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Candida auris: An emerging multidrug-resistant pathogen
Accepted Manuscript Title: Candida auris: an emerging multidrug-resistant pathogen Authors: David Sears, Brian S. Schwartz PII: DOI: Reference:
S1201-9712(17)30223-0 http://dx.doi.org/10.1016/j.ijid.2017.08.017 IJID 3022
To appear in:
International Journal of Infectious Diseases
Received date: Accepted date:
30-8-2017 30-8-2017
Please cite this article as: Sears David, Schwartz Brian S.Candida auris: an emerging multidrug-resistant pathogen.International Journal of Infectious Diseases http://dx.doi.org/10.1016/j.ijid.2017.08.017 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Candida auris: an emerging multidrug-resistant pathogen David Sears1 and Brian S. Schwartz1 1Division
of Infectious Diseases, University of California San Francisco, USA
Corresponding author: David Sears, M.D. 513 Parnassus Ave. Box 0654 San Francisco, CA 94143 Telephone: 415-353-9363 Fax: 415-353-9364 [email protected] INTRODUCTION Candida auris was first identified from samples of external ear drainage from one Japanese patient1 and 15 Korean patients in 20092. This organism can be challenging to identify using standard microbiologic techniques and frequently exhibits multidrugresistance. In the eight years since these initial cases, C. auris has become an emerging global health threat, implicated in a host of invasive infections and outbreaks in healthcare facilities. To date, cases have now been identified in India3,4, South Africa5, Kuwait6, the United Kingdom7, Venezuela8, Brazil9, the United States10, Colombia11, Pakistan12, Spain13, Germany14, Israel15, Norway14, and Oman16.
This review will detail the
microbiology, clinical features, therapeutic options, and infection control measures relevant to C. auris infection.
MICROBIOLOGY AND DIAGNOSIS Candida auris is phylogenetically related to C. haemulonii and C. ruelliae1. Four distinct clades have been identified from separate geographic origins, suggesting a recent and nearly simultaneous emergence of different clonal populations12. C. auris grows
readily at 37-42oC and forms light pink colonies on chromogenic media17,18. Unlike C. haemulonii, C. auris does not form pseudohyphae. Only some C. auris strains produce the virulence factors phospholipase and proteinase, which may account for the variability in pathogenicity demonstrated in a murine model19,20. C. auris is capable of forming biofilms21 and adhering to catheter material, although not with to the same degree as C. albicans20. Traditional biochemical methods of identification commonly misdiagnose C. auris as other yeast. The United States Centers for Disease Control and Prevention (CDC) recommends further testing for C. auris whenever C. haemulonii is identified or in a number of other scenarios depending on the organism reported and the method of identification (Table 1). Accurate identification can be performed with VITEK MS and Bruker Biotyper matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) devices using their “research use only” databases. Molecular sequencing of the D1-D2 domain of the 28s rDNA can also identify C. auris22.
For laboratories without the
capability to perform these tests, Kumar et al. propose a low-cost alternative that can accurately distinguish C. auris from C. haemulonii using CHROMagar medium supplemented with Pal’s medium23.
CLINICAL FEATURES Risk factors for Candida auris infection appear to be similar to infections from Candida in general.
These include immunosuppressed state, significant medical
comorbidities, central venous catheters, urinary catheters, recent surgery, parenteral nutrition, exposure to broad spectrum antimicrobials, intensive care unit admission, and residence in a high-acuity skilled nursing facility10,24. In a case-control study investigating risk factors for C. auris fungemia compared to bloodstream infection from other Candida species in Indian ICUs, those with C. auris fungemia were more likely to have had longer antecedent hospitalizations, underlying respiratory conditions, vascular surgery, prior antifungal exposure, and low APACHE II scores. Patients with C. auris fungemia in this study were also more frequently from public-sector ICUs from the north of India25. C. auris has been recovered in samples from blood, catheter tips, cerebrospinal fluid, bone, ear discharge, pancreatic fluid, pericardial fluid, peritoneal fluid, pleural fluid,
respiratory secretions (including sputum and bronchoalveolar lavage), skin and soft tissue samples (both tissue and swab cultures), urine, and vaginal secretions. Clinically, it has been implicated as a causative agent in fungemia, ventriculitis, osteomyelitis, malignant otitis (including otomastoiditis), complicated intra-abdominal infections, pericarditis, complicated pleural effusions, and vulvovaginitis1–3,5–8,10–13,15,16,19,26–30. Much like other Candida species, there is uncertainty about the ability of C. auris to cause true respiratory, urinary, and skin and soft tissue infections despite being isolated from such samples. While one study reported no C. auris attributable deaths among nine patients with fungemia, crude mortality rates for C. auris fungemia have ranged from 28-66% across a wide range of healthcare settings and patient populations4,8,10–12,16,17,25,26.
ANTIFUNGAL THERAPIES Source control measures, including removal of indwelling catheters, are likely as important to the successful treatment of invasive Candida auris infections as they are to other forms of invasive candidiasis. Regarding antifungal therapy, there are no Clinical and Laboratory Standards Institute (CLSI) or European Committee for Antimicrobial Susceptibility Testing (EUCAST) defined breakpoints for C. auris susceptibility. CDC recommends that all C. auris isolates undergo susceptibility testing and provides guidance for MIC breakpoints based on related Candida species and expert opinion (Table 2)22. Fluconazole (tentative MIC breakpoint >2) is associated with high minimum inhibitory concentrations (MICs) and is likely almost always resistant. Susceptibility testing from four studies involving between 54 and 123 clinical isolates revealed MIC50 results between 64 and 128mg/L and MIC90 results between 64 and 256mg/L by CLSI microbroth dilution. Echinocandins (tentative MIC breakpoint >4 for anidulafungin and micafungin, >2 for caspofungin) appear to be most active in these studies with favorable results for anidulafungin (MIC50 range 0.125 – 0.5, MIC90 range 0.5 – 1), caspofungin (MIC50 0.25 – 0.5, MIC90 1), and micafungin (MIC50 0.125 – 0.25, MIC90 0.25 – 2). Amphotericin B (tentative MIC breakpoint >2) susceptibility testing exhibits a wider range of MIC results (MIC50 0.5 – 1, MIC90 2 – 4) and is likely less reliable as empiric therapy9,12,18,31.
