Cédric Durand

Fabrice Casset

Pascal Ancey

Fabienne Judong

et al.. SILICON ON Alexandre Talbot

Rémi Quenouillère

Denis Renaud

Stéphan Borel

Brigitte Florin

Lionel Buchaillot

Rémi Quenouillère

SILICON ON NOTHING MEMS ELECTROMECHANICAL RESONATOR

la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

INTRODUCTION

Recent demand in single chip, multi-standard wireless transceivers has focused research efforts towards developing integrated Radio Frequency (RF) Micro or Nano Electro Mechanical Systems (MEMS or NEMS) in order to replace existing off-chip oscillators like quartz or ceramics. The small sizes of the electromechanical resonators and their single wafer, multi frequencies possibilities has focussed tremendous interest in the development of demonstrators using standard CMOS process.

Table 1 gives an overview of the state of the art on the MEMS electromechanical resonators. We can distinguish different resonator families: vibrating beam [START_REF] Nguyen | High-Q HF Microelectromechanical Filters[END_REF], longitudinal beam [START_REF] Koskenvuori | Active post processing method to increase the electro mechanical coupling in microresonators[END_REF], bulk square extensional plate [START_REF] Kaajakai | Square-Extensional Mode Single Crystal Silicon Micromechanical RF resonator[END_REF], elliptic [START_REF] Pourkamali | High Frequency Capacitive Micromechanical Resonators with Reduced Motional Resistance using the HARPSS Technology[END_REF] or contour [START_REF] Nguyen | 1.51GHz nanocrystalline diamond micromechanical disk resonator with material mismatched isolating support[END_REF] mode disk, rings [START_REF] Nguyen | Micromechanical "Hollow-disk" ring resonators[END_REF], solid dielectric capacitive gap resonator [START_REF] Lin | Vibrating micromechanical resonator with solid dielectric capacitive transducer gaps[END_REF] and bulk mode beam [START_REF] Ayazi | High aspect ratio SOI Vibrating Micromechanical resonators and filters[END_REF]. We can focus on the simplest case to understand how a resonator works. For a vibrating beam, we can express the mechanical resonant frequency with the following simplified equation:

2 , r n Beam R L h E A f ρ = Equation 1
A n is a coefficient depending on the harmonic of vibration. E is the Young modulus, ρ the density, h and L r respectively the thickness and the length of the beam which have an "out of plan" displacement (Figure 1). Thus, the resonant frequency depends on the material properties and on the movable mechanical structure dimensions photolithographically defined.

The vibrating beam is polarized with a DC bias V p . The RF signal is applied to the resonator. At the resonant frequency, the vibrating beam presents a maximum displacement detected by an output electrode as detailed in Figure 1. The electrode to resonator initial gap d 0 has to be as small as possible because the motional resistance R x (illustrates the level of signal transmitted to the resonator) is strongly dependant on this factor as explained in the following equation [START_REF] Lin | Vibrating micromechanical resonator with solid dielectric capacitive transducer gaps[END_REF]:

) ( 2 2 2 0 4 0 2 0 ) ( 1 airgap r P r airgap x Q S d V k R ε ε ω = Equation 2
k r is the stiffness, ω 0 the pulsation, ε 0 the air dielectric constant, ε r the material dielectric constant, S the electrode surface, and Q the quality factor. For an integrated resonator we aim to obtain a motional resistance between 50 ohms and 10kohms. The resonant frequency increases when the beam stiffness increases, so smaller resonator sizes induce a resonant frequency increase. Moreover, the smaller the gap, the smaller the motional resistance. Thus reducing the size is a major challenge for resonators development. The resonator performances described in the state of the art demonstrate the electromechanical resonators potentialities for quartz replacement. However, temperature stability, packaging, motional impedance constitutes major challenges to the integration of multi frequencies MEMS or NEMS resonators in Integer Circuits (IC).

In this paper, we will first be taking a look at the applications and specifications for such components. Then we will outline our "Front End" resonator technological developments on both capacitive and Metal Oxide Semiconductor (MOS) transistor detection demonstrators. We will conclude with the IC integration perspective from a device point of view.

STATE OF THE ART ON MEMS RESONATOR AND OPPORTUNITIES

Table 1 reveals that resonators can be classed by the vibrating direction:

• Out of plane (vertical resonators)

• In plane (lateral resonators)

Initially, people were more interested in working on vertical resonators because it was technologically easier to fabricate. The majority of recent demonstrator devices are using lateral technologies mainly because of the design flexibility: squares, disks, beams… In terms of frequency, Table 1 shows resonators with very different resonance frequencies that make devices hard to compare. So we consider the factor Frequency multiplied by Quality Factor (F x Q) as a comparison factor. Compared to the quartz F.Q factor (<60MHz, Q nearly 15000, F.Q=9x10 6 ), the state of the art analysis demonstrates the electromechanical resonators potentialities for quartz replacement.

Table 1 : Electromechanical resonators state of the art

APPLICATIONS AND SPECIFICATIONS

A simple RF transceiver architecture schematic is given in Figure 2. We can identify the major applications using resonators:

• Reference oscillator to provide stable and precise frequency reference. Today, quartz is commonly used.

• Voltage Controlled Oscillator (VCO) which can insure a controlled variation of the frequency with bias variation. LC resonators are used today.

• Filters to extract the useful signal from the noise. Today, Surface Acoustic Waves (SAW) or Bulk Acoustic Waves (BAW) filters are used.

The overview of the main applications and specifications is given in Table 2.

Table 2 : Resonator applications and specifications

We can make a few observations about the specifications needed for the different applications describe in Error! Reference source not found.. VCO will require frequencies as high as 2GHz with a large frequency tuning. Looking at the electromechanical resonator state of the art, we can see that the highest obtained resonant frequency is around 1.5GHz. Moreover the electromechanical resonator frequency tuning is inversely proportional to the stiffness and also the frequency. Therefore it is difficult to reach the VCO specifications. The filter applications require, in general, a large band pass whereas electromechanical resonators are characterised by a high quality factor which induces a narrow band pass. A mechanical coupling could be used to enlarge the resonator band pass [START_REF] Nguyen | High-Q HF Microelectromechanical Filters[END_REF]. But in this way, it could be difficult to reach the drastic specifications needed. So, electromechanical resonators seem to be not adapted to satisfying filtering specifications. The third main application using resonator consists in providing a stable and precise reference frequency. Today, these reference oscillators are constituted by quartz oscillators which have large size and have to be built off-chip (then reported). MEMS or NEMS electromechanical resonators are good candidates to replace quartz oscillators. Its present high frequencies compared to quartz (limited around 60MHz) and use CMOS process from an integration solution perspective. We notice a good agreement between analytic and FEM results. Displacements are amplified and not representative.

