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Multidrug-resistant Candida auris: ‘new kid on the block’ in hospital-associated infections?

  • A. Chowdhary
    Correspondence
    Corresponding author. Address: Department of Medical Mycology, Vallabhbhai Patel Chest Institute, University of Delhi, Post Box 2101, Delhi 110007, India. Tel.: +91 011 27667560; fax: +91 011 27666549.
    Affiliations
    Department of Medical Mycology, Vallabhbhai Patel Chest Institute, University of Delhi, Delhi, India
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  • A. Voss
    Affiliations
    Department of Medical Microbiology, Radboudumc, Nijmegen, The Netherlands

    Department of Medical Microbiology and Infectious Diseases, Canisius–Wilhelmina Hospital, Nijmegen, The Netherlands
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  • J.F. Meis
    Affiliations
    Department of Medical Microbiology, Radboudumc, Nijmegen, The Netherlands

    Department of Medical Microbiology and Infectious Diseases, Canisius–Wilhelmina Hospital, Nijmegen, The Netherlands
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Published:August 15, 2016DOI:https://doi.org/10.1016/j.jhin.2016.08.004

      Summary

      Since being first reported in an ear swab in 2009, and in blood cultures in 2011, invasive infections with Candida auris have been reported in many countries across several continents. We review current knowledge of the epidemiology of this emerging multidrug-resistant pathogen. The importance of species identification and the inadequacies of many widely used identification systems are considered. We recommend that hospitals develop their own policies for the prevention and control of infections with this pathogen. Elements of such policies and the limitations of the existing knowledge base are discussed.

      Keywords

      Candida bloodstream infections and implications of non-albicans Candida species

      Although an estimate of the annual global occurrence of Candida spp. bloodstream infections (BSIs) suggests ∼400,000 cases, with the most occurring in developed regions of the world, the true burden of Candida spp. BSIs is unknown due to the paucity of data from the developing world.
      • Brown G.D.
      • Denning D.W.
      • Gow N.A.
      • Levitz S.M.
      • Netea M.G.
      • White T.C.
      Hidden killers: human fungal infections.
      Nonetheless, crude and attributable mortality rates of 42% and 27%, respectively, of Candida spp. BSIs are very high when compared to severe bacterial and viral infections.
      • Brown G.D.
      • Denning D.W.
      • Gow N.A.
      • Levitz S.M.
      • Netea M.G.
      • White T.C.
      Hidden killers: human fungal infections.
      Candida spp. colonization of patients has been reported to occur in up to 80% of critically ill patients after one week of intensive care.
      • Vincent J.L.
      • Rello J.
      • Marshall J.
      • et al.
      International study of the prevalence and outcomes of infection in intensive care units.
      Despite recent advances in rapid diagnostic microbiological techniques, early diagnosis of invasive candidiasis remains problematic and microbiological documentation often occurs late in the course of infection. This may partly explain the high crude and attributable mortalities in invasive Candida spp. infections compared with bacterial sepsis. The species distribution of Candida spp. has witnessed extensive change over the past decades with a substantial emergence of non-albicans Candida spp. in different healthcare settings worldwide. This shift in context of non-albicans Candida spp. is attributable to the use of prophylactic antifungal drugs, such as azoles and echinocandins among high-risk populations.
      • Pfaller M.A.
      • Andes D.R.
      • Diekema D.J.
      • et al.
      Epidemiology and outcomes of invasive candidiasis due to non-albicans species of Candida in 2,496 patients: data from the prospective antifungal therapy (PATH) registry 2004–2008.
      • Kulberg B.J.
      • Arendrup M.C.
      Invasive candidiasis.
      The scenario is concerning as these species exhibit decreased in-vitro susceptibility to antifungals, thus challenging clinicians and microbiologists with regard to their proper identification and limited options of therapy. In the last five years, multidrug-resistant (MDR) Candida auris has emerged as a notorious healthcare-associated yeast causing invasive infections with high rates of clinical treatment failures. Candida auris has a predilection for epidemic spread and is difficult to treat; it is resistant to the first-line antifungal, fluconazole (FLC), and exhibits variable susceptibility to other azoles, amphotericin B (AMB), and echinocandins. The serious threat posed by C. auris has prompted the US Centers for Disease Control and Prevention (CDC) to issue an alert to healthcare facilities on notifying cases of C. auris to local or public health authorities.

      US Centers for Disease Control and Prevention. Global emergence of invasive infections caused by the multidrug-resistant yeast Candida auris. Available at: http://www.cdc.gov/fungal/diseases/candidiasis/candida-auris-alert.html [last accessed July 2016].

