Prescription antifongique et émergence de la résistance

Olivier Lortholary M.D.; Ph.D

Centre National de Référence Mycoses Invasives & Antifongiques,

Unité de Mycologie Moléculaire, CNRS URA3012 Institut Pasteur,

& Centre d’Infectiologie Necker-Pasteur Université Paris Descartes, Hôpital Necker Enfants malades,

IHU Imagine Paris, France. Impossible d’afficher l’image.

Impossible d’afficher l’image.

Polling Question

Which of the following infectious organisms have increased in resistance at your institution over the past several years? Select all that apply.

1. Aspergillus

2. Candida

3. Coccidioides

4. Fusarium

5. Mucorales

DNA/RNA synthesis Flucytosine (R permease, deaminase, …)

Ergosterol synthesis

Polyens : Amphotericin B rare R

Membrane modifications Triazoles R target, efflux Terbinafine

Beta D glucan synthesis Echinocandins

R target

Mechanisms of action of current antifungals

Resistance in fungi

Susceptible species Resistant species

Intrinsic resistance +++ Acquired resistance

Resistant isolate

Susceptible isolate

1. Appropriate identification at the species level +++ 2. ATF: most often selection of species with higher MIC values

« low process » No horizontal transmission

Antifungal spectrum of current antifungals

Polyens Fluco Itraco Vorico Posaco Isavuco Candins

C. albicans + + + + + + +

C. krusei + - - + + + +

C. glabrata +

- - +/-

+/-

+/- +

Cryptococcus + + + + + + - ! Aspergillus + - + + + + +

Mucorales + - - - + + - ! Fusarium + - - +/- +/- +/- - !

C A N D I D A

Fluconazole R Candida albicans

• C. albicans : 2.1% Fluco R (1992–2000) 1.6% (2005) Houston Lewis. Curr Med Res Opin 2009 • C. albicans : 0% Fluco R (SENTRY 2008–2009) International Pfaller et al. AAC 2011 • C. albicans : 0–2% Fluco R (6082 isolates 1992–2001) International Pfaller et al. AAC 2011 • C. albicans : 0% Fluco R (107 candidemia 33 months, 2005–2008) UK Das et al. Int J Infect Dis 2011 • C. albicans : 2% Fluco R (348 candidemia 2008–2010) Italy Bassetti et al. PLoS ONE 2011

MAXIMUM 2% (invasive candidiasis)

No increased resistance to azoles among susceptible Candida species during fungemia in

Paris area

Unpublished data, provided by the NRCMA (French National Reference Center for Mycoses and Antifungals), Institut Pasteur Paris.

MICs; EUCAST Fcz > 4 µg/ml Vcz > 0.12 µg/ml

0.2% FCZ R

Similar conclusion by US CDC [Cleveland, CID 2012]

Public health impact of fluconazole resistance in Candida ?

http://www.cdc.gov ; Threats Report 2013

Echinocandin resistant Candida isolates

• 5% Caspofungin R (168 Candida sp 2001–2007) Houston Sipsas et al. Cancer 2009

• 0–1% MIC >2 Caspofungin (13147 Candida sp 1992–2006) International database Lewis et al. Curr Med Res Opin 2009 • 0–2% Caspofungin R (238 bloodstream isolates 2005–2006) Sweden Axner-Elings et al. JCM 2011 • 0.4% (6/1643) Caspofungin R among C. albicans, C. glabrata and C. krusei isolates (1643 isolates, 2002–2009) Paris

Dannaoui et al. Emerg Infect Dis 2012 • 1% Echinocandin R (2329 Candida spp. 65% C. glabrata 2008–2011) Atlanta & Baltimore Cleveland et al. CID 2012 Recent increase: 1.2 to 2.9% (+ 147%) and 2.0 to 3.5% (+ 77%) from

2008 to 2013 in Atlanta and Baltimore Cleveland et al. PLoS ONE 2015

Historically rare in the absence of prior exposure !

% Echinocandin R % MDR (azoles & echinocandins)

Reference

1 CDC Sentry, Pfaller JCM 2012

1 Pham AAC 2014

11 (18% FKS mutants) - Beyda CID 2014

6.7 (increase 2001-2010) 3.5 Alexander CID 2013 10.3 6.8 Farmakiotis EID 2014

2.6 Cleveland PLoS ONE 2015

Echinocandin resistant / MDR Candida glabrata isolates (2012-2014)

Does exist in the absence of prior exposure !

