Current trends in global fungal epidemiology and resistance

Maiken Cavling Arendrup [email protected] Unit of Mycology Statens Serum Institute Denmark

Disclosures: ESCMIDResearch Online grants & Speaker: Astellas Lecture, Basilea, Gilead, MSD & Pfizer; Library Advisory board: MSD, Pcovery, Pfizer; Acted as consultant for: Alcimed, Astellas, Gilead & Pfizer Chair(wo)man for EUCAST-AFST @ by author M Cavling ARENDRUP Agenda

Types of Fungal infection

Severe Fungal infections in numbers . in a global perspective

Focus on . Cryptococcus infections . Acute and chronic infections . Invasive Candida infections

Highlight the main challenges . in the high income countries . in the Resource limited countries ESCMID Online Lecture Library

@ by author M Cavling ARENDRUP Fungal infections

Mucosal . e.g. oral or vulvovaginal Cutaneous . e.g. athlete’s foot, ringworm and Other non-invasive . e.g. fungal keratitis Chronic fungal infections . e.g. chronic pulmonary , Allergic . e.g. allergic fungal sinusitis and allergic bronchopulmonary aspergillosis (ABPA) Invasive and life-threatening fungal infections . e.g. candidaemia, invasive aspergillosis and cryptococcal meningitis ESCMID Online Lecture Library

@ by author M Cavling ARENDRUP Fungal infections

Mucosal . e.g. oral or vulvovaginal candidiasis Cutaneous . e.g. athlete’s foot, ringworm and onychomycosis Other non-invasive Life threatening/ . e.g. fungal keratitis shortening Chronic fungal infections . e.g. chronic pulmonary aspergillosis, chromoblastomycosis Allergic . e.g. allergic fungal sinusitis and allergic bronchopulmonary aspergillosis (ABPA) Invasive and life-threatening fungal infections . e.g. candidaemia, invasive aspergillosis and cryptococcal meningitis ESCMID Online Lecture Library

@ by author M Cavling ARENDRUP Global burden of common life threatening infections

GAFFI: Global Action Fund for Fungal Infections Fungal infection Case fatality rate Estimated deaths Comments Cryptococcal meningitis 15-20% USA >50% developing world 600,000 CDC estimate ~50% in developed world if Many missed diagnoses Invasive Aspergillosis >100,000 treated globally Chronic pulmonary Under-diagnosed and ~15% in developed world >450,000 aspergillosis mistaken for tuberculosis Severe asthma with fungal ~100,000 asthma deaths – <1% but no good figures Uncertain sensitisation (SAFS) ~50% related to SAFS Candida bloodstream ~40% if treated >120,000 infection Most cases in Africa not ~15% in AIDS >80,000 diagnosed and 100% ~50% non-AIDS mortality Probably a significant Total >1,350,000 ESCMID Online Lecture Libraryunderestimate www.gaffi.org @ by author M Cavling ARENDRUP Global burden of common life threatening infections

GAFFI: Global Action Fund for Fungal Infections Fungal infection Case fatality rate Estimated deaths Comments Cryptococcal meningitis 15-20% USA >50% developing world 600,000 CDC estimate ~50% in developed world if Many missed diagnoses Invasive Aspergillosis >100,000 treated globally Chronic pulmonary Under-diagnosed and ~15% in developed world >450,000 aspergillosis mistaken for tuberculosis Severe asthma with fungal ~100,000 asthma deaths – <1% but no good figures Uncertain sensitisation (SAFS) ~50% related to SAFS Candida bloodstream ~40% if treated >120,000 infection TB 2012 Malaria Most2013 cases in Africa not 1,420,000~15% in AIDS Pneumocystis pneumonia >80,000 584,000diagnosed and 100% ~50% non-AIDS mortality Probably a significant Total >1,350,000 ESCMID Online Lecture Libraryunderestimate www.gaffi.org; www.who.int@ by author M Cavling ARENDRUP Cryptococcus related deaths

Worldwide ~ 600,000 deaths/year Deaths in Africa 800,000 sub-Saharan Arica sub-Saharan Africa only 700,000 . ≥ 500,000 deaths/year 600,000

‒ ≥ possibly TB 500,000

. Case mortality 35%-65% 400,000 ‒ vs. 10%-20% in developed 300,000 countries 200,000 100,000

0 Malaria Cryptococcus TB Malaria Cryptococcus TB ESCMID Online Lecture Library

WHO Rapid advice@ HIV/AIDS programmeby author Dec 2011, www.who.int reports for 2013 M Cavling ARENDRUP Cryptococcal meningitis in AIDS Impact of therapy

Survival at 10 weeks 75%

Best treatment with 50% amphotercin B and 5FC

No treatment, Fluconazole always fatal

0% ESCMID Online Lecture Library www.gaffi.org; Nussbaum@ CID by 2010; Longley author CID 2008, Day NEJM 2013 M Cavling ARENDRUP + 5FC superior!

Crypto-meningitis. 299 pts.

