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First report of sporadic cases of Candida auris in Colombia
Accepted Manuscript Title: First report of sporadic cases of Candida auris in Colombia Authors: Claudia M. Parra-Giraldo, Sandra L. Valderrama, Gloria Cortes-Fraile, Javier R. Garz´on, Beatriz E. Ariza, Florent Morio, Melva Y. Linares-Linares, Andr´es Ceballos-Garz´on, Alejandro de la Hoz, Catalina Hernandez, Carlos Alvarez-Moreno, Patrice Le Pape PII: DOI: Reference:
S1201-9712(18)30035-3 https://doi.org/10.1016/j.ijid.2018.01.034 IJID 3164
To appear in:
International Journal of Infectious Diseases
Received date: Revised date: Accepted date:
22-11-2017 29-1-2018 30-1-2018
Please cite this article as: Parra-Giraldo Claudia M, Valderrama Sandra L, Cortes-Fraile Gloria, Garz´on Javier R, Ariza Beatriz E, Morio Florent, LinaresLinares Melva Y, Ceballos-Garz´on Andr´es, de la Hoz Alejandro, Hernandez Catalina, Alvarez-Moreno Carlos, Le Pape Patrice.First report of sporadic cases of Candida auris in Colombia.International Journal of Infectious Diseases https://doi.org/10.1016/j.ijid.2018.01.034 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.
First report of sporadic cases of Candida auris in Colombia
Claudia M. Parra-Giraldo 1,4§,&, Sandra L. Valderrama2,4,&, Gloria Cortes-Fraile3,4, Javier R. Garzón2,4,
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Beatriz E. Ariza3,4 , Florent Morio5, Melva Y. Linares-Linares 1,4, Andrés Ceballos-Garzón 1, Alejandro de la Hoz4; Catalina Hernandez4, Carlos Alvarez-Moreno 4, Patrice Le Pape5 1
Unidad de Proteómica y Micosis Humanas, Grupo de Enfermedades Infecciosas Departamento de
Microbiología, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá D.C, Colombia. 2
Unidad de Infectología, Departamento de Medicina Interna, Facultad de Medicina, Grupo de
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Investigación en enfermedades infecciosas. Hospital Universitario San Ignacio, Pontificia
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Laboratorio clínico, Área de Microbiología, Hospital Universitario San Ignacio, Bogotá D.C,
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Colombia.
Grupo de Investigación en Enfermedades Infecciosas, Hospital Universitario San Ignacio. Pontificia
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Universidad Javeriana.
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Universidad Javeriana. Bogotá D.C, Colombia.
Département de Parasitologie et de Mycologie Médicale, Université de Nantes, Nantes Atlantique
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Universités, EA1155-IICiMed, Institut de Recherche en Santé 2, Nantes, France.
Corresponding author
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Claudia M. Parra G, Assistant professor, Director Unidad de Proteómica y Micosis Humanas
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E-mail address: [email protected]
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these authors contributed equally to this work.
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Highlights
The emerging fungus Candida auris is a serious global threat. It is often multidrugresistant, It has caused outbreaks in healthcare settings, being a public health problem.
Candida auris yeast is difficult to identify with standard laboratory tools, and it can be misidentified in labs without specific technology. Since was discovered Candida auris in 2009 it has spread quickly and caused infections in
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more than a dozen countries this is the first reported case associated with Candida auris in Colombia.
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Abstract
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Background. Candida auris is a recently reported Candida species which is phenotypically
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similar to Candida haemulonii and related to hospital outbreaks. This organism can be
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misidentified as C. haemulonii, C. famata, C. catenulata or Rhodotorula glutinis by phenotypic approaches. MALDI-TOF MS and DNA sequence analysis using ITS rDNA
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barcoding provide an accurate identification.
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Case presentations. Three cases of C. auris infection in patients with risk factors for fungal infection (Admitted to the intensive care unit, lymphoma and HIV respectively, all
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three with previous antibiotic use) and not epidemiologically related. Yeast isolates were
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recovered from blood, ocular secretion, and bronchoalveolar lavage and were misidentified as C. catenulata and C. albicans by the phenotypic MicroScan® method. By means of
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MALDI-TOF MS and DNA sequence analysis we confirmed it to be C. auris. Antifungal susceptibility testing was performed on these C. auris isolates, which exhibited high minimal inhibitory concentrations (MICs) to triazole and amphotericin B. One patient survived and the other two died. Only one could be related to fungaemia.
