Glycopeptides, Oxazolidinones, Streptogramins and Aminoglycosides Hail M. Al-Abdely, MD Consultant, Adult Infectious Diseases King Faisal Specialist Hospital and Research Center

AIM OF THIS PRESENTATION Practical use of these antibiotics No sophisticated stuff!!

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

Glycopeptides

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

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

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

When do you need Vancomycin Nafcillin Vancomycin

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

Disadvantages of Vancomycin Parentral Parentral Poor penetration to CSF Poor penetration to CSF Lower efficacy than penicillins Lower efficacy than penicillins Mild to moderate toxicity Mild to moderate toxicity Resistance Resistance VRSA VRSA VRE VRE

Nosocomial Enterococci Reported as Resistant to Vancomycin, by Year *National Nosocomial Infections Surveillance (NNIS) System Data,

Vancomycin-resistant enterococci Non-Intensive Care Unit Patients Intensive Care Unit Patients Source: National Nosocomial Infections Surveillance (NNIS) System

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

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

When you may need Teicoplanin Dosing advantages for out-patient treatment Dosing advantages for out-patient treatment VRSA VRSA Some strains of VRE Some strains of VRE

Lipopepetides

Daptomycin

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

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

Streptogramins

dalfopristin quinupristin

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

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

When you may ask for Synercid™ Serious VRE infection Serious VRE infection MRSA infection for which you can not use vancomycin +/- linezolid MRSA infection for which you can not use vancomycin +/- linezolid

Safety of Synercid™ Safe with no major toxicities Safe with no major toxicities Thrombophlebitis, GI Thrombophlebitis, GI Mostly given through a CVL Mostly given through a CVL

Oxazolidinones

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

Linezolid

Linezolid Approved for use in adults April 2000 and for pediatrics December 2002 Approved for use in adults April 2000 and for pediatrics December 2002 Works against aerobic gram-positive organisms Works against aerobic gram-positive organisms Linezolid inhibits bacterial protein synthesis by interfering with translation 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 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

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

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

Resistance to Linezolid linezolid-resistant VRE organisms were being discovered in various institutions linezolid-resistant VRE organisms were being discovered in various institutions Also some MRSA Also some MRSA

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

AMINOGLYCOSIDES

AMINOGLYCOSIDES Members of the Group StreptomycinDibekacin NeomycinNetilmicin KanamycinSisomycin GentamycinAminosidine TobramycinParomomycin Amikacin Spectinomycin Arbikacin

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

AMINOGLYCOSIDES Antibacterial activity Antibacterial activity Spectrum: aerobic gram (-) bacteria mycobacteria Brucella gram (+) bacteria Characteristics Highly polar cations  limited distribution Low activity in low PH

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

AMINOGLYCOSIDES Pharmacokinetics Absorptionvery poorly absorbed  parenteral Distributionnegligible binding to plasma proteins excluded from most cells VD = ECF in renal cortex / inner ear in renal cortex / inner ear ExcretionGF

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

PROBLEMS OF AMINOGLYCOSIDES Adverse Effects Adverse Effects Ototoxicity Ototoxicity Nephrotoxicity  Monitoring Nephrotoxicity  Monitoring Neurotoxicity Neurotoxicity Distribution  Combined with other agents Distribution  Combined with other agents Resistance  Alternatives Resistance  Alternatives

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

Final Statement Microbes are going to stay with us no mater what we do to them 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 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, let’s try to keep facing the less resilient ones; those that we can treat effectively So, let’s 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. We do that by a “wise” management of the battle with microbes through judicious use of antimicrobials.