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Lass-Flörl Cornelia Innsbruck Medical University Divison of Hygiene and Medical Microbiology

Is azole resistance increasing amongst Aspergillus species?. Lass-Flörl Cornelia Innsbruck Medical University Divison of Hygiene and Medical Microbiology. Innsbruck Medical University. Faculty disclosure. Invited speaker: Pfizer, Gilead, MSD, Schering-Plough

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Lass-Flörl Cornelia Innsbruck Medical University Divison of Hygiene and Medical Microbiology

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  1. Is azole resistance increasing amongst Aspergillus species? Lass-Flörl Cornelia Innsbruck Medical University Divison of Hygiene and Medical Microbiology

  2. Innsbruck Medical University

  3. Faculty disclosure • Invited speaker: Pfizer, Gilead, MSD, Schering-Plough • Consultant: Pfizer, Gilead, Schering-Plough • Research Grants: Pfizer, Gilead, Schering-Plough

  4. To determine the susceptibility of fungi to antifungal agents Concentration that inhibits the growth of fungi = Minimum inhibitory concentration(expressed as µg/ml) Several methods can be used to define the MIC MIC reading = depends on the method used(EUCAST, CLSI, E-test,…)

  5. MICs defined via E-test Growth of fungus MIC= zone of inhibition

  6. Susceptibility testing: The big gaps • MICs help, but hard to standardize • Correlations appear possible based on individual isolates. Broad correlations based on multiple isolates are still lacking • Understanding this helps a lot when trying to correlate outcome with MIC - Some patients get better despite MICs - Some patients just don’t get better despite MICs • No rule when it correlates/not correlates Rex, 2005

  7. Facing In Vitro/In Vivo Correlation with Fungi Has Antifungal Susceptibility Testing Come of Age? Pfaller, Rex 2002

  8. In vitro Azole-Resistance Differences within the world! • 1997: first published case of ITC-resistant isolates of A. fumigatus (UK) • 2000: 4.2% with higher MICs to ITC (>8 µg/ml) in a surveillance study (UK) • 1945-1998: 0.3% in the Netherlands • 2000: 2.5%; 2002: 4.9%; 2006: 6.6% (NL) • 2006: 2% in Spain • 2007: 0% in Austria Lass-Flörl, 2009

  9. In vivo resistance • 2002 first cases of what appears to be multiple-azole resistant in A. fumigatus • In vitro and in vivo correlations • Treatment: polyene or candine or azoles! • Reports derive from UK and The Netherlands Denning 1997, Verweij, 1998, Moore 2001, Howard, 2006

  10. Multiple-triazole-resistant aspergillosis. Verweij PE, Mellado E, Melchers WJ N Engl J Med. 2007 356 (14):1481-3.

  11. Lass-Flörl, 2009

  12. Frequency doese increase in some centres! • Resistance of A. fumigatus clinical isolates to triazoles (ITC, VOR, POS) has been reported with increasing frequency, • although it is generally considered an uncommon phenomenon.

  13. Azoles: Voriconazole, Posaconazole, Itraconazole Ergosterol 14-α-sterol demethylase Lanosterol

  14. Azole Resistance Mechanisms Altered drug uptake Increased drug efflux 1. Changes in drug import/export cyp 51A cyp 51A 2. Alterations in sterol biosynthesis cyp 51A cyp 51A Overexpression of drug target Mutations in cyp51A

  15. AZOLE RESISTANT ASPERGILLUS FUMIGATUS

  16. Mellado (2004,2005, 2007), Verweij 2007, Snelders 2009

  17. Defintions: Azole- Resistance • Azole:a single drug resistance (ITC and VOR > 4µg/ml, POS > 2µg/ml) • Multi-azole resistance: resistant against at least two or more drugs • Panazole: resistant against all azoles tested Denning, Verweij, 2009

  18. Cross resistance • Cross-resistance between azole drugs appears to exist in vivo and in vitro and depends on specific mutations in Cyp51A • Between ITC and POS • Not so evident between ITC and VOR Oakley 2000, Moore 2000

  19. Conclusion • Increase in some centres • In vivo and in vitro • Associated with prolonged azole treatment • Molecular mechanisms are well knwon

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