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Conclusions. C. auris is an emerging and opportunistic multidrug resistant human pathogen. It is necessary to strengthen measures to both achieve an accurate and quick identification, and also to avoid its dissemination, therefore improving health and infection
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control measures as well as promoting the antifungal stewardship in healthcare facilities. Keywords: Candida auris; Multi Drug Resistance, Sporadic, fungal; Colombia
Part of this study was presented at the ECCMID 2016 26th European Congress of Clinical Microbiology and Infectious Diseases, 9-12 April 2016, Amsterdam, Netherlands poster session Abstract #5556. Performance of MALDI-TOF MS for the identification of
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emerging yeast of hospital patients, species distribution, in a third level hospital Bogotá-
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Colombia.
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Background
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Uncommon Candida species are being increasingly recognized to cause candida infections and are being associated to hospital outbreaks [1–3]. Candida auris is a recently described
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Candida species which is phenotypical and phylogenetic closely related to the Candida
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haemulonii species complex (Candida duobushaemulonii and Candida pseudohaemulonii).
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C. auris was first recovered in 2009 from the external ear canal of a 70 year old-female Japanese patient in Tokyo [4]. Subsequently, three more cases of nosocomial candidemia
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were diagnosed in Korea [5]. These C. auris isolates, identified by internal transcribed space (ITS) regions and D1/D2 rRNA sequencing, had been previously misidentified as C.
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haemulonii and Rhodotorula glutinis by the commercial Vitek 2 and API 20C phenotypical systems respectively. Since then, C. auris infections have been described in India, South Africa, Kuwait, Brazil, United Kingdom, Pakistan, and most recently in Venezuela and USA [6–12].
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Accurate identification of Candida species can has important implications in the treatment of invasive candidiasis since C. auris is often described as a multidrug resistant species. Indeed, antifungal susceptibility studies demonstrated that C. auris generally exhibited high
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MICs to fluconazole but less frequently to voriconazole, amphotericin B or echinocandins [13,14].
The existence of C. auris in Colombia was first reported by us during a prospective study
[15]. More recently, 17 new cases have been diagnosed in Valledupar city, a geographically distant location from Bogotá [16]. Here we describe the clinical and biological
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characteristics of the three Candida cases caused by the species C. auris, which occurred
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during the prospective study over a 4-year period in a Bogotá’s hospital, Colombia.
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Cases Presentation
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Case 1
A 74-year-old male was admitted on November 2013 with alteration of his mental status
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with a Glasgow Coma Scale of 7/15 and a personal history of major depression,
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hypertension, mitral valve replacement, and hypothyroidism. On physical examination the
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patient had an oxygen saturation (SO2) of 88%, hyporesponsive pupils, rales on both pulmonary bases, fever, and high creatinin phosphokinase. He was intubated and admitted
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to the intensive care unit (ICU) where acute myocardial infarction and stroke were ruled out. According to his evolution, a neuroleptic malignant syndrome was diagnosed. He
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developed rhabdomyolysis and acute kidney failure. During his stay in the ICU a nosocomial pneumonia caused by an extended-spectrum β-lactamase (ESBL)-producer K. pneumoniae was diagnosed. He received empiric treatment with cefepime and then with ertapenem. During his in-hospital stay, mental status deterioration persisted and fifteen days after admission he developed multiple organ failure. Since blood culture set reported 4
yeasts, anidulafungin (100mg/day) was administrated, in spite of which, two days later, the patient died. Case 2
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A 45-year-old man with a history of cutaneous T cell non-hodgkin lymphoma nonresponsive to multiple chemotherapy regimens who received the last cycle 17 days before admission with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) was
admitted to this hospital on December 2014. He presented to the emergency room for a 3day fever associated to infection signs in skin tumoral lesions on his face and parietal
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region, which were erythematous and desquamating. Also, the patient presented palpebral
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swelling and abundant conjunctival and skin purulent secretion, so diagnosis of preseptal
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cellulitis was done. Treatment was started with cefepime plus vancomycin. Topical
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mupirocin 2% with oxytetracycline hydrochloride, fluorometholone and polymyxin B sulfate in ophthalmic ointment. One set of blood cultures were negative 5 days after
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hospitalization. The patient did not show improvement and the treatment was switched to
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meropenem and linezolid. Conjunctival secretion and skin biopsy culture of the parietal
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lesion were positive for Candida catenulata and Candida parapsilosis respectively as identified using Microscan® system. Treatment with caspofungin (50 mg/day) was started
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for 15 days and subsequently, samples were negative for Candida. During the inpatient treatment, the malignancy progressed and the patient’s conditions continued to deteriorate.
