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Unpublished data, provided by the NRCMA (French National Reference Center for Mycoses and Antifungals), Institut Pasteur Paris.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