RESONATOR DESIGN AND DETECTION

Analytical design & Detection

It is well know that this displacement is in the nanometre range (nearly 10-20 nm for the beam, 1-5 nm for the disk). Due to very low displacements, capacitance variation is too low for output detection using capacitive detection technique. In this way, we investigate MOS detection.

Capacitive versus MOS Detection

MOS detection is well adapted for the output signal acquisition [START_REF] Abelé | Comparison of RSG-MOSFET and capacitive MEMS resonator detection[END_REF]: Figure 6 gives a schematic with the principle of MOS detection. The gate is the resonant structure. Figure 5 shows that when dimensions of resonators decrease (frequencies increase and consequently displacements decrease), the MOS detection is more efficient compared to the capacitive one. This is why MOS detection has been integrated for our technological developments.

V g Gate V gin C g Gat Channe H L Sourc Drai V g V gi C g Gate

SON TECHNOLOGICAL DEVELOPMENTS

Decrease sizes and gap is still a challenge for useful component. In this way, a front end resonator using the Silicon on Nothing (SON) process based on Silicon Germanium (SiGe) and Silicon (Si) epitaxy (Figure 7a) and equally used for MOS realization [10], is under development. The goal is to obtain sub 100nm gap allowing the realization of NEMS with a reduced motional resistance. To make the MOS for detection, the monocrystalline Si layer is Boron doped in situ at a level doping corresponding to the MOS channel doping, around 5.10 15 at/cm 3 . A phosphorous doping is necessary to make Source, Drain, and Gate (= resonator). Figure 9 shows the depth doping level characterization with a comparison of simulation, SIMS method and a chemical doping level revelation [START_REF] Wang | 2D ultrashallow junction characterization of MOSFET with strained silicon[END_REF], with a good agreement. The doping level is not continuous with depth because of technological constraints. The minimum doping level of around 3.10 18 at/cm 3 seems to be enough for the application. The physical revelation enables the study of lateral doping diffusion (Figure 10).

Figure 10 : Lateral doping diffusion after thermal annealing

In order to limit the high motional resistance of devices, it is desirable to make small gaps between resonators and electrodes. It is why the gap has been defined by e-beam photolithography and etched (Figure 7b & c) using a highly anisotropic plasma process. Some pictures of the technological results are presented in Figure 11 and Figure 12. 12 gives a cross section view a of 90nm gap obtained after a 400nm Si etching with an enlargement of less that 10nm due to the etching process.

After the gap etching, the SiGe (sacrificial layer) has to be etched (Figure 7d) with a high selectivity SiGe/Si and SiO 2 /SiGe. The aim is to release resonators that will be suspended. The process has been developed initially mainly for CMOS using SON technology purposes with tunnel to etch around 500nm [START_REF] Borel | Isotropic Etching of Si1-xGex Buried Layers Selectively to Si for the Realization of Advanced Devices[END_REF]. Here the process has been adapted to be able to etch longer tunnels as shown in Figure 13 and Figure 14. The process selectivity is strongly dependant of the tunnel depth. For a 1.19µm tunnel depth, the initial gap measured at 90nm has been enlarged and measured at 130nm after release. The process is under progress so as to improve selectivity.

Work is in progress in collaboration with the CEA-LETI & IEMN to obtain electrical demonstrators in the close future.

CONCLUSION

MEMS or NEMS electromechanical resonator is a very important component in order to integrate frequency reference oscillator in chips. Some developments to obtain capacitive and MOS demonstrators were presented. The electromechanical resonator state of the art highlights the importance of sub 100nm gaps and packaging. The SON process seems to be well adapted to obtain promising components. Process developments have started from electrical demonstrators' realization. Future work on packaging and IC integration will be investigated in a close future.

Figure 1 :

 1 Figure 1: Top view of an « out of plan » vibrating beam (schematic)

Figure 2 : 1 2

 21 Figure 2 : RF architecture view

Figure 3 :Figure 4 :

 34 Figure 3 : FEM modal simulation of a clamped-clamped beam Dimensions: Length:10µm, Width: 0.46µm, Height: 0.4µm Coventor: 39.0MHz Analytic: 38.8MHz Delta: 0.5 %

Figure 5 :

 5 Figure 5 : Comparison of MOS & Capacitive detection for a flexural mode clamped-clamped beam

Figure 6 :

 6 Figure 6 : Schematic of a suspended resonator using MOS detection

Figure 7 :

 7 Figure 7 : STMicroelectronics SON process

Figure 8 :Figure 8

 88 Figure 8 : SEM pictures of Si & SiGe epitaxy

Figure 9 :

 9 Figure 9 : Depth doping level characterization after phosphorous doping

Figure 11 :

 11 Figure 11 : Top SEM view of a nano beam

Figure 12 :

 12 Figure 12 : Gap etch cross SEM picture

Figure

  Figure[START_REF] Wang | 2D ultrashallow junction characterization of MOSFET with strained silicon[END_REF] gives an idea of the precision of technological gap definition after etching. Figure12gives a cross section view a of 90nm gap obtained after a 400nm Si etching with an enlargement of less that 10nm due to the etching process.After the gap etching, the SiGe (sacrificial layer) has to be etched (Figure7d) with a high selectivity SiGe/Si and SiO 2 /SiGe. The aim is to release resonators that will be suspended.

Figure 13 :

 13 Figure 13 : Tilt SEM view of SiGe released areas

Figure 14 :

 14 Figure 14 : Cross section view of a released tunnel

  Cédric Durand, Fabrice Casset, Pascal Ancey, Fabienne Judong, Alexandre Talbot, Rémi Quenouillère, Denis Renaud, Stéphan Borel, Brigitte Florin, Lionel Buchaillot Silicon On Nothing MEMS Electromechanical Resonator

©EDA Publishing/DTIP 2007 -page-ISBN: ….


Maurizio Sanguinetti

Ying-Chun Xu

Stéphane Bretagne
email: stéphanebretagnebretagne@pasteur.fr

Marie Desnos-Ollivier

Karine Sitbon

Olivier Lortholary

Didier Che

Françoise Dromer

No Impact of Fluconazole to Echinocandins Replacement as First-Line Therapy on the Epidemiology of Yeast Fungemia (Hospital-Driven Active Surveillance, 2004-2017, Paris, France)

Keywords: fungemia, candidemia, epidemiology, hematological malignancy, solid cancer, intensive care unit, echinocandins, fluconazole

des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

INTRODUCTION

Candidiasis is associated with mortality as high as 40%, acknowledging that patients with this condition usually present several entangled risk factors impacting the prognosis [START_REF] Kullberg | Invasive candidiasis[END_REF].