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He died 2 months after admission. Case 3 A 51-year-old woman admitted to the emergency room on February 2015 for respiratory failure and oral candidiasis. She was previously diagnosed with HIV (since 2000 during her pregnancy screening) with a history of poor adherence to her antiretroviral therapy, 5
which she hadn’t been taking for a year before her admission (her last absolute CD4 lymphocyte count was 115 cells/mm3). Bronchoalveolar lavage (BAL) confirmed pneumonitis by Pneumocystis jirovecii on Gomori-Grocott stain. She received treatment
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with TMP/SMX and steroids during 21 days and fluconazole 7 days. She required orotracheal intubation in ICU due to acute respiratory distress syndrome (ARDS) for 7
days. After 23 days, she was discharged with a favorable evolution. BAL cultures taken at admission reported Candida albicans by phenotypic method. Yeast identification
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Clinical isolates were initially seeded on CHROMagar Candida medium (Becton
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Dickinson, Meylan, France) and Sabouraud dextrose agar (Difco, St Louis, Mo) at 35° C
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for 24 - 36 hours. Subsequently, identification was carried out using both the automated
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system MicroScan® WalkAway 96 Plus (Siemens, Deerfield, IL, USA) and the matrixassisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF-MS)
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Bruker Microflex LT (Biotyper system Bremen, Germany). The isolates exhibited pinked
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colonies on CHROMagar® Candida medium. The phenotypic MicroScan® method failed
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to identify the first isolate which was only identified by MALDI-TOF-MS as C. auris. The ocular secretion sample exhibited isolates identified as C. catenulata and C. parapsilosis
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by MicroScan®, but these were then identified as C. auris and C. metapsilosis respectively by MALDI-TOF-MS. The isolate of BAL was phenotypically misdiagnosed as C. albicans.
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Identification of these three clinical isolates was finally obtained by ITS rDNA barcoding using ITS1 and ITS4 primer pairs [17]. Antifungal susceptibility assay In vitro antifungal susceptibility profile of the three isolates was performed using the commercial Etest method (bioMérieux, Marcy l'étoile, France) to echinocandins 6
(anidulafungin, caspofungin and micafungin), triazoles (fluconazole, itraconazole, voriconazole, posaconazole and isavuconazole) and polyene (amphotericin B) according to the manufacturer’s instructions. Briefly, yeast inoculum was adjusted with a
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spectrophotometer by adding sterile 0.85% NaCl to match 0.5 McFarland. The MICs were read after 24h - 48h of incubation at 35 °C. The MIC values were determined at the point of intersection of the inhibition growth ellipse with E-test strip. The MICs of the quality
control strains C. parapsilosis ATCC 22019 and C. krusei ATCC 6258 were all within the reference ranges (data not shown). Table 1 shows MICs of the nine antifungals tested
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against C. auris. Fluconazole demonstrated no activity (MIC: 12 - >256 g/ml) against the
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three isolates, whereas the third isolate of C. auris was fully resistant to amphotericin B and
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Mass Spectra Phylogenetic Analysis.
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itraconazole. All three echinocandins were the most efficient antifungals.
For phylogenetic analysis of mass spectra for 3 C. auris isolates, the dendrogram was
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generated by using the respective functionality of the MALDI-TOF Biotyper 3.1 offline
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client. The mass spectra of each quadruplicate of the respective isolates with a score value
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of >2 were considered for dendrogram preparation. The spectra of all the isolates tested were analyzed as a core-oriented dendrogram using an arbitrary distance level of 1,000 as
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the cutoff [18,19]. The dendrogram obtained showed two clades when compared to the MS of each isolate (Figure 1).
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Discussion
Concerning epidemiology of candidemia, the Latin America Invasive Mycosis Network estimated an incidence of 1.18/1,000 hospital admissions for the region. Colombia and
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Argentina showed the highest incidence (1.96 and 1.95/1,000 hospital admissions retrospectively) and Chile the lowest (0.33/1,000 hospital admissions) [20]. Since last years, an increasing number of emerging or cryptic Candida species such as C.
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orthopsilosis, C. metapsilosis, C. bracariensis, C. nivariensis, which are difficult to identify by phenotypic methods have been reported from human infections [3,21]. Among them,
C. auris was described in 2009 to be genetically close to species of C. haemulonii complex and suggested to be a new opportunistic fungal pathogen implicated in candidemia [21].