Treatment doses Treatment strategy Amphotericin B 1 mg/kg 5-FC 100 mg/kg/day Combo: 2 weeks  fluconazole 400 mg/d 8 weeks Fluconazole 800 mg/day Mono: 4 weeks  fluconazole 400 mg/d 6 weeks

ESCMID Online Lecture Library

Day NEJM 2013 @ by author M Cavling ARENDRUP Drug availability

Amphotericin B

Flucytosine

Fluconazole

ESCMID Online Lecture Library www.gaffi.org @ by author M Cavling ARENDRUP Cryptococcal meningitis in AIDS

 Common cause of death in many communities  Excellent antigen test  Can identify disease before symptoms  Takes 10 mins and costs $2  ESCMID OnlineHighly Lecture cost effective Library www.gaffi.org; Lourens@ JCM 2014by author M Cavling ARENDRUP Agenda

Types of Fungal infection

Severe Fungal infections in numbers40 -50% of the 1,350,000 IFI deaths/y . in a global perspective  Drug availability & cost challenges  Rapid bed-side test available Focus on  Huge potential to save lives . Cryptococcus infections . Acute and chronic Aspergillus infections . Invasive Candida infections

Highlight the main challenges . in the high income countries . in the Resource limited countries ESCMID Online Lecture Library

@ by author M Cavling ARENDRUP Aspergillus: Host interaction & spectrum of disease

Aspergillus inoculum

Colonisation Disease

Normal Host Overreacting immune Impaired (lung) tissue Compromised immune system architecture system Transient ABPA TB Haematological disease colonisation Sinusitis Sarcoidosis HSCT, GVHD Asthma w fungal COPD Wegeners granulomatosis sensitisation etc Steroids Chronic forms of aspergillosis Influenza…

Semi  acute invasive ESCMID Online Lecture Libraryaspergillosis

@ by author M Cavling ARENDRUP Aspergillus disease in Europe

Type of Predominant risk Risk Aspergillosis Annual aspergillosis aspergillosis groups population rate burden size (000’s) (000’s) ABPA Asthma 42,500 2.1% (0.7-3.5%) 893 (298 – 1,488) 2.65 Cystic fibrosis 29 15% 4.3 Mill SAFS Severe asthma 2,450 – 6,380 33% 1,457 (765 – 2,125) CPA COPD, TB, Sarcoidosis, >13,600 1-10% 240 0.24 ABPA, Pneumothorax Mill IA Myeloid leukaemia, 46 7% 3.2 Other haematological 3.2

HSCT 11.4 0.8 63.43 COPD hospital 2,830 1.2% 34.0 Thou- admissions sand Solid organ 30 (SOT) 0.75% 0.23 transplantation ESCMIDMedical ICU Online1,100 ( all ICU ) Lecture2% Library22

Denning, Personal communication: Beasley 2004; Denning 2010, 2011 & In press; Stevens 2003; Mehta 2010; Sant 2010; Pagano M Cavling ARENDRUP 2006; Perkhofer 2010;@ Baldomero by2011; Bulpa 2007;author NHS 2010; Pappas 2010; Trick 2002; Lortholary 2012. Chronic Pulmonary Aspergillosis

3 mill people worldwide (of whom 1,2 mill has TB); >450,000 deaths South-Africa

Denmark

5-y prevalence rate W-Europe 1.2/100,000 ~65 cases 5-year EU prevalences Lithuania: 8.8/100,000 Portugal: 3.3/100,000 The NL: 0.65/100,000

5-y prevalence rate 128/100,000 ESCMID Online Lecture Library~64 094 cases www.gaffi.org @ by author M Cavling ARENDRUP Chronic Aspergillosis after TB

Frequency of Aspergillus antibodies after TB . UK 1970: 34% . India 2001: 27% . Brazil 1988: 21% . Japan 1989: 20%

1992 1994 1997 ESCMID Onlinenot on Lecture tx still Library not on antifungal tx

Iwata Kekkaku 1989, Shahid Indian J Med Microbiol 2001, Kurhade Indian J. Med Microbiol 2002, Ferreira-da-Cruz et al. Memórias do M Cavling ARENDRUP Instituto Oswaldo Cruz@ 1988; Courtesy by David Denning,author www.gaffi.org; Prognosis of chronic pulmonary aspergillosis

Study summary

1.0 p<0.0001 Retrospective observational study Study period: 2001-9 0.8 129 Aspergillus cult+ Colonization - 42 CPA (32.6%) 0.6 - 87 colonisation (67.4%)

BMI was an independent 0.4 predictor of prognosis (Odds Ratio, 1.973; p = 0.0223) 0.2

Probability of survival Probability CPA 0 0 10 20 30 40 50 60 70 80 ESCMID OnlineMonths Lecture Library

Ohba et al. Resp Med@ 2012;106:724; by www.gaffi.org author M Cavling ARENDRUP for chronic pulmonary aspergillosis

India: Post TB chronic aspergillosis Clinical response Prospective, randomised controlled Oral trial Control Itraconazole CPA patients ±6 months oral therapy 80% 60% 40% 31 patients (mean age, 37 years) 20% . itraconazole (n = 17) Improved . control (n = 14) group. 0% Stable Worsened -20%

Overall response -40% . Itraconazole 75.5% -60% . Control 35.7 (P 0.02) -80% ESCMID Online Lecture Library

Agarwal R et al, Mycoses@ 2013; by 56:559 author M Cavling ARENDRUP Drug availability

ESCMID Online Lecture Library www.gaffi.org @ by author M Cavling ARENDRUP Agenda

Types of Fungal infection Chronic pulm aspergillosis Severe Fungal infections in numbers 500,000 IFI deaths/y . in a global perspective  global infection but  Huge variation High income >< Focus on Resource limited countries . Cryptococcus infections  Under-/ misdiagnosed cases . Acute and chronic Aspergillus infections . Invasive Candida infections