To improve the prognosis and to harmonize diagnostic and therapeutic strategies, several guidelines have been released worldwide for different patient populations [START_REF] Bow | Canadian clinical practice guidelines for invasive candidiasis in adults[END_REF][START_REF] Colombo | Brazilian guidelines for the management of candidiasis-a joint meeting report of three medical societies: sociedade Brasileira de Infectologia, Sociedade Paulista de Infectologia and Sociedade Brasileira de Medicina Tropical[END_REF][START_REF] Cornely | ESCMID * guideline for the diagnosis and management of Candida diseases 2012: non-neutropenic adult patients[END_REF][START_REF] Hsueh | Consensus statement on the management of invasive candidiasis in Intensive Care Units in the Asia-Pacific Region[END_REF][START_REF] Mousset | Treatment of invasive fungal infections in cancer patients-updated recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO)[END_REF][START_REF] Pappas | Executive summary: clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America[END_REF][START_REF] Ruhnke | Diagnosis and therapy of Candida infections: joint recommendations of the German Speaking Mycological Society and the Paul-Ehrlich-Society for Chemotherapy[END_REF][START_REF] Tissot | ECIL-6 guidelines for the treatment of invasive candidiasis, aspergillosis and mucormycosis in leukemia and hematopoietic stem cell transplant patients[END_REF][START_REF] Ullmann | ESCMID * guideline for the diagnosis and management of Candida diseases 2012: adults with hematological malignancies and after haematopoietic stem cell transplantation (HCT)[END_REF]. One of the recommendations is the strong incentive for using echinocandin instead of fluconazole as first-line therapy based on analysis of randomized trials [START_REF] Andes | Impact of treatment strategy on outcomes in patients with candidemia and other forms of invasive candidiasis: a patient-level quantitative review of randomized trials[END_REF][START_REF] Reboli | Anidulafungin versus fluconazole for invasive candidiasis[END_REF]. One the reasons usually advocated is the limited spectrum of activity of fluconazole and the resistance or decreased susceptibility to fluconazole of some Candida species. Indeed, the possible shift toward non-albicans Candida species and the emergence of resistance to antifungal drugs pose a serious potential health threat considering the poor prognosis of candidiasis and the limited number of systemic antifungal drugs available [START_REF] Kullberg | Invasive candidiasis[END_REF][START_REF] Chowdhary | Candida auris: a rapidly emerging cause of hospital-acquired multidrug-resistant fungal infections globally[END_REF]. It is therefore of utmost interest to evaluate the impact of such therapeutic recommendations on both the epidemiology of the different species and the associated mortality rate.

To measure the burden of candidiasis, an active surveillance program on yeast fungemia within university hospitals in the Paris area was set up by the French National Reference Center of Invasive Mycoses and Antifungals (NRCMA). This surveillance includes all the episodes of yeast fungemia, and the centralization of all isolates by the NRCMA allowing for standardized characterization of the fungal species and their susceptibility to antifungal drugs. We describe here the epidemiology of yeastassociated fungemia, mainly candidemia, and the trends in mortality in correlation with individual treatment over 14 years in the Paris area.

MATERIALS AND METHODS

Yeasts Program

The YEASTS program is an active surveillance program on yeast fungemia described in details elsewhere [START_REF] Bretagne | Predisposing factors and outcome of uncommon yeast species-related fungemia based on an exhaustive surveillance programme (2002-14)[END_REF][START_REF] Lortholary | Worrisome trends in incidence and mortality of candidemia in intensive care units (Paris area, 2002-2010)[END_REF]. The current analysis concerns all episodes of yeast fungemia (excluding only Cryptococcus neoformans) diagnosed in all ages, notified by the 14 university hospitals which sustainably participated from January 2004 to December 2017. All sent the corresponding yeast isolates to the NRCMA where the species identification was checked and antifungal susceptibility determination performed using European Committee on Antimicrobial Susceptibility Testing (EUCAST) methodology as described [START_REF] Bretagne | Predisposing factors and outcome of uncommon yeast species-related fungemia based on an exhaustive surveillance programme (2002-14)[END_REF][START_REF] Lortholary | Worrisome trends in incidence and mortality of candidemia in intensive care units (Paris area, 2002-2010)[END_REF]. In parallel, clinical data, treatment and outcome were reported through a secure website.

The day of blood sampling was considered as the date of fungemia. An incident case corresponded to the first episode of positive blood culture. A recurrent episode was considered in case of isolation of the same species at least 10 days after the initial isolation or of a new species with no time limit. Both single (one species) and mixed (>1 species) episodes were considered. Patients were grouped into three categories (hematological malignancy hereafter "Hematology"), solid tumor (any kind of solid tumor at the time of sampling, hereafter "Oncology") or no malignancy (all other cases, hereafter "No-malignancy"). Cases were classified regarding their occurrence during a stay in intensive care unit (ICU) or not. All isolates were considered for the analysis of species distribution overtime, and all episodes were analyzed for the impact of antifungal prescription (prior exposure or therapeutic), but only incident episodes were considered for the rest of the analysis to avoid autocorrelation.

Initial (first 48 h) prescription of antifungal treatment and outcome within 30 days after sampling were recorded with the notion of antifungal prior exposure, whatever the drug, dosage and duration, within 30 days before fungemia. Mortality regarding first-line therapy was analyzed for patients with available outcome and only if the positivity of blood culture was known before death. Initial prescription was divided in four groups: fluconazole alone, echinocandin alone (aggregating caspofungin and micafungin), other antifungal treatments (liposomal amphotericin B, voriconazole, posaconazole, itraconazole and drug combinations), and no treatment, providing that the patient was still alive at the time of fungemia diagnosis and that treatment were prescribed for at least 48 h before death eventually occurred.

