First case of Candida auris in Switzerland : discussion about preventive strategies

a Service of Laboratory Medicine, Geneva University Hospitals and Faculty of Medicine, Switzerland b Service of Infectious Diseases, Geneva University Hospitals and Faculty of Medicine, Switzerland c Institute of Microbiology, Lausanne University Hospital, Switzerland d Infection Control Programme, Geneva University Hospitals and Faculty of Medicine, Switzerland e Service of Hospital Preventive Medicine, Lausanne University Hospital, Switzerland f Intensive Care Unit, Geneva University Hospitals and Faculty of Medicine, Switzerland g Infectious Diseases Service, Department of Medicine, Lausanne University Hospital, Switzerland


Introduction
Candida spp.are a major cause of bloodstream infections associated with high mortality.The epidemiology of Candida infections is evolving, with a progressive shift from Candida albicans to non-albicans Candida spp.characterised by decreased susceptibility to azoles [1].Most concerning is Candida auris, a previously unrecognised Candida species, which emerged as a novel cause of candidaemia and invasive candidiasis in 2009 [2,3].This new fungal pathogen is a serious public health problem because of its potential for nosocomial transmission and its ability to develop resistance to all antifungal drug classes [2,4].Outbreaks of strains with different clonal origins have been reported from all continents [2,4].C. auris has become the fifth most common cause of candidaemia in India and multiple cases have been reported in Pakistan, South Korea, Israel, Kuwait, South Africa, Kenya, United States, Colombia and Venezuela [4,5].In Europe, major outbreaks have occurred in London (UK) and Valencia (Spain) [6,7].However, C. auris has rarely been reported in other European countries, where it has been isolated only from travellers from endemic regions [4].This epidemiological situation raises important concerns about strategies that should be implemented to prevent the importation and spread of C. auris in countries that are currently spared.We present here an update of the situation in Switzerland and our recommended approach in terms of preventive strategies.

Candida auris in Switzerland
In Switzerland, the first case of C. auris was documented in Geneva in October 2017.A 74-year-old female who was on vacation in north-eastern Spain was admitted to a local hospital with severe community-acquired pneumonia requiring mechanical ventilation.C. auris was isolated from tracheal aspirates and the patient was treated with meropenem and fluconazole.At day 18 of the hospital stay, she was transferred to Geneva with acute respiratory distress syndrome.Screening at various sites (tracheal aspirates, groin, auditory canal, urine) was positive for C. auris, whereas multiple sets of blood cultures were negative for yeasts.After initial improvement and antibiotic discontinuation, the patient developed septic shock of unknown origin and ultimately died.C. auris was considered as a coloniser and was probably not the cause of this fatal outcome.C. auris was identified with MALDI-TOF, with subsequent confirmation by sequencing of the internal transcribed spacer (ITS) region.Antifungal susceptibility testing with Sensititre YeastOne™ (Trek Diagnostics Systems) showed minimum inhibitory concentrations (MICs) of 256, 4, 1, 0.06, 0.12, 0.06 µg/ml for fluconazole, voriconazole, amphotericin B, caspofungin, anidulafungin and micafungin, respectively.The patient was placed on contact precautions, and her room was cleaned with a chlorine-based solution and an active oxygen-based surface disinfectant after discharge.Multiple environmental samples obtained from the room after cleaning were all negative for C. auris.We retrospectively analysed the national cohort of candidaemia of the Fungal Infection Network of Switzerland (FUNGINOS) comprising 2102 Candida bloodstream isolates collected from 25 Swiss hospitals between 2004 and 2013.C. auris was not recovered during this period.All isolates belonging to species closely related to C. auris, which may have been potentially misidentified (four Candida famata, two unspecified Candida spp.and five Saccharomyces cerevisiae), were retrospectively tested by mass spectrometry (matrix-assisted laser desorption ionisation-time of flight, MALDI-TOF) for confirmation.cannot distinguish it from other Candida of the haemulonii complex, C. famata, C. lusitaniae and C. sake.API-20C AUX (BioMérieux) misidentified it as Rhodotorula glutinis [8,9].It can be correctly identified by sequencing the D1-D2 region of the 28S rDNA or by a qPCR targeting a specific rDNA region of C. auris [10,11].Accurate and fast identification is also achieved with MALDI-TOF, either the Biotyper (Bruker) or Vitek-MS (BioMérieux) systems, but only the "research use only" (RUO) libraries contain C. auris spectra (the FDA-approved IVD version does not) [8].Some difficulties in obtaining a high score with direct deposit of C. auris on the MALDI plate when using the Biotyper have been reported [9].Complete extraction following the manufacturer's instructions is needed, and several deposits are recommended to obtain better results.Additionally, the use of a homemade database containing more spectra of C. auris significantly improves the identification results [12].