Highlight the main challenges . in the high income countries . in the Resource limited countries ESCMID Online Lecture Library

@ by author M Cavling ARENDRUP IPA - Patient groups and Host Factors

Haematological malignancy -  anti-IA- Cancer & chemotherapy ≥ the last 3 months SOT recipient (Particularly Lung)

Immunosuppressive treatment or condition Steroid use - ≥ 4 mg prednisolone/day in 7 days within 3 weeks or 5 days at the ICU - ≥ 250 mg in the past 3 months

COPD and other pulmonary disease - H1N1 Liver disease - Child C cirrhosis - ESCMIDSevere Alcoholic hepatitis Online Lecture Library

Meersseman Am J Resp@ Crit Care Med.by 2008; Adaljaauthor Influ Resp Viruses. 2011; Wouters Int Care Med 2012, Gustot J Hepatol. 2014 M Cavling ARENDRUP Invasive Fungal Infections in HSCT recipients

983 IFIs among 875 HSCT recipients (23 centres) (2001-6) . Aspergillus 43% w 74.6% 1-y mortality . Candida 28% w 66.4% 1-y mortality . Zygomycetes 8% w 72.0% 1-y mortality . Fusarium 3% w 93.4% 1-y mortality . Pneumocystis 2% . other mould 7% ‒ Acremonium, Alternaria, Arthrographis, Bipolaris, Chaetomium, , Cladophialophora, Curvularia, Exophiala, Exserohilum, Microsascus, Paecilomyces, Penicillium, Phialemonium, Pseudallescheria, Scedosporium, Scopulariopsis and Trichoderma species

Allo MisMatched Related 8.1%

12-month incidence (first IFI) Allo Matched Unrelated 7.7% . Correlation to transplant type Allo Matched related 5.8%

Overall 3.4% Cumulative incidence Cumulative ESCMID Online Lecture LibraryAutologous 1.2% Days from transplantation Kontoyiannis CID 2010@ by author M Cavling ARENDRUP Invasive Fungal Infections in HSCT recipients

1.25 1.25 1.5 1.75 Mould infections: 61%

Median time to diagnosis 61 days candidiasis 99 days aspergillosis 123 days

Cumulative incidence (%) incidence Cumulative 135 days

15.6% Inv mould inf 0 0.25 0.5 0.75 0 0.75 1 0.5 0.25 diagnosed > 1 year

ESCMID Online Lecture Library

Kontoyiannis CID 2010@ by author M Cavling ARENDRUP Invasive Mould Infection: Solid organ transplant Pts

2557 SOT (2000-9) – 62 invasive mould infections Inv mould inf (culture & biopsy detected only): . 12.5% (21/168) lung; 3,8% (6/156) heart . 3.5% (17/485) liver; 1% (18/1748) kidney

st

IMI the 1 year post-transplant Lung (∞12.5%)

Liver (∞ 3.5%)

Heart (∞ 3.8%)

Probability Probability of IMI Kidney (∞ 1%) 0% 5% 10%

Aspergillus (21) Zygomycetes (8) Fusarium (1) Scedosporium (1) Other (7) LungESCMID (21) 80% Online5% Lecture0 Library0 14% Other (41) 50-65% 17% 2% 2% 10% Neofytos Transplant@ Inf Dis 2013by author M Cavling ARENDRUP Invasive Aspergillosis in the ICU

Adults w Pos Aspergillus . Culture/Microscopy/Histopath during ICU stay 30 ICUs in 8 countries (Belgium, France, Brazil, China, Spain, Greece, India and Portugal) . Jan 2000-Jan 2011

563 patients: 92% A. fumigatus Cases classification . Proven IA 17% w 79% mortality 72% . Putative IA 36% w 67% mortality . Aspergillus colonisation 47% w 38% mortality

Proven: Putative: Colonisation: Asp pos Asp pos culture Asp pos culture sterile tissue + Clin Signs & Symp ≥ 1 criteria for sample + Abnormal Imaging putative IA not met ESCMID Online+ Host factors / semiLecture-quantitative Library Asp pos Bact neg culture Taccone Crit Care 2015@ by author M Cavling ARENDRUP Invasive Aspergillosis in the ICU: Mortality

Highest mortality Cerebral 90% Endovascular 86% Abdominal 81%

Aspergillus colonisation

Putative IA

Cumulative Survival Cumulative P <0.001 vs colonisation Proven IA Mortality drivers Multivariate Analysis Proven IA HR 1.51 Older age OR 1.034 BMT OR 3.352 0 2 4 6 8 10 12 SOFA OR 1.140 ESCMIDTime (weeks) Online LectureMechanical Library V OR 3.916 Dialysis OR 2.339 Taccone Crit Care 2015@ by author M Cavling ARENDRUP Aspergillus and susceptibility

Clinical isolates from DK Itraconazole

40

35

30 A. terreus 25 A. niger 20 A. nidulans ~var. echinulata

15 A. nidulans

10 A. fumigatus

5 A. flavus A. calidoustus 0 <0.125 0.125 0.25 0.5 1 2 4 >4 >16

MIC range categorised as ESCMIDsusceptible for A. fumigatus Online Lecture Library

Unpublished data and@ Arendrup by JAC 2012, author Astvad AAC 2014 M Cavling ARENDRUP Azole resistant A. fumigatus in azole naïve patients in Europe