Isolates with decreased susceptibility to fluconazole were those intrinsically resistant (Candida krusei) or those tested with fluconazole minimum inhibitory concentration (MIC) >32 mg/L according to EUCAST Antifungal Agents Breakpoint tables for interpretation of MICs (https://www.eucast.org/fileadmin/ src/media/PDFs/EUCAST_files/AFST/Clinical_breakpoints/ Antifungal_breakpoints_v_9.0_180212.pdf), while those with decreased susceptibility to caspofungin were those intrinsically resistant (basidiomycetes and Geotrichum spp.) or those tested with a caspofungin MIC >0.25 mg/L [START_REF] Desnos-Ollivier | Mutations in the fks1 gene in Candida albicans, C. tropicalis, and C. krusei correlate with elevated caspofungin MICs uncovered in AM3 medium using the method of the European Committee on Antibiotic Susceptibility Testing[END_REF].

Incidence rates of the 14 participant hospitals were calculated per 1,000 admissions and 10,000 hospitalization days using annual hospital activity data for the years 2010-2017, because of a change in 2009 preventing use of the earlier years (Statistique annuelle des établissements de Santé, French Ministry of Health: https://www.sae-diffusion.sante.gouv.fr/saediffusion/recherche.htm). Univariate analysis was based on Chi2 or Fisher's exact-test for discrete variables. Chi2-test for trends was used to determine trends over time. Survivals were determined by Kaplan-Meier analysis and compared by the log rank-test. Data were analyzed using Stata R Software (version 15.0; College Station, TX).

Ethics

The research described herein was carried out in compliance with the French law and the Declaration of Helsinki (as adopted in 2000), and was approved by the Institut Pasteur institutional review board (IRB #2009-34) and the "Commission Nationale de l'Informatique et des Libertés" according to French regulation.

RESULTS

Global Epidemiology

Over the 14 years of the survey, 3,257 episodes of yeast fungemia were recorded including 165 recurrences [median onset (IQR) = 23 [67] days after incident episode], and 97 episodes with more than one species. Oncology patients experienced less recurrent episodes of fungemia (37/1,025, 3.6%) than did hematology patients (39/657, 5.9%) or patients with no malignancy (89/1,575, 5.5%) (p = 0.036). Overall, 3,092 patients were concerned including 136 children < 15-year-old. The male: female ratio was 1.6 (not different in adults and children < 15-year-old) and did not change over time (p = 0.7966). The median age was 61.0 years (IQR: 23.8) with a significant increase over time. While the proportion of children remained stable (4.4%), that of patients over 60-year of age increased from 48.7% (91/187) in 2004 to 56.8% (133/234) in 2017 (p = 0.0002) and that of patients over 80-year of age increased from 9.1% (17/187) in 2004 to 15.4% (36/234) in 2017 (p = 0.039).

The population was composed of patients with malignancy (n = 1,606, i.e., 51.9%) including 618 (20.0%) Hematology patients, 988 (31.9%) Oncology patients, and 1,486 (48.1%) Nomalignancy patients (Table 1). No significant variation in the proportion of the three different groups was observed over time (data not shown). Almost half of the patients (1,444/3,092; 46.7%) were in ICU when fungemia was diagnosed. In ICU, most of the patients had no malignancy (950/1,444; 65.8%) while Oncology patients represented the first group outside ICU (690/1,648; 41.9%). In the Hematology group only the proportion of stay in ICU significantly increased over time when considering incident episodes of yeast fungemia (from 24.5 to 34.0%, p = 0.0002) or all episodes (not shown). Central venous catheters were reported in the majority of episodes (2,324/3,257; 71.4%), more often in ICU (1,161/1,526; 76.1%) than outside ICU (1,163/1,731; 67.2%; p < 0.0001), and more often in the Hematology (561/657 85.4%) and Oncology (788/1,025; 76.9%) than in the No-malignancy (975/1,575; 61.9%) groups (p < 0.0001) with no significant change over time. Considering the 14 centers, the incidence rate/1,000 admissions increased from 0.63 to 0.77 (2010-2017). The incidence rate/10,000 hospitalization day increased from 1.12 to 1.26 (2010-2017). In the same period, the number of beds decreased by 5.6% (from 7,033 to 6,638).

Trends in Mortality

The outcome was available for 2,868 patients and 1,103 (38.5%) died within 30 days of diagnosis of candidemia. Of note, 326 of them (30.7%) died before diagnosis was made. The global mortality was significantly higher in ICU (690/1,358, 50.8%) than outside (413/1,510, 27.4%, p < 0.0001), but it did not change significantly over the study period (69/180; 38.3% in 2004 to 86/207; 41.6% in 2017, p = 0.221). There was no trend whatever the environment considered (ICU or no ICU) and the population studied (Hematology, Oncology or No-malignancy) (Figure 1A).

Trends in Species Recovered and MICs

A total of 3,363 isolates were recovered with five major species [Candida albicans (n = 1,614, 48.0%), Candida glabrata (n = 607, 18.1%), Candida parapsilosis (n = 390, 11.6%), Candida tropicalis (n = 299, 8.9%), C. krusei (n = 96, 2.9%)], and rare species defined as accounting for <2% each (n = 357, 10.6%) listed in Supplementary Table 1. Globally, there was no significant evolution in this distribution over time (Figure 2). The distribution of species varied according to the underlying risk factor with more non-albicans species in hematology compared to other groups species (p < 0.0001) but the distribution did not differ significantly in ICU compared to outside ICU (Supplementary Figure 1). The distribution of species differed significantly between incident (n = 3,092) and recurrent episodes (n = 165) with less C. albicans, more C. parapsilosis, and C. krusei, and more of rare and mixed species during recurrent episodes (Supplementary Figure 2). The same species in recurrent episode was observed in only 14 cases (8.5%) and increased echinocandin MIC was observed in only two C. glabrata isolates (associated with mutation in the FKS gene for 1 patient), increased caspofungin MIC in one Clavispora lusitaniae (associated with mutation in FKS gene) and increased fluconazole MIC in two C. lusitaniae isolates.

There was no significant change in the proportion of isolates with fluconazole MIC >32 mg/L or caspofungin MIC >0.25 mg/L (Supplementary Figures 3A,B). Among the 2,661 isolates of common species with natural susceptibility to candins, only 18 isolates (0.68%) had acquired resistance (3 C. albicans, 12 C. glabrata, 2 C. krusei, and 1 C. tropicalis) and they were evenly distributed over time (not shown).

Trends in Drug Prescription

Drug prescription after blood sampling was analyzed for 2,677 episodes. There was a significant decreased in fluconazole prescription and that of other treatments, and a significant increase in echinocandin prescription over time (p < 0.0001, Figure 3), while the proportion of patients receiving no treatment was stable. This was observed both in ICU and outside ICU, and in the three groups studied (Figure 1B). The time to switch from fluconazole to echinocandins differed according to the environment. Outside ICU, it occurred as soon as 2006 in Hematology, 2014 in Oncology, and 2011 in Nomalignancy, and for the three groups around 2009-2010 in ICU (Figure 1B). Echinocandins were massively represented by caspofungin since only 39 patients were prescribed micafungin and 10 anidulafungin over the period studied.

