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Is azole resistance increasing amongst Aspergillus species?

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Presentation on theme: "Is azole resistance increasing amongst Aspergillus species?"— Presentation transcript:

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,…)


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

7 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

8 Facing In Vitro/In Vivo Correlation with Fungi
Aspergillus terreus Amphotericin B Intrinsic Candida glabrata Azoles Intrinsic and acquired Candida krusei Candida lusitaniae Histoplasma capsulatum Fluconazole Acquired Has Antifungal Susceptibility Testing Come of Age? Pfaller, Rex 2002


10 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) : 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

11 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

12 Multiple-triazole-resistant aspergillosis.
Verweij PE, Mellado E, Melchers WJ N Engl J Med (14):

13 Lass-Flörl, 2009

14 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.

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

16 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


18 Mellado (2004,2005, 2007), Verweij 2007, Snelders 2009

19 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

20 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

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

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