Patients with C. auris isolates in this report had similar risk factors to those described in the
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literature such as immunosuppression, diabetes, chronic renal disease, use of broad
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spectrum antibiotics, hospitalization in ICU, urinary catheters, recent surgery, and central
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venous catheters [5,8,11,22]. While most reports worldwide are of patients with fungemia
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(28.6%), there are few reports on isolation from other sites such as wounds, urine, peritoneal fluid and pleural effusion [12,21,22]. To our knowledge, this is the first report of
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C. auris isolated from ocular secretion and the second from BAL; it is important to
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emphasize that the BAL isolate was not interpreted as infection but only as colonization.
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Currently, there is no information about the ecologic niche of C. auris, neither about the colonization rate in the general population.
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These present cases are clearly not related to epidemiological outbreaks as described previously in India, Venezuela, the United Kingdom, Spain and Oman [10,11,13,24–26].
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Each case in this report presented itself independently with no time relationship between them. Proteomic dendrograms which show different spectra seem to be in agreement with this epidemiologic finding. However, caution should be used when interpreting MALDITOF MS relatedness models, this preliminary data will need to be completed by a molecular biology approach. The lack of outbreak could be due to the strong infection 8
control program in our hospital where adherence to hand hygiene in healthcare workers was very high (90 %) during the study period. On the other hand, a hypothesis of the appearance of C. auris could be a consequence of an increase in the antifungal selection pressure but
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these patients had not received previous treatment, which diminishes this possibility still, we cannot completely rule out a cross infection.
Difficulties in mycological identification of C. auris using conventional phenotypic systems and the low access to MALDI-TOF and molecular biology tools in routine
laboratories can contribute to its underestimation. According to literature, Phoenix® and
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Vitek® technologies can misidentify C. auris as C. haemulonii, Rodothorula glutinis, C.
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famata and C. catenulata [6,10]. Using MicroScan®, our isolates were identified initially
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as C. catenulata and C. albicans. It is also possible that some systems cannot identify any
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species from the sample. Misidentification may lead to inadequate treatment of these patients due to the multidrug-resistance pattern of this yeast species.
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Susceptibility profile of C. auris exhibited high MICs towards fluconazole and other
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triazoles. Overestimation of MICs to amphotericin B and caspofungin has been described
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using the Vitek system compared to CLSI reference methods [23,27]. According to E-test, both of our two first isolates were susceptible to all antifungal agents except for
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fluconazole. The third isolate had a high MIC for fluconazole, itraconazole and amphotericin B.
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Conclusions and recommendations It is important to search actively and achieve a correct identification of Candida species by MALDI-TOF or molecular biology considering the increased circulation of cryptic species with resistance patterns to multiple antifungal agents reported in Latin America and the alert from the Centers for Disease Control and Prevention, [28] related to the dissemination 9
of C. auris [11,15,16]. It is necessary to strengthen measures to not only achieve accurate and rapid identification, but also to avoid its dissemination improving the infection control
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measures and to promote the antifungal stewardship in healthcare facilities.
Declarations • Funding
This work has been financial by grant with ID 2014-52 for researcher office of Hospital
Universitario San Ignacio and grant with ID 00006457 for researcher vice rectory Pontificia
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Universidad Javeriana.
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• Authors' contributions
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SLV, JRG, AH, CH, CAA analyzed the clinical data and GC, MYL, BEA performance of antifungal susceptibility experiments. AC, CMPG analyzed microbial data by MALDI-TOF
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designed the experiments.
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MS, FM, PLP molecular identification and SLV, CAA, CMPG, PLP conceived and
•Ethics approval and consent to participate
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This study was approved by the research and ethics committee of Hospital Universitario
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San Ignacio (HUSI).
•Competing interests The authors declare that they have no competing interests
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•Acknowledgements We would like to thank Diana Milena Paipilla Arena for her technical support, in the strain identification by MALDI-TOF-MS from the Unidad de Investigación en Proteómica y
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Micosis Humanas, Pontificia Universidad Javeriana.
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Figure 1. (A) Candida auris isolate spectra (upper three panels PUJ/HUSI) compared with C. haemulonii spectra from clinical isolate (lower panel). (B) Bruker BiotyperTM PCA dendrogram clustering of the MSPs representative spectra from each isolate/strain with distances displayed in
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relative units on y axis
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Table 1 MIC (µg/mL) of drug
1 2
MYC
ANI
0.19
0.12
0.125
0.004
0.094
0.016
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AMB FLC ITR VOR POS ISA CAS Isolates source 0001 0.75 24 0.25 0.64 0.023 0.125 0.47 Blood PUJ/HUSI 0435 Ocular 0.75 12 0.25 0.047 0.023 0.19 0.094 PUJ/HUSI Secretion 00537 > 32 > 256 2 0.75 0.5 1.5 0.016 BAL PUJ/HUSI AMB: anfotericine B; FLC: Floconazole; ITR: Itraconazole; VOR: Voriconazole; POS: Posaconazole; ISA: isavuconazole; CAS: Caspofungin; MYC: Micafungin; ANI: Anidulafungin.