The effect of initial antifungal drug prescription was assessed on survival after incident episodes of fungemia due to the 5 major Candida species or to rare or mixed species. Overall, being infected by C. krusei was significantly associated with mortality compared with any other species, and C. parapsilosis had the best prognosis (log rank-test p < 0.0001, Figure 4). In all cases, the lack of antifungal treatment was significantly associated with mortality except for C. parapsilosis fungemia (p < 0.001) (not assessable for C. krusei for lack of non-treated cases) (Supplementary Figures 4,5D). For all species, including rare and mixed species but excluding C. tropicalis, the choice of the first-line drug had no significant impact on survival (Supplementary Figure 4). For C. tropicalis, survival following "other treatment" was improved only when compared to echinocandin alone. Overall, fluconazole alone was associated with similar survival whatever the infecting species (Supplementary Figure 5A, not assessable for C. krusei for lack of prescription), whereas survival associated with echinocandin alone (Supplementary Figure 5B) or other prescriptions (Supplementary Figure 5C) differed according 3C,D) except for echinocandins [increase from 1.2% (2/190) in 2004 to 13.5% (23/248) in 2017, p = 0.0008], in relation with an increase before incident episode of fungemia (p = 0.0071) in ICU (p = 0.0001) for patients with no malignancies [from 0 (0/55) to 10.3% (8/78), p = 0.0014]. There was no difference in the mortality rate when comparing patients according to prior exposure to antifungal drugs and those without (data not shown).

DISCUSSION

This present surveillance program within 14 university hospitals shows over the last 14 years (i) a steady mortality rate around 38.2% (51.0% in ICU) for the whole population of patients at day 30 with no improvement over time (ii) a progressive replacement of fluconazole in favor of echinocandins as first-line treatment, and (iii) a stable Candida species distribution with no dramatic increase in antifungal resistance.

The global mortality reported here in the YEASTS program is in the same order as recently reported in a meta-analysis of European studies, between 37 and 38% [START_REF] Koehler | Morbidity and mortality of candidemia in Europe: an epidemiologic meta-analysis[END_REF]. The present sustained mortality rate over time cannot be ascribed to an increase in a specific underlying disease since the figures were unchanged between hematology, oncology or no-malignancy. This could not either be ascribed to a modification in the microbial ecosystem since the species distribution remained globally unchanged and resistance either to fluconazole or echinocandins remained low, and even globally decreased for fluconazole. In contrast, the increasing age of the population (from 48.7% over 60-year of age in 2004 to 56.8% in 2017) plays certainly a role in the sustained high mortality rate (18). In the same way, the proportion of hematology patients in ICU significantly increased, suggesting that fungemia was associated with more severe conditions over time. We also show the constant increase in the mean incidence rate/1,000 admissions from 0.63 to 0.77 (2010-2017) and the incidence rate/10,000 bed days (patient days) from 1.12 to 1.26 (2010-2017) in the 14 hospitals of the survey. These figures are in the same range as those reported in a recent meta-analysis, between 0.96/1,000 admissions in tertiary care centers and 0.52/1,000 in a mixed group of teaching and general hospitals [START_REF] Koehler | Morbidity and mortality of candidemia in Europe: an epidemiologic meta-analysis[END_REF]. The increase from 0.63 to 0.77 per 1,000 admissions can be due in part to the increase in incident cases but the parallel decrease by 5.6% of hospital beds could have mitigated this explanation. Patients with more severe conditions and thus more prone to fungal infections could have been more often hospitalized. If this hypothesis were true, this might have hampered the improvement of fungemia prognosis expected with the new treatments and recommendations. Unexpectedly, we also found that the prescription of echinocandin was associated with a poorer outcome compared to fluconazole (p = 0.041) and this could reflect the clinicians' preference for echinocandins when the patient condition is worsening. Since we could not collect severity markers in the different populations, we cannot assess this hypothesis.

The other major point is the progressive replacement of fluconazole by echinocandins as first line therapy for fungemia. The length of our study allowed covering the launch of caspofungin and micafungin in France and its increasing use over time following the different guidelines [START_REF] Cornely | ESCMID * guideline for the diagnosis and management of Candida diseases 2012: non-neutropenic adult patients[END_REF][START_REF] Pappas | Executive summary: clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America[END_REF][START_REF] Tissot | ECIL-6 guidelines for the treatment of invasive candidiasis, aspergillosis and mucormycosis in leukemia and hematopoietic stem cell transplant patients[END_REF][START_REF] Ullmann | ESCMID * guideline for the diagnosis and management of Candida diseases 2012: adults with hematological malignancies and after haematopoietic stem cell transplantation (HCT)[END_REF] mortality [OR: 0.65 (95% CI, 0.45-0.94); P = 0.02] (11). However, observational studies in France [START_REF] Bailly | Impact of echinocandin on prognosis of proven invasive candidiasis in ICU: a post-hoc causal inference model using the AmarCAND2 study[END_REF][START_REF] Bienvenu | Evaluation of first-line therapies for the treatment of candidemia in ICU patients: a propensity score analysis[END_REF], Brasil [START_REF] Lana | Candidemia mortality has not changed over the last 2 decades in Brazil[END_REF], or Spain [START_REF] López-Cortés | Empirical and targeted therapy of candidemia with fluconazole versus echinocandins: a propensity score-derived analysis of a population-based, multicentre prospective cohort[END_REF] have not shown that fluconazole was associated with an excess of mortality. Our observation confirms that the replacement of fluconazole by echinocandin as first line therapy was not associated with the expected improvement of yeast fungemia prognosis. Indeed, as mentioned above, the prescription of echinocandin was associated with a poorer outcome compared to fluconazole (p = 0.041). However, this statement warrants to be nuanced since multivariate analysis showed that a diagnosis before 2010 was associated with a poorer prognosis. This could suggest a positive impact of the switch fluconazole/echinocandin after this date, although this improvement over time could also be due to a better global management of fungemia after 2010 or a better prognosis of the underlying disease.

