Aspergillosis Patient Support Meeting July 2011 - Sue Howard

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

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

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

Aspergillus fumigatus
Aspergillus flavus
Aspergillus terreus
Aspergillus niger

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

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

Acquired resistance
Mostly azole resistance in A. fumigatus reported
1) most common species
2) primary therapy (itra, vori, posa)
Standardised methodology
First resistant case late 1980s
but most >2000
Denning et al, 1997. AAC 41:1364-8

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?

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

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

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?

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

Agenda

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

Agenda

Lanosterol Ergosterol
E
Resistance mechanism
Azole drug

stop codon
start codon
intron
The cyp51A gene

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

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

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

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

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

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

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

Patient case
Oct 2004 vori, 500 > 400 mg daily
Radiological and serological improvement
20 mo isolate vori resistant (G448S), posa MIC 1mg/L
Sept 2006 posa therapy 800mg daily
Slow continued improvement
keep checking MICs!
?same/different genetic type -> microsatellite typing

Howard EID 2009;15:1068-76

Evolution in the lung!

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

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

Agenda

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

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

Agenda

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

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

Thank you

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

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

New Fungal Research Trust website

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

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

Drug Interactions database

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

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

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

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)

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

Aspergillosis Patient Support Meeting July 2011 - Sue Howard

by Graham Atherton on Jul 21, 2011

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Aspergillosis Patient Support Meeting July 2011 - Sue Howard — Webinar Transcript