Regarding second generation triazole susceptibility, fluconazole
susceptibility can be used as a surrogate although fluconazole-resistant isolates may
occasionally respond to other triazole antifungals22. In comparison to CLSI microbroth dilution, similar MIC50 and MIC90 results can likely be obtained by the EUCAST method31, although caution should be used when interpreting Etest and Vitek antifungal susceptibility testing results18. Based on these results, echinocandins are the empiric drugs of choice for C. auris infections in adults and children over the age of 2 months. Amphotericin B—while less reliable--should be considered for patients not responding to echinocandin therapy, depending on MIC results. A mouse model testing antifungal therapy on nine strains of C. auris suggested that micafungin may be particularly fungicidal and more active than tentative MIC breakpoints may suggest32, however further clinical studies in humans are needed. It is important to note that resistance may develop on therapy and close clinical follow-up and potentially repeat MIC testing may be indicated for patients who are responding poorly to antifungal therapy. Much like colonization with other multidrug-resistant species, CDC does not recommend systemic antifungal therapy for patients who are colonized with C. auris22.
INFECTION CONTROL Candida auris can cause widespread and persistent contamination of environmental surfaces within healthcare facilities and has been associated with both intra-hospital
and
inter-hospital
transmission
of
clonal
strains
in
multiple
countries2,4,7,8,11,14,15,30,33. The largest reported outbreaks to date were in a cardio-thoracic center in the United Kingdom (22 patients infected and an additional 28 patients colonized)7 and a surgical intensive care unit in Spain (33 cases of C. auris fungemia)14. From 77 clinical cases in the United States, CDC used groin and axilla swabs to screen an additional 390 close contacts (mainly patients on the same ward of a known clinical case) and identified C. auris colonization in another 45 individuals. Patients within similar geographic regions in this study commonly had overlapping stays in the same acute care hospital or long-term care facility, further supporting healthcare exposure as a key method of transmission30. Given the risk of nosocomial transmission of this multidrug-resistant pathogen, infection control measures are vital to slowing the spread of C. auris. CDC recommends
that all hospitalized patients with C. auris infection or colonization be treated using both Standard Precautions and Contact Precautions34 and housed in a private room with daily and terminal cleaning with a disinfectant agent active against Clostridium difficile spores35,36. Receiving healthcare facilities should also be notified prior to transfer of an infected or colonized patient. Infection control precautions should be maintained until a patient is no longer infected or colonized with C. auris although there is uncertainty as to how best to monitor for ongoing colonization22. There are no clear data on the efficacy of decolonization measures for patients with colonized with C. auris, however this has been attempted with chlorhexidine in healthcare facilities during outbreaks7,8,14.
FUTURE DIRECTIONS As Candida auris cases continue to be found throughout the world, there is urgent need for improved diagnostics, antifungal therapies, and infection control measures. PCR and real-time PCR assays to rapidly identify C. auris have shown excellent accuracy in development and could be performed in laboratories that do not have the ability to perform MALDI-TOF or molecular sequencing techniques37. The development of new antifungal medications with activity against C. auris will be vital to controlling C. auris as therapeutic options are already limited. SCY-078, a novel triterpene glucan synthase inhibitor, is currently in phase III trials for invasive and mucocutaneous candidiasis and has recently shown promising activity in vitro against C. auris20,38. Finally, aggressive infection control measures are critical to reducing the spread of C. auris. Antimicrobial stewardship, hand hygiene, and contact precautions will continue to be of paramount importance. More information is needed, however, about effective measures to reduce patient colonization and environmental contamination in healthcare facilities which have served as sites of ongoing transmission of this emerging pathogen.
References 1 Satoh Kazuo, Makimura Koichi, Hasumi Yayoi, Nishiyama Yayoi, Uchida Katsuhisa, Yamaguchi Hideyo. Candida auris sp. nov., a novel ascomycetous yeast isolated from the external ear canal of an inpatient in a Japanese hospital. Microbiol Immunol 2009;53(1):41–4. Doi: 10.1111/j.1348-0421.2008.00083.x. 2 Kim Mi-Na, Shin Jong Hee, Sung Heungsup, Lee Kyungwon, Kim Eui-Chong, Ryoo Namhee, et al. Candida haemulonii and Closely Related Species at 5 University Hospitals in Korea: Identification, Antifungal Susceptibility, and Clinical Features. Clin Infect Dis 2009;48(6):e57– 61. Doi: 10.1086/597108. 3 Sarma S, Kumar N, Sharma S, Govil D, Ali T, Mehta Y, et al. Candidemia caused by amphotericin B and Fluconazole resistant Candida auris. Indian J Med Microbiol 2013;31(1):90. Doi: 10.4103/0255-0857.108746. 