The positive observation made possible by the centralization of isolates and their characterization is the unchanged ecology of major fungal species despite changes in drug prescriptions although we confirmed the different fungal species distribution according to the underlying disease with less C. albicans in hematology than in solid cancers and in no-malignancy [START_REF] Lortholary | The risk and clinical outcome of candidemia depending on underlying malignancy[END_REF][START_REF] Puig-Asensio | Epidemiology and predictive factors for early and late mortality in Candida bloodstream infections: a populationbased surveillance in Spain[END_REF]. Thus, we did not observe the emergence of rare species nor did we see the emergence of isolates/species with decreased susceptibility to antifungal drugs, as reported with the SENTRY antifungal Surveillance program [START_REF] Pfaller | Twenty years of the SENTRY antifungal surveillance program: results for Candida species from 1997-2016[END_REF]. In particular, the increase of echinocandin resistance and multidrug resistant candida reported elsewhere was not observed [START_REF] Alexander | Increasing echinocandin resistance in Candida glabrata: clinical failure correlates with presence of FKS mutations and elevated minimum inhibitory concentrations[END_REF][START_REF] Astvad | Update from a twelve-year nationwide fungemia surveillance: increasing intrinsic and acquired resistance causes concern[END_REF][START_REF] Cleveland | Changes in incidence and antifungal drug resistance in candidemia: results from population-based laboratory surveillance in Atlanta and Baltimore, 2008-2011[END_REF]. More specifically, we did not observe an increase in multidrug resistant C. glabrata isolates over 14 years in contrast with other reports [START_REF] Chapman | Changing epidemiology of candidemia in Australia[END_REF][START_REF] Farmakiotis | Drug-resistant Candida glabrata infection in cancer patients[END_REF], nor an increase in fluconazole resistance in C. parapsilosis [START_REF] Israel | The epidemiology and susceptibility of Candidemia in Jerusalem, Israel[END_REF]. Therefore, if we did observe an overall increase in prior exposure of caspofungin from 1.2% in 2004 to 13.5% in 2017, we did not observe an increase in antifungal MICs or acquired resistance to antifungal drugs in breakthrough fungemia, at least until 2017. Instead, we observed a change in the species distribution between breakthrough fungemia and the other fungemia as already reported [START_REF] Lortholary | Recent exposure to caspofungin or fluconazole influences the epidemiology of candidemia: a prospective multicenter study involving 2,441 patients[END_REF].

Improving the prognosis of fungemia, still associated with a mortality rate of 38.5% at day 30 in the present study, remains therefore challenging and cannot rely only on the adherence to starting treatment with an echinocandin according to our observation. In reporting a decreased incidence of candidemia, Cleveland et al. argue that the better trends were ascribed to (i) better management of catheters, (ii) use of antifungal prophylaxis, and (iii) improvements in infection control such as hand hygiene [START_REF] Cleveland | Changes in incidence and antifungal drug resistance in candidemia: results from population-based laboratory surveillance in Atlanta and Baltimore, 2008-2011[END_REF]. Central venous catheters are present in candidemia in the vast majority of cases (here 71.4%) and there is a strong incitation to remove them when feasible [START_REF] Kullberg | Invasive candidiasis[END_REF][START_REF] Cornely | ESCMID * guideline for the diagnosis and management of Candida diseases 2012: non-neutropenic adult patients[END_REF][START_REF] Pappas | Executive summary: clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America[END_REF][START_REF] Tissot | ECIL-6 guidelines for the treatment of invasive candidiasis, aspergillosis and mucormycosis in leukemia and hematopoietic stem cell transplant patients[END_REF]), although no randomized clinical trial supports these practices [START_REF] Janum | Central venous catheter (CVC) removal for patients of all ages with candidemia[END_REF]. Regarding antifungal drug prophylaxis, its wider use reported by Cleveland et al. was followed by an increase in echinocandin-resistant and multidrug resistant Candida [START_REF] Cleveland | Declining incidence of candidemia and the shifting epidemiology of Candida resistance in two US metropolitan areas, 2008-2013: results from population-based surveillance[END_REF]. Prophylaxis was probably not very common in our cohort, except for the hematological patients for whom prophylaxis targets mold infections. Thus, the number of patients with prior exposure was limited (10.7% of incident episodes and 59.8% of recurrent episodes). Therefore, it is possible that we did not observe emergence of resistance simply because, even if increasing, echinocandin prescription has not reached the level it has in the USA, especially as prophylaxis [START_REF] Arastehfar | The quiet and underappreciated rise of drug-resistant invasive fungal pathogens[END_REF]. However, prophylaxis is clearly not advocated in ICU by some authors [START_REF] Bassetti | Intensive care medicine research agenda on invasive fungal infection in critically ill patients[END_REF], and even empirical treatment initiated for suspected fungal infection does not modify the fungal infection-free survival at day 28, at least in non-neutropenic critically ill patients with ICU-acquired sepsis [START_REF] Timsit | Empirical micafungin treatment and survival without invasive fungal infection in adults with ICU-acquired sepsis, Candida colonization, and multiple organ failure: the EMPIRICUS randomized clinical trial[END_REF]. Finally, global hygiene control might decrease the incidence and spread of resistant Candida isolates as recently underlined with Candida auris outbreak control [START_REF] Eyre | A Candida auris outbreak and its control in an intensive care setting[END_REF]. Diagnosis tools could also be improved. Fungal DNA amplification has not shown decisive results [START_REF] Cambau | Performance and economic evaluation of the molecular detection of pathogens for patients with severe infections: the EVAMICA open-label, cluster-randomized, interventional crossover trial[END_REF], whereas T2 magnetic resonance shows promising results [START_REF] Clancy | Detecting infections rapidly and easily for candidemia trial, part 2 (DIRECT2): a prospective, multicenter study of the T2Candida panel[END_REF]. The means of improvement could also be different according to the underlying settings, ICU vs. non-ICU, as recently proposed [START_REF] Poissy | Risk factors for candidemia: a prospective matched case-control study[END_REF].