First isolation of cholesterol dependent MDR C. glabrata (AmB & azoles) Khan BMC Infect Dis 2014

No increased resistance to caspofungin among susceptible Candida species during

fungemia in Paris area

Unpublished data, provided by the NRCMA (French National Reference Center for Mycoses and Antifungals), Institut Pasteur Paris. MICs; EUCAST

Cas > 0.25 µg/ml

2.8% caspo high with fks mutation

Candida isolates and candidemia in HSCT after prophylactic FCZ

albicans

glabrata

krusei

parapsilosis

others

FCZ resistance

7% 99%

585 assessable patients

Oral colonization with Candida

34 (5%) candidemia

95% not infected

Marr, JID 2000

Risk of candidemia due to fluconazole non-susceptible isolates

Candipop study, 29 hospitals, Spain 2010-2011: 617 patients (21.7% FCZ non-susceptible) Independent factors with FCZ-NS:

Transplant recipient (AOR 2.13; 95% CI 1.01-4.55) Hospitalization in a unit with high prevalence (≥ 15%) of FCZ-NS strains

(7.53; 4.68-12.10) Previous azole therapy (≥ 3d, within 30 d) (2.04; 1.16-3.62)

Definition and validation of a predictive score

Cuervo et al. CMI 2015

Influence of recent* FCZ / CAS exposure on Candida spp. distribution during fungemia

56% 18%

13%

10%

3% C.albicansC.glabrataC.parapsilosisC.tropicalisC.krusei

36%

29%

14%

13%

8%

29%

35%

31%

13%

Fluconazole (n=159) (P<0.001)

Caspofungin (n=61) (P<0.001)

Lortholary et al. AAC 2011

*recent ≤ 30 d

Echinocandin exposure in hematology associated with echinocandin reduced activity during

subsequent candidemia

Multivariate analysis OR CI 95% p

Prior exposure to caspofungin (< 30 d) 5.25 [1.68-16.35] 0.004

Age at fungemia (≤ 65 yrs vs > 65 yrs) 3.27 [1.26-8.50] 0.015

Matched case-control study (51/102 pts) in Paris October 2002–February 2010 Matching for center and date; MIC ≥ 0.5 µg/ml

Blanchard, AAC 2011

Impact of echinocandin exposure confirmed in various studies: Shields AAC 2012, Alexander CID 2013, Beyda CID 2014, Farmakiotis EID 2014

Role of micafungin low dosage (50 mg/d) as prophylaxis : Bizerra

AAC 2014

Emergence of Candida spp. infections with acquired echinocandin resistance in France

20 episodes in patients (19 prior treatment by caspofungin including 13/19 currently receiving it [median 27 d (10–270 d)])

10 C. glabrata, 8 C. albicans and 2 C. krusei

14 episodes with initial and subsequent isolates : same genotype

All mutated in Fksp sequence (Hot Spot 1 FKS1 for C. albicans ; FKS1 or 2 for C. glabrata)

Dannaoui, Emerg Infect Dis 2012

« Cross resistance »

C. glabrata (/ C. albicans)

OR*

Gender male 0·76 Age <45 yrs 1

45-64 yrs 1·39

65-79 yrs 1·56 ≥80 yrs 2·09 Caspofungin pre-exposure 5·77 Fluconazole pre-exposure 2·60

* 95% CI not including 1

Patients Infected by C. glabrata Bivariate Analysis / Multinomial analysis

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Unpublished data, provided by the NRCMA (French National Reference Center for Mycoses and Antifungals) Institut Pasteur Paris.

Impact of echinocandin exposure on C. glabrata

Multiply resistant C. glabrata: 78 FCZ R isolates => 14.1% with resistance to ≥ 1 echinocandin

Failure of echinocandin therapy during invasive candidiasis Relationship with prior echinocandin exposure

Impact of FKS mutations and elevated MICs

Failure rate : 60-91%

Alexander, CID 2013 ; Shields AAC 2012, 2013 ; Beyda CID 2014

Echinocandin exposure and C. parapsilosis experience in Grenoble, France

Fournier JAC 2011

C. parapsilosis (// C. albicans)

OR* Gender male 1·36

Age < 45 yrs 1

45-64 yrs 0·67

65-79 yrs 0·50

≥ 80 yrs 0·46

Intensive Care Unit 0·60

Caspofungin pre-exposure 5·92

Patients infected by C. parapsilosis Bivariate analysis Multinomial analysis

* 95% IC not including 1

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

NRCMA unpublished data

Impact of resistance during candidemia in onco-hematology patients

138 episodes; 39 FCZ resistant; CLSI; Australia 2001−2004

Increased mortality

146 episodes C. glabrata; 30 FCZ/15 CAS resistant; CLSI; Houston 2005−2013

Slavin et al. JAC 2010

Farmakiotis et al. EID 2014

Early acquired flucytosine resistance during combination with caspofungin

for C. glabrata cystitis

2 episodes of cystitis with rapid acquired resistance to flucytosine due to nonsense mutations in the FUR1 gene

Identical MLST profile before and after flucytosine Observed as early as d6 and d10 of combination

therapy Combination does not protect against resistance if

single therapy at infectious site (… echinocandin in urine)

Charlier AAC 2015

Why so few Candida spp. amphotericin B resistant ?

