Native human and mouse skin infection models to study Candida auris-host interactions
Saskia SeiserHossein ArzaniTanya AyubTrinh Phan-CanhClement StaudChristof WordaKarl KuchlerAdelheid Elbe‐Bürger
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The World Health Organization (WHO) declared certain fungal pathogens as global health threats for the next decade. Candida auris (C. auris) is a newly emerging skin-tropic multidrug-resistant fungal pathogen that can cause life-threatening infections of high mortality in hospitals and healthcare settings. Here, we address an unmet need and present novel native ex vivo skin models, thus extending previous C. auris-host interaction studies. We exploit histology and immunofluorescence analysis of ex vivo skin biopsies of human adult and fetal, as well as mouse origin infected with C. auris via distinct routes. We demonstrate that an intact skin barrier efficiently protects from C. auris penetration and invasion. Although C. auris readily grows on native human skin, it can reach deeper layers only upon physical disruption of the barrier by needling or through otherwise damaged skin. By contrast, a barrier disruption is not necessary for C. auris penetration of native mouse skin. Importantly, we show that C. auris undergoes morphogenetic changes upon skin penetration, as it acquires pseudohyphal growth phenotypes in deeper human and mouse dermal layers. Taken together, this new human and mouse skin model toolset yields new insights into C. auris colonization, adhesion, growth and invasion properties of native versus damaged human skin. The results form a crucial basis for future studies on skin immune defense to colonizing pathogens, and offer new options for testing the action and efficacy of topical antimicrobial compound formulations.Keywords:
Candida auris
Human skin
Ex vivo
Candida auris is an emerging multidrug-resistant fungus associated with high mortality rates. With a predilection for immunocompromised patients, C. auris has been reported to be the cause of several nosocomial outbreaks. Conventional biochemical methods are inaccurate in identifying this species of Candida. We report the first prospectively identified case in the United States of a patient presenting with a colonization of C. auris in the ear. Due to the limited nature of clinical data and treatment results, our experience may provide insight for otolaryngologists in the identification, treatment and proper precautions with regards to C. auris.
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Candida auris is a rapidly emerging multidrug-resistant pathogenic yeast. In recent years, an increasing number of C. auris invasive infections and colonized patients have been reported, and C. auris has been associated with hospital outbreaks worldwide, mainly in intensive care units (ICUs). Here, we describe the first two cases of C. auris in The Netherlands. Both cases were treated in a healthcare facility in India prior to admission. The patients were routinely placed in contact precautions in a single room after admission, which is common practice in The Netherlands for patients with hospitalization outside The Netherlands. No transmission of C. auris was noticed in both hospitals. Routine admission screening both for multidrug-resistant (MDR) bacteria and MDR yeasts should be considered for patients admitted from foreign hospitals or countries with reported C. auris transmission.
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Current perspective on emergence, diagnosis and drug resistance in Candida auris Smita Sarma, Shalini Upadhyay Department of Microbiology, Medanta – The Medicity, Gurgaon, Haryana, India Abstract: Candida auris is an emerging fungus that presents a serious threat to global health. The organism is difficult to identify using conventional biochemical methods. C. auris has also attracted attention because of its reduced susceptibility to azoles, polyenes, and echinocandins, with a few strains even resistant to all three classes of antifungals. In this review paper we discuss the trends in emergence of C. auris in different parts of the world, associated risk factors, drug resistance, and diagnostic challenges. Strategies for prevention and therapeutic options for such infections is also addressed. Keywords: Candidemia, Candida haemulonii, outbreak, drug resistance
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Candida auris is an emerging pathogen with resistance to many commonly used antifungal agents. Infections with C. auris require rapid and reliable detection methods to initiate successful medical treatment and contain hospital outbreaks. Conventional identification methods are prone to errors and can lead to misidentifications. PCR-based assays, in turn, can provide reliable results with low turnaround times. However, only limited data are available on the performance of commercially available assays for C. auris detection. In the present study, the two commercially available PCR assays AurisID (OLM, Newcastle Upon Tyne, UK) and Fungiplex Candida Auris RUO Real-Time PCR (Bruker, Bremen, Germany) were challenged with 29 C. auris isolates from all five clades and eight other Candida species as controls. AurisID reliably detected C. auris with a limit of detection (LoD) of 1 genome copies/reaction. However, false positive results were obtained with high DNA amounts of the closely related species C. haemulonii, C. duobushaemulonii and C. pseudohaemulonii. The Fungiplex Candida Auris RUO Real-Time PCR kit detected C. auris with an LoD of 9 copies/reaction. No false positive results were obtained with this assay. In addition, C. auris could also be detected in human blood samples spiked with pure fungal cultures by both kits. In summary, both kits could detect C. auris-DNA at low DNA concentrations but differed slightly in their limits of detection and specificity.
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Abstract Currently, most burn models for preclinical testing are on animals. For obvious ethical, anatomical, and physiological reasons, these models could be replaced with optimized ex vivo systems. The creation of a burn model on human skin using a pulsed dye laser could represent a relevant model for preclinical research. Six samples of excess human abdominal skin were obtained within one hour after surgery. Burn injuries were induced on small samples of cleaned skin using a pulsed dye laser on skin samples, at varying fluences, pulse numbers and illumination duration. In total, 70 burn injuries were performed on skin ex vivo before being histologically and dermato-pathologically analyzed. Irradiated burned skin samples were classified with a specified code representing burn degrees. Then, a selection of samples was inspected after 14 and 21 days to assess their capacity to heal spontaneously and re-epithelize. We determined the parameters of a pulsed dye laser inducing first, second, and third degree burns on human skin and with fixed parameters, especially superficial and deep second degree burns. After 21 days with the ex vivo model, neo-epidermis was formed. Our results showed that this simple, rapid, user-independent process creates reproducible and uniform burns of different, predictable degrees that are close to clinical reality. Human skin ex vivo models can be an alternative to and complete animal experimentation, particularly for preclinical large screening. This model could be used to foster the testing of new treatments on standardized degrees of burn injuries and thus improve therapeutic strategies.