4 Chowdhary Anuradha, Sharma Cheshta, Duggal Shalini, Agarwal Kshitij, Prakash Anupam, Kumar Singh Pradeep, et al. New Clonal Strain of Candida auris, Delhi, India. Emerg Infect Dis 2013;19(10):1670–3. Doi: 10.3201/eid1910.130393. 5 Magobo Rindidzani, Corcoran Craig, Seetharam Sharona, Govender Nelesh. Candida auris– Associated Candidemia, South Africa. Emerg Infect Dis 2014;20(7):1250–1. Doi: 10.3201/eid2007.131765. 6 Emara Maha, Ahmad Suhail, Khan Ziauddin, Joseph Leena, Al-Obaid Ina ’m, Purohit Prashant, et al. Candida auris Candidemia in Kuwait, 2014. Emerg Infect Dis 2015;21(6):1091–2. Doi: 10.3201/eid2106.150270. 7 Schelenz Silke, Hagen Ferry, Rhodes Johanna L, Abdolrasouli Alireza, Chowdhary Anuradha, Hall Anne, et al. First hospital outbreak of the globally emerging Candida auris in a European hospital. Antimicrob Resist Infect Control 2016;5:35. Doi: 10.1186/s13756-016-0132-5. 8 Calvo Belinda, Melo Analy SA, Perozo-Mena Armindo, Hernandez Martin, Francisco Elaine Cristina, Hagen Ferry, et al. First report of Candida auris in America: Clinical and microbiological aspects of 18 episodes of candidemia. J Infect 2016;73(4):369–74. Doi: 10.1016/j.jinf.2016.07.008. 9 Prakash A, Sharma C, Singh A, Kumar Singh P, Kumar A, Hagen F, 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. Clin Microbiol Infect 2016;22(3):277.e1-277.e9. Doi: 10.1016/j.cmi.2015.10.022. 10 Vallabhaneni S, Kallen A, Tsay S, Chow N, Welsh R, Kerins J, et al. Investigation of the First Seven Reported Cases of Candida auris, a Globally Emerging Invasive, Multidrug-Resistant Fungus—United States, May 2013–August 2016. Morb Mortal Wkly Rep 2016;65(44):1234–7. 11 Morales-López Soraya, Parra-Giraldo Claudia, Ceballos-Garzon Andres, Martinez Heidys, Rodriguez Gerson, Alvarez-Moreno Carlos, et al. Invasive Infections with Multidrug-Resistant Yeast Candida auris, Colombia. Emerg Infect Dis 2017;23(1):162–4. Doi: 10.3201/eid2301.161497. 12 Lockhart Shawn R, Etienne Kizee A, Vallabhaneni Snigdha, Farooqi Joveria, Chowdhary Anuradha, Govender Nelesh P, et al. Simultaneous Emergence of Multidrug-Resistant Candida auris on 3 Continents Confirmed by Whole-Genome Sequencing and Epidemiological Analyses. Clin Infect Dis 2017;64(2):134–40. Doi: 10.1093/cid/ciw691.
13 Ruiz Gaitán Alba Cecilia, Moret Ana, López Hontangas José Luis, Molina José Miguel, Aleixandre López Ana Isabel, Cabezas Alicia Hernández, et al. Nosocomial fungemia by Candida auris: First four reported cases in continental Europe. Rev Iberoam Micol 2017;34(1):23–7. Doi: 10.1016/j.riam.2016.11.002. 14 European Centre for Disease Prevention and Control. Candida auris in healthcare settings Europe 2016. 15 Ben-Ami Ronen, Berman Judith, Novikov Ana, Bash Edna, Shachor-Meyouhas Yael, Zakin Shiri, et al. Multidrug-Resistant Candida haemulonii and C. auris, Tel Aviv, Israel. Emerg Infect Dis 2017;23(2):195–203. Doi: 10.3201/eid2302.161486. 16 Al-Siyabi Turkiya, Al Busaidi Ibrahim, Balkhair Abdullah, Al-Muharrmi Zakariya, Al-Salti Maya, Al’Adawi Badriya. First report of Candida auris in Oman: Clinical and microbiological description of five candidemia cases. J Infect 2017. Doi: 10.1016/j.jinf.2017.05.016. 17 Chowdhary A, Kumar V Anil, Sharma C, Prakash A, Agarwal K, Babu R, et al. Multidrugresistant endemic clonal strain of Candida auris in India. Eur J Clin Microbiol Infect Dis 2014;33(6):919–26. Doi: 10.1007/s10096-013-2027-1. 18 Kathuria Shallu, Singh Pradeep K, Sharma Cheshta, Prakash Anupam, Masih Aradhana, Kumar Anil, 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. J Clin Microbiol 2015;53(6):1823–30. Doi: 10.1128/JCM.00367-15. 19 Borman Andrew M, Szekely Adrien, Johnson Elizabeth M. Comparative Pathogenicity of United Kingdom Isolates of the Emerging Pathogen Candida auris and Other Key Pathogenic Candida Species. mSphere 2016;1(4):e00189-16. Doi: 10.1128/mSphere.00189-16. 20 Larkin Emily, Hager Christopher, Chandra Jyotsna, Mukherjee Pranab K, Retuerto Mauricio, Salem Iman, et al. The Emerging Pathogen Candida auris: Growth Phenotype, Virulence Factors, Activity of Antifungals, and Effect of SCY-078, a Novel Glucan Synthesis Inhibitor, on Growth Morphology and Biofilm Formation. Antimicrob Agents Chemother 2017;61(5):e02396-16. Doi: 10.1128/AAC.02396-16. 21 Oh Bong Joon, Shin Jong Hee, Kim Mi-Na, Sung Heungsup, Lee Kyungwon, Joo Min Young, et al. Biofilm formation and genotyping of Candida haemulonii, Candida pseudohaemulonii, and a proposed new species (Candida auris) isolates from Korea. Med Mycol 2011;49(1):98– 102. Doi: 10.3109/13693786.2010.493563. 22 Candida auris Interim Recommendations for Healthcare Facilities and Laboratories | Fungal Diseases | CDC. Available at: https://www.cdc.gov/fungal/diseases/candidiasis/recommendations.html (Accessed June 27, 2017, 2017). 23 Kumar Anil, Sachu Arun, Mohan Karthika, Vinod Vivek, Dinesh Kavitha, Karim Shamsul. Simple low cost differentiation of Candida auris from Candida haemulonii complex using CHROMagar Candida medium supplemented with Pal’s medium. Rev Iberoam Micol 2017;34(2):109–11. Doi: 10.1016/j.riam.2016.11.004. 24 Sarma Smita, Upadhyay Shalini. Current perspective on emergence, diagnosis and drug resistance in Candida auris. Infect Drug Resist 2017;Volume 10:155–65. Doi: 10.2147/IDR.S116229.
