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Experience of treating Candida auris cases at a general hospital in the state of Qatar

Highlights • Candida. auris can cause invasive infections, including bloodstream, urinary tract, skin and ssoft tissue and lower respiratory tract infections.• Identification of C. auris requires specialized laboratory methods.• C. auris is associated with high morbidity and mortality.• C. auris isolates were resistant to the common antifungal agents such as fluconazole and amphotericin B.


Introduction
Candida auris is a novel multidrug-resistant yeast with high overall mortality that was first isolated from the external auditory canal of a patient in Japan in 2009 [1]. Since then, this fungal infection has been reported from various countries across the world [2][3][4], and over time it has become a serious global health concern as one of the most serious emerging pathogens that critical care physicians should be aware of [5].
C. auris being resistant to major antifungal classes used to treat Candida including azole antifungal agents, poses a challenge to routine microbiology laboratories, as C. auris can be misidentified with standard laboratory techniques, and have a tendency to cause outbreaks in healthcare settings especially critical care areas despite adequate infection prevention and control measures [4,5].
In Qatar, there is no published data on Candida aurisso far. In this series, we reported the first outbreak of C. auris infection in Qatar, to describe the clinical spectrum and outcome of this infection in the affected patients.

Methods and patients
We conducted this descriptive observational study in a general hospital in Qatar. We involved all patients with Candida Auris infection and colonization in the intensive care units and other wards from December 2018 to August 2019. This study was given ethical approval by the medical research committee at Hamad Medical Corporation, under number: MRC-01-19-503..

Definitions
Colonization is defined as isolation of C. auris from endotracheal aspiration fluid, throat swabs, sputum, urine, and samples from central venous catheters or other parts of the body in absence of clinical signs or symptomes of infection. C.auris infection is defined as the isolation of Cauris from clinical specimens with compatible clinical signs and symptoms of infection [5].

Candida auris identification
All clinical specimens, from different sites, were cultured by quantitative technique on Sabouraud Dextrose Agar (OXOID, UK) and incubated at 35À37 C for 48 h. Preliminary fungal strain identification was based on colony morphology on Chromogenic Candida Agar (OXOID, UK), while the identification to the species level was confirmed by Vitek 2 XL automated system (bioMerieux). Susceptibility of strains to Amphotericin B, Fluconazole, 5fluorocytosine, and voriconazole was determined by using Sensititre TM YeastOne TM plate and by interpreting results according to closely related Candida species and on expert opinion. As per the Centers for Disease Control and Prevention (CDC), there are currently no established C. auris-specific susceptibility breakpoints [6].
Pulsed-field gel electrophoresis (PFGE) typing, which consisted of electrophoretic karyotyping (EK), was performed to compare the isolates from different sites. Following the results of the PFGE, an outbreak of C. auris infection in critical care unit and medical unit was confirmed by identifying five5 cases and patient screening revealed colonization of eight additional patients. Intensive efforts were done to find out the cause of cross-transmission and environmental and surface swabbing was done in affected areas, but all results were negative.

Data analysis
The results of analyses of continuous variables are expressed as means and standard deviations (SD) unless otherwise specified.

Results
During the study period, we identified 13 patients with confirmed C. auris infection/colonization, of which five cases represented an actual Candida infection, while the remaining eight cases were considered colonization. The mean age of the patients with infection was 76.6 AE 8.4 years (range: 65-90 years), while the mean age of the patients with colonization was 66.4 AE 24.7 years (range: 23-91 years). Table 1 describes the demographic characteristics of the patients involved in this study.
Among the individuals clinically infected with C. auris, two had urinary tract infections, one had candidemia, one acquired soft tissue infection, and one had a lower respiratory tract infection. All patients had bacterial or viral infections prior to or concomitantly with C. auris infection/colonization, as shown in Table 1.
For the typing of C. auris isolates, the molecular technique PFGE, which consisted of electrophoretic karyotyping (EK), was utilized to compare the isolates from different sites. The PFGE karyotype of the outbreak isolates of C. auris in our series is shown in Fig. 1. Antifungal susceptibility tests were performed on isolates from infected subjects. All strains of C. auris shared the same susceptibility profile, being susceptible to echinocandins (especially anidulafungin), flucytosine, and posaconazole while resistance to fluconazole and amphotericin B. Table 2 shows the susceptibility pattern in the form of minimal inhibitory concentrations (MIC) of antifungal agents for the C. auris isolates. All patients with C. auris infection received systemic antifungal drugs, while the eight patients who were colonized were appropriately decolonized with topical nystatin and terbinafine as recommended by the CDC (Table 1).
Among the patients with C. auris infection who received systemic antifungal therapy, three (60 %) died during antifungal therapy. The other two patients were successfully treated and appropriately decolonized of C. auris (Table 1).

