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Importancia Clínica Resistencia Miceliales En enfermos oncohematológicos

This article discusses the clinical significance of fungal resistance in oncohematological patients, with a focus on the epidemiology and resistance mechanisms of fungal infections. It also highlights the challenges in conducting representative studies and the current situation of antifungal susceptibility testing.

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Importancia Clínica Resistencia Miceliales En enfermos oncohematológicos

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  1. Importancia Clínica Resistencia MicelialesEn enfermos oncohematológicos Manuel Cuenca Estrella Febrero, 2015

  2. Conflict of interest disclosure • In the past 5 years, M.C.E. has received grant support from AstellasPharma, bioMerieux, Gilead Sciences, Merck Sharp and Dohme, Pfizer, Schering Plough, SoriaMelguizo SA, FerrerInternational • He has been an advisor/consultant to the Panamerican Health Organization, AstellasPharma, 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, AstellasPharma and Schering Plough.

  3. Relevant Mycoses. Global burdenAccording to LIFE and GAFFI (www.life-worldwide.org)

  4. Perfil de actividad en miceliales

  5. Epidemiology of aspergillosis and other mold infections is tough, because………….. • 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

  6. Results from Spain FILPOP_2012 • Population-based survey • Molds isolated from deep samples (including respiratory ones) • Two months (spring and fall) • 30 Spanish hospitals • Molecular ID and AST

  7. AAC 2013; 57:3380

  8. Epidemiology of moulds

  9. No patients with a +ve culture % patients with azole R isolates

  10. Results from Spain. FILPOP. Population-based survey. 325 isolates

  11. Aspergillus cryptic species 15% crypticspecies 11% crypticspecies FILPOP Balajee et al, JCM 2009 Alastruey-Izquierdo et al. AAC 2013 Alastruey-Izquierdo et al. ANYAS 2012

  12. Cryptic Species By Alastruey-Izquierdo

  13. World Surveys on A. fumigatus complex resistance. Rates of resistance according to ECOFFs Journals and Congresses

  14. Haematologica. 2012;97(7):963-5.

  15. Aguado et al. Clin Infect Dis. 2014;Oct 21. pii: ciu833

  16. PCRAGA STUDY P=0.027 Aguado et al. Clin Infect Dis. 2014;Oct 21. pii: ciu833

  17. Azole ABC Strain with low MIC Cyp51A Cyp51B

  18. Azole Mutations in Cyp51A Strain with high MIC ABC Cyp51A Cyp51B

  19. Azole UP regulation of Cyp51A Strain with high MIC ABC Cyp51A Cyp51B

  20. L98H x 8 Gen Cyp51A in a resistant strain Duplication of 34-bp sequence in the promoter Cyp51A TR-R-ITC 237

  21. New mechanisms of resistance in Aspergillus • 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 Arendrup et al, Denning et al, Mellado et al, Verweij et al

  22. No patients with a +ve culture % patients with azole R isolates

  23. 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

  24. Descripción en muchos países JCM 2012;50:2531

  25. 30% resistencia en paciente hematológico y 88% mortalidad

  26. 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)

  27. PCR in tissues. Proven IFI

  28. 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%)

  29. Sequencing and analysis

  30. 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

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