Resistance epidemiology

Transcription

1 ECMM/EFISG symposium: Multidrug resistance in fungi? A formidable foe Resistance epidemiology Ana Alastruey Izquierdo Mycology Reference Lab Spain Instituto de Salud Carlos III

2 Disclousure I have received grant, travel support or honoraria from GILEAD F2G Scynexis Amplix

3 Multidrug resistance Only three main classes of antifungals for systemic treatment available Magiorakos AP et al. Clin Microbiol Infect 2012; 18:

4 PORES Manoproteins Cell wall β-1,3-glucan β -1,6-glucan Chitin Membrane Fks1 Polyens Amphotericin B Ergosterol Isopentenyl-PP Azoles Fluconazole Voriconazole Itraconazole Posaconazole Isavuconazole Echinocandins Caspofungin Micafungin Anidulafungin Acetyl-coA Leucine Pyruvate + g3p-glyceraldehyde Courtesy of O. Zaragoza

5 Azole resistance Mutaciones Mutations ERG11 /Cyp51 Overexpression of efflux pumps Cowen L E, and Steinbach W J Eukaryotic Cell 2008;7:

6 Echinocandin resistance Mutations FKS HS1 HS2 Out N T M 6 T M 7 In D. S. Perlin C Cowen L E, and Steinbach W J Eukaryotic Cell 2008;7:

7 Public Health Threat of drug resistant fungal infections Subimtted by HLeSueur on Fri, 04/22/ Resistance in emerging

8 AF resistance Delayed diagnosis High mortality rates Empiric and prophylactic treatment Resistance Secondary R Intrinsic R

9 Candida Intrinsic resistance - Epidemiological change - Species such as C. krusei or C. guilliermondii Secondary resistance: - Acquire azole resistance mucosal candidiasis (AIDS) - Echinocandin resistance mainly in C. glabrata

10 Epidemiology Species AMB FCZ EC C. albicans S S S C. glabrata S I S C. parapsilosis S S I C. tropicalis S S S C. krusei S R S Lass-Flörl, Mycoses 2009 Quindos RIAM 2014

11 Epidemiology Tan et al. CID 2015 Guinea Clin. Microb. Infection 2014

12 Change in the epidemiology 100% 80% 60% 40% 20% 0% SENTRY ARTEMIS C. albicans Non-albicans Adapted from Fernández-Ruiz ECCMID 2017 J Clin Microbiol 2002;40:852-6 J Clin Microbiol 2006;44: J Clin Microbiol 2009;47: J Clin Microbiol 2011;49:396-9 Diagn Microbiol Infect Dis 2016;85:200-4 Guinea Clin. Microb. Infection 2014

13 SENTRY % 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Candida spp. guilliermondii dubliniensis lusitaniae krusei tropicalis parapsilosis glabrata albicans 2,085 isolates 79 medical centers Asian-Pacific (16 centers; 51 isolates), European (25/750), Latin American (10/348) North American (28/936) Pfaller J. Clin. Micro 2011

14 SENTRY 2013 Castanheira Diagn. Micro Infec. Dis. 2013

15 Latin America: Azole resistance % Fluco R Argen na 2006(265) Argen na 2011(420) Brazil 2003(200) Brazil 2004(120) Brazil 2005(131) Brazil 2006(712) Brazil 2007(282) Brazil 2007(1000) Brazil 2012(100) Brazil 2013(300) Brazil 2014(422) Brazil 2014(108) Mexico 2014(398) Mexico 2014(74) Peru 2014(153) Mul center 2003(103) Mul center 2013(672) tropicalis parapsilosis albicans albicans parapsilosis tropicalis Da Mata Journal of Fungi 2017

16 Latin America: Azole resistance % VCZ R Argen na 2011(420) Brazil 2006(712) Brazil 2007(1000) Brazil 2012(100) Brazil 2013(300) Brazil 2014(422) Brazil 2014(108) Mexico 2014(398) Mexico 2014(74) Peru 2014(153) Mul center 2013(672) albicans albicans parapsilosis tropicalis Da Mata Journal of Fungi 2017

17 Echinocandin resistance Arendrup & Perlin Curr. Opin. Infect. Dis 2015

18 Candida glabrata Arendrup & Perlin Curr. Opin. Infect. Dis 2015 Perlin et al. Lancet Inf. Dis 2017 Alexander et al. Clin Inf. Dis 2013

19 Japan Candida auris Korea, Venezuela India S. Africa Kenya Kuwait Pakistan Israel Colombia Panama USA Spain Oman Some hospitals have reported 40% candidemia by C. auris Slide kindly provided by Diego Caceres CDC

20 Candida auris

21 Candida auris Not correctly identified with classical methods Difficult to control Colonization Environment Antifungal resistance Colonization and bloodstream infection by C. auris (April 2016 to August 2017) Colonizations (n=250) Candidaemia (n=64) * S18 08/10/17 17:30 Alba Ruiz Room: Mediterranean/Adriatic

