
Source: National Nosocomial Infections Surveillance (NNIS) System
Due you need to measure Due you need to measure levelslevels
No exceptNo exceptPre-existing renal impairmentPre-existing renal impairmentRising creatinineRising creatinineCo-administered nephrotoxic drugsCo-administered nephrotoxic drugsAssure therapeutic levels (serious Assure therapeutic levels (serious
infections)infections)Measure only trough levels (pre-dose)Measure only trough levels (pre-dose)Dialysis patients: pre-dialysis levelDialysis patients: pre-dialysis level
STOP weekly vancomycin dosing in HD STOP weekly vancomycin dosing in HD patientspatients
TeicoplaninTeicoplanin
Similar to vancomycin in spectrumSimilar to vancomycin in spectrumOnce daily and I.M dosingOnce daily and I.M dosingMay retain activity against May retain activity against
vancomycin-resistant vancomycin-resistant Staphylococcus Staphylococcus aureusaureus
More active against enterococcus More active against enterococcus than vancomycin than vancomycin
When you may need When you may need TeicoplaninTeicoplanin
Dosing advantages for out-patient Dosing advantages for out-patient treatmenttreatment
VRSAVRSASome strains of VRESome strains of VRE
LipopepetidesLipopepetides
DaptomycinDaptomycin Approval by FDA September 2003 for treatment Approval by FDA September 2003 for treatment
of complicated skin and soft tissue infections of complicated skin and soft tissue infections Mechanism of action: disruption of the plasma Mechanism of action: disruption of the plasma
membrane function. membrane function. Bacteriocidal against multidrug-resistant, gram-Bacteriocidal against multidrug-resistant, gram-
positive bacteriapositive bacteria Methicillin-resistant Methicillin-resistant Staphylococcus aureusStaphylococcus aureus Vancomycin-resistant enterococciVancomycin-resistant enterococci Glycopeptide-intermediate and -resistant Glycopeptide-intermediate and -resistant S. aureusS. aureus. . Penicillin-resistant Penicillin-resistant Streptococcus pneumoniaeStreptococcus pneumoniae
DaptomycinDaptomycin
Fast bacteriocidal actionFast bacteriocidal actionConcentration-dependent killingConcentration-dependent killingPost antibiotic effectPost antibiotic effectOnce daily dosingOnce daily dosingExcreted mainly through kidneysExcreted mainly through kidneys
StreptograminsStreptogramins
Isolated from Isolated from Streptomyces pristinaespiralisStreptomyces pristinaespiralis Used as oral agents in France since the 1960sUsed as oral agents in France since the 1960s Dalfopristin and quinupristin are the only Dalfopristin and quinupristin are the only
parentral agentsparentral agents The combination product (Synercid®) has up to The combination product (Synercid®) has up to
16 times the activity of each agent alone 16 times the activity of each agent alone Streptogramins inhibit bacterial protein synthesis Streptogramins inhibit bacterial protein synthesis
by irreversibly blocking ribosome functioning by irreversibly blocking ribosome functioning Each component is bacteriostatic but the Each component is bacteriostatic but the
combination is bacteriocidal combination is bacteriocidal The main reason for development and approval is The main reason for development and approval is
VREVRE
Synercid™Synercid™
Combination of dalfopristin and Combination of dalfopristin and quinupristinquinupristin
administered by intravenous infusion administered by intravenous infusion Metabolism is not dependent on Metabolism is not dependent on
cytochrome P450. But a major cytochrome P450. But a major inhibitor of the activity of cytochrome inhibitor of the activity of cytochrome P450 3A4 isoenzyme P450 3A4 isoenzyme
Elimination through fecal excretion Elimination through fecal excretion
When you may ask for When you may ask for Synercid™Synercid™
Serious VRE infectionSerious VRE infection
MRSA infection for which you can not MRSA infection for which you can not use vancomycin +/- linezoliduse vancomycin +/- linezolid
Safety of Synercid™Safety of Synercid™
Safe with no major toxicitiesSafe with no major toxicitiesThrombophlebitis, GIThrombophlebitis, GIMostly given through a CVLMostly given through a CVL
OxazolidinonesOxazolidinones
Synthetic antibiotics Synthetic antibiotics One approved (Linezolid), some are One approved (Linezolid), some are
still investigational (Eperezolid, still investigational (Eperezolid, furazolidone) furazolidone)
LinezolidLinezolid
Approved for use in adults April 2000 and Approved for use in adults April 2000 and for pediatrics December 2002for pediatrics December 2002
Works against aerobic gram-positive Works against aerobic gram-positive organisms organisms
Linezolid inhibits bacterial protein synthesis Linezolid inhibits bacterial protein synthesis by interfering with translation by interfering with translation
binds to a site on the bacterial 23S binds to a site on the bacterial 23S ribosomal RNA of the 50S subunit; this ribosomal RNA of the 50S subunit; this action prevents the formation of a functional action prevents the formation of a functional 70S initiation complex, an essential step in 70S initiation complex, an essential step in the bacterial translation process the bacterial translation process