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Case
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S1201-9712(18)30035-3 https://doi.org/10.1016/j.ijid.2018.01.034 IJID 3164
To appear in:
International Journal of Infectious Diseases
Received date: Revised date: Accepted date:
22-11-2017 29-1-2018 30-1-2018
Please cite this article as: Parra-Giraldo Claudia M, Valderrama Sandra L, Cortes-Fraile Gloria, Garz´on Javier R, Ariza Beatriz E, Morio Florent, LinaresLinares Melva Y, Ceballos-Garz´on Andr´es, de la Hoz Alejandro, Hernandez Catalina, Alvarez-Moreno Carlos, Le Pape Patrice.First report of sporadic cases of Candida auris in Colombia.International Journal of Infectious Diseases https://doi.org/10.1016/j.ijid.2018.01.034 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.
First report of sporadic cases of Candida auris in Colombia
Claudia M. Parra-Giraldo 1,4§,&, Sandra L. Valderrama2,4,&, Gloria Cortes-Fraile3,4, Javier R. Garzón2,4,
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Beatriz E. Ariza3,4 , Florent Morio5, Melva Y. Linares-Linares 1,4, Andrés Ceballos-Garzón 1, Alejandro de la Hoz4; Catalina Hernandez4, Carlos Alvarez-Moreno 4, Patrice Le Pape5 1
Unidad de Proteómica y Micosis Humanas, Grupo de Enfermedades Infecciosas Departamento de
Microbiología, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá D.C, Colombia. 2
Unidad de Infectología, Departamento de Medicina Interna, Facultad de Medicina, Grupo de
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Investigación en enfermedades infecciosas. Hospital Universitario San Ignacio, Pontificia
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Laboratorio clínico, Área de Microbiología, Hospital Universitario San Ignacio, Bogotá D.C,
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Colombia.
Grupo de Investigación en Enfermedades Infecciosas, Hospital Universitario San Ignacio. Pontificia
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Universidad Javeriana.
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Universidad Javeriana. Bogotá D.C, Colombia.
Département de Parasitologie et de Mycologie Médicale, Université de Nantes, Nantes Atlantique
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Universités, EA1155-IICiMed, Institut de Recherche en Santé 2, Nantes, France.
Corresponding author
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Claudia M. Parra G, Assistant professor, Director Unidad de Proteómica y Micosis Humanas
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E-mail address: [email protected]
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these authors contributed equally to this work.
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Highlights
The emerging fungus Candida auris is a serious global threat. It is often multidrugresistant, It has caused outbreaks in healthcare settings, being a public health problem.
Candida auris yeast is difficult to identify with standard laboratory tools, and it can be misidentified in labs without specific technology. Since was discovered Candida auris in 2009 it has spread quickly and caused infections in
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more than a dozen countries this is the first reported case associated with Candida auris in Colombia.
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Abstract
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Background. Candida auris is a recently reported Candida species which is phenotypically
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similar to Candida haemulonii and related to hospital outbreaks. This organism can be
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misidentified as C. haemulonii, C. famata, C. catenulata or Rhodotorula glutinis by phenotypic approaches. MALDI-TOF MS and DNA sequence analysis using ITS rDNA
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barcoding provide an accurate identification.
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Case presentations. Three cases of C. auris infection in patients with risk factors for fungal infection (Admitted to the intensive care unit, lymphoma and HIV respectively, all
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three with previous antibiotic use) and not epidemiologically related. Yeast isolates were
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recovered from blood, ocular secretion, and bronchoalveolar lavage and were misidentified as C. catenulata and C. albicans by the phenotypic MicroScan® method. By means of
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MALDI-TOF MS and DNA sequence analysis we confirmed it to be C. auris. Antifungal susceptibility testing was performed on these C. auris isolates, which exhibited high minimal inhibitory concentrations (MICs) to triazole and amphotericin B. One patient survived and the other two died. Only one could be related to fungaemia.
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Conclusions. C. auris is an emerging and opportunistic multidrug resistant human pathogen. It is necessary to strengthen measures to both achieve an accurate and quick identification, and also to avoid its dissemination, therefore improving health and infection
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control measures as well as promoting the antifungal stewardship in healthcare facilities. Keywords: Candida auris; Multi Drug Resistance, Sporadic, fungal; Colombia
Part of this study was presented at the ECCMID 2016 26th European Congress of Clinical Microbiology and Infectious Diseases, 9-12 April 2016, Amsterdam, Netherlands poster session Abstract #5556. Performance of MALDI-TOF MS for the identification of
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emerging yeast of hospital patients, species distribution, in a third level hospital Bogotá-
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Colombia.