Recommendations for infection control and prevention
The potential of C. auris for inter-human transmission and nosocomial outbreaks is unusual for a fungus, and may be partly explained by its ability to form biofilms and survive on dry or moist surfaces [4].High rates of candidaemia, persistent patient colonisation and persistence in the environment despite adequate infection control measures were the hallmarks of the C. auris outbreaks in the UK and Spain [6,7].Therefore, effective infection control strategies are crucial to prevent the emergence and spread of this pathogen, especially in intensive care units.The decision to establish a systematic C. auris screening policy should be assessed by each hospital on the basis of the local epidemiology.A listing of preventive measures that can be recommended in a country of very low prevalence, such Switzerland, is presented in table 1.We currently suggest targeted screening of patients with (1) documented C. auris infection or colonisation in the past, (2) previous contact with a known C. auris case, or (3) a recent stay in a hospital where C. auris is endemic.Importantly, each institution should prepare to deal with an emerging C. auris outbreak by establishing protocols for screening and disinfection procedures that can be applied as soon as a case of C. auris infection or colonisation is detected.Screening should involve swabbing axilla and groin, which have been associated with the highest yield of detection [13], with the optional addition of other sites (e.g., nose and/or clinically relevant sites).Cultures can be performed directly on commercial chromogenic Candida agar plates, where C. auris produce colonies that usually appear white to rose or light purple (depending on the culture medium) after 48 hours of incubation at 37°C (fig.1).In countries with a high prevalence or in the setting of nosocomial outbreaks, pre-culture at 40°C in selective Sabouraud broths with a high-salt content and dulcitol or mannitol as carbon source in accordance with the Centers for Disease Control and Prevention protocol is recommended [14].Patients with C. auris should be isolated in a single-patient room with contact precautions.Strict adherence to hand hygiene is required.Equipment used for the infected/ colonised patient should not be shared with other patients.Quaternary ammonium is not active against C. auris.Therefore, for surface cleaning, chlorine-based or active oxygen-based products with sporicidal activity (similar to those used against Clostridium difficile) should be used [15].Decontamination of the room and medical equipment with hydrogen peroxide vapour after discharge of the patient has been performed during outbreaks [7].

Recommendations for clinical management of C. auris colonisation and infection
Treating C. auris colonisation with systemic antifungal agents is not recommended.Persistent skin colonisation is common and there are no well-established decolonisation protocols.Daily chlorhexidine washes are recommended, but their efficacy has not been demonstrated [7,13].For documented or suspected cases of C. auris infection, echinocandins represent the first-line treatment, with >90% of strains remaining susceptible.Resistance to fluconazole is present in most cases, while voriconazole and amphotericin B have variable activity [2,10].According to antifungal susceptibility testing results, these later drugs may be considered as second-line or salvage therapies.

Conclusions
The threat of C. auris is a serious consideration because of the virulence of this pathogen, its multi-resistant profile and its potential for nosocomial transmission and prolonged outbreaks, in particular among critically ill patients.Microbiology laboratories should be aware of the diagnos-  tic challenges related to the identification of this pathogen.Infection control protocols for screening and management of C. auris infection/colonisation should be planned in order to anticipate outbreaks, which can rapidly become overwhelming and difficult to eradicate.

Figure 1 :
Figure 1: Typical white to pale pink aspect of two different C. auris isolates named isolate 1 (panel A) and isolate 2 (panel B) after 48 h of growth on BBL CHROMagar Candida medium (Becton Dickinson Diagnostics Systems).Differentiation between C. auris (white to pale pink colonies) and C. albicans (green to blue colonies) on BBL CHROMagar Candida (panel C) and chromID Candida (bioMérieux) (panel D).

Table 1 :
Recommendations for the prevention and management of Candida auris.
Infection: treat with an echinocandin as first-line therapy.Reassess treatment according to antifungal susceptibility testing results Which measures of decontamination should be applied for C. auris?Direct environment of C. auris case (room, shared equipment) Use of chlorine-based or active oxygen-based products with sporicidal activity (daily and at discharge) Consider hydrogen peroxide vaporization at discharge * Duration of isolation and contact precautions is not well defined.The Centers for Disease Control and Prevention recommends at least two negative screenings at least 1 week apart in the absence of antifungal treatment.