Fungal Research Trust 20th Anniversary Meeting June 2011 - Dr Sue Howard
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Dr Sue Howard gives a talk entitled "Aspergillus resistance - it's on the increase" to the 20th Anniversary Meeting of the Fungal Research Trust
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Fungal Research Trust 20th Anniversary Meeting June 2011 - Dr Sue Howard
- 1. 20 th Anniversary Meeting of the Fungal Research Trust Aspergillus resistance – it's on the increase Dr Sue Howard June 2011 London, UK
- 2. Aspergillus resistance – it's on the increase Dr Susan J Howard The University of Manchester Manchester Academic Health Science Centre NIHR Translational Research Facility in Respiratory Medicine University Hospital of South Manchester NHS Foundation Trust
- 3. Aspergillus fumigatus Aspergillus terreus Aspergillus flavus Aspergillus niger
- 4. Other Aspergillus species Klick MA. Identification of common Aspergillus species. CBS.
- 5. Intrinsic resistance in Aspergillus flavus - ++ ++ ++ + ++ - ++ fumigatus - ++ ++ ++ + ++ +/- ++ FLU ITR VOR POS RAV AMB 5FC CANDINS niger - ++ ++ ++ + ++ - ++ terreus - ++ ++ ++ + - - ++ Acquired resistance development
- 9. Clinical azole resistance reported Frequency ~2% (0-15%)
- 10. overall 10% Significant increase since 2004 (Fishers exact test P<0.0001)
- 11. Manchester as a centre -> Specialist service for the management of aspergillosis 2009 N ational A spergillosis C entre www.nationalaspergillosiscentre.org.uk -> Susceptibility testing is routinely conducted may explain high frequency of itra resistance but does not explain the change in frequency why?
- 12. Denning AAC 1997;41:1364-8 Verweij DRU 2009 ;12:141-7
- 16. Resistance mechanism Azole drug Lanosterol Ergosterol E
- 17. The cyp51A gene intron start codon stop codon
- 18. “ hot-spots” The cyp51A gene 54 98 220 intron start codon stop codon
- 19. Snelders PLoS M 2009;5:e219 Holland 98 220 297 495
- 20. Rodriguez-Tudela AAC 2008;52:2468-72 Holland 98 220 297 495 Spain 98 54 220
- 21. Manchester 216 147 431 138 448 434 Bueid JAC 2010; 65:2116-8 Howard EID 2009;15:1068-76 284 219 495 Holland 98 220 297 495 Spain 98 54 220 54 98 220 28% 19% 53% 94% 3% 14% 6% 11%
- 30. Evolution in the lung!
- 31. Environmental sampling Snelders PLoS M 2008;5:e219 ?agricultural azole use
- 32. Harrison E ICAAC 2009 M-1720 cyp51A mutation identified no cyp51A mutation
- 33. Resistance mechanism Azole drug Lanosterol Ergosterol E
- 34. Resistance mechanism Azole drug Lanosterol Ergosterol E E E E E E E E E
- 35. Al-Barrag unpublished Relative expression of CAP51A to Beta tubulin WT WT codon 138 (GGC -> TGC) codon 138 (GGC -> TGC) codon 431 (TAC -> TGC) codon 434 (GGC -> TGC) 11/04 11/04 06/05 06/05 CYP51A overexpression with target mutations
- 36. Resistance mechanism Azole drug Lanosterol Ergosterol E Azole Azole Azole Azole Azole Azole
- 37. expression of efflux transporters Al-Barrag unpublished Limited evidence in Aspergillus currently
- 38. Other as yet un-identified mechanisms??
- 40. Azole cross-resistance Itra resistance = almost all Posa resistance = 74% Vori resistance = 65% Amb resistance = 0% Howard EID 2009;15:1068-76
- 41. Bueid JAC 2010; 65:2116-8 0% 0% 7% 3% 0% 5% 5% 5% 7% 17% 0% 14% 20%
- 45. Thank you