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Background
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Uncommon Candida species are being increasingly recognized to cause candida infections and are being associated to hospital outbreaks [1–3]. Candida auris is a recently described
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Candida species which is phenotypical and phylogenetic closely related to the Candida
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haemulonii species complex (Candida duobushaemulonii and Candida pseudohaemulonii).
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C. auris was first recovered in 2009 from the external ear canal of a 70 year old-female Japanese patient in Tokyo [4]. Subsequently, three more cases of nosocomial candidemia
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were diagnosed in Korea [5]. These C. auris isolates, identified by internal transcribed space (ITS) regions and D1/D2 rRNA sequencing, had been previously misidentified as C.
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haemulonii and Rhodotorula glutinis by the commercial Vitek 2 and API 20C phenotypical systems respectively. Since then, C. auris infections have been described in India, South Africa, Kuwait, Brazil, United Kingdom, Pakistan, and most recently in Venezuela and USA [6–12].
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Accurate identification of Candida species can has important implications in the treatment of invasive candidiasis since C. auris is often described as a multidrug resistant species. Indeed, antifungal susceptibility studies demonstrated that C. auris generally exhibited high
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MICs to fluconazole but less frequently to voriconazole, amphotericin B or echinocandins [13,14].
The existence of C. auris in Colombia was first reported by us during a prospective study
[15]. More recently, 17 new cases have been diagnosed in Valledupar city, a geographically distant location from Bogotá [16]. Here we describe the clinical and biological
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characteristics of the three Candida cases caused by the species C. auris, which occurred
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during the prospective study over a 4-year period in a Bogotá’s hospital, Colombia.
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Cases Presentation
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Case 1
A 74-year-old male was admitted on November 2013 with alteration of his mental status
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with a Glasgow Coma Scale of 7/15 and a personal history of major depression,
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hypertension, mitral valve replacement, and hypothyroidism. On physical examination the
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patient had an oxygen saturation (SO2) of 88%, hyporesponsive pupils, rales on both pulmonary bases, fever, and high creatinin phosphokinase. He was intubated and admitted
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to the intensive care unit (ICU) where acute myocardial infarction and stroke were ruled out. According to his evolution, a neuroleptic malignant syndrome was diagnosed. He
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developed rhabdomyolysis and acute kidney failure. During his stay in the ICU a nosocomial pneumonia caused by an extended-spectrum β-lactamase (ESBL)-producer K. pneumoniae was diagnosed. He received empiric treatment with cefepime and then with ertapenem. During his in-hospital stay, mental status deterioration persisted and fifteen days after admission he developed multiple organ failure. Since blood culture set reported 4
yeasts, anidulafungin (100mg/day) was administrated, in spite of which, two days later, the patient died. Case 2
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A 45-year-old man with a history of cutaneous T cell non-hodgkin lymphoma nonresponsive to multiple chemotherapy regimens who received the last cycle 17 days before admission with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) was
admitted to this hospital on December 2014. He presented to the emergency room for a 3day fever associated to infection signs in skin tumoral lesions on his face and parietal
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region, which were erythematous and desquamating. Also, the patient presented palpebral
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swelling and abundant conjunctival and skin purulent secretion, so diagnosis of preseptal
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cellulitis was done. Treatment was started with cefepime plus vancomycin. Topical
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mupirocin 2% with oxytetracycline hydrochloride, fluorometholone and polymyxin B sulfate in ophthalmic ointment. One set of blood cultures were negative 5 days after
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hospitalization. The patient did not show improvement and the treatment was switched to
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meropenem and linezolid. Conjunctival secretion and skin biopsy culture of the parietal
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lesion were positive for Candida catenulata and Candida parapsilosis respectively as identified using Microscan® system. Treatment with caspofungin (50 mg/day) was started
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for 15 days and subsequently, samples were negative for Candida. During the inpatient treatment, the malignancy progressed and the patient’s conditions continued to deteriorate.