      Public Health England has also issued guidelines for actively identifying and reporting C. auris to prevent its transmission in hospitals.
      • Public Health England
      Guidance for the laboratory investigation, management and infection prevention and control for cases of Candida auris..

      Worldwide emergence and nosocomial spread of multidrug-resistant (MDR) Candida auris in healthcare settings

      Candida auris was first described in 2009; the type strain was cultured from the external ear canal of a patient in Japan.
      • Satoh K.
      • Makimura K.
      • Hasumi Y.
      • Nishiyama Y.
      • Uchida K.
      • Yamaguchi H.
      Candida auris sp. nov., a novel ascomycetous yeast isolated from the external ear canal of an inpatient in a Japanese hospital.
      The first report of BSIs by C. auris in 2011 from Korea highlighted the feature of persistent fungaemia in patients while on FLC and AMB therapy.
      • Lee W.G.
      • Shin J.H.
      • Uh Y.
      • et al.
      First three reported cases of nosocomial fungemia caused by.
      Thereafter, in a short span of five years C. auris fungaemia and deep-seated infections have been reported or notified from hospitals in India, South Africa, Kuwait, Brazil, Venezuela, USA, UK and Pakistan.

      US Centers for Disease Control and Prevention. Global emergence of invasive infections caused by the multidrug-resistant yeast Candida auris. Available at: http://www.cdc.gov/fungal/diseases/candidiasis/candida-auris-alert.html [last accessed July 2016].

      • Public Health England
      Guidance for the laboratory investigation, management and infection prevention and control for cases of Candida auris..
      • Chowdhary A.
      • Sharma C.
      • Duggal S.
      • et al.
      New clonal strain of Candida auris, Delhi, India.
      • Chowdhary A.
      • Anil Kumar V.
      • Sharma C.
      • et al.
      Multidrug-resistant endemic clonal strain of Candida auris in India.
      • Girard V.
      • Mailler S.
      • Chetry M.
      • et al.
      Identification and typing of the emerging pathogen Candida auris by matrix-assisted laser desorption ionisation time of flight mass spectrometry.
      • Emara M.
      • Ahmad S.
      • Khan Z.
      • et al.
      Candida auris candidemia in Kuwait, 2014.
      • Calvo B.
      • Melo A.S.
      • Perozo-Mena A.
      • et al.
      First report of Candida auris in America: clinical and microbiological aspects of 18 episodes of candidemia.
      It is anticipated that C. auris is not limited to the above-mentioned countries and its true burden has not yet been explored based on the fact that this yeast is phenotypically misidentified as Candida haemulonii, Candida famata, Candida sake, Saccharomyces cerevisiae, and Rhodotorula glutinis by commercial identification systems, such as Vitek 2 and API20C-AUX. Its correct identification requires molecular sequencing (ITS or LSU region) or matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.
      • Girard V.
      • Mailler S.
      • Chetry M.
      • et al.
      Identification and typing of the emerging pathogen Candida auris by matrix-assisted laser desorption ionisation time of flight mass spectrometry.
      • Kathuria S.
      • Singh P.K.
      • Sharma C.
      • et al.
      Multidrug-resistant Candida auris misidentified as Candida haemulonii: characterization by matrix-assisted laser desorption ionization–time of flight mass spectrometry and DNA sequencing and its antifungal susceptibility profile variability by Vitek 2, CLSI Broth Microdilution, and Etest method.
      Therefore, C. auris infections pose a challenge regarding identification and therapy, especially in the developing world where modern identification facilities and access to antifungals other than FLC are limited. The recent introduction of the culture-independent T2 Candida Panel, that can rapidly detect and identify the causative pathogen of candidaemia directly from a patient blood sample, might also neglect C. auris detection because only the five most common inciting species are included. Patients with C. auris infections have risk factors similar to those of other Candida spp. including diabetes mellitus, abdominal surgery, broad-spectrum antibiotics, and presence of central venous catheters.
      • Lee W.G.
      • Shin J.H.
      • Uh Y.
      • et al.
      First three reported cases of nosocomial fungemia caused by.
      • Chowdhary A.
      • Sharma C.
      • Duggal S.
      • et al.
      New clonal strain of Candida auris, Delhi, India.
      • Chowdhary A.
      • Anil Kumar V.
      • Sharma C.
      • et al.
      Multidrug-resistant endemic clonal strain of Candida auris in India.
      • Emara M.
      • Ahmad S.
      • Khan Z.
      • et al.
      Candida auris candidemia in Kuwait, 2014.
      • Calvo B.
      • Melo A.S.
      • Perozo-Mena A.
      • et al.
      First report of Candida auris in America: clinical and microbiological aspects of 18 episodes of candidemia.
      The overall crude in-hospital mortality rate of C. auris candidaemia ranges from 30% to 60% and infections typically occur several weeks (10‒50 days) into a patient's hospital stay, being caused by endemic clonal strains of C. auris. Amplified length polymorphism and multi-locus sequence typing suggest geographical clonal strains in different countries.
      • Chowdhary A.
      • Sharma C.
      • Duggal S.
      • et al.
      New clonal strain of Candida auris, Delhi, India.
      • Chowdhary A.
      • Anil Kumar V.
      • Sharma C.
      • et al.
      Multidrug-resistant endemic clonal strain of Candida auris in India.
      • Calvo B.
      • Melo A.S.
      • Perozo-Mena A.
      • et al.
      First report of Candida auris in America: clinical and microbiological aspects of 18 episodes of candidemia.
      • Prakash A.
      • Sharma C.
      • Singh A.
      • et al.
      Evidence of genotypic diversity among Candida auris isolates by multilocus sequence typing, matrix-assisted laser desorption ionization time-of-flight mass spectrometry and amplified fragment length polymorphism.
      A recent study applying whole genome sequencing demonstrated highly related C. auris isolates in four Indian hospitals, suggesting that this pathogen exhibits low diversity and possibly has emerged only recently.
      • Sharma C.
      • Kumar N.
      • Pandey R.
      • Meis J.F.
      • Chowdhary A.
      Whole genome sequencing of emerging multidrug resistant Candida auris isolates in India demonstrates low genetic variation.

