Presentation on theme: "Lass-Flörl Cornelia Innsbruck Medical University Divison of Hygiene and Medical Microbiology Is azole resistance increasing amongst Aspergillus species?"— Presentation transcript:
Lass-Flörl Cornelia Innsbruck Medical University Divison of Hygiene and Medical Microbiology Is azole resistance increasing amongst Aspergillus species?
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,…) To determine the susceptibility of fungi to antifungal agents
MICs defined via E-test Growth of fungus MIC= zone of inhibition
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 dont get better despite MICs –No rule when it correlates/not correlates Rex, 2005
Aspergillus terreusAmphotericin BIntrinsic Candida glabrataAzolesIntrinsic and acquired Candida kruseiAzolesIntrinsic Candida lusitaniaeAmphotericin BIntrinsic and acquired Histoplasma capsulatumFluconazoleAcquired Has Antifungal Susceptibility Testing Come of Age? Pfaller, Rex 2002 Facing In Vitro/In Vivo Correlation with Fungi
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
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
Multiple-triazole-resistant aspergillosis. Verweij PE, Mellado E, Melchers WJ N Engl J Med (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.
Azole Resistance Mechanisms Altered drug uptake Increased drug efflux 1. Changes in drug import/export cyp 51A Mutations in cyp51A Overexpression of drug target 2. Alterations in sterol biosynthesis
Defintions: Azole- Resistance 1.Azole:a single drug resistance (ITC and VOR > 4µg/ml, POS > 2µg/ml) 2.Multi-azole resistance: resistant against at least two or more drugs 3.Panazole: resistant against all azoles tested Denning, Verweij, 2009
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
Conclusion Increase in some centres In vivo and in vitro Associated with prolonged azole treatment Molecular mechanisms are well knwon