1st pos sample TR34/L98H detected NL 1998 UK 1999 NO 2001 “New” azole resistance ES 2002-3 mechanisms detected in DK 2007 azole naïve patients or in BE 2008 the environment AU 2006-9 NL:

GE 2006-9 TR46/Y121F/T289A FR 2010-11 France: IT 2011-12 G432S ESCMID Online Lecture Library

Denning CID 2011, Snelders PLoS Med 2008, Mortensen AAC 2010, Kuipers AAC 2011, Mellado AAC 2007, Rath AAC 2012, Stensvold Curr Fungal Inf M Cavling ARENDRUP Reports 2012, Bader AAC@ 2013, van by der Linden CIDauthor 2013 & Emerg Inf Dis 2015, Prigitano Eurosurv 2014, Ozmerdiven ICAAC 2014, Steinmann JAC 2015. Fungicide use & Azole “R” A. fumigatus reports

Global market share of fungicide use in agriculture; TR34/L98H A. fumigatus TR46/Y121F/T289A A. fumigatus 9% N-America 37% W-Eur. 5% E-Eur.

24% Asia- Pacific

22% S- & 1st pos sample Latin America IR 2005 IN 2008 ESCMID Online LectureChina 2008 -9Library … Mellado AAC 2007, Denning CID 2011, Snelders PLoS Med 2008, Mortensen AAC 2010, Kuipers AAC 2011, Lockhart AAC 2011, Rath AAC 2012, Stensvold Curr Fungal Inf Reports 2012, Bader AAC 2013, van der Linden CID 2013 & Emerg Inf Dis 2015, Prigitano Eurosurv 2014, M Cavling ARENDRUP Steinmann JAC 2015, Chowdhary@ Plosby One 2012, author JAC 2014 Jan & Nov., Badali Mycoses 2013; Seyedmousavi Emerg Inf Dis 2013 Environmental azole resistance - in DK Aspergillus

2007- 2012: TR34/L98H found only in CF patients

2012 TR34/L98H in 3 non-CF patients 2 of whom = azole naive

CASE Day Species MIC (µg/mL)*) CYP51A genotype STRAf (2A-2B-2C-3A-3B- 3C-4A-4B-4C) POS VOR ITRA AMB CAS

7 A. fumigatus 0.06 1 0.5 0.5 0.064 wt 18-19-8-26-10-21-9-9-5 2012 7 A. fumigatus 1 2 >8 0.5 0.064 TR34/L98H +S297T+F495I 14-10-9-30-9-6-8-10-20

17 A. fumigatus 0.5 1 >8 0.5 0.064 TR34/L98H+S297T +F495I 14-10-9-30-9-6-8-10-20

2013 5 A. fumigatus 0.5 4 >8 0.25 0.064 TR34/L98H 20-20-28-32-9-6-8-10-20 44 A. fumigatus 0.03 0.25 0.25 0.25 0.064 wt 14-20-11-34-9-7-8-10-12

90 A. fumigatus 0.5 4 >8 0.5 0.032 TR34/L98H 25-10-12-79-9-9-8-10-11 90 R. pusillus 0.25 >4 2 0.5 >32 NA NA 2013 106 R. pusillus 0.125 >4 0.5 0.5 NA NA NA 110 R. pusillus 0.125 >4 0.5 0.5 NA NA NA 117 A. fumigatus ≤0.03 0.5 0.5 1 0.064 wt 25-16-19-48-17-23-8-9-5 ESCMID117 R. pusillus 0.25 Online>4 0.5 0.5 Lecture>32 NA LibraryNA

Astvad AAC 2014 @ by author M Cavling ARENDRUP Environmental azole resistance - in DK

2014

. TR46/Y121F/T289A (LTX patient w agammaglobulinaemia) CASE Day Species MIC (µg/mL)*) CYP51A genotype STRAf (2A-2B-2C-3A-3B-3C- 4A-4B-4C) POS VOR ITRA AMB CAS 0 A. fumigatus 0.06 0.5 0.25 0.75 0.125 wt 18-25-15-26-11-7-26-30-8

2014 43 A. fumigatus 0.125 >4 0.5 1 0.032 TR46/Y121F/T289A 26-21-16-32-9-10-8-14-10

62 A. fumigatus 0.25 >4 1 1 0.032 TR46/Y121F/T289A 26-21-16-32-9-10-8-14-10

. 2/4 were azole naïve  . 3/4 polyfungal infection All 4 died

ESCMID Online Lecture Library

Astvad AAC 2014 @ by author M Cavling ARENDRUP Azole “R” in the Netherlands 2007-9

Screening: 4 mg/L itraconazole

. note TR46/Y121F/T289A would not be detected 2062 Aspergillus isolates; 1385 pts . A. fumigatus 86.9% . 90 screening pos . 84/90 (93%)  itraconazole R ‒ 79/84 (94%)  voriconazole I/R ‒ 58/84 (69%)  R

CYP51A Prev ITR MIC VRC MIC PSC MIC

TR34/L98H 88% >16 (16->16) 8 (1-16) 0.5 (0.25-2) Highest (9.4%) G54W 1% >16 0.5 >16 Azole R rate among haem/onc patients P216L 1% 16 2 0.5 P 0.02 F219I 1% >16 0.25 0.25 7/8 IPA patients died Several 1% >16 >16 1 ESCMID Online Lecture5/5 Library on voriconazole None 5% >16 (16->16) 4 (0.5-4) 0.25 (0.125-1) monotherapy died van der Linden Emerg@ Inf Dis by2011 author M Cavling ARENDRUP Voriconazole “R” TR46/Y121F/T289A in the NL