25 Rudramurthy Shivaprakash M, Chakrabarti Arunaloke, Paul Raees A, Sood Prashant, Kaur Harsimran, Capoor Malini R, et al. Candida auris candidaemia in Indian ICUs: analysis of risk factors. J Antimicrob Chemother 2017;72(6):1794–801. Doi: 10.1093/jac/dkx034. 26 Lee Wee Gyo, Shin Jong Hee, Uh Young, Kang Min Gu, Kim Soo Hyun, Park Kyung Hwa, et al. First Three Reported Cases of Nosocomial Fungemia Caused by Candida auris. J Clin Microbiol 2011;49(9):3139–42. Doi: 10.1128/JCM.00319-11. 27 Khillan Vikas, Rathore Neha, Kathuria Shallu, Chowdhary Anuradha. A rare case of breakthrough fungal pericarditis due to fluconazole‐resistant Candida auris in a patient with chronic liver disease. JMM Case Rep 2014;1(3). Doi: 10.1099/jmmcr.0.T00018. 28 Choi Hyoung Il, An Jin, Hwang Jae Joon, Moon Soo-youn, Son Jun Seong. Otomastoiditis caused by Candida auris: Case report and literature review. Mycoses 2017:n/a-n/a. Doi: 10.1111/myc.12617. 29 Chowdhary Anuradha, Sharma Cheshta, Meis Jacques F. Candida auris: A rapidly emerging cause of hospital-acquired multidrug-resistant fungal infections globally. PLOS Pathog 2017;13(5):e1006290. Doi: 10.1371/journal.ppat.1006290. 30 Tsay Sharon, Welsh Rory, Adams Eleanor, Chow Nancy, Gade Lalitha, Berkow Elizabeth, et al. Notes from the Field: Ongoing Transmission of Candida auris in Health Care Facilities — United States, June 2016–May 2017. Morb Mortal Wkly Rep 2017;66(19):514–5. Doi: 10.15585/mmwr.mm6619a7. 31 Arendrup MC, Prakash Anupam, Meletiadis Joseph, Sharma Cheshta, Chowdhary Anuradha. Comparison of EUCAST and CLSI Reference Microdilution MICs of Eight Antifungal Compounds for Candida auris and Associated Tentative Epidemiological Cutoff Values. Antimicrob Agents Chemother 2017;61(6):e00485-17. Doi: 10.1128/AAC.00485-17. 32 Lepak Alexander J, Zhao Miao, Berkow Elizabeth L, Lockhart Shawn R, Andes David R. Pharmacodynamic Optimization for Treatment of Invasive Candida auris Infection. Antimicrob Agents Chemother 2017:AAC.00791-17. Doi: 10.1128/AAC.00791-17. 33 Piedrahita Christina T, Cadnum Jennifer L, Jencson Annette L, Shaikh Aaron A, Ghannoum Mahmoud A, Donskey Curtis J. Environmental Surfaces in Healthcare Facilities are a Potential Source for Transmission of Candida auris and Other Candida Species. Infect Control Hosp Epidemiol 2017:1–3. Doi: 10.1017/ice.2017.127. 34 Isolation Precautions | Guidelines Library | Infection Control | CDC. Available at: https://www.cdc.gov/infectioncontrol/guidelines/isolation/index.html (Accessed July 5, 2017, n.d.). 35 US EPA OCSPP. LIST K: EPA’s Registered Antimicrobial Products Effective against Clostridium difficile Spores. US EPA. Available at: https://www.epa.gov/pesticideregistration/list-k-epas-registered-antimicrobial-products-effective-against-clostridium (Accessed July 5, 2017, 2015). 36 Cadnum Jennifer L, Shaikh Aaron A, Piedrahita Christina T, Sankar Thriveen, Jencson Annette L, Larkin Emily L, et al. Effectiveness of Disinfectants Against Candida auris and Other Candida Species. Infect Control Hosp Epidemiol 2017:1–4. Doi: 10.1017/ice.2017.162. 37 Kordalewska Milena, Zhao Yanan, Lockhart Shawn R, Chowdhary Anuradha, Berrio Indira, Perlin David S. Rapid and accurate molecular identification of the emerging multidrug resistant pathogen Candida auris. J Clin Microbiol 2017:JCM.00630-17. Doi: 10.1128/JCM.00630-17. 38 Berkow Elizabeth L, Angulo David, Lockhart Shawn R. In Vitro Activity of a Novel Glucan Synthase Inhibitor, SCY-078, against Clinical Isolates of Candida auris. Antimicrob Agents Chemother 2017;61(7):e00435-17. Doi: 10.1128/AAC.00435-17.
Table 1. When to suspect Candida auris based on the organism presumptively identified and the method of identification22 Organism reported
Method
Candida haemulonii
Any
Candida spp.