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He died 2 months after admission. Case 3 A 51-year-old woman admitted to the emergency room on February 2015 for respiratory failure and oral candidiasis. She was previously diagnosed with HIV (since 2000 during her pregnancy screening) with a history of poor adherence to her antiretroviral therapy, 5
which she hadn’t been taking for a year before her admission (her last absolute CD4 lymphocyte count was 115 cells/mm3). Bronchoalveolar lavage (BAL) confirmed pneumonitis by Pneumocystis jirovecii on Gomori-Grocott stain. She received treatment
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with TMP/SMX and steroids during 21 days and fluconazole 7 days. She required orotracheal intubation in ICU due to acute respiratory distress syndrome (ARDS) for 7
days. After 23 days, she was discharged with a favorable evolution. BAL cultures taken at admission reported Candida albicans by phenotypic method. Yeast identification
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Clinical isolates were initially seeded on CHROMagar Candida medium (Becton
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Dickinson, Meylan, France) and Sabouraud dextrose agar (Difco, St Louis, Mo) at 35° C
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for 24 - 36 hours. Subsequently, identification was carried out using both the automated
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system MicroScan® WalkAway 96 Plus (Siemens, Deerfield, IL, USA) and the matrixassisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF-MS)
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Bruker Microflex LT (Biotyper system Bremen, Germany). The isolates exhibited pinked
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colonies on CHROMagar® Candida medium. The phenotypic MicroScan® method failed
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to identify the first isolate which was only identified by MALDI-TOF-MS as C. auris. The ocular secretion sample exhibited isolates identified as C. catenulata and C. parapsilosis
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by MicroScan®, but these were then identified as C. auris and C. metapsilosis respectively by MALDI-TOF-MS. The isolate of BAL was phenotypically misdiagnosed as C. albicans.
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Identification of these three clinical isolates was finally obtained by ITS rDNA barcoding using ITS1 and ITS4 primer pairs [17]. Antifungal susceptibility assay In vitro antifungal susceptibility profile of the three isolates was performed using the commercial Etest method (bioMérieux, Marcy l'étoile, France) to echinocandins 6
(anidulafungin, caspofungin and micafungin), triazoles (fluconazole, itraconazole, voriconazole, posaconazole and isavuconazole) and polyene (amphotericin B) according to the manufacturer’s instructions. Briefly, yeast inoculum was adjusted with a
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spectrophotometer by adding sterile 0.85% NaCl to match 0.5 McFarland. The MICs were read after 24h - 48h of incubation at 35 °C. The MIC values were determined at the point of intersection of the inhibition growth ellipse with E-test strip. The MICs of the quality
control strains C. parapsilosis ATCC 22019 and C. krusei ATCC 6258 were all within the reference ranges (data not shown). Table 1 shows MICs of the nine antifungals tested
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against C. auris. Fluconazole demonstrated no activity (MIC: 12 - >256 g/ml) against the
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three isolates, whereas the third isolate of C. auris was fully resistant to amphotericin B and
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Mass Spectra Phylogenetic Analysis.
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itraconazole. All three echinocandins were the most efficient antifungals.
For phylogenetic analysis of mass spectra for 3 C. auris isolates, the dendrogram was
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generated by using the respective functionality of the MALDI-TOF Biotyper 3.1 offline
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client. The mass spectra of each quadruplicate of the respective isolates with a score value
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of >2 were considered for dendrogram preparation. The spectra of all the isolates tested were analyzed as a core-oriented dendrogram using an arbitrary distance level of 1,000 as
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the cutoff [18,19]. The dendrogram obtained showed two clades when compared to the MS of each isolate (Figure 1).
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Discussion
Concerning epidemiology of candidemia, the Latin America Invasive Mycosis Network estimated an incidence of 1.18/1,000 hospital admissions for the region. Colombia and
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Argentina showed the highest incidence (1.96 and 1.95/1,000 hospital admissions retrospectively) and Chile the lowest (0.33/1,000 hospital admissions) [20]. Since last years, an increasing number of emerging or cryptic Candida species such as C.
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orthopsilosis, C. metapsilosis, C. bracariensis, C. nivariensis, which are difficult to identify by phenotypic methods have been reported from human infections [3,21]. Among them,
C. auris was described in 2009 to be genetically close to species of C. haemulonii complex and suggested to be a new opportunistic fungal pathogen implicated in candidemia [21].
Patients with C. auris isolates in this report had similar risk factors to those described in the
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literature such as immunosuppression, diabetes, chronic renal disease, use of broad
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spectrum antibiotics, hospitalization in ICU, urinary catheters, recent surgery, and central
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venous catheters [5,8,11,22]. While most reports worldwide are of patients with fungemia
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(28.6%), there are few reports on isolation from other sites such as wounds, urine, peritoneal fluid and pleural effusion [12,21,22]. To our knowledge, this is the first report of
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C. auris isolated from ocular secretion and the second from BAL; it is important to
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emphasize that the BAL isolate was not interpreted as infection but only as colonization.
