Glycopeptides, Oxazolidinones, Streptogramins and Aminoglycosides

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

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

3. 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

4. Glycopeptides

5. Glycopeptides • Vancomycin • Licensed throughout the world • Teicoplanin • Not FDA approved

6. 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

7. 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

8. When do you need Vancomycin Nafcillin Vancomycin

9. 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

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

12. Nosocomial Enterococci Reported as Resistant to Vancomycin, by Year *National Nosocomial Infections Surveillance (NNIS) System Data, 1989-1999.

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

14. 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

15. 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

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

17. Lipopepetides

18. Daptomycin

19. 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

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

21. Streptogramins

22. quinupristin dalfopristin

23. 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

24. 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

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

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

27. Oxazolidinones

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

29. Linezolid

30. 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

31. 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)

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

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

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

35. AMINOGLYCOSIDES

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

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

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

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

40. 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

41. 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

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

43. 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

44. 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, 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.

45. Thank you