Any validated identification method
Rhodotorula glutinis
API 20C if red color is not present
Candida sake
API 20C
Candida catenulata
BD Phoenix
Candida catenulata
MicroScan
Candida famata
MicroScan
Candida guilliermondii
MicroScan
Candida lusitaniae
MicroScan
Source: US Centers for Disease Control and Prevention
Table 2. Tentative MIC (mg/L) breakpoints for Candida auris susceptibility22 and published MIC ranges by CLSI microbroth dilution9,12,18,31 Antifungal drug
Tentative MIC Published Published breakpoint MIC50 Range MIC90 Range
Fluconazole
>32
64 – 128
64 – 256
Voriconazole A
N/A B
0.5 – 2
4–8
Amphotericin B
>2
0.5 – 1
2–4
Anidulafungin
>4
0.125 – 0.5
0.5 – 1
Caspofungin
>2
0.25 – 0.5
1
Micafungin
>4
0.125 – 0.25
0.25 – 2
A Also
applies to other second generation triazole antifungals
B Consider
using fluconazole susceptibility as a surrogate, although fluconazole-resistant
isolates may occasionally respond to other triazole antifungals
S1201-9712(17)30223-0 http://dx.doi.org/10.1016/j.ijid.2017.08.017 IJID 3022
To appear in:
International Journal of Infectious Diseases
Received date: Accepted date:
30-8-2017 30-8-2017
Please cite this article as: Sears David, Schwartz Brian S.Candida auris: an emerging multidrug-resistant pathogen.International Journal of Infectious Diseases http://dx.doi.org/10.1016/j.ijid.2017.08.017 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Candida auris: an emerging multidrug-resistant pathogen David Sears1 and Brian S. Schwartz1 1Division
of Infectious Diseases, University of California San Francisco, USA
Corresponding author: David Sears, M.D. 513 Parnassus Ave. Box 0654 San Francisco, CA 94143 Telephone: 415-353-9363 Fax: 415-353-9364 [email protected] INTRODUCTION Candida auris was first identified from samples of external ear drainage from one Japanese patient1 and 15 Korean patients in 20092. This organism can be challenging to identify using standard microbiologic techniques and frequently exhibits multidrugresistance. In the eight years since these initial cases, C. auris has become an emerging global health threat, implicated in a host of invasive infections and outbreaks in healthcare facilities. To date, cases have now been identified in India3,4, South Africa5, Kuwait6, the United Kingdom7, Venezuela8, Brazil9, the United States10, Colombia11, Pakistan12, Spain13, Germany14, Israel15, Norway14, and Oman16.
This review will detail the
microbiology, clinical features, therapeutic options, and infection control measures relevant to C. auris infection.
MICROBIOLOGY AND DIAGNOSIS Candida auris is phylogenetically related to C. haemulonii and C. ruelliae1. Four distinct clades have been identified from separate geographic origins, suggesting a recent and nearly simultaneous emergence of different clonal populations12. C. auris grows
readily at 37-42oC and forms light pink colonies on chromogenic media17,18. Unlike C. haemulonii, C. auris does not form pseudohyphae. Only some C. auris strains produce the virulence factors phospholipase and proteinase, which may account for the variability in pathogenicity demonstrated in a murine model19,20. C. auris is capable of forming biofilms21 and adhering to catheter material, although not with to the same degree as C. albicans20. Traditional biochemical methods of identification commonly misdiagnose C. auris as other yeast. The United States Centers for Disease Control and Prevention (CDC) recommends further testing for C. auris whenever C. haemulonii is identified or in a number of other scenarios depending on the organism reported and the method of identification (Table 1). Accurate identification can be performed with VITEK MS and Bruker Biotyper matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) devices using their “research use only” databases. Molecular sequencing of the D1-D2 domain of the 28s rDNA can also identify C. auris22.
For laboratories without the
capability to perform these tests, Kumar et al. propose a low-cost alternative that can accurately distinguish C. auris from C. haemulonii using CHROMagar medium supplemented with Pal’s medium23.
CLINICAL FEATURES Risk factors for Candida auris infection appear to be similar to infections from Candida in general.
These include immunosuppressed state, significant medical
comorbidities, central venous catheters, urinary catheters, recent surgery, parenteral nutrition, exposure to broad spectrum antimicrobials, intensive care unit admission, and residence in a high-acuity skilled nursing facility10,24. In a case-control study investigating risk factors for C. auris fungemia compared to bloodstream infection from other Candida species in Indian ICUs, those with C. auris fungemia were more likely to have had longer antecedent hospitalizations, underlying respiratory conditions, vascular surgery, prior antifungal exposure, and low APACHE II scores. Patients with C. auris fungemia in this study were also more frequently from public-sector ICUs from the north of India25. C. auris has been recovered in samples from blood, catheter tips, cerebrospinal fluid, bone, ear discharge, pancreatic fluid, pericardial fluid, peritoneal fluid, pleural fluid,
respiratory secretions (including sputum and bronchoalveolar lavage), skin and soft tissue samples (both tissue and swab cultures), urine, and vaginal secretions. Clinically, it has been implicated as a causative agent in fungemia, ventriculitis, osteomyelitis, malignant otitis (including otomastoiditis), complicated intra-abdominal infections, pericarditis, complicated pleural effusions, and vulvovaginitis1–3,5–8,10–13,15,16,19,26–30. Much like other Candida species, there is uncertainty about the ability of C. auris to cause true respiratory, urinary, and skin and soft tissue infections despite being isolated from such samples. While one study reported no C. auris attributable deaths among nine patients with fungemia, crude mortality rates for C. auris fungemia have ranged from 28-66% across a wide range of healthcare settings and patient populations4,8,10–12,16,17,25,26.
ANTIFUNGAL THERAPIES Source control measures, including removal of indwelling catheters, are likely as important to the successful treatment of invasive Candida auris infections as they are to other forms of invasive candidiasis. Regarding antifungal therapy, there are no Clinical and Laboratory Standards Institute (CLSI) or European Committee for Antimicrobial Susceptibility Testing (EUCAST) defined breakpoints for C. auris susceptibility. CDC recommends that all C. auris isolates undergo susceptibility testing and provides guidance for MIC breakpoints based on related Candida species and expert opinion (Table 2)22. Fluconazole (tentative MIC breakpoint >2) is associated with high minimum inhibitory concentrations (MICs) and is likely almost always resistant. Susceptibility testing from four studies involving between 54 and 123 clinical isolates revealed MIC50 results between 64 and 128mg/L and MIC90 results between 64 and 256mg/L by CLSI microbroth dilution. Echinocandins (tentative MIC breakpoint >4 for anidulafungin and micafungin, >2 for caspofungin) appear to be most active in these studies with favorable results for anidulafungin (MIC50 range 0.125 – 0.5, MIC90 range 0.5 – 1), caspofungin (MIC50 0.25 – 0.5, MIC90 1), and micafungin (MIC50 0.125 – 0.25, MIC90 0.25 – 2). Amphotericin B (tentative MIC breakpoint >2) susceptibility testing exhibits a wider range of MIC results (MIC50 0.5 – 1, MIC90 2 – 4) and is likely less reliable as empiric therapy9,12,18,31.
