Candida auris: A rapidly emerging cause of hospital-acquired multidrug-resistant fungal infections globally

Contains fulltext : 177553.pdf (Publisher’s version ) (Open Access)

section_content: bloodstream infections. Where Candida isolates are tested for antifungal susceptibility, resistance to fluconazole is another characteristic that should alert the laboratory to further identify Candida isolates.

section_content: Good standard infection control, including environmental cleaning, adequate reprocessing of medical devices and adequate capacity of microbiological laboratories as well as sufficient capacity of healthcare facilities for patient isolation, are the basis for the prevention of transmission of any pathogen, including C. auris, in healthcare settings. Prompt notification of the clinical team and the infection prevention and control/hospital hygiene team is essential to implement infection control precautions in a timely manner.
section_name: Infection control measures

section_content: Early identification of carriers by using active surveillance cultures in cross-infection epidemic settings is an important tool for outbreak control. Active surveillance cultures should be conducted in accordance with a specified protocol. Sites that could be considered for sampling include nose/throat, axilla, groin, rectum, insertion sites of venous catheters and clinical samples such as urine, faeces, wound drain fluid and respiratory specimens. Further clinical experience will ascertain which sampling sites are the most sensitive to detect and monitor patient colonisation with C. auris.
section_name: Targeting patients at high risk for carriage of C. auris

section_content: Hospitals should consider enhanced control measures such as contact precautions, single room isolation or patient cohorting, and dedicated nursing staff for patients who are colonised or infected with C. auris. 

Emphasis should also be placed on the terminal cleaning of rooms after discharge of patients who carry, or are infected with, C. auris, using disinfectants and methods with certified antifungal activity.
section_name: Preventing transmission from patients known to carry C. auris

section_content: Prompt initiation of an epidemiological investigation, complemented by cross-sectional patient screening and environmental sampling, is useful to establish the source of the outbreak and thus prevent further cases. The detection of even a single case of C. auris should trigger such an investigation. Potentially effective enhanced measures for outbreak settings include regular active surveillance cultures for patients admitted to, and resident in, affected wards, cohorting of patients with dedicated nursing staff in separate areas, as well as rigorous environmental cleaning and disinfection. Preliminary hospital experience from the United Kingdom points to the usefulness of chlorine and hydrogen peroxide products, and to limited in vitro activity of chlorhexidine against C. auris. Education and practice audits to improve compliance of healthcare workers with hand hygiene and contact precautions are important supportive interventions.
section_name: Specific recommendations for outbreak settings

section_content: Antimicrobial stewardship programmes aim to improve the clinical effectiveness of antimicrobial treatment and limit antimicrobial resistance by reducing the selective pressure for the development of resistance to currently effective antimicrobials. Although there is no evidence for a specific beneficial effect of antifungal stewardship on the emergence and spread of C. auris, it is likely that an environment with high antifungal use will favour the emergence of a multidrug-resistant yeast, such as C. auris. Therefore, the implementation of antifungal stewardship is recommended. Fluconazole prophylaxis should be avoided in settings with evidence of C. auris transmission.
section_name: Antifungal stewardship

section_content: Admission screening for yeast carriage and pre-emptive isolation of patients who are transferred from, or had recently been admitted to, hospitals in the same or other countries that have detected cases colonised or infected with C. auris should be considered in order to reduce the risk of outbreaks subsequent to the introduction of C. auris in healthcare facilities. This implies that affected facilities should notify the receiving healthcare facilities and clinicians in the case of patient transfer. Documentation of known colonisation or infection by C. auris associated with cross-border patient transfer would optimise the implementation of measures to prevent the international spread of C. auris. Moreover, gathering reliable epidemiological data through notification of cases to public health authorities and exchange of information through electronic early warning platforms, such as the Epidemic Intelligence System (EPIS), will enable informed and coordinated risk management actions by public health authorities across the EU/EEA.
section_name: Prevention of inter-hospital transmission, including cross-border transmission

section_content: Member States should consider alerting clinicians and microbiologists in their healthcare facilities and associated reference mycology laboratories to raise awareness for this epidemic fungal pathogen with the aim of adapting laboratory testing practice at primary and reference levels and establishing specific control measures in a timely manner. National guidelines for laboratory testing and control measures for C. auris will enable the implementation of appropriate measures in healthcare facilities. Sharing of outbreak experience and control measures can be facilitated by ECDC.
section_name: Improvement of preparedness in EU/EEA Member States