Our surveillance program suffers from several limitations common to observational studies. Beside the limited geographic coverage, we did not record the number of positive blood cultures, the timing of central venous catheter removal, or potential concomitant mold infections or organ failure which can interfere with the choice of an antifungal drug. Moreover, only the first antifungal prescribed was considered whereas one knows that several lines are often prescribed because of unsatisfactory evolution, side effects, therapeutic interactions, or subsequent results on species identification. All the above parameters could have impacted the prognosis. In some instances, clinicians may also have decided to maintain only palliative cares, which is evidenced here by the poor prognosis of patients not receiving antifungal drugs. As a consequence, the cause of death could not be assessed. However, the lack of difference in survival of fungemia due to specific species whatever the drug prescribed is consistent with the absence of differential effect of the drugs. This is a strong argument for the pre-eminent role of the underlying conditions on survival. This is shown by multivariate analysis on the independent parameters involved for hematology patients when the species is not anymore a parameter influencing death, nor is the initial antifungal drug choice as long as a treatment is prescribed [START_REF] Lortholary | The risk and clinical outcome of candidemia depending on underlying malignancy[END_REF]. Another independent study on the antifungal therapy according to susceptibility breakpoints on Candida spp. concluded that appropriate antifungal treatment was not associated with a better survival [START_REF] González-Lara | Impact of inappropriate antifungal therapy according to current susceptibility breakpoints on Candida bloodstream infection mortality, a retrospective analysis[END_REF].

In conclusion, our data show that mortality associated with fungemia-related bloodstream infection has not improved over the last decade. The continuous increase in echinocandin prescription has not been accompanied by an improvement in the mortality rate whatever the underlying disease. The steady mortality rate would be a sign that fungemia occurred in sicker patients rather than a poor efficacy of the current treatments. Although this observation is not per se a proof of the no better efficacy of echinocandin over fluconazole, the global care strategy for fungemia seems non-optimal at least in our setting. Therefore, even if new antifungals are urgently needed [START_REF] Mccarthy | Future research priorities in fungal resistance[END_REF], other trails should be explored such as improvement in catheter management [START_REF] Cleveland | Changes in incidence and antifungal drug resistance in candidemia: results from population-based laboratory surveillance in Atlanta and Baltimore, 2008-2011[END_REF], analysis of immune response or inherited patient-specific factors [START_REF] Pappas | Invasive candidiasis[END_REF], and better diagnostic tools [START_REF] Clancy | Detecting infections rapidly and easily for candidemia trial, part 2 (DIRECT2): a prospective, multicenter study of the T2Candida panel[END_REF].

DATA AVAILABILITY STATEMENT

The original contributions generated in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.

YEASTS PROGRAM OF THE FRENCH MYCOSES STUDY GROUP

No

  Impact of Fluconazole to Echinocandins Replacement as First-Line Therapy on the Epidemiology of Yeast Fungemia (Hospital-Driven Active Surveillance, 2004-2017, Paris, France) Stéphane Bretagne, Marie Desnos-Ollivier, Karine Sitbon, Olivier Lortholary, Didier Che, Françoise Dromer To cite this version: Stéphane Bretagne, Marie Desnos-Ollivier, Karine Sitbon, Olivier Lortholary, Didier Che, et al.. No Impact of Fluconazole to Echinocandins Replacement as First-Line Therapy on the Epidemiology of Yeast Fungemia (Hospital-Driven Active Surveillance, 2004-2017, Paris, France). Frontiers in Medicine, 2021, 8, pp.641965. 10.3389/fmed.2021.641965. pasteur-03208488

FIGURE 1 |

 1 FIGURE 1 | Evolution of global mortality and first-line antifungal drug prescription in patients with hematological malignancy, oncology or no malignancy, inside or outside intensive care unit (ICU) (YEASTS program, Paris area, 2004-2017). (A) Global mortality did not change significantly over time inside (solid black line) and outside (dotted black line) ICU in the various categories of patients. (B) The evolution of fluconazole (solid blue line) and echinocandins (dotted blue line) prescription significantly (p < 0.001) differed inside and outside ICU in the three populations of patients. The switch from fluconazole to echinocandins as first-line therapy did not occur at the same date in the six populations studied.

  . The switch fluconazole/echinocandin was almost complete in 2016 although with different timings according to the underlying disease and the ICU context, sooner in hematology and later in oncology outside ICU. This switch is mainly supported by the observed benefit of echinocandin use over azole treatment in the analysis of seven clinical trials by Andes et al. who observed a decreased

FIGURE 2 |

 2 FIGURE 2 | Stable global distribution of species responsible for fungemia during the YEASTS program (Paris area, 2004-2017). Figures in the histograms indicate the number of fungemia due to the five more frequent species, the last category regrouping fungemia due to rare species (<2% of isolates) or to mixed species. A total of 3,363 isolates was recovered during 3,257 episodes in 3,092 patients. The black line represents the evolution of the number of episodes over time (linear regression, R² = 0.5101).

FIGURE 3 |FIGURE 4 |

 34 FIGURE 3 | Evolution of first-line antifungal drug prescription for treatment of yeast fungemia (YEAST program, Paris area, 2004-2017). First-line treatment was analyzed for the 2,677 episodes for which time to potential death exceeded 48 h. Figures represent the number of episodes treated each year by fluconazole alone, echinocandin alone, other treatments (liposomal amphotericin B, voriconazole, posaconazole, itraconazole, or drug combination), or not treated.

TABLE 1 |

 1 Characteristics of the 3,092 patients who experienced a first episode of yeast fungemia (Paris,YEASTS program, 2004YEASTS program, -2017)).

	Total (n= 3,092)	ICU (n = 1,444)	No ICU (n = 1,648)	p

*Including other foreign devices.

to the species involved. Compared to C. albicans, survival was significantly better for C. glabrata and C. parapsilosis fungemia (p = 0.0098) following echinocandin treatment (Supplementary Figure

5B

), and for fungemia due to C. parapsilosis and rare/mixed species following other treatments (Supplementary Figure

5C

, p = 0.0361). In the multivariate analysis (

Table 2

 2

	), the parameters independently associated with
	increased death at day 30 were a stay in ICU, an age over
	70 years, malignancy as underlying disease (hematology or
	solid tumor), a diagnosis before 2010, and the absence of
	antifungal treatment in the first 48 h or, to a lesser extent,
	the prescription of echinocandin (prescription of fluconazole as
	reference), whereas an infection by C. glabrata or C. parapsilosis
	were protective.
	Prior exposure to antifungal drugs (fluconazole or
	echinocandins) was reported in 331/3,092 (10.7%) of
	incident episodes and 97/165 (59.8%) of recurrent
	episodes (p < 0.001) with no significant change over time
	(Supplementary Figures

TABLE 2 |

 2 Independent parameters associated with outcome at 30 days in 2,868 patients diagnosed with incident yeast fungemia, univariate, and multivariate analysis (YEASTS program, Paris area, 2004-2017).