December 2009 - January 2011 R in 1315 A. fumigatus isolates from 921 patients environment - 21 TR46/Y121F/T289A (voriconazole MIC ≥ 16 mg/L) • 15 Pts in 6 hospitals

IPA in 8/15 Pts R in hosp 1st tx - Voriconazole • 5 patients – all died - L-amphotericin B (±anidulafungin or surgery) • 3 patients – all survived Environmental sampling (140 azole R samples)

- 10% TR46/Y121F/T289A - 90% TR34/L98H No R ESCMID Online Lecture Library

Van der Linden CID@ 2013 by author M Cavling ARENDRUP Azole “R” Aspergillus in German patients 2011-12

527 A. fumigatus isolates during 18 months EUCAST/Etest . sample type ‒ pulmonary/oropharyngeal 353 - ≥ 163 cystic fibrosis ‒ 30 ‒ invasive/wound infections 39

. 17 (3.2%) Azole “R” . Highest in CF (5.2%)

CYP51A No. ITR MIC VRC MIC PSC MIC

TR34/L98H 6 >32 2 (1-8) 0.5 (0.125-1) G54W+ 1 >32 0.25 >32 duplication M220I 1 >32 0.25 0.5 Not done F219CESCMID 1 >32 Online0.25 Lecture0.125 LibraryNo mutations None 8 >32 (0.125->32) 2 (0.25-8) 0.5 (0.125-1) TR34/L98H other non-environmental Bader AAC 2013 @ by author mutations M Cavling ARENDRUP Azole “R” Aspergillus in German haem patients

762 HSCT patients 2012-13 (Essen & Cologne) 27 with A. fumigatus . 8 Azole “R” (30%) CYP51A No. ITR VRC PSC MIC MIC MIC ‒ 5/8 TR34/L98H TR34/L98H 5 >16 2-4 0.5 ‒ 2/8 TR46/Y121F/T289A ‒ 1/8 no CYP51A mutations TR46/Y121F/T289A 2 1- >16 16->16 0.5 ‒ genetically unrelated None 1 >16 4 0.5 . 7 died (88%; 7/7 w prov/prob) ‒ vs 74% with azole “S” infection . 7/8 on prophylaxis ‒ 5/7 triazole . HSCT  Azole “R” ‒ median 115 days

ESCMID30% Azole OnlineR among Lecture Library haem cult+ patients Steinmann JAC 2015@ by author M Cavling ARENDRUP Agenda

Types of Fungal infection Chronic pulm aspergillosis Severe Fungal infections in numbers 500,000 IFI deaths/y . in a global perspective  global infection but  Huge variation high >< Resource Focus on limited countries . Cryptococcus infections  Under-/ misdiagnosed cases . Acute and chronic Aspergillus infections . Invasive Candida infections Invasive Aspergillosis 45-50,000 IFI deaths/y in EU Highlight the main challenges  BUT close to 90-100% mortality . in the high income countries if azole resistant . in the Resource limited countries  Emerging azole resistance is a ESCMID Online Lectureglobal Library concern

@ by author M Cavling ARENDRUP Epidemiology 4th most Common ???

4th most Common Blood Stream Infection pathogen! (?) no. 10 2.9/100,000 2004-7 no. 7 0.7/100,000 2007-8

no. 11 0.3/100,000 2004-10 no. 4 4.6/10,000 admissions no. 9 1995-2002 no. 10 8.7/100,000 2.9/100,000 2001-11 2013 ESCMID Online Lecture Library https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/356740/hpr3614_cnddm13.pdf, M Cavling ARENDRUP Skogberg 2012, Poikonen@ 2010, by Gradel 2014,author Nielsen 2014, Josefson 2011, Hongsuwan 2014, Wisplinghoff 2004 Epidemiology 4th most Common ???

4th most Common Blood Stream Infection pathogen! (?) no. 10 2.9/100,000 2004-7 no. 7 0.7/100,000 In general the statement is 2007-8 WRONG… no. 11 0.3/100,000 But, it Ranks no. 2-4 in ICUs in 2004-10 no. 4 4.6/10,000 W-Europe & N-America admissions no. 9 1995-2002 no. 10 8.7/100,000 2.9/100,000 2001-11 2013 ESCMID Online Lecture Library https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/356740/hpr3614_cnddm13.pdf, M Cavling ARENDRUP Skogberg 2012, Poikonen@ 2010, by Gradel 2014,author Nielsen 2014, Josefson 2011, Hongsuwan 2014, Wisplinghoff 2004 Epidemiology Incidence rates per 100,000 popul.