section_content: As not all laboratories serving healthcare facilities have the capacity for C. auris identification and susceptibility testing of the whole panel of antifungal agents, a national mycology reference laboratory could assist clinical laboratories with the identification of C. auris, conduct (and/or assist with) antimicrobial susceptibility testing and epidemiological investigations. The reference laboratory should also issue guidance for local laboratories on how to proceed with difficult-to-identify isolates of Candida species and possible C. auris isolates, and provide instructions for referring samples for testing and for reporting results.
section_name: Improvement of laboratory capacity for detection and antifungal susceptibility testing of C. auris

section_content: To determine the background prevalence of C. auris in Member States, it would be advisable to perform a retrospective investigation of the collections of non-albicans Candida spp. clinical isolates at national reference mycology laboratories. Member States might also consider laboratory-based notification of C. auris invasive infections and prospective data collection at national level. Surveillance systems for healthcare-associated infections should be updated to include C. auris in the list of reportable pathogens associated with healthcareassociated infections.
section_name: Retrospective case finding and improved surveillance for C. auris infections

section_name: Source and date of request

section_content: Candida auris is an emerging fungal pathogen associated with outbreaks of invasive infection, including candidemia, in healthcare settings worldwide. In Europe, hospital outbreaks caused by Candida auris have occurred in the UK and Spain. These hospital outbreaks have been difficult to control despite enhanced control measures.
section_name: Public health issue

section_name: C. auris can cause invasive infections in

section_content: Internal experts consulted (in alphabetical order): Barbara Albiger, Anke Kohlenberg, Dominique Monnet, Diamantis Plachouras, Marc Struelens, Sergio Brusin. 

External experts consulted (in alphabetical order): Ana Alastruey-Izquierdo (Mycology Reference Laboratory, Instituto de Salud Carlos III, Madrid, Spain), Andy Borman (PHE Mycology Reference Laboratory, Bristol, UK), Colin Brown (Public Health England, London, UK), Anne Hall (Royal Brompton Hospital, London, UK), Katie Jeffery (Oxford University Hospitals NHS Foundation Trust, Oxford, UK), Elizabeth Johnson (PHE Mycology Reference Laboratory, Bristol, UK), Javier Peman (La Fe University Hospital, Valencia, Spain), Silke Schelenz (Royal Brompton Hospital, London, UK), Oscar Zaragoza Hernandez (Mycology Reference Laboratory, Instituto de Salud Carlos III, Madrid, Spain).
section_name: Consulted experts

section_content: Invasive candidiasis is the most common fungal disease in hospitalised patients [1]. In the ECDC point prevalence survey of healthcare-associated infections and antimicrobial use in European acute care hospitals 2011-2012, Candida spp. was the fifth most common pathogen associated with bloodstream infections, isolated in 7. 4% of all documented cases [2]. While C. albicans remains the predominant cause of invasive candidiasis, there has been a shift towards an increasing proportion of non-albicans Candida species such as C. glabrata in recent years [1, 3]. 

Candida auris is a newly emerging yeast that was first described in 2009 after isolation from the ear canal of a Japanese patient [4] and has subsequently been associated with invasive infections and outbreaks in healthcare settings. C. auris infections have been reported from South Korea [5], South Africa [6], India [7], Pakistan [8],

Kuwait [9], Venezuela [10], Israel [11], Kenya [12], the UK [13] and the USA [14]. The US Centers of Disease Control and Prevention (CDC) report on their website that C. auris has also been identified in Colombia [15], and a published laboratory-based study has included isolates from Brazil [16]. 

C. auris infections include bloodstream infections, wound infections and ear infections [4, 5, 9, 13]. The majority of the published cases have been C. auris bloodstream infections. C. auris has also been isolated from urine [14], though this may have represented carriage rather than infection. 