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Currently, there is no information about the ecologic niche of C. auris, neither about the colonization rate in the general population.
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These present cases are clearly not related to epidemiological outbreaks as described previously in India, Venezuela, the United Kingdom, Spain and Oman [10,11,13,24–26].
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Each case in this report presented itself independently with no time relationship between them. Proteomic dendrograms which show different spectra seem to be in agreement with this epidemiologic finding. However, caution should be used when interpreting MALDITOF MS relatedness models, this preliminary data will need to be completed by a molecular biology approach. The lack of outbreak could be due to the strong infection 8
control program in our hospital where adherence to hand hygiene in healthcare workers was very high (90 %) during the study period. On the other hand, a hypothesis of the appearance of C. auris could be a consequence of an increase in the antifungal selection pressure but
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these patients had not received previous treatment, which diminishes this possibility still, we cannot completely rule out a cross infection.
Difficulties in mycological identification of C. auris using conventional phenotypic systems and the low access to MALDI-TOF and molecular biology tools in routine
laboratories can contribute to its underestimation. According to literature, Phoenix® and
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Vitek® technologies can misidentify C. auris as C. haemulonii, Rodothorula glutinis, C.
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famata and C. catenulata [6,10]. Using MicroScan®, our isolates were identified initially
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as C. catenulata and C. albicans. It is also possible that some systems cannot identify any
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species from the sample. Misidentification may lead to inadequate treatment of these patients due to the multidrug-resistance pattern of this yeast species.
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Susceptibility profile of C. auris exhibited high MICs towards fluconazole and other
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triazoles. Overestimation of MICs to amphotericin B and caspofungin has been described
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using the Vitek system compared to CLSI reference methods [23,27]. According to E-test, both of our two first isolates were susceptible to all antifungal agents except for
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fluconazole. The third isolate had a high MIC for fluconazole, itraconazole and amphotericin B.
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Conclusions and recommendations It is important to search actively and achieve a correct identification of Candida species by MALDI-TOF or molecular biology considering the increased circulation of cryptic species with resistance patterns to multiple antifungal agents reported in Latin America and the alert from the Centers for Disease Control and Prevention, [28] related to the dissemination 9
of C. auris [11,15,16]. It is necessary to strengthen measures to not only achieve accurate and rapid identification, but also to avoid its dissemination improving the infection control
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measures and to promote the antifungal stewardship in healthcare facilities.
Declarations • Funding
This work has been financial by grant with ID 2014-52 for researcher office of Hospital
Universitario San Ignacio and grant with ID 00006457 for researcher vice rectory Pontificia
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Universidad Javeriana.
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• Authors' contributions
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SLV, JRG, AH, CH, CAA analyzed the clinical data and GC, MYL, BEA performance of antifungal susceptibility experiments. AC, CMPG analyzed microbial data by MALDI-TOF
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designed the experiments.
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MS, FM, PLP molecular identification and SLV, CAA, CMPG, PLP conceived and
•Ethics approval and consent to participate
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This study was approved by the research and ethics committee of Hospital Universitario
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San Ignacio (HUSI).
•Competing interests The authors declare that they have no competing interests
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•Acknowledgements We would like to thank Diana Milena Paipilla Arena for her technical support, in the strain identification by MALDI-TOF-MS from the Unidad de Investigación en Proteómica y
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Micosis Humanas, Pontificia Universidad Javeriana.
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Figure 1. (A) Candida auris isolate spectra (upper three panels PUJ/HUSI) compared with C. haemulonii spectra from clinical isolate (lower panel). (B) Bruker BiotyperTM PCA dendrogram clustering of the MSPs representative spectra from each isolate/strain with distances displayed in
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relative units on y axis
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Table 1 MIC (µg/mL) of drug
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MYC
ANI
0.19
0.12
0.125
0.004
0.094
0.016
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AMB FLC ITR VOR POS ISA CAS Isolates source 0001 0.75 24 0.25 0.64 0.023 0.125 0.47 Blood PUJ/HUSI 0435 Ocular 0.75 12 0.25 0.047 0.023 0.19 0.094 PUJ/HUSI Secretion 00537 > 32 > 256 2 0.75 0.5 1.5 0.016 BAL PUJ/HUSI AMB: anfotericine B; FLC: Floconazole; ITR: Itraconazole; VOR: Voriconazole; POS: Posaconazole; ISA: isavuconazole; CAS: Caspofungin; MYC: Micafungin; ANI: Anidulafungin.
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Case
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