2. Conflict of interest disclosure
• In the past 5 years, M.C.E. has received grant support from
Astellas Pharma, bioMerieux, Gilead Sciences, Merck
Sharp and Dohme, Pfizer, Schering Plough, Soria
Melguizo SA, Ferrer International
• He has been an advisor/consultant to the Panamerican
Health Organization, Astellas Pharma, Gilead Sciences,
Merck Sharp and Dohme, Pfizer, and Schering Plough.
• He has been paid for talks on behalf of Gilead Sciences,
Merck Sharp and Dohme, Pfizer, Astellas Pharma and
Schering Plough.
4. Perfil de actividad en miceliales
Especies
Antifúngicos
ANF FC FLC ITC VRC POS EQUIN
A. fumigatus S R R S S S S
Aspergillus flavus S R R S S S S
Aspergillus terreus I-R R R S S S S
Aspergillus niger S R R S-I-R** S S S
Fusarium spp. S-I-R** R R R S-I-R** S-I-R** R
Scedosporium spp. S-I-R** R R R S-I-R** S-I-R** R
Mucorales S-I-R** R R R R S-I-R** R
5. • EORTC criteria: Probable aspergillosis
(50-80% in last clinical trials)
• Proven aspergillosis (50-75%) by
microscopic examination only. No ID of
species
• Low performance of cultures
• Laboratory contaminants
Epidemiology of aspergillosis and other mold
infections is tough, because…………..
6.
7. • Population-based survey
• Molds isolated from deep samples (including
respiratory ones)
• Two months (spring and fall)
• 30 Spanish hospitals
• Molecular ID and AST
Results from Spain
FILPOP_2012
12. Results from Spain. FILPOP.
Population-based survey.
325 isolates
Aspergillus spp. (sensu
stricto)
N %
TOTAL 277 85% (4 cases
per 100,000 pop)
A. fumigatus 156 48%
A. flavus 26 8%
A. terreus 26 8%
A. tubingensis (section Nigri) 22 6.8%
A. niger 21 6.5%
A. nidulans 8 2.5%
14. Cryptic Species
n AMB ICZ VCZ PCZ CPF MCF ANF
A. lentulus 26 3 2.3 3.4 0.23 1.6 0.1 0.1
N. hiratsukae 9 1.7 0.9 1.1 0.16 0.11 0.03 0.03
N. pseudofischerii 6 0.25 4 2.51 0.22 0.86 0.03 0.03
A. fumigatiaffiinis 6 4.8 5 3.1 0.4 0.22 0,03 0,03
N. udagawae 5 2 0.6 2.3 0.25 0.3 0.03 0.03
A. viridinutans 3 0,7 16 4 0,25 5,66 0,06 0,09
A. tubingensis 22 0.11 0.42 0.76 0.09 0.3 0.05 0.03
A. calidoustus 19 0.9 8.6 6.2 6.8 0.5 0.04 0.04
A. insuetus 2 0.7 11.3 8 2.8 5.6 1.4 0.9
A. keveii 1 0,25 16 16 16 16 16 16
A. alliaceus 30 19.25 0.2 0.5 0.11 12.15 3.8 1.9
By Alastruey-Izquierdo
15.
16. World Surveys on A. fumigatus complex
resistance.
Rates of resistance according to ECOFFs
Journals and Congresses
Country Itraconazole Voriconazole Posaconazole
Spain
Cuenca-Estrella et al
8% 4.5% 4.4%
USA
Diekema et al
7% 1% 8%
France
Bretagne et al
2% 1% 2%
Holland
Snelders et al
12.8% 10% 10%
United Kingdom
Howard et al
17% 8% 10%
25. • The azole target cyp51A is a hotspot for
mutations that confer phenotypic resistance, but
in an increasing number of resistant isolates the
underlying mechanism remains unknown.
(TR46/Y121F/T289A)
• Increase of expression and mutations related to
efflux pumps
• Mutation in the CCAAT-binding transcription
factor complex subunit HapE. A P88L
substitution in HapE. Camps et al Plos One 2012
New mechanisms of resistance in
Aspergillus
Arendrup et al, Denning et al, Mellado et al, Verweij et al
29. Figure 3
3D Representation of three aligned structures of CYP51 with the ligands in
their active site, constructed by using the Yasara software. Snelders Plos
One 2012
32. Epidemiología de la EFI
• La resistencia clínica en hongos filamentosos es relevante si
la prevalencia de Mucorales, Scedosporium y Fusarium es
elevada (tratamiento empírico y primera línea)
• La resistencia a azoles en España en Aspergillus se mantiene
por debajo del 10%
• Parece estar más asociadas a especies crípticas aunque ya
hay casos en A. fumigatus
• Los casos con cepas resistentes son difíciles de tratar (90%
mortalidad en paciente hematológico)
• Problemas para hacer estudios representativos:
– Cepas ambientales
– Pruebas moleculares
– Estudios con medios suplementados con itraconazol en muestras
respiratorias (FILPOP 2)
35. •84 patients were analyzed. 68/84 (81%) were
cultured. 56% of sensitivity (38/68 cases)
•PCR-based technique detected fungal DNA in 75/84
patients (89.3%)
Species Nb of cases Rate
Aspergillus 50/75 66.6%
Mucorales 9/75 12%
Candida 11/75 14.6%
38. Antifungal
agents
Fungal species
Availability of
reference
procedures
Breakpoint
setting
Extension of
AST in clinical
practice
Molecular
description of
resistance
Prevention
and control
strategies
Amphotericin B Candida spp.
Aspergillus spp.
YES
YES
YES
YES
YES
YES
NO
NO
NO
NO
Azoles Candida spp.
Aspergillus spp.
YES
YES
YES
YES
YES
YES
IN PROGRESS
IN PROGRESS
NO
NO
Echinocandins Candida spp.
Aspergillus spp.
YES
YES
YES
NO
YES
IN PROGRESS
IN PROGRESS
NO
NO
NO
Table 1. Current situation of the antifungal susceptibility testing field by antifungal agent,
by species and by stages of standardization process
FILPOP 2, In progress