Non-albicans Candida spp. have emerged in healthcare settings worldwide, presumably related to the use of prophylactic antifungal drugs in high-risk populations [17], but C. auris seems to be unique in its propensity to be transmitted between patients and cause outbreaks in healthcare settings. A number of hospital outbreaks has been reported and several molecular studies confirming intra-or interhospital transmission of C. auris have been published [7, 10, 13].
section_name: Disease background information

section_content: Most of the described C. auris isolates worldwide were resistant to fluconazole, but their susceptibility to other azoles, to amphotericin B, and echinocandins, varied depending on the isolate. A study including 54 C. auris isolates from three continents found that 50 (93%) isolates were resistant to fluconazole, 19 (35%) were resistant to amphotericin B, and four (7%) were resistant to echinocandins [8]. Overall, 22 (41%) isolates were resistant to ≥2 classes of antifungals, and two isolates were resistant to three classes of antifungals [8].
section_name: Antifungal resistance

section_content: C. auris cannot be identified based on microscopy or growth on chromogenic agars [18]. In addition, biochemical testing performed with Vitek-2, BD Phoenix, MicroScan or API strips may misidentify C. auris as being another Candida species or yeast, for example as C. haemulonii, C. famata, C. lusitaniae, C. guillermondii, C. parapsilosis, C. sake, Rhodotorula glutinis or Saccharomyces cerevisiae [6, 15, 18, 19]. Nevertheless, matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry can reliably differentiate C. auris from other Candida species as long as C. auris is included in the reference database and care is taken regarding the extraction method [19, 20]. Alternatively, molecular identification of C. auris can be performed by sequencing internal transcribed spacer and D1/D2 regions [7]. In addition to the above-mentioned difficulties with laboratory identification, C. auris might remain undetected if laboratories do not attempt identification of Candida isolates at the species level, but rather report them as non-albicans Candida species. 

Minimum inhibitory concentration (MIC) breakpoints for C. auris have not yet been established, therefore breakpoints of related Candida species have been used for the interpretation of antifungal susceptibility testing [8]. 

The EUCAST broth microdilution method can be used to test for fluconazole susceptibility that can be interpreted with non-species-related clinical breakpoints [21]. 

Active surveillance cultures are an important part of outbreak control measures. In the 2015/2016 UK outbreak, contact patients were screened for C. auris at the following sites: nose, axilla, groin, throat, rectum/faeces, vascular line and drain exit sites as well as from clinical samples such as urine, wound, drain fluid and respiratory specimens [13].
section_name: Laboratory identification and antimicrobial susceptibility testing

section_name: Event background information

section_content: An outbreak of C. auris infection at a 296-bed cardio-thoracic surgery centre was reported in October 2016 [13]. Over a 16-month period from April 2015 to July 2016, 50 cases of C. auris infection occurred in this centre. 

Twenty-two (44%) of these cases required antifungal treatment, nine (18%) of which had a bloodstream infection (candidemia) [13].
section_name: Cases and outbreaks of C. auris in EU/EEA Member States United Kingdom

section_content: An outbreak of C. auris bloodstream infections occurred in 2016 in the surgical intensive care unit of a hospital in Spain. After identification of the first case by sequencing in April 2016, 33 cases of C. auris bloodstream infection were detected by the end of November 2016. The screening of about 100 healthcare workers did not return any positive cultures. The implemented control measures included contact precautions, active surveillance for yeasts, decolonisation baths with chlorhexidine, preventive isolation of patients with a positive culture for yeasts, cohorting of cases with dedicated nursing staff, use of disposable chlorhexidine alcohol wipes before intravenous catheter manipulation, and cleaning of environmental surfaces three times per day with disposable chlorhexidine towels. 

The incidence of C. auris bloodstream infections decreased after these measures were applied, and 95% compliance with hand hygiene was achieved.
section_name: Spain

section_content: In Norway, one isolate of C. auris resistant to fluconazole was detected among isolates from invasive Candida infections sent routinely to the national reference laboratory for characterisation. Although this case of C. auris infection was diagnosed in Norway, the infection was probably acquired abroad as the concerned patient was transferred directly from a hospital outside of the EU/EEA. The German national reference centre for invasive fungal infections reported on its website that it detected an isolate of C. auris resistant to fluconazole isolated from a blood culture in November 2015 [22].
section_name: Other EU/EEA countries

section_name: ECDC threat assessment for the EU Impact on human health

section_content: Healthcare-associated C. auris bloodstream infections have mainly affected patients with severe underlying diseases and immunosuppression, such as patients with diabetes mellitus, chronic kidney disease, HIV, solid tumours and haematological malignancies [7, 14]. Neonates have also been affected [8]. 