			Univariate analysis		Multivariate analysis
		Death (n = 1,103)	Survival (n = 1,765)	p	OR [95% CI]	p
	Male sex	60.9% (672)	60.6% (1,070)	0.872
	Age over 70 years	37.2 (410)	23.5% (415)	<0.0001	1.72 [1.41-2.10]	<0.0001
	Diagnosis before 2010	43.0% (474)	39.3 (694)	0.053	1.37 [1.13-1.67]	0.001
	Stay in intensive care unit	62.6% (690)	37.9% (668)	<0.0001	2.88 [2.36-3.50]	<0.0001
	Main underlying condition			0.078
	Haematology	19.1% (311)	22.2% (391)		1.47 [1.40-1.89]	<0.0001
	Oncology	31.1% (343)	31.8% (562)		1.60 [1.28-1.99]	0.011
	No malignancy	49.8% (549)	46.1% (812)		1
	Species involved			<0.0001
	C. albicans	51.0% (563)	47.1 (832)		1
	C. glabrata	17.0% (188)	16.9% (298)		0.71 [0.54-0.92]	0.011
	C. parapsilosis	6.8% (75)	13.9% (245)		0.54 [0.39-0.75]	<0.0001
	C. tropicalis	8.4% (93)	8.6% (151)		0.88 [0.63-1.23]	0.455
	C. krusei	3.8% (42)	2.0% (35)		1.36 [0.77-2.39]	0.291
	Rare and mixed species	12.9% (142)	11.6% (204)		1.48 [0.86-1.53]	0.346
	First-line antifungal treatment			<0.0001
	Fluconazole alone	33.1% (257/776)	40.7% (711/1,749)		1
	Echinocandin alone	40.6% (315/776)	43.2% (755/1,749)		1.26 [1.01-1.58]	0.041
	Other drug or combination	11.7% (91/776)	13.6% (237/1,749)		1.06 [0.78-1.45]	0.689
	No treatment	14.6% (113/776)	2.6% (46/1,749)		7.85 [5.31-11.60]	<0.0001

  The following investigators participated in the YEASTS program of the French Mycosis Study Group (by alphabetical order of the hospital name):Nawel Ait-Ammar, Anne-Laure Roux, Jean Dunand (hôpital Ambroise Paré, Boulogne); Claire Bouges-Michel, Sophie Brun (hôpital Avicenne, Bobigny); Christian Chochillon, Christine Bonnal (hôpital Bichat, Paris), Françoise Botterel, Adela Angoulvant, Christine Bonnal (hôpital du Kremlin Bicêtre, Kremlin-Bicêtre); André Paugam, Naima Dahane (hôpital Cochin, Paris); Stéphane Bretagne, Françoise Botterel, Nawel Ait-Ammar (hôpital Henri Mondor, Créteil); Elisabeth Chachaty (Institut Gustave Roussy, Villejuif); Isabelle Poilane (hôpital Jean Verdier, Bondy); Claire Lacroix, Stéphane Bretagne, Samia Hamane, Alexandre Alanio (hôpital Lariboisière, Paris); Liliana Mihahila, Najiby Kassis-Chikhany, Adela Angoulvant (hôpital Paul Brousse, Villejuif); Patricia Mariani (hôpital Robert Debré, Paris); Christine Lawrence, Anne-Laure Roux (hôpital Raymond Poincaré, Garches); Claire Lacroix, Alexandre Alanio, Stéphane Bretagne, Blandine Denis, Samia

Frontiers in Medicine | www.frontiersin.org

April 2021 | Volume 8 | Article 641965

ACKNOWLEDGMENTS

Part of this work has been presented at 8th Trends in Medical Mycology, October 6-9, 2017, Belgrade, Serbia (oral presentation S08.6). We are indebted to Dea Garcia-Hermoso, Damien Hoinard, Dorothée Raoux-Barbot, and Anne Boullié for technical analysis of the isolates at the National Reference Center for Invasive Mycoses and Antifungals.

FUNDING

The YEASTS program was supported in part by Santé publique France and Institut Pasteur. The funders had no role in study design, data collection, analysis, or interpretation of data.

AUTHOR CONTRIBUTIONS

SB and FD designed the study. KS, MD-O, and the French Mycoses Study Group provided data. SB, MD-O, KS, OL, and FD analyzed the data. SB and FD drafted the first manuscript. SB, MD-O, OL, and FD revised the manuscript. DC analyzed data and revised manuscript. All authors validated the final version of the manuscript.

SUPPLEMENTARY MATERIAL

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fmed.

2021.641965/full#supplementary-material

Supplementary Figure 1 | Uneven distribution of species according to the underlying risk factors and the hospitalization in or outside intensive care unit (ICU) during the YEASTS program (Paris area, 2004-2017, p < 0.0001). Figures indicate the number of fungemia due to the five more frequent species, the last category regrouping fungemia due to rare species (<2% of isolates) or to mixed species. A total of 3,363 isolates was recovered during 3,257 episodes in 3,092 patients. Supplementary Figure 4 | Kaplan-Meier curves illustrating survival rate after incident candidemia according to the first line antifungal drug prescription in case of single infection due to the five major species or to rare or mixed species (YEASTS program, Paris area, 2004-2017). The total number of patients concerned is provided. Fluconazole (solid blue line), echinocandins (solid thick black line), other drugs or combinations (dash gray line), no treatment (solid thin black line). For C. krusei, the small number of patients treated with fluconazole (n = 2) and not treated (n = 3) prevented their inclusion in the analysis. P-value provided after logrank-test.

Supplementary Figure 5 | Kaplan-Meier curves illustrating survival rate according to first-line antifungal treatment on survival after incident episode of fungemia due to 5 major species of Candida or to rare/mixed species (logrank test). Fluconazole (A, 966 patients), candins (B, 1,070 patients), other drugs or combinations (C, 328 patients), or no antifungal drug (D, 159 patients). Candida albicans (solid blue line), C. glabrata (dash line blue), C. parapsilosis (dash gray line), C. tropicalis (solid gray line), C. krusei (short dash blue line), and rare or mixed species (thin solid black line). The small number of patients infected by C. krusei and treated with fluconazole (n = 2) and not treated (n = 3) prevented their inclusion in the analysis.

Supplementary Table 1 | Number of isolates corresponding to the rare species accounting for <2% of the 3,363 isolates recovered during the YEASTS program (Paris area, 2004(Paris area, -2017)).

Conflict of Interest: SB has received travel grant from Pfizer in 2018 and has served on scientific advisory board for Gilead until 2018.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Bretagne, Desnos-Ollivier, Sitbon, Lortholary, Che, Dromer and Participants of the YEASTS. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.