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Staphylococcus aureus is both a major bacterial pathogen as well as a common member of the human skin microbiota. Due to its widespread prevalence as an asymptomatic skin colonizer and its importance as a source of skin and soft tissue infections, an improved understanding of how S. aureus attaches to, grows within, and breaches the stratified layers of the epidermis is of critical importance. Three-dimensional organotypic human skin culture models are informative and tractable experimental systems for future investigations of the interactions between S. aureus and the multifaceted skin tissue. We propose that S. aureus virulence factors, primarily appreciated for their role in pathogenesis of invasive infections, play alternative roles in promoting asymptomatic bacterial growth within the skin. Experimental manipulations of these cultures will provide insight into the many poorly understood molecular interactions occurring at the interface between S. aureus and stratified human skin tissue.
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Candida auris (C. auris) belongs to the Candida genus and is a fungal yeast resistant to multiple drugs. It is highly virulent and evades current therapeutic remedies. It was first discovered in a Japanese hospital in 2009 from a patient’s external auditory canal1. C. auris infection has a high worldwide mortality, which ranges from 30% to 60%, and is frequently associated with bloodstream infections2. The rapid spread of C. auris infection occurred after 2009. The Centers for Disease Control and Prevention (CDC) has estimated the presence of C. auris isolates in 41 countries, typically in hospital settings, as of March 20203. CDC also reported outbreaks of infections with C. auris in 47 countries globally on February 15, 20214. The United States reported 2377 clinical cases and 5754 screening cases from January 2022 to December 20225. Twenty-six isolates of C. auris from India were different genetically and phenotypically from the ones found in Japan and Korea, which provided evidence for C. auris’s ability to mutate and its resistance to Azoles6. The mechanism of C. auris virulence factors is relatively unknown. According to genomic comparison, C. auris has the ability to adapt to different environments. Two mechanisms of its pathogenesis have been identified, which include hydrolytic enzyme production and attack host cells and tissues. It can also form biofilms that protect it from antifungal drugs and increase its ability in nosocomial transmission4. C. auris can be spread in health care facilities such as hospitals and nursing homes through direct patient-to-patient contact. Contaminated surfaces are a significant culprit in the spread when a person comes in contact with them. As C. auris colonizes the skin and can be transmitted into the environment, both properties make it easily transmissible. Population susceptible are immunocompromised people, recently hospitalized patients in areas where C. auris is endemic; catheter use, extended stay in ICU, previous history of antimicrobial exposure, and resistance to antifungal therapy7. Identifying this pathogen is tricky as the methods used to determine the yeast in laboratories often must be corrected for other fungi. Detection of C. auris requires reliable sampling procedures from the most common sites of colonization, including the axillae and groin. Nares, external auditory canals, urine, rectum, catheter sites, and vagina also serve as colonization sites8. Making use of water and soaps or using a hand sanitizer with a 60% alcohol content is effective in preventing infection. Health care workers should take proper precautions to use gowns and gloves in the hospital setting. Regular disinfection and cleaning of surfaces prevent the survival of C. auris. When referring a patient with C. auris, the health care facility on the receiving end should be informed of the patient’s infection or colonization status to take appropriate measures promptly9. The steadily rising incidence of C. auris outbreaks poses a significant public health threat. C. auris outbreaks are a challenge to control due to poor routine diagnostic detection, prompt transmission, and resistance to disinfection techniques. It is now a leading cause of fungal infections in many medical setups with high mortality rates. Rapid detection methods that provide reliable identification and diagnosis, as well as control measures and necessary precautions, will help contain the spread of C. auris in health care systems. Ethical approval None. Consent for publication None. Sources of funding None. Author contributions The conceptualization was done by H.F. and H.S.R. The literature and drafting of the manuscript were conducted by H.F., A.M.S., F.R., and B.S.R. The editing and supervision were performed by H.S.R. All authors have read and agreed to the final version of the manuscript. Conflict of interest disclosures The authors declare that they have no financial conflict of interest with regard to the content of this report. Research registration unique identifying number (UIN) Not applicable. Guarantor All authors take responsibility for the work, access to data and decision to publish. Provenancer and Peer review Not commissioned, externally peer reviewed.
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Abstract Candida auris is an emerging fungal pathogen that is typically resistant to fluconazole and is known to cause healthcare-associated outbreaks. We retrospectively reviewed 28 patients who had >1 positive culture for C. auris within a multisite health system in Illinois, USA, during May 2018–April 2019. Twelve of these patients were treated as inpatients for C. auris infections; 10 (83%) met criteria for clinical success, defined as absence of all-cause mortality, C. auris recurrence, and infection-related readmission at 30 days from the first positive culture. The other 2 patients (17%) died within 30 days. Most patients (92%) were empirically treated with micafungin. Four (14%) of 28 total isolates were resistant to fluconazole, 1 (3.6%) was resistant to amphotericin B, and 1 (3.6%) was resistant to echinocandins. Our findings describe low rates of antifungal resistance and favorable clinical outcomes for most C. auris patients.
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