Amphotericin B resistant mutants : hypersensitive to oxidative stress, febrile temperatures, killing by neutrophils defects in filamentation and tissue invasion avirulent in a murine model

Oct 2013

ASPERGILLUS

Triazole resistant Aspergillus spp.

How to get a resistant infection “Primary” resistance in antifungal naïve Pts

• Intrinsically resistant species • Isolate with acquired resistance (environment)

“Acquired” resistance in the AF-treated patient • long term treatment in the individual patient (chronic infection)

Aspergillus section Fumigati

10 anamorphs A. brevipes A. duricaulis A. fumigatiaffinis * A. fumigatus A. fummisynnematus A. lentulus * A. novofumigatus A. turcosus A. unilateralis A. viridinutans *

23 telemorphs (Neosartorya) – N. assulata – N. aurata – N. aureola – N. australensis – N. coreana – N. denticulata – N. ferenczii – N. fennelliae – N. fischeri – N. galapagensis – N. glabra – N. hiratsukae

– N. laciniosa – N. mulplicata – N. papuensis – N. pseudofischeri * – N. quadricincta – N. spinosa – N. stramenia – N. spathulata – N. tatenoi – N. udagawae – N. warcupii

Samson in “Aspergillus fumigatus and Aspergillosis” 2008; courtesy M Arendrup Isolates in red have been isolated from humans, * resistant to one or more AFs

Resistance mechanisms in Aspergillus fumigatus (cyp51a-related)

Aspergillus fumigatus cyp51A-related resistance mechanisms to azole antifungals. The position of the different mutations are shown with the associated phenotypes. MIC=minimum inhibitory concentration. TR=tandem repeat.

Verweij P et al, Lancet Inf Dis 2009

Azole-resistance in A. fumigatus

Verweij Drug Resist Updates 2009; Howard Emerg Infect Dis 2009

Manchester

Numerous different

resistance mechanisms

Nijmegen

One mechanism responsible for

>94% R

(TR34/L98H)

TR34/L98H TR53

TR46/Y121F/T289A G54?

Medical azoles

The environmental route

C l

C l

O

O

N N

N

H

C l

O O

N N

N

H

H

C l

O N

N

N

H

C l

O

N N

N

H C l C l

O

O

O N

N

N

H

Propiconazole; tebuconazole; epoxiconazole; difenoconazole; bromuconazole

37% W-Eur.

24% Asia- Pacific

22% S- & Latin America

9% N-America

5% E-Eur.

Fungicide use & TR34/L98H reports Global market share of fungicide use in agriculture TR34/L98H

Stensvold Curr Fungal Inf Reports 2012, Rath AAC 2012

Middle East

Tanzania

China

India

Australia

Azole resistance in A. fumigatus TR34/L98 + TR46/Y121F/T289A

PLoS Pathog. 2013;9:e1003633; kindly provided by P Verweij

Yeast Fungemia due to Uncommon Species (<2%, ODL 2002-2013)

7.4% (306/4136); stable incidence 33 different species: 26 ascomycetes, 7 basidiomycetes 10 had CAS MIC >0.5 mg/L, 13 had FCZ MIC >8 mg/L

Prior exposure to CAS, but not to FCZ: Predisposing factor for uncommon species with high MICs for

both CAS and FCZ (ORs=13.8 and 11.4, respectively, p<0.001)

Bretagne S, et al. ECCMID 2015. Abstract O181.

Multidisciplinary antifungal stewardship programs: Madrid experience

Knowledge survey: room for improvement. Valerio, Enf Infecc Microbiol Clin 2014

Antifungal use audit : identifies how AF are used and targets for intervention. Valerio, JAC 2014

Non restrictive bed-side

intervention: safe and very cost-effective. Valerio, JAC 2015

Combination of Candida biomarkers : help for stopping antifungals. Martinez-Jimenez, JAC 2015

Courtesy: P Munoz

Antifungal failure may be multifactorial Resistance in fungi: +++ intrinsic but may be acquired Prevention of acquired resistance: Adequate ATF indications Limited duration of exposure (stop/switch) Good tissue penetration & drug monitoring Combination therapy if flucytosine Improve host status (HIV+)

Documentation of acquired resistance: Appropriate methodology Comparison with initial isolate Molecular characterization ± therapeutic failure

Conclusions