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![Page 1: Lass-Flörl Cornelia Innsbruck Medical University Divison of Hygiene and Medical Microbiology Is azole resistance increasing amongst Aspergillus species?](https://reader036.fdocuments.net/reader036/viewer/2022062511/5515c3c455034689058b467d/html5/thumbnails/1.jpg)
Lass-Flörl CorneliaInnsbruck Medical University
Divison of Hygiene and Medical Microbiology
Is azole resistance increasing amongst Aspergillus species?
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Innsbruck Medical University
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Faculty disclosure
• Invited speaker: Pfizer, Gilead, MSD, Schering-Plough
• Consultant: Pfizer, Gilead, Schering-Plough• Research Grants: Pfizer, Gilead, Schering-Plough
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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
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AmB
5FC
FLU
ITRA
VORI
CASPO
Increasing Concentrations
candida
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MICs defined via E-test
Growth of fungus
MIC= zone of inhibition
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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
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Aspergillus terreus Amphotericin B Intrinsic
Candida glabrata Azoles Intrinsic and acquired
Candida krusei Azoles Intrinsic
Candida lusitaniae Amphotericin B Intrinsic and acquired
Histoplasma capsulatum Fluconazole Acquired
Has Antifungal Susceptibility Testing Come of Age?Pfaller, Rex 2002
Facing In Vitro/In Vivo Correlation with Fungi
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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
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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
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Multiple-triazole-resistant aspergillosis.
Verweij PE, Mellado E, Melchers WJ
N Engl J Med. 2007 356 (14):1481-3.
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Clinical Feature Primary resistance + Secondary resistance
++
In vivo-in vitro correlation
++
Risk factors Long term azole treatment: ++ Long term azole prophylaxis: ++
Cross-resistance ++ Multi-drug azole resistance
++
Outcome Lethal: ++ Plus signs (+) indicate the severity Lass-Flörl, 2009
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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.
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14-α-sterol demethylase
Azoles: Voriconazole, Posaconazole, Itraconazole
Ergosterol
Lanosterol
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Azole Resistance Mechanisms
Altered drug uptake Increased drug efflux
1. Changes in drug import/export
cyp 51A
cyp 51A
Mutations in cyp51A
cyp 51Acyp 51A
Overexpression of drug target
2. Alterations in sterol biosynthesis
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AZOLE RESISTANT ASPERGILLUS FUMIGATUS
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Amino acid changes Resistant drugs M220I, M220V, M220K, M220T
ITC-resistance and reduced activity to POS, VOR, RAV
G54R, G54E, G54W, G54V
ITC and POS
L98H Multidrug-azole resistance (ITC, POS, VOR, ravuconazole)
G138C ITC, VRC and long-term treatment
Mellado (2004,2005, 2007), Verweij 2007, Snelders 2009
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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
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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
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Conclusion
• Increase in some centres
• In vivo and in vitro
• Associated with prolonged azole treatment
• Molecular mechanisms are well knwon