Regarding second generation triazole susceptibility, fluconazole
susceptibility can be used as a surrogate although fluconazole-resistant isolates may
occasionally respond to other triazole antifungals22. In comparison to CLSI microbroth dilution, similar MIC50 and MIC90 results can likely be obtained by the EUCAST method31, although caution should be used when interpreting Etest and Vitek antifungal susceptibility testing results18. Based on these results, echinocandins are the empiric drugs of choice for C. auris infections in adults and children over the age of 2 months. Amphotericin B—while less reliable--should be considered for patients not responding to echinocandin therapy, depending on MIC results. A mouse model testing antifungal therapy on nine strains of C. auris suggested that micafungin may be particularly fungicidal and more active than tentative MIC breakpoints may suggest32, however further clinical studies in humans are needed. It is important to note that resistance may develop on therapy and close clinical follow-up and potentially repeat MIC testing may be indicated for patients who are responding poorly to antifungal therapy. Much like colonization with other multidrug-resistant species, CDC does not recommend systemic antifungal therapy for patients who are colonized with C. auris22.
INFECTION CONTROL Candida auris can cause widespread and persistent contamination of environmental surfaces within healthcare facilities and has been associated with both intra-hospital
and
inter-hospital
transmission
of
clonal
strains
in
multiple
countries2,4,7,8,11,14,15,30,33. The largest reported outbreaks to date were in a cardio-thoracic center in the United Kingdom (22 patients infected and an additional 28 patients colonized)7 and a surgical intensive care unit in Spain (33 cases of C. auris fungemia)14. From 77 clinical cases in the United States, CDC used groin and axilla swabs to screen an additional 390 close contacts (mainly patients on the same ward of a known clinical case) and identified C. auris colonization in another 45 individuals. Patients within similar geographic regions in this study commonly had overlapping stays in the same acute care hospital or long-term care facility, further supporting healthcare exposure as a key method of transmission30. Given the risk of nosocomial transmission of this multidrug-resistant pathogen, infection control measures are vital to slowing the spread of C. auris. CDC recommends
that all hospitalized patients with C. auris infection or colonization be treated using both Standard Precautions and Contact Precautions34 and housed in a private room with daily and terminal cleaning with a disinfectant agent active against Clostridium difficile spores35,36. Receiving healthcare facilities should also be notified prior to transfer of an infected or colonized patient. Infection control precautions should be maintained until a patient is no longer infected or colonized with C. auris although there is uncertainty as to how best to monitor for ongoing colonization22. There are no clear data on the efficacy of decolonization measures for patients with colonized with C. auris, however this has been attempted with chlorhexidine in healthcare facilities during outbreaks7,8,14.
FUTURE DIRECTIONS As Candida auris cases continue to be found throughout the world, there is urgent need for improved diagnostics, antifungal therapies, and infection control measures. PCR and real-time PCR assays to rapidly identify C. auris have shown excellent accuracy in development and could be performed in laboratories that do not have the ability to perform MALDI-TOF or molecular sequencing techniques37. The development of new antifungal medications with activity against C. auris will be vital to controlling C. auris as therapeutic options are already limited. SCY-078, a novel triterpene glucan synthase inhibitor, is currently in phase III trials for invasive and mucocutaneous candidiasis and has recently shown promising activity in vitro against C. auris20,38. Finally, aggressive infection control measures are critical to reducing the spread of C. auris. Antimicrobial stewardship, hand hygiene, and contact precautions will continue to be of paramount importance. More information is needed, however, about effective measures to reduce patient colonization and environmental contamination in healthcare facilities which have served as sites of ongoing transmission of this emerging pathogen.
References 1 Satoh Kazuo, Makimura Koichi, Hasumi Yayoi, Nishiyama Yayoi, Uchida Katsuhisa, Yamaguchi Hideyo. Candida auris sp. nov., a novel ascomycetous yeast isolated from the external ear canal of an inpatient in a Japanese hospital. Microbiol Immunol 2009;53(1):41–4. Doi: 10.1111/j.1348-0421.2008.00083.x. 2 Kim Mi-Na, Shin Jong Hee, Sung Heungsup, Lee Kyungwon, Kim Eui-Chong, Ryoo Namhee, et al. Candida haemulonii and Closely Related Species at 5 University Hospitals in Korea: Identification, Antifungal Susceptibility, and Clinical Features. Clin Infect Dis 2009;48(6):e57– 61. Doi: 10.1086/597108. 3 Sarma S, Kumar N, Sharma S, Govil D, Ali T, Mehta Y, et al. Candidemia caused by amphotericin B and Fluconazole resistant Candida auris. Indian J Med Microbiol 2013;31(1):90. Doi: 10.4103/0255-0857.108746. 