Patients who developed a C. auris infection had frequently been exposed to medical procedures and devices including central venous and urinary catheters, surgery, treatment with broad-spectrum antibiotics, and admission to intensive care units [7, 17]. Treatment with systemic antifungals prior to C. auris infection has also been reported for a proportion of patients [8].
section_name: Healthcare-associated C. auris infections

section_content: Fluconazole and the echinocandins are the antifungal agents most commonly used for the treatment of Candida bloodstream infection (candidemia). Both are better tolerated than amphotericin B, which is given less often due to the risk of toxicity. Fluconazole cannot be used for treatment of C. auris as nearly all isolates are resistant. 

Resistance to other antifungals seems to be more variable; however, isolates with resistance to all three major classes of antifungals (azoles, echinocandins, and amphotericin B) have been described outside of Europe [15]. This is worrisome as it seriously limits available treatment options for patients with invasive C. auris infections.
section_name: Limited treatment options

section_content: The case-fatality rate of Candida bloodstream infection has been reported to be around 30 to 40% in previous studies, even in patients receiving antifungal treatment [1, 23]. There is currently limited information on the casefatality rate for C. auris bloodstream infections due to the small number of patients included in published case series or outbreak descriptions. A study published in 2013 reported case-fatality rates for C. auris bloodstream infections of 33% for all patients and 57% for the subgroup of patients admitted to intensive care units, but these rates might be attributable to the severity of underlying diseases in these patients [7]. In the UK outbreak, no fatalities could be directly attributed to C. auris infection [13]. In a recent in vitro study, the pathogenicity of the most virulent C. auris strains was comparable to that of C. albicans [24].
section_name: Mortality

section_name: Potential for spread

section_content: Based on molecular typing, transmission of C. auris between separate wards that did not share healthcare personnel has been reported from a hospital in India [7]. Inter-hospital transmission of C. auris has also been reported in the same study [7]. The majority of C. auris infections reported in the published literature were acquired in healthcare settings. In addition, molecular typing has shown that C. auris isolates from the same geographical areas were closely related, which suggests clonal spread. The capacity for intra-and interhospital spread combined with multi-drug resistance suggest that C. auris has the typical characteristics of a healthcareassociated pathogen and that further spread in healthcare settings should be expected. 

C. auris outbreaks have been difficult to control, with cases in the affected hospitals being detected over periods longer than a year [10, 13]. Widespread environmental contamination of surfaces and equipment surrounding patients carrying C. auris has been demonstrated [13, 14]. Carriers also represent an important reservoir, and continuous carriage for up to three months after initial isolation of C. auris has been documented [14]. 

Decolonisation has been attempted in one outbreak, but patients remained carriers despite daily chlorhexidine washes [13]. There is currently insufficient evidence regarding decolonisation regimens and their effectiveness to eradicate C. auris carriage. 

Clinicians and infection control staff, even if experienced in the control of multidrug-resistant bacteria, may not expect outbreaks of Candida species. Combined with the additional difficulties in laboratory identification, this lack of awareness might result in outbreaks of C. auris remaining unnoticed or only being detected after a number of patients developed severe infections. 

The CDC had issued a clinical alert to US health facilities regarding the global emergence of C. auris in June 2016 [15]. Public Health England published a notification on C. auris identified in England as well as a document entitled Guidance for the laboratory investigation, management and infection prevention and control for cases of Candida auris [18, 25].
section_name: Outbreaks and spread in healthcare settings

section_content: Due to the difficulties with laboratory identification, little is known about the prevalence of C. auris in different regions of the world. Nevertheless, C. auris isolates, cases and outbreaks have now been reported from five different continents: Europe, Asia, North America, South America, and Africa. The case reported by Norway is presumed to have been imported from a country outside of the EU/EEA, and it is likely that there is a risk of importation of C. auris via hospital transfer of patients and subsequent outbreaks in healthcare settings in the EU/EEA. Indeed, a recent study has shown that isolates of C. auris present in the UK have several diverse geographic origins, suggesting multiple introductions into the country [26].
section_name: Cross-border transmission