2.9 3-4 3 2004-7 2004-8 2003-4 4.2 2005-6

4.8 2006 0.3 2004-10

8.9-10 2.9 2010-13 13 & 26 2013 2008-2011 9.5 & 14.4 8.1 3.6 3.6 2012-13 2010-2011 2010 2009 2.8 ESCMID Online Lecture Library1999-2008 https://www.gov.uk, Skogberg 2012, Poikonen 2010, Gradel 2014, Nielsen 2014, Josefson 2011, Hongsuwan 2014, Wisplinghoff 2004, Odds 2007, Bitar 2014, Tortorano 2013, Arendrup JCM Jan. 2011 and CMI 2013, Nordøy TIMM4 2009, Poikonen BMC Infectious Diseases 2010 & personal communication, Ericsson CMI 2013, Cleveland CID 2012 and PlosOne 2015, St-Germain Can J M Cavling ARENDRUP Inf MM 2008, Playford J Hosp Inf 2010, Puig-Assensio CMI 2014 @ by author

Epidemiology Incidence rates per 100,000 popul.

2.9 3-4 3 2004-7 2004-8 2003-4 4.2 2005-6 210,000 Candidaemia/year

4.8 (3/100,000) 2006 0.3 315,000 Inv candidiasis/year 2004-10 (1/3 BC-negative) 119,700 deaths/year 8.9-10 2.9 (38% mortality)2010-13 13 & 26 2013 2008-2011 9.5 & 14.4 8.1 3.6 3.6 2012-13 2010-2011 2010 2009 2.8 ESCMID Online Lecture Library1999-2008 https://www.gov.uk, Skogberg 2012, Poikonen 2010, Gradel 2014, Nielsen 2014, Josefson 2011, Hongsuwan 2014, Wisplinghoff 2004, Odds 2007, Bitar 2014, Tortorano 2013, Arendrup JCM Jan. 2011 and CMI 2013, Nordøy TIMM4 2009, Poikonen BMC Infectious Diseases 2010 & personal communication, Ericsson CMI 2013, Cleveland CID 2012 and PlosOne 2015, St-Germain Can J M Cavling ARENDRUP Inf MM 2008, Playford J Hosp Inf 2010, Puig-Assensio CMI 2014 @ by author

Fungaemia in the Nordic countries

1 1 D e n m a rk 100% 1 0 N o rw a y 90% 9 F in la n d 80% 8 70% 7 60% 6

5 50%

4 40%

3 30%

Rate per 100,0002 population 20%

1 10%

0 0% 1990 1995 2000 2005 2010 Denmark Norway Finland Y e a r 2012-13 2009-13 2008-12 C. albicans C. dubliniensis C. glabrata C. krusei ESCMID Online LectureC. parapsilosis LibraryC. tropicalis Other Arendrup JCM 2005, CMI 2008, JCM Jan. 2011, CMI 2013; Sandven JCM 2006, M Cavling ARENDRUP Poikonen Emerg Infect@ Dis 2003 &by BMC Inf Dis 2010author & Pers communication; Nordøy TIMM4 2009, Asmundsdottir JCM 2013. Age Dependent Incidence Nordics

70 Denmark  Maximum at the extremes of age! 60 Female  Male > Female Male  <1 y: ~7-10/100,000

50 Incidens overall  >65 y: DK: 20-40 > NO: 10-15 > FI: 8-10

10 40 Finland

5

30 Population 0 Cases/100,000 Cases/100,000 <1 1-15 16-65 >65

20 Incidence rate (no. (no. isolates/100.000) rate Incidence 18 Norway 16 14 12 10 10 8 6 4 2 0 /100,000 Cases population 0 <1 <1 1-9 80- 1-9 10-19 20-29 30-39 40-49 50-59 60-69 70-79 10-19 20-29 30-39 40-49 50-59 60-69 70-79 80-89 90-99 ESCMIDAge group (years) Online Lecture Library Age group Arendrup JCM Jan.@ 2011; Nordøy by TIMM 2009,author Poikonen BMC Infectious Diseases 2010 M Cavling ARENDRUP Candidaemia Over Time: Outside EU

Atlanta Baltimore Queensland Australia Canada 20 years 11 years 10 years 5 years

8%  25 0.8

0.7 245%  20 0.6

15 46%  beddays 0.5 0.4 131%  10 0.3

Incidence /100,000 population 0.2 5 Cases/10.000 0.1 0 0 1999 2008 Year 1999 2000 2001 2002 2003 2004 1992-1993 2008-2011 1998-2000 2008-2011 ESCMIDYear Online Lecture Library

Cleveland CID 2012,@ Playford byJ Hosp Infect author 2010, Laupland JAC 2005 M Cavling ARENDRUP Candidaemia: Atlanta-Baltimore 2008-13

3,848 cases . 2,324 (60%) in Atlanta (25 hosp; 3.8 mill population) . 1,524 (40%) in Baltimore (15 hosp; 1.4 mill population) Demography . median age: 58 . 52%  . 60% black Baltimore Incidence ↓ Atlanta Annual Annual Incidence Rate . Baltimore>Atlanta

ESCMID Online Lecture Library

Cleveland PlosOne@ 2015 by author M Cavling ARENDRUP Candidaemia: Atlanta-Baltimore 2008-13

3,848 cases . 2,324 (60%) in Atlanta (25 hosp; 3.8 mill population) . 1,524 (40%) in Baltimore (15 hosp; 1.4 mill population) Demography . median age: 58 . 52%  . 60% black Baltimore Incidence ↓ Atlanta Annual Annual Incidence Rate . Baltimore>Atlanta . pts w CVC

Baltimore Atlanta

Atlanta +CVC ≥ 65 y

Baltimore +CVC < 1 y

No. of cases No. of Atlanta -CVC 45-64 y Baltimore -CVC ESCMID Online Annual Incidence Rate Lecture20-44 yLibrary 1-19 y Cleveland PlosOne@ 2015 by author M Cavling ARENDRUP Candidaemia: Atlanta-Baltimore 2008-13

