etude prospective multicentrique (radar) de la … · etude prospective multicentrique (radar) de...
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Etude prospective multicentrique (RADAR)
de la résistance d’Aspergillus fumigatus aux
azolés en FranceJ.B. MURAT1,2, F. CHOUKRI1, J.M. COSTA3, I. ACCOCEBERRY4, C. ANGEBAULT5, M.E.BOUGNOUX5, N. BOURGEOIS6, M. CORNET7, L. DELHAES8, N. FAUCHET9, O.FAURE7, A. FEKKAR10, J. GUITARD11, C. HENNEQUIN11, L. LACHAUD12, A. PAUGAM13,R. KIM2, E. SITTERLE1, J. GUILLOT1, F. BOTTEREL1,2, E. DANNAOUI1,14.
1Dynamyc, UPEC, ENVA, 2Hosp. Mondor, Créteil, 3Lab. CERBA, 4Hosp. Pellegrin, Bordeaux, 5Hosp. Necker-Enfants malades, Paris, 6CHRU, Montpellier, 7CHU, Grenoble, 8CHU, Lille, 9CHIC, Créteil,10Hosp. Pitié, Paris, 11Hosp. Saint-Antoine, Paris, 12Hosp. Caremeau, Nimes, 13Hosp. Cochin, Paris,14Hosp. Pompidou, Paris, France.
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Aspergillus and aspergillosis
Filamentous fungus Infection - Treatment
A. fumigatus: the
most common +++
Soil-borne
microorganism
Aspergillus heads �
numerous spores
spores inhalation � pulmonary disease
Da
ge
na
is, T
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9. C
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Mic
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iol
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-65
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Aspergillose pulmonaire invasive (API)
Aspergillome (balle fongique)
Aspergillose brocho-pulmonaire allergique (ABPA)
Aspergillose pulmonaire invasive (API)
Aspergillome (balle fongique)
Aspergillose brocho-pulmonaire allergique (ABPA)
� Voriconazole +++
Aspergillus – Azole resistance
Emergence of resistance Worldwide distribution
Snelders et al. 2008 PLoS Med. 5:e219
Detection of resistance in clinical samples (irrespective to mecanism)
Iran
India
China
Japan
Iran
India
China
Japan
AustraliaAustralia
Iran
India
China
Japan
Australia
The Netherlands
Germany
Norway
Spain
The Netherlands
Germany
Norway
Spain
Denmark
UK
France
Sweden
Denmark
UK
France
Sweden
Belgium
Greece
Italy
Austria
Belgium
Greece
Italy
Austria
The Netherlands
Germany
Norway
Spain
Denmark
UK
France
Sweden
Belgium
Greece
Italy
Austria
USAUSAUSA
Azole resistance - France
1. Dannaoui, E., et al. 1999. JAC 44, 553-555
2. Dannaoui, E., et al. 2001. JAC 47, 333-340
3. Morio, F., 2012. JAC 67:1870-3.
4. Burgel, P. R., 2012.. AAC 56:869-74
5. Rocchi, S. 2014, JCM 52, 1724-6
6. Lavergne RA., 2015, AAC Apr 27
7. Choukri, F., et al. 2015 Med Mycol, in Press
8. Choukri, F., et al. 2013 - TIMM
Few data
� First detection in the late 1990s1,2
� Few data3-6
� Mostly in selected populations
� Retrospective analysis7 – 1 year (2012) – all patientso Prevalence 1.8% (isolates)
� Retrospective analysis8 – 12 years (2000-2012) –Lung Tx patients
o Prevalence 8.9% (isolates)
Detection of resistance in clinical samples (irrespective to mecanism)
Aspergillus
Azole resistance
Aim of the study
Aim
Risk in
Aspergillosis:
Detection of
Azole
Resistance
C
ITZ VRZ
� Surveillance study – Evaluation ofprevalence and mechanisms
� Prospective - Multicenter
� All Aspergillus spp. screened onazole-containing plates
The RADAR prospective study
Lille
Laurence Delhaes
Bordeaux
Isabelle Accoceberry
Montpellier
Nathalie Bourgeois
Nîmes
Laurence Lachaud
Grenoble
Odile Faure
Muriel Cornet
NeckerCecile Angebault
Marie-Elisabeth Bougnoux
PitiéArnaud Fekkar
CochinAndré Paugam
Saint-AntoineJuliette Guitard
Christophe Hennequin
HEGPEric Dannaoui
HMNFrançoise Botterel
CHICNathalie Fauchet
RADAR
� Screening – 1 year
� 2013 – 2014
� Standardized protocol
� Meeting pre-study
� Video
� QC exercise
� Video
� All samples – 1 colony
� Incubation 48h – 37°C
RADAR study – Study design
http://www.dynamyc.fr/en-55-dynamyc-mycology-videos.html
Methods
Methods
Screening
EUCAST
Speciesidentification
(Beta-tubulin)
Mutations
(Cyp51 sequencing)
Resistant
isolates
Resistant
isolates
12 centers
Isolates centralized in
one lab
Screening results
Total isolates A. fumigatus resistant
isolates
0
500
1000
1500
2000
2500
3000
3500
4000
4500
5000
Nu
mb
er
of
iso
late
s
screened expected
screened real
0
20
40
60
80
100
120
140
160
août-13 nov.-13 mars-14 juin-14 sept.-14 déc.-14
Resistant Af expected
Resistant Af real
Screening results
Number by center Distribution of species
0
100
200
300
400
500
1 2-3 4 5 6 7 8 9 10 11-
12
Nu
mb
er
of
iso
late
s
Center #
N=3049
A. fumigatus
A. niger
A. flavus
A. nidulans
A. terreus
A. versicolor
Other
PRELIMINARY
results EUCAST
N=134
110 R/I
2 N.
pseudofisheri
108 A.
fumigatus
24 S
A. fumigatus resitant isolates - Analysis in progress
Prevalence: 4.2%
Results108 A. fumigatus resistant isolates
TR34/L98H
mutation
Cyp51 mutation n Cyp51 mutation n
TR34/L98H 66 G448S 1
Pas de mutation 19 G54W 1
G54R 5 M220V 1
TR34/L98H/H147Y 5 TR34/L98H/S297T/F495I 1
H285Y 3 TR46/Y121F/T289A 1
M220I 2 Y121F 1
The RADAR prospective study
� Various underlying diseases� CF
� SOT
� Kc
� Hematol malignancies
� …
� Various aspergillosis� Colonization
� ABPA
� IA
� Aome
� …
Conclusions � Our results provide new data about azoleresistance in France
� Azole resistant A. fumigatus isolates can berecovered in France from patients with differentunderlying diseases
� The TR34/L98H mutation is the most frequentCyp51A mutation involved
� AFST of Aspergillus spp. is recommendedand further surveillance epidemiological studiesare needed