Discussion
Recent reports showed that C. auris is an emerging yeast that has been identified worldwide as a cause of severe invasive healthcare infections, which mostly affect critically ill patients and cause substantial morbidity and mortality [7,8]. To our knowledge, our series is the first designed to study this infection in Qatar.
Many C. auris outbreaks have been reported worldwide. In India, the first C. auris outbreak was reported in 2013 by Chowdhary et al. [9] [10]. All the isolates were initially identified as C. haemulonii. However, the isolation of C. auris was later confirmed by genome sequencing [9,10]. Similarly, we have reported the first outbreak of C. auris infection in Qatar, identifying 13 patients. The emergence of C. auris in our hospital raises concerns that this fungus may spread to other healthcare settings, particularly critical care facilities in Qatar, requiring intensified measures to control the spread of this infection. Therefore, knowing the source of infection and detection of possible routes of transmission can help in preventing the clonal spread of this infection and hospital outbreaks among various health facilities in Qatar [5,7,8]. Similarly, intensive efforts have been made in our hospital to find the cause of the crosstransmission. Environmental and surface swabs were carried out in the affected areas, but all results were negative.
Diagnosing C. auris infection is difficult because the clinical presentation is non-specific or may not be recognizable since patients infected with C. auris often have another serious illness or condition. Moreover, C. auris can be misidentified with standard laboratory techniques as C. haemulonii [11,12]. As a result, a high index of suspicion is required to diagnose this infection. In addition, accurate identification of C. auris through specialized laboratory methods is required to avoid misidentification and inappropriate treatment that may make it difficult to control the spread of C. auris in the healthcare settings [10]. In this study, the diagnosis of C. auris infection was suspected because of the resistance of the isolates to fluconazole and amphotericin B. The diagnosis was confirmed by molecular methods.
The spectrum of C. auris infection ranges from superficial infections that affect the skin to widespread infections that affect the brain, heart, lungs, liver, spleen, and kidneys [5]. Antifungal therapy should be administered to eradicate and control C. auris infection. On the other hand, C. auris can be isolated from the skin, rectum, wounds or mouth of some patients who do not show symptoms of infection. This condition is referred to as  asymptomatic colonization and treatment with antifungal drugs does not eradicate C. auris colonization. However, the identification of C. auris colonization is significant because it carries the risk of transmission, which requires the immediate implementation of adequate infection control measures [13]. Likewise, our patients showed different clinical presentations, and cases with colonization were identified and appropriately decolonized with topical nystatin and terbinafine as recommended by the CDC.
In agreement with other reports [3][4][5]7,13], our isolates showed resistance to the most important antifungal agents such as fluconazole and amphotericin B. The all cause mortality among our patients was 60 % which is in line with the mortality rate seen in other studies ranging from 30 to 60% [3].
One of the limitations of this study is the retrospective nature of the research. In addition, the small sample size is another factor that limits the generalizability of these findings.

Conclusion
C. auris can cause a wide variety of invasive infections, including bloodstream infections, urinary tract infection, skin infection, and lower respiratory tract infection, especially in critically ill patients. In addition, all isolates showed resistance to fluconazole and amphotericin B and were sensitive to echinocandins especially anidulafungin.

Authors contribution (Authorship)
Adila Shaukat: Desgning, interpretation of data, revising and approving the final draft.
Nasir Al Ansari: conception of the study, revising and approving the final draft.
Walid Al Wali: interpretation of data, revising and approving the final draft.
Edin Karic: interpretation of data, revising and approving the final draft.
Ihab El Madhoun: acquisition of data, revising and approving the final draft.
Hassan Mitwally: interpretation of data, revising and approving the final draft.
Manal Hamed: acquisition of data, revising and approving the final draft.
Feah Alutra-Visan: interpretation of data, drafting the article and approving the final draft.