2 hour support meeting for patients & carers that live with aspergillosis. Main speaker is Dr Sue Howard of Manchester University and the National Aspergillosis Centre

1. Aspergillosis Patients Support Meeting – July 2011 National Aspergillosis Centre Manchester, UK Led by Dr Graham Atherton, Specialist Nurse Georgina Powell Main speaker Dr Sue Howard, Researcher at the National Aspergillosis Centre & Manchester University Funding assisted by the Fungal Research Trust www.fungalresearchtrust.org

2. Programme 2pm Graham Atherton: Welcome & Introduction 2.05 Sue Howard: Aspergillus resistance – it’s on the increase 3.00 Break: Tea & Coffee – your opportunity to chat with fellow patients and staff members 3.15 Graham Atherton: Report on Fungal Research Trust Anniversary meeting, London Patients Support meeting and feedback on progress with various projects. Need comments on 2 new patients information leaflets Complications with ABPA SAFS 4.00 Close

3. 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

4. Aspergillus fumigatus Aspergillus flavus Aspergillus terreus Aspergillus niger

5. Other Aspergillus species Klick MA. Identification of common Aspergillus species. CBS.

6. Acquired resistance development Intrinsicresistance in Aspergillus FLU ITR VOR POS RAV AMB 5FC CANDINS fumigatus -++ ++ ++ + ++ +/- ++ terreus-++ ++ ++ +--++ flavus-++ ++ ++ + ++ - ++ niger-++ ++ ++ + ++ - ++

8. First resistant case late 1980s but most >2000 Denning et al, 1997. AAC 41:1364-8

9. Agenda How common are resistant infections? What are the clinical risk factors? How does resistance occur? Is cross-resistance a clinical problem? How can we detect resistance?

10. Agenda How common are resistant infections? What are the clinical risk factors? How does resistance occur? Is cross-resistance a clinical problem? How can we detect resistance?

11. Clinical azole resistance reported Frequency ~2% (0-15%)

12. overall 10% Significant increase since 2004 (Fishers exact test P<0.0001)

13. Manchester as a centre -> Specialist service for the management of aspergillosis2009National Aspergillosis Centre 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?

14. Denning AAC 1997;41:1364-8 VerweijDRU2009;12:141-7

15. Agenda How common are resistant infections? What are the clinical risk factors? How does resistance occur? Is cross-resistance a clinical problem? How can we detect resistance?

16. Clinical data Clinical data were available for 14 patients 2 invasive aspergillosis (IA) 9 chronic pulmonary aspergillosis (CPA) 2 allergic bronchopulmonary aspergillosis (ABPA) 1 Aspergillus bronchitis Highest frequency in those with aspergillomas 13 had prior azole exposure (1 – 30 months) 6 had low drug exposures 8 patients failed therapy and 5 failed to improve (1 not treated) Howard EID 2009;15:1068-76 Howard CMI 2010;16:683-8

17. Agenda How common are resistant infections? What are the clinical risk factors? How does resistance occur? Is cross-resistance a clinical problem? How can we detect resistance?

18. Lanosterol Ergosterol E Resistance mechanism Azole drug

19. stop codon start codon intron The cyp51A gene

20. stop codon start codon intron The cyp51A gene 54 98 220 “hot-spots”

21. Holland 297 495 98 220 Snelders PLoS M 2009;5:e219

22. Holland 297 495 98 220 Spain 98 54 220 Rodriguez-Tudela AAC 2008;52:2468-72

23. 94% 3% Holland 297 495 98 220 28% 19% 53% Spain 98 14% 6% 11% 54 54 98 220 220 Manchester 216 138 448 284 219 147 431 495 434 Bueid JAC 2010; 65:2116-8 Howard EID 2009;15:1068-76

24. Manchesterfindings Striking variety of cyp51A mutations Including previously reported mutations (including the hot-spots) Some novel (147, 216, 431 & 434) – as yet uncharacterised Of 7 patients with multiple resistant isolates, 4 revealed different mutations over time Howard EID 2009;15:1068-76

25. Patient case 64 M COPD, bronchiectasis, Mycobacterium avium pulmonary infection Chronic pulmonary aspergillosis 2003 Azole susceptible A. fumigatus Itra therapy Low itra drug exposure (rifabutin) Ambisome twice for 2wk - some clinical improvement 4 mo itra resistant isolate (G54R) 4 mo later, another itra res isolate (G54E) Increased precipitins titre, radiological progression

27. Patient case Oct 2004 vori, 500 > 400 mg daily Good levels (0.72-1.66mg/L) Radiological and serological improvement

29. Patient case Oct 2004 vori, 500 > 400 mg daily Good levels (0.72-1.66mg/L) Radiological and serological improvement

31. Good levels (1.18-1.9mg/L)

33. Evolution in the lung!

34. ?agricultural azole use Environmental sampling Snelders PLoS M 2008;5:e219

35. cyp51A mutation identified no cyp51A mutation Harrison E ICAAC 2009 M-1720

36. Agenda How common are resistant infections? What are the clinical risk factors? How does resistance occur? Is cross-resistance a clinical problem? How can we detect resistance?

