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  1. Susceptibility testing new agents. Dr. Ian Morrissey Chief Executive GR Micro Ltd. London, UK.

  2. New Agents • Linezolid (Pfizer) • Tigecycline (Wyeth) • Daptomycin (Novartis) • Dalbavancin (Pfizer)

  3. Basic principles still important.

  4. Linezolid • Approved in 2000 in the USA. • Community-acquired and nosocomial pneumonia. • Complicated and uncomplicated skin and soft-tissue infections. • Methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. • Protein synthesis inhibitor • Bacteriostatic agent • Oral and parenteral formulations.

  5. Linezolid susceptibility • Non-susceptibility is rare • Some development signs in Enterococci esp. E. faecium. • Occasional cases in S. aureus. • Very rare in S. pneumoniae.

  6. CLSI modified guidelines • QC ranges changed from 27-31 mm to 25-32 mm after 4-5 yrs of use. • Bacteriostatic agents may be more problematical when measuring zones or MICs by Etest. Biedenbach & Jones 2003 CMI 9:1035

  7. Tigecycline • Launched 2005 in USA for SSTI. • First glycylcycline • Derivative of minocycline • Evades Tet A-E & K efflux pumps • But not those of Proteae or Pseudomonas • Unique amongst newer agents having activity against Gram-negative bacteria. • But is active against MRSA and VRE. • Acinetobacter baumannii • Parenteral administration only. • Bacteriostatic.

  8. Tigecycline susceptibility • High against Gram-positive bacteria, E. coli & K. oxytoca. • Some resistance found in Gram-negs • K. pneumoniae (92-95% susceptibility) • E. aerogenes (96% susceptibility) • E. cloacae (93% susceptibility) • S. marcescens (97% susceptibility) Waites et al 2006 AAC 50: 3479

  9. Tigecycline breakpoints

  10. Medium batch & Tigecycline activity • Inconsistencies were noticed in QC data. • Linked to medium batch variation. • Tetracyclines are prone to inactivation by oxidation. • Studies carried out to investigate. • Petersen & Bradford 2005 AAC 49:3910 • Bradford et al 2005 AAC 49:3903.

  11. Old vs new

  12. Resolved by addition of Oxyrase

  13. Chromatographic evidence H2O H2O & Oxyrase Aged MHB

  14. Medium effect • Important for agar dilution or broth dilution. • Media >12h old affected. • Does not effect disc diffusion or Etest methods. • If using broth microdilution frozen panels are also not affected. • Solved by boiling or addition of oxyrase.

  15. Daptomycin • First glycolipopeptide • Launched in 2003 in the USA – 2006 in Europe • SSTI • Endocarditis in the USA • Gram-positives only • Parenteral application only • Rapidly bactericidal

  16. Daptomycin Susceptibility • Non-susceptibility rare. • Some reports but case studies only. [CLSI only]

  17. Daptomycin – requires Calcium

  18. Calcium effect MIC at zero Ca++ = 64 mg/L GR Micro Ltd, data on file.

  19. Daptomycin diffusion assays • Daptomycin discs supplemented with 50 mg/L Ca++ have been developed. • Only for CLSI methodology (i.e. MHB) • Discontinued in 2005 • Isosensitest discs have proved problemmatical and have never been available. Why are dapto & Ca++ discs no longer available even for CLSI?

  20. Daptomycin treatment failure Susceptible BP was ≥16 mm • Hayden et al 2005 JCM 43:5285.

  21. Multicentre evaluation Jevitt et al 2006 JCM 44:3098

  22. Etest to the rescue! Jevitt et al 2006 JCM 44:3098

  23. Dalbavancin • New lipoglycopeptide • Derived from teicoplanin • Extended half-life • Once weekly dosing • Bactericidal • 8-16-fold more active than vancomycin • No resistance found to date • Except for cross-resistance to vanA Enterococci. • Not clinically available but has ‘FDA Approval’

  24. Dalbavancin Susceptibility • Breakpoints not currently set. • Broth microdilution requires addition of polysorbate-80 into wells for accurate and reproducible results. • Agar diluton has not been proposed as a standard method • Fritsche et al 2006 JCM 44:2988 • Problems with disc development • Poor agar diffusion • Jones et al 2006 JCM 44:2622 • Etest is available. • Correct interpretation is essential.

  25. Dalbavancin Etest Biedenbach et al 2007 JCM 45:998

  26. BSAC agar dilution method • BSAC method compares well with CLSI (NCCLS) • Mustaq et al 2004 JAC 54:617. • Agar dilution commonly 1 dilution higher

  27. Surrogate marker for dalbavancin Jones et al 2006 JCM 44:2622

  28. Summary • Linezolid • Continued use has ironed-out previous QC issues • Tigecycline • For broth: fresh medium or oxyrase is essential • Daptomycin • Discs not available – but Etests work. • Ca++ supplement required • Dalbavancin • Some question over agar dilution but BSAC seems OK. • Polysorbate-80 supplement in broth. • No disc but Etest is available.