3,848 cases . 2,324 (60%) in Atlanta (25 hosp; 3.8 mill population) . 1,524 (40%) in Baltimore (15 hosp; 1.4 mill population) Demography . median age: 58 . 52%  Drivers . 60% black a) Patient specific susceptibility Baltimore Incidence ↓ b) What we do to the patient Atlanta Annual Annual Incidence Rate . Baltimore>Atlanta . pts w CVC Modifiable

Baltimore Atlanta

Atlanta +CVC ≥ 65 y

Baltimore +CVC < 1 y

No. of cases No. of Atlanta -CVC 45-64 y Baltimore -CVC ESCMID Online Annual Incidence Rate Lecture20-44 yLibrary 1-19 y Cleveland PlosOne@ 2015 by author M Cavling ARENDRUP C. parapsilosis outbreak in adult Pts

July 2006: - 4 C. parapsilosis candidaemia cases - 10 isolates 2001-5

- 1 case in in the same Haematol. ward Identical MLST genotype 1/7 loci difference

Dept. hospital hygiene investigation - routines while flushing intravascular catheters were not strictly followed - sterile vials of saline • occasionally reused • carried between patients Intervention: routines strictly enforced - maintenance of intravenous catheters - basic hygiene procedures incl. • disinfection of hands before & after patient contact. No cases afterwards ESCMID Online Lecture Library Brillowska -Dabrowska@ SJID 2009by author M Cavling ARENDRUP

C. albicans genotyping 2 hospitals Spain

179 C. albicans BSI 145 C. albicans genotypes - 21 in clusters 2 to 7 pts/cluster

Hosp A: 9 clusters involving 20.7% of pts Hosp B: 10 clusters involving 38.1% of pts ESCMID Online Lecture Library

Marcos-Zambrano @CMI 2015 by author M Cavling ARENDRUP Age & Race Dependent Incidence Globally

100 90 Spain Iceland

80 70 60 50 40 30

Incidence per 100,000 20 10 0 <1 1-10 11-20 '21-30 31-40 41-50 51-60 61-70 71-80 81-90 >90

Age group (years)

The US Australia

ESCMID Online Lecture Library Indicates an incidence of 10/100,000 population for comparison Puig-Assensio CMI @2014, Chen by Emerg Inf author Dis 2006, Asmundsdottir JCM 2013, Hajjeh JCM 2004 M Cavling ARENDRUP Candidaemia Indian ICUs

Nationwide, 27 Indian ICUs, 2011-12 - 11 public sector - 16 private/corporate - 913 adults patients • median age 50 y

Rate: 6.51 cases/1,000 ICU adm. - 3.61 in the West  8.95 in the North - 44.7% mortality (d 30) 5 teach hosp, Italy & Spain, 2008-10 - 995 patients median age 66.2 - 1.55 cases/1,000 ICU adm 50 • 0.8 in Udine 2.53 in Rome 40

• 39.9% mortality (d 30) 30

60 20 40 Per cent % cent Per 10 20 ESCMID0 Online Lecture % cent Per 0 Library

Chakrabarti Intens@ Care Med by2015, Bassetti author JCM 2013 M Cavling ARENDRUP Echinocandin resistant Blood Stream isolates DK

16 20/24 molecularly 14 confirmed

12 Multidrug Resistance:

10 75% (18/24) Echinocandin R & 8 Fluconazole I/R (MIC ≥ 4 mg/L) 6

4 Note: Only initial BSI isolates 2 included 0  underestimate? 2004-5 2006-7 2008-9 2010-11 2012-13 C. glabrata C. dubliniensis C. albicans ESCMIDC. krusei C. tropicalisOnline Lecture Library Arendrup P1256 ECCMID@ 2015 by author M Cavling ARENDRUP Echinocandin R in C. glabrata

14 America Europe 12 10

8 75% of which were C. glabrata 6 4 % isolates % isolates 2 0

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Shields AAC 2013; Alexander CID 2013; Nucci PlosOne 2013; Cleveland PlosOne 2015; Pfaller JCM 2011; Arendrup M Cavling ARENDRUP Unpubl data; Tortorano@ Infection by 2009. author Candida Echinocandin resistance: FKS

FKS1p FKS2p AFG EUCAST Hot spot 1 Hot spot 2 Hot spot 1 Hot spot 2 ECOFF 1st AA 1st AA 1st AA 1st AA AA (mg/L) no. AA sequence no. AA sequence no. AA sequence no. sequence C. albicans 0.03 641 FLTLSLRDP 1357 DWIRRYTL C. dubliniensis 0.03 641 FLTLSLRDP 1357 DWIRRYTL R C. glabrata 0.06 625 FLILSLRDP 1340 DWVRRYTL 659 FLILSLRDP 1374 DWI RYTL C. kefyr (0.03) 54* FLTLSLRDP 769* DWVRRYTL C. krusei 0.06# 655 FLILSIRDP 1364 DWIRRYTL C. lusitaniae (0.06) 634* FLTLSLRDP ** DWIRRYTL C. tropicalis 0.06 76* FLTLSLRDP 792* DWIRRYTL C. parapsilosis 4 652 FLTLSLRDA 1369 DWIRRYTL C. metapsilosis (4) 104* FLTLSLRDA 821* DWIRRYTL C. orthopsilosis (4) 39* FLTLSLRDA 756* DWVRRYTL C. guilliermondii (4) 632 FMALSLRDP 1347 DWIRRYTL C. lipolytica NA 662 FLILSLRDP 1387 DWIRRCVL S. cerevisiae (1) 639 FLVLSLRDP 1353 DWVRRYTL 658 FLILSLRDP 1372 DWVRRYTL