37. Azole cross-resistance Itra resistance = almost all Posa resistance = 74% Vori resistance = 65% Amb resistance = 0% Howard EID 2009;15:1068-76

38. 20% 14% 5% 17% 7% 5% 3% 0% 0% 5% 7% 0% 0% Bueid JAC 2010; 65:2116-8

39. Agenda How common are resistant infections? What are the clinical risk factors? How does resistance occur? Is cross-resistance a clinical problem? How can we detect resistance?

40. Detection options MICs slow Cultures frequently falsely negative in all forms of aspergillosis Direct cyp51A mutation from primary specimen by real-time PCR  most common mutations = G54, L98, M220, TR 55.1% cyp51A mutations (culture –ve) Pro’s and con’s (other/no mutations & cost vs. -ve cultures & speed) Need to do MICs still! Denning CID 2011; 52:1123-9

41. Conclusions Resistance is clinically significant Evidence of both environmental acquisition and emergence of resistance in the lung Increasing frequency Risk of cross-resistance is high/limited options Need to monitor susceptibility routinely

42. Thank you

43. Graham Atherton National aspergillosis centre UHSM Manchester Support Meeting for Aspergillosis Patients Fungal Research Trust

44. Current ideas for fundraising Campaign ribbons – cost us 75p each, donate what you can Cook book FUNGUIDE patient’s cookery book Combining your recipes with ‘good news’ about fungi, how useful they can be Any of your recipes including the use of any of the following: Mushrooms, soy sauce, Quorn, Marmite, Stilton, Brie, camembert and so on

45. New Fungal Research Trust website

46. New FRT fundraising campaign To fund a Postdoctoral scientist who will carry out work to increase our understanding of fungal diseases 1. Why Aspergillus causes disease, especially slowly progressive disease such as ABPA, bronchiectasis, chronic pulmonary aspergillosis and/or lung scarring. 2. What are protective factors for fungal infection? Why do some people with the same risk factors not get colonised or infected? 3. Why do fungi become resistant to antifungal drugs? Target £150 000 which will fund research for 3 years

47. Raising the money Lewis Fraser Himalayan run (100 miles) in memory of Steph Smith. Target £10 000 Gem’s little Gems. Target £10 000 this year Christmas raffle 2010 raised £1500 A patient raised £250 last year making and selling greetings cards 2010 raised approx £13 000 Can you help? Your ideas & time will be the lifeblood of this challenge Sign up for our newsletter http://www.aspergillus.org.uk/newpatients/donations.php

48. Drug Interactions database

49. Drug Interactions database

50. Drug Interactions database

51. Current ideas for fundraising Campaign ribbons – cost us 75p each, donate what you can Cook book FUNGUIDE patient’s cookery book Combining your recipes with ‘good news’ about fungi, how useful they can be Any of your recipes including the use of any of the following: Mushrooms, soy sauce, Quorn, Marmite, Stilton, Brie, camembert and so on

52. Involving you in our work The Fungal Research Trust have appointed a new trustee who is a patient Derek Stewart is to put forward the patients’ point of view to the board on a regular basis, eg with regard to research interests Elisabeth Kershaw is working on behalf of patients by assisting with the formulation of future research proposals

53. Thank You “The best chance we have of beating this illness is to work together” Living with it, Working with it, Treating it Fungal Research Trust

54. What is this meeting for? For you to socialise with fellow patients For you to receive support from NAC staff We are here to answer your questions, feel free to approach any one of us We are here to listen about what we can do better We can use these meeting to assess our service, to ask for more help with research We occasionally feedback results of the research already in progress Fundraising for research (Fungal Research Trust)

55. What can you do for us? Feedback comments & suggestions on what we already do. What isn’t working? What is working? What do you need to know more about? How can we improve? What more can we do? Help us with fundraising The Fungal Research Trust