4 Chowdhary Anuradha, Sharma Cheshta, Duggal Shalini, Agarwal Kshitij, Prakash Anupam, Kumar Singh Pradeep, et al. New Clonal Strain of Candida auris, Delhi, India. Emerg Infect Dis 2013;19(10):1670–3. Doi: 10.3201/eid1910.130393. 5 Magobo Rindidzani, Corcoran Craig, Seetharam Sharona, Govender Nelesh. Candida auris– Associated Candidemia, South Africa. Emerg Infect Dis 2014;20(7):1250–1. Doi: 10.3201/eid2007.131765. 6 Emara Maha, Ahmad Suhail, Khan Ziauddin, Joseph Leena, Al-Obaid Ina ’m, Purohit Prashant, et al. Candida auris Candidemia in Kuwait, 2014. Emerg Infect Dis 2015;21(6):1091–2. Doi: 10.3201/eid2106.150270. 7 Schelenz Silke, Hagen Ferry, Rhodes Johanna L, Abdolrasouli Alireza, Chowdhary Anuradha, Hall Anne, et al. First hospital outbreak of the globally emerging Candida auris in a European hospital. Antimicrob Resist Infect Control 2016;5:35. Doi: 10.1186/s13756-016-0132-5. 8 Calvo Belinda, Melo Analy SA, Perozo-Mena Armindo, Hernandez Martin, Francisco Elaine Cristina, Hagen Ferry, et al. First report of Candida auris in America: Clinical and microbiological aspects of 18 episodes of candidemia. J Infect 2016;73(4):369–74. Doi: 10.1016/j.jinf.2016.07.008. 9 Prakash A, Sharma C, Singh A, Kumar Singh P, Kumar A, Hagen F, 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. Clin Microbiol Infect 2016;22(3):277.e1-277.e9. Doi: 10.1016/j.cmi.2015.10.022. 10 Vallabhaneni S, Kallen A, Tsay S, Chow N, Welsh R, Kerins J, et al. Investigation of the First Seven Reported Cases of Candida auris, a Globally Emerging Invasive, Multidrug-Resistant Fungus—United States, May 2013–August 2016. Morb Mortal Wkly Rep 2016;65(44):1234–7. 11 Morales-López Soraya, Parra-Giraldo Claudia, Ceballos-Garzon Andres, Martinez Heidys, Rodriguez Gerson, Alvarez-Moreno Carlos, et al. Invasive Infections with Multidrug-Resistant Yeast Candida auris, Colombia. Emerg Infect Dis 2017;23(1):162–4. Doi: 10.3201/eid2301.161497. 12 Lockhart Shawn R, Etienne Kizee A, Vallabhaneni Snigdha, Farooqi Joveria, Chowdhary Anuradha, Govender Nelesh P, et al. Simultaneous Emergence of Multidrug-Resistant Candida auris on 3 Continents Confirmed by Whole-Genome Sequencing and Epidemiological Analyses. Clin Infect Dis 2017;64(2):134–40. Doi: 10.1093/cid/ciw691.
13 Ruiz Gaitán Alba Cecilia, Moret Ana, López Hontangas José Luis, Molina José Miguel, Aleixandre López Ana Isabel, Cabezas Alicia Hernández, et al. Nosocomial fungemia by Candida auris: First four reported cases in continental Europe. Rev Iberoam Micol 2017;34(1):23–7. Doi: 10.1016/j.riam.2016.11.002. 14 European Centre for Disease Prevention and Control. Candida auris in healthcare settings Europe 2016. 15 Ben-Ami Ronen, Berman Judith, Novikov Ana, Bash Edna, Shachor-Meyouhas Yael, Zakin Shiri, et al. Multidrug-Resistant Candida haemulonii and C. auris, Tel Aviv, Israel. Emerg Infect Dis 2017;23(2):195–203. Doi: 10.3201/eid2302.161486. 16 Al-Siyabi Turkiya, Al Busaidi Ibrahim, Balkhair Abdullah, Al-Muharrmi Zakariya, Al-Salti Maya, Al’Adawi Badriya. First report of Candida auris in Oman: Clinical and microbiological description of five candidemia cases. J Infect 2017. Doi: 10.1016/j.jinf.2017.05.016. 17 Chowdhary A, Kumar V Anil, Sharma C, Prakash A, Agarwal K, Babu R, et al. Multidrugresistant endemic clonal strain of Candida auris in India. Eur J Clin Microbiol Infect Dis 2014;33(6):919–26. Doi: 10.1007/s10096-013-2027-1. 18 Kathuria Shallu, Singh Pradeep K, Sharma Cheshta, Prakash Anupam, Masih Aradhana, Kumar Anil, 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. J Clin Microbiol 2015;53(6):1823–30. Doi: 10.1128/JCM.00367-15. 19 Borman Andrew M, Szekely Adrien, Johnson Elizabeth M. Comparative Pathogenicity of United Kingdom Isolates of the Emerging Pathogen Candida auris and Other Key Pathogenic Candida Species. mSphere 2016;1(4):e00189-16. Doi: 10.1128/mSphere.00189-16. 20 Larkin Emily, Hager Christopher, Chandra Jyotsna, Mukherjee Pranab K, Retuerto Mauricio, Salem Iman, et al. The Emerging Pathogen Candida auris: Growth Phenotype, Virulence Factors, Activity of Antifungals, and Effect of SCY-078, a Novel Glucan Synthesis Inhibitor, on Growth Morphology and Biofilm Formation. Antimicrob Agents Chemother 2017;61(5):e02396-16. Doi: 10.1128/AAC.02396-16. 21 Oh Bong Joon, Shin Jong Hee, Kim Mi-Na, Sung Heungsup, Lee Kyungwon, Joo Min Young, et al. Biofilm formation and genotyping of Candida haemulonii, Candida pseudohaemulonii, and a proposed new species (Candida auris) isolates from Korea. Med Mycol 2011;49(1):98– 102. Doi: 10.3109/13693786.2010.493563. 22 Candida auris Interim Recommendations for Healthcare Facilities and Laboratories | Fungal Diseases | CDC. Available at: https://www.cdc.gov/fungal/diseases/candidiasis/recommendations.html (Accessed June 27, 2017, 2017). 23 Kumar Anil, Sachu Arun, Mohan Karthika, Vinod Vivek, Dinesh Kavitha, Karim Shamsul. Simple low cost differentiation of Candida auris from Candida haemulonii complex using CHROMagar Candida medium supplemented with Pal’s medium. Rev Iberoam Micol 2017;34(2):109–11. Doi: 10.1016/j.riam.2016.11.004. 24 Sarma Smita, Upadhyay Shalini. Current perspective on emergence, diagnosis and drug resistance in Candida auris. Infect Drug Resist 2017;Volume 10:155–65. Doi: 10.2147/IDR.S116229.