      Multidrug resistance in C. auris isolates

      Notwithstanding that minimum inhibitory concentration (MIC) breakpoints of C. auris are not available, antifungal susceptibility data demonstrate that this species is highly resistant to FLC (MIC90 >64mg/L) and that one-third of the isolates exhibit elevated MIC (≥2mg/L) of voriconazole and AMB.
      • Kathuria S.
      • Singh P.K.
      • Sharma C.
      • et al.
      Multidrug-resistant Candida auris misidentified as Candida haemulonii: characterization by matrix-assisted laser desorption ionization–time of flight mass spectrometry and DNA sequencing and its antifungal susceptibility profile variability by Vitek 2, CLSI Broth Microdilution, and Etest method.
      Also, a few isolates are reported to have high echinocandin MIC.
      • Kathuria S.
      • Singh P.K.
      • Sharma C.
      • et al.
      Multidrug-resistant Candida auris misidentified as Candida haemulonii: characterization by matrix-assisted laser desorption ionization–time of flight mass spectrometry and DNA sequencing and its antifungal susceptibility profile variability by Vitek 2, CLSI Broth Microdilution, and Etest method.
      Thus C. auris may exhibit elevated MIC to all three major antifungal classes, leaving no further treatment options; this poses a serious threat for the future if C. auris becomes more prevalent. Candida auris is phylogenetically related to C. haemulonii, which is also known for its intrinsic resistance to AMB and FLU.
      • Kumar A.
      • Prakash A.
      • Singh A.
      • et al.
      Candida haemulonii species complex: an emerging species in India and its genetic diversity assessed with multilocus sequence and amplified fragment-length polymorphism analyses.
      At present the mechanism of antifungal resistance in C. auris is unclear. Resistance is probably inducible under antifungal pressure with rapid mutational changes leading to resistance. The recently published draft genome of C. auris revealed the presence of single copies of ERG3, ERG11, FKS1, FKS2, and FKS3 genes and a significant portion of its genome encodes the ABC and MFS transporter families along with drug transporters that may explain the exceptional multidrug resistance in this pathogen.
      • Sharma C.
      • Kumar N.
      • Pandey R.
      • Meis J.F.
      • Chowdhary A.
      Whole genome sequencing of emerging multidrug resistant Candida auris isolates in India demonstrates low genetic variation.
      • Sharma C.
      • Kumar N.
      • Meis J.F.
      • Pandey R.
      • Chowdhary A.
      Draft genome sequence of a fluconazole-resistant Candida auris strain from a candidemia patient in India.
      • Chatterjee S.
      • Alampalli S.V.
      • Nageshan R.K.
      • Chettiar S.T.
      • Joshi S.
      • Tatu U.S.
      Draft genome of a commonly misdiagnosed multidrug resistant pathogen Candida auris.
      It is likely that the undiscerning use of antifungals has resulted in the emergence of C. auris as a successful MDR pathogen. Considering the high rate of resistance among azoles and the considerable number of isolates exhibiting high AMB MIC, first-line therapy for C. auris infections remains an echinocandin, provided that specific susceptibility testing is undertaken at the earliest. Further, resistance surveillance is recommended in patients who are infected or colonized with C. auris and are on antifungals.

