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

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

Nafcillin

Vancomycin

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

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

dalfopristindalfopristin

quinupristinquinupristin

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

OxazolidinonesOxazolidinones

Synthetic antibiotics Synthetic antibiotics One approved (Linezolid), some are One approved (Linezolid), some are

still investigational (Eperezolid, still investigational (Eperezolid, furazolidone) furazolidone)

LinezolidLinezolid

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

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.