LinezolidLinezolid
Linezolid is administered by intravenous Linezolid is administered by intravenous infusion or orally infusion or orally
oral bioavailability for linezolid is 100%. oral bioavailability for linezolid is 100%. have significant penetration into bone, fat, have significant penetration into bone, fat,
muscle, and hematoma fluid muscle, and hematoma fluid metabolism is non-enzymatic and does not metabolism is non-enzymatic and does not
involve CYP450involve CYP450 does not inhibit or induce CYP450 does not inhibit or induce CYP450
isoenzymes. isoenzymes. Non-renal clearance accounts for 65% of Non-renal clearance accounts for 65% of
an administered linezolid dosage (no an administered linezolid dosage (no adjustment in renal failure)adjustment in renal failure)
Indications of LinezolidIndications of Linezolid
Mainly developed because of VREMainly developed because of VREfirst new antibiotic approved to first new antibiotic approved to
target methicillin-resistant target methicillin-resistant staphylococci in 35 yearsstaphylococci in 35 years
Resistance to LinezolidResistance to Linezolid
linezolid-resistant VRE organisms linezolid-resistant VRE organisms were being discovered in various were being discovered in various institutionsinstitutions
Also some MRSAAlso some MRSA
Safety of LinezolidSafety of Linezolid
linezolid is a non-selective inhibitor of linezolid is a non-selective inhibitor of monoamine oxidase (MAO) monoamine oxidase (MAO)
AMINOGLYCOSIDESAMINOGLYCOSIDES
Members of the GroupMembers of the Group
StreptomycinStreptomycin DibekacinDibekacin
NeomycinNeomycin NetilmicinNetilmicin
KanamycinKanamycin SisomycinSisomycin
GentamycinGentamycin AminosidineAminosidine
TobramycinTobramycin ParomomycinParomomycin
Amikacin Amikacin SpectinomycinSpectinomycin
ArbikacinArbikacin
AMINOGLYCOSIDESAMINOGLYCOSIDES
Mechanism of Action interfere with protein synthesis active transport mechanism
Mode of Actionbactericidal
AMINOGLYCOSIDESAMINOGLYCOSIDES
Antibacterial activityAntibacterial activitySpectrum:
aerobic gram (-) bacteriamycobacteriaBrucellagram (+) bacteria
CharacteristicsHighly polar cations limited distributionLow activity in low PH
AMINOGLYCOSIDESAMINOGLYCOSIDES
PharmacodynamicsPharmacodynamicsConcentration dependent killingPostantibiotic effect
Once daily dosingSimilar efficacyLow nephrotoxicity
AMINOGLYCOSIDESAMINOGLYCOSIDES
PharmacokineticsPharmacokinetics
AbsorptionAbsorption very poorly absorbedvery poorly absorbedparenteralparenteral
DistributionDistribution negligible binding to plasma proteinsnegligible binding to plasma proteinsexcluded from most cellsexcluded from most cellsVD = ECFVD = ECF in renal cortex / inner earin renal cortex / inner ear
ExcretionExcretion GFGF
AMINOGLYCOSIDESAMINOGLYCOSIDES
Mechanisms of ResistanceMechanisms of Resistance inactivation by microbial enzymesinactivation by microbial enzymes
Plasmid-mediatedPlasmid-mediated Acetylases, adnylases, phosphorylasesAcetylases, adnylases, phosphorylases Amikacin is the most stableAmikacin is the most stable
impaired intracellular transport / failure of impaired intracellular transport / failure of permeationpermeation
altered ribosomal binding site / low affinity of the altered ribosomal binding site / low affinity of the drugdrug
Enterococcus: In cases of high level resistance to Enterococcus: In cases of high level resistance to gentamicin, you can only use streptomycingentamicin, you can only use streptomycin
PROBLEMS OF AMINOGLYCOSIDESPROBLEMS OF AMINOGLYCOSIDES
Adverse EffectsAdverse EffectsOtotoxicityOtotoxicityNephrotoxicityNephrotoxicity MonitoringMonitoringNeurotoxicityNeurotoxicity
DistributionDistribution Combined with other Combined with other agentsagents
Resistance Resistance AlternativesAlternatives
Monitoring levels of Monitoring levels of AminoglycosidesAminoglycosides
Trough levels correlate with nephrotoxicity Trough levels correlate with nephrotoxicity and a lesser extent ototoxicityand a lesser extent ototoxicity
High peak levels in elderly can be High peak levels in elderly can be associated with nephrotoxicity and associated with nephrotoxicity and ototoxicityototoxicity
If dosing once daily, check trough levels. If dosing once daily, check trough levels. They should be non-detectableThey should be non-detectable
Close monitoring is essential in renal Close monitoring is essential in renal impairmentimpairment
Final StatementFinal Statement
Microbes are going to stay with us no mater Microbes are going to stay with us no mater what we do to themwhat we do to them
Those who are going to stay with us are those Those who are going to stay with us are those that are most resilient (i.e. resistant) ones that that are most resilient (i.e. resistant) ones that can adapt to all of our weaponscan adapt to all of our weapons
So, let’s try to keep facing the less resilient ones; So, let’s try to keep facing the less resilient ones; those that we can treat effectivelythose that we can treat effectively
We do that by a “wise” management of the battle We do that by a “wise” management of the battle with microbes through judicious use of with microbes through judicious use of antimicrobials.antimicrobials.