      Infection prevention and control

      There are no published reports of the extent of or anatomical sites of colonization by C. auris, although respiratory, urinary and intestinal colonization have been observed.
      • Public Health England
      Guidance for the laboratory investigation, management and infection prevention and control for cases of Candida auris..
      Recent guidelines by Public Health England on infection prevention and control of C. auris report that colonization is difficult to eradicate and that it tends to persist.
      • Public Health England
      Guidance for the laboratory investigation, management and infection prevention and control for cases of Candida auris..
      Epidemic spread of other Candida species has occurred in the past for which an environmental reservoir was the source. Therefore, infection prevention and control strategies are of paramount importance. The recommendations are primarily based on strategies to prevent and/or treat colonization including adherence to central and peripheral catheter care bundles, urinary catheter care bundle, and care of tracheostomy sites. In a recent outbreak of BSIs due to C. auris in 18 patients admitted to a tertiary care hospital in Venezuela, control measures included implementation of a multi-disciplinary quality-improvement intervention, including a central line insertion care bundle, strict reinforcement of hand hygiene, maximal sterile barriers upon insertion, and use of chlorhexidine for skin disinfection.
      • Calvo B.
      • Melo A.S.
      • Perozo-Mena A.
      • et al.
      First report of Candida auris in America: clinical and microbiological aspects of 18 episodes of candidemia.
      Skin decontamination and oral gargles with chlorhexidine-containing mouth wash, and use of topical nystatin and terbinafine for targeted topical management of key sites such as venous cannula entry sites are recommended. There are no data currently available to determine whether C. auris hand carriage can be eradicated with chlorhexidine or alcoholic hand rub. It is pertinent to emphasize that so far the evidence as to whether C. auris infection is exogenous or endogenous in origin is lacking. Thus, it is not known to what extent patients become colonized with strains from the hospital environment or are endogenous carriers of C. auris. Whole genome sequencing of environmental and clinical isolates of C. auris might provide a clue. Until this is solved, screening of these sites is suggested, based on the predilection of Candida species to colonize skin and mucosal surfaces (i.e. genitourinary tract, mouth and respiratory tract). CDC recommends that healthcare facilities should place patients with C. auris colonization or infection in single rooms and that healthcare personnel should use standard contact precautions. Weekly screens for recurrence of colonization should be undertaken in patients admitted for prolonged duration in healthcare facilities.
      Development of better-targeted measures to prevent C. auris infection warrants in-depth environmental studies from regions reporting large numbers of C. auris cases. However, in the meantime, to curb the spread of this MDR yeast in healthcare facilities it is essential that a multi-disciplinary team comprising clinical microbiologists and infection prevention control specialists devise and implement a policy for their institution. Key elements of such a policy include:
      • 1.
        Hand hygiene compliance. Levels of hand hygiene and environmental cleaning can vary significantly between wards and hospitals both on a national and international scale.
      • 2.
        General infection prevention and control measures for environment and fomites. This includes general cleaning, for which using chlorine-releasing agents may be recommended, and terminal decontamination, for which hydrogen peroxide vapour or ultraviolet light devices may be considered.
        • Boyce J.M.
        Modern technologies for improving cleaning and disinfection of environmental surfaces in hospitals.
        However, despite being effective against yeasts in general, none of these cleaning and decontamination methods has been shown to be effective against C. auris; in-vitro experiments should be undertaken to investigate their efficacies. Attention should also be paid to the management and cleaning of multiple-use equipment from the bed space of an infected/colonized patient. This includes everyday items such as blood pressure cuffs and stethoscopes, as well as larger items such as monitoring equipment or X-ray machines.
      • 3.
        A waste and linen disposal policy, as for any other MDR healthcare-associated micro-organism, must be strictly enforced.
      • 4.
        Antifungal stewardship may become increasingly important; in particular, the benefits of antifungal prophylaxis may need to be weighed against the increasing risk of potential harm in units where C. auris has been seen, and may be promoted by widespread use of fluconazole as prophylaxis.
      In summary, the potentially devastating impact of invasive infections caused by MDR yeasts such as C. auris both for individual patients, and for medical services in hospitals where these micro-organisms are endemic, should not be underestimated. The need to improve our knowledge of the global epidemiology of, and how to manage and prevent infections caused by, these pathogens is emphasized.

      Conflict of interest statement

      J.F.M. has received grants from Astellas , Basilea , and Merck ; has been a consultant to Astellas, Basilea, and Merck; and has received speaker's fees from Merck , United Medical , and Gilead .

      Funding sources

      None.

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