25 Rudramurthy Shivaprakash M, Chakrabarti Arunaloke, Paul Raees A, Sood Prashant, Kaur Harsimran, Capoor Malini R, et al. Candida auris candidaemia in Indian ICUs: analysis of risk factors. J Antimicrob Chemother 2017;72(6):1794–801. Doi: 10.1093/jac/dkx034. 26 Lee Wee Gyo, Shin Jong Hee, Uh Young, Kang Min Gu, Kim Soo Hyun, Park Kyung Hwa, et al. First Three Reported Cases of Nosocomial Fungemia Caused by Candida auris. J Clin Microbiol 2011;49(9):3139–42. Doi: 10.1128/JCM.00319-11. 27 Khillan Vikas, Rathore Neha, Kathuria Shallu, Chowdhary Anuradha. A rare case of breakthrough fungal pericarditis due to fluconazole‐resistant Candida auris in a patient with chronic liver disease. JMM Case Rep 2014;1(3). Doi: 10.1099/jmmcr.0.T00018. 28 Choi Hyoung Il, An Jin, Hwang Jae Joon, Moon Soo-youn, Son Jun Seong. Otomastoiditis caused by Candida auris: Case report and literature review. Mycoses 2017:n/a-n/a. Doi: 10.1111/myc.12617. 29 Chowdhary Anuradha, Sharma Cheshta, Meis Jacques F. Candida auris: A rapidly emerging cause of hospital-acquired multidrug-resistant fungal infections globally. PLOS Pathog 2017;13(5):e1006290. Doi: 10.1371/journal.ppat.1006290. 30 Tsay Sharon, Welsh Rory, Adams Eleanor, Chow Nancy, Gade Lalitha, Berkow Elizabeth, et al. Notes from the Field: Ongoing Transmission of Candida auris in Health Care Facilities — United States, June 2016–May 2017. Morb Mortal Wkly Rep 2017;66(19):514–5. Doi: 10.15585/mmwr.mm6619a7. 31 Arendrup MC, Prakash Anupam, Meletiadis Joseph, Sharma Cheshta, Chowdhary Anuradha. Comparison of EUCAST and CLSI Reference Microdilution MICs of Eight Antifungal Compounds for Candida auris and Associated Tentative Epidemiological Cutoff Values. Antimicrob Agents Chemother 2017;61(6):e00485-17. Doi: 10.1128/AAC.00485-17. 32 Lepak Alexander J, Zhao Miao, Berkow Elizabeth L, Lockhart Shawn R, Andes David R. Pharmacodynamic Optimization for Treatment of Invasive Candida auris Infection. Antimicrob Agents Chemother 2017:AAC.00791-17. Doi: 10.1128/AAC.00791-17. 33 Piedrahita Christina T, Cadnum Jennifer L, Jencson Annette L, Shaikh Aaron A, Ghannoum Mahmoud A, Donskey Curtis J. Environmental Surfaces in Healthcare Facilities are a Potential Source for Transmission of Candida auris and Other Candida Species. Infect Control Hosp Epidemiol 2017:1–3. Doi: 10.1017/ice.2017.127. 34 Isolation Precautions | Guidelines Library | Infection Control | CDC. Available at: https://www.cdc.gov/infectioncontrol/guidelines/isolation/index.html (Accessed July 5, 2017, n.d.). 35 US EPA OCSPP. LIST K: EPA’s Registered Antimicrobial Products Effective against Clostridium difficile Spores. US EPA. Available at: https://www.epa.gov/pesticideregistration/list-k-epas-registered-antimicrobial-products-effective-against-clostridium (Accessed July 5, 2017, 2015). 36 Cadnum Jennifer L, Shaikh Aaron A, Piedrahita Christina T, Sankar Thriveen, Jencson Annette L, Larkin Emily L, et al. Effectiveness of Disinfectants Against Candida auris and Other Candida Species. Infect Control Hosp Epidemiol 2017:1–4. Doi: 10.1017/ice.2017.162. 37 Kordalewska Milena, Zhao Yanan, Lockhart Shawn R, Chowdhary Anuradha, Berrio Indira, Perlin David S. Rapid and accurate molecular identification of the emerging multidrug resistant pathogen Candida auris. J Clin Microbiol 2017:JCM.00630-17. Doi: 10.1128/JCM.00630-17. 38 Berkow Elizabeth L, Angulo David, Lockhart Shawn R. In Vitro Activity of a Novel Glucan Synthase Inhibitor, SCY-078, against Clinical Isolates of Candida auris. Antimicrob Agents Chemother 2017;61(7):e00435-17. Doi: 10.1128/AAC.00435-17.
Table 1. When to suspect Candida auris based on the organism presumptively identified and the method of identification22 Organism reported
Method
Candida haemulonii
Any
Candida spp.
Any validated identification method
Rhodotorula glutinis
API 20C if red color is not present
Candida sake
API 20C
Candida catenulata
BD Phoenix
Candida catenulata
MicroScan
Candida famata
MicroScan
Candida guilliermondii
MicroScan
Candida lusitaniae
MicroScan
Source: US Centers for Disease Control and Prevention
Table 2. Tentative MIC (mg/L) breakpoints for Candida auris susceptibility22 and published MIC ranges by CLSI microbroth dilution9,12,18,31 Antifungal drug
Tentative MIC Published Published breakpoint MIC50 Range MIC90 Range
Fluconazole
>32
64 – 128
64 – 256
Voriconazole A
N/A B
0.5 – 2
4–8
Amphotericin B
>2
0.5 – 1
2–4
Anidulafungin
>4
0.125 – 0.5
0.5 – 1
Caspofungin
>2
0.25 – 0.5
1
Micafungin
>4
0.125 – 0.25
0.25 – 2
A Also
applies to other second generation triazole antifungals
B Consider
using fluconazole susceptibility as a surrogate, although fluconazole-resistant
isolates may occasionally respond to other triazole antifungals