22 Candida auris 93% resistant to Fluconazole 54% resistant to voriconazole 35% resistant to amphotericin B 7% resistant to echinocandins 41% multidrug resistance 4% resistant to all antifungals Lockhart et al. Clin Infect Dis 2017 Chowdary et al. Hosp Infect 2016

23 What about Aspergillus??

24 AF resistance Delayed diagnosis High mortality rates Empiric and prophylactic treatment Resistance Agricultural use of azoles Intrinsic R secondary R

25 Secondary resistance Secondary resistance Snelders et al., PLOS 2008 Vol. 5:11 Howard et al., EID 2009, Vol. 15, No. 7 Chowdhary et al. PLoS Pathog. Oct 2013; 9(10)

26 Secondary resistance Turn de world RED Verweij Clin. Inf. Dis. 2016

27 Secondary resistance Chowdhari Future Micro 2015 G54/W/R/E/V/A M220/T/I/V/K/R/L G448S TR 34 /L98H TR 46 /Y121F/T289A Rivero-Menéndez Journal of Fungi 2016

28 Secondary resistance Rivero-Menéndez Journal of Fungi 2016

29 Clinical significance Aspergillosis Susceptible strains Resistant strains Mortality 30-50% 88% van der Linden et al. Emerg Infect Dis 2011; 17:

30 AF resistance Delayed diagnosis High mortality rates Empiric and prophylactic treatment Resistance Agricultural use of azoles Intrinsic R secondary R

31 Cryptic species A. terreus complex A. fumigatus complex Cryptic species are defined as those which are morphologically indistinguishable, although their identifications can be confirmed using other techniques A. niger complex A. flavus complex

32 Cryptic species Clinical samples

33 Cryptic species FILPOP Balajee et al, JCM 2009 Alastruey-Izquierdo et al. AAC 2013 Alastruey-Izquierdo et al. ANYAS 2012

34 Cryptic species 11% cryptic species FILPOP 14% cryptic species Chowdhary et al. (2016) 16.6% cryptic species Balajee et al, JCM 2009 Alastruey-Izquierdo et al. AAC 2013 Alustruey- Izquierdo A et al. 2012, Ann N Y Acad Sci. 1273:18-24

35 Cryptic species n AMB ICZ VCZ PCZ CPF MCF ANF A. lentulus N. hiratsukae N. pseudofischerii A. fumigatiaffiinis ,03 0,03 N. udagawae A. viridinutans 3 0, ,25 5,66 0,06 0,09 A. tubingensis A. calidoustus A. insuetus A. keveii 1 0, A. alliaceus

36 A. lentulus Zbinden et al, TID 2012

37 MICs distribution for AMB A. fumigatus A. terreus >32 Data obtained from Mycology Reference Laboratory. Spain

38 Aspergillus terreus 20% 47% Lass-Florl BJH 2005

39 Alcazar-Fuoli et al AAC 2009 A. niger complex 36% A. awamori 90% A. tubingensis 33% A. niger 100% A. acidus 67% unknown Howard et al, AAC 2011

40 Alastruey-Izquierdo et al, Medical Mycology 2010 Aspergillus ustus complex n AMB ICZ VCZ PCZ A. calidoustus A. insuetus A. keveii

41 And Other species?

42 Lomentospora prolificans No AmB Itraconazole Voriconazole Posaconazole -5 MICs (mg/l) Data obtained from Mycology Reference Laboratory. Spain

43 Mucorales Species N AmB GM IZ GM VZ GM PZ GM Rhizopus arhizus Rhizopus microsporus Mucor spp Rhizomucor spp Lichtheimia corymbifera Cunninghamella bertholletiae Data obtained from Mycology Reference Laboratory. Spain Alastruey-Izquierdo Clin. Micro. Infect 2009 Chowdhary et al. AAC 2015

44 Fusarium spp Al Hatami et al. Plos. Path. 2016

45 Emerging species Lass-Florl & Cuenca-Estrella JCM 2017

46 Conclusions Antifungal resistance is increasing Both in yeast and moulds Development of secondary resistance (C. glabrata A. fumigatus ) Intrinsically resistant species (C. auris, A. lentulus, Mucorales ) Important to know local epidemiology Perform AFST to any isolate coming from invasive infection

47 Conclusions Antifungal resistance is increasing Both in yeast and moulds Development of secondary resistance (C. glabrata A. fumigatus ) Intrinsecally resistant species (C. auris, A. lentulus, Mucorales ) AFST Important to know local epidemiology Monitor their Epidemiological Perform AFST to any isolate coming from studies prevalence invasive infection

48 But NGS Microbiome??? Low sensitivity of culture Lack of isolates in many infections Real Epidemiology Unknown

49 Thanks for your attention Ana Alastruey-Izquierdo Mycology Reference Lab Spain Instituto de Salud Carlos III