high X "strong R" mutation, low letters indicate the codon involves a mutation or deletion; letters indicate the codon involves a mutation or stop codon; X "weak R" mutation; X "silent" mutation, acquired or naturally occurring; X naturally occurring mutation proven or possibly related to the intrinsic lower susceptibility; X naturallyESCMID occurring mutation of unknown impact; Online * Inaccurate annotation, sequencingLecture of entire gene-sequence required;Library # Micafungin ECOFF elevated for C. krusei compared to C. albicans and C. glabrata, but not the anidulafungin ECOFF. Arendrup Cur Op Inf@ Dis 2014 by author M Cavling ARENDRUP C. glabrata in mice “S >< I >< R

Mice challenged iv with 3 strains: caspofungin MIC 0.25, MIC 1 & MIC 16 Treated ip with caspofungin

8 768

7 7 56

6 6 5 4 RR#24 Fks1p S629P 5 5 +1.139 log growth 4 CFU/g CFU/g CFU/g 4 34 10 10 10 R#83 Fks2p S663F 3 Log Log Log 3 3 -1.850 log reduction 2 2 2 S#3 wild type 2 -2.728 log reduction

Log CFU kidney tissue CFU Log kidney 1 1 1 1

0 00 100 100 200 200 300 300 400 400 500 500 600 600700 800 700 900 800 900 ESCMID OnlineCaspofunginCaspofungin AUC AUCLecture Library

Arendrup AAC 2012@ by author M Cavling ARENDRUP Same Fks1 mutation D  Y …. different impact

MIC elevation greater in C. krusei D662Y than in C. albicans D648Y Anidulafungin Micafungin Caspofungin EUCAST MIC EUCAST MIC Etest (MIC) 16 4 steps 8 ≥5 steps 4 ≥3 steps 2 2 steps 1 0.5 0.25 0.125 1 step 2 steps 0.0625 0.03125 0.015625 0.0078125 C. krusei C. albicans C. krusei C. albicans C. krusei C. albicans ESCMID OnlineWT MutantLecture Library WT MIC range EUCAST MIC >1 mg/L (the highest concentration tested) Jensen AAC 2014 @ by author M Cavling ARENDRUP C. glabrata echinocandin MIC & outcome

Cancer patients w 93 blood isolates in 2005-13)

Survival day 28 74.6% (50/67) caspofungin MIC<0.25 mg/L

58.3% (7/12) caspofungin MIC 0.25 mg/L 50% (5/10) caspofungin MIC 0.5 mg/L

25% (1/4) caspofungin MIC >2 mg/L log-rank p = 0.001 for linear trend ESCMID Online Lecture Library

Farmakiotis Emerg@ Inf Dis 2014 by author M Cavling ARENDRUP Agenda

Types of Fungal infection

Severe Fungal infections in numbers . in a global perspective

Focus on . Cryptococcus infections . Acute and chronic Aspergillus infections / Candidaemia . Invasive Candida infections 100,000+ deaths/y

 incidence vary by age, gender, Highlight the main challenges type/severity of disease & level . in the high income countries of hygiene routines . in the Resource limited countries  Emerging echinocandin resistance is a significant ESCMID Online Lecture Libraryconcern

@ by author M Cavling ARENDRUP Main challenges and areas for future attention

High income countries . Invasive infections ‒ diagnostic issues ‒ further potential for prevention ‒ emerging resistance - Azole resistance in Aspergillus - Echinocandin resistance in Candida - Timely detection not broadly available

Resource limited countries Nordic country . Unacceptably high number of deaths ‒ >½ million Crypto-deaths in sub-Saharan Africa ‒ ↑ rate of Candida, Aspergillus and Zygomycetes in e.g. India . Unacceptable lack of access to ‒ diagnostics ‒ antifungal medication

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@ by author M Cavling ARENDRUP All the topics I did NOT address !!!

All the topics I did NOT address . Endemic fungal infections ‒ e.g. , ,… . Pneumocystis . Keratitis . Superficial infections

Expressed my personal views

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@ by author M Cavling ARENDRUP Acknowledgements

David Denning www.gaffi.org International collaborators . Cuenca-Estrella M, Hope WW, Howard SJ, Kullberg BJ, Lass-Flörl C, Lortholary O, Perlin DS, Meletiadis J, Pfaller M, Sanglard D, Verweij P, and many more Danish Fungaemia Study group . Schønheyder HC, Johansen HK, Knudsen JD, Lemming LE, Røder B, Rosenvinge FS, www.LIFE-Worldwide.org Kristensen L, Nielsen L, Olesen B, Dzajic E, Kjældgaard P SSI Colleagues . Jensen RM, Astvad K, Brandt B To You for Your Attention ESCMID Online Lecture Library

@ by author M Cavling ARENDRUP 7th Trends in Medical Mycology | 9-12 October 2015

www.TIMM2015.org ESCMID Online Lecture Library

@ by author M Cavling ARENDRUP