Epidemiology, Clinical Features and Antifungal Resistance Profile of Candida auris in Africa: Systematic Review

Isidore Wendkièta Yerbanga^1,2, Seydou Nakanabo Diallo^2,3, Toussaint Rouamba⁴, Delwendé Florence Ouedraogo⁴, Katrien Lagrou⁵, Rita Oladele⁶, Jean-Pierre Gangneux⁷, Olivier Denis^8,9, Hector Rodriguez-Villalobos¹⁰, Isabel Montesinos⁸, Sanata Bamba^2,11

¹Centre Hospitalier Universitaire Régional de Ouahigouya, Ouahigouya, Burkina Faso.
²Ecole Doctorale des Sciences De la Santé, Université Nazi Boni, Bobo-Dioulasso, Burkina Faso.
³Centre Muraz/Institut National de Santé Publique, Bobo-Dioulasso, Burkina Faso.
⁴Clinical Research Unit of Nanoro, Institute for Research in Health Sciences, National Center for Scientific and Technological Research, Ouagadougou, Burkina Faso.
⁵Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium and Department of Laboratory Medicine and National Reference Center for Mycosis, Excellence Center for Medical Mycology (ECMM), University Hospitals Leuven, Leuven, Belgium.
⁶College of Medicine, University of Lagos, Lagos, Nigeria.
⁷Univ Rennes, CHU Rennes, Inserm, Irset (Institut de recherche en santé, environnement et travail), European ECMM Excellence Center in Medical Mycology, Université de Rennes, Rennes, France.
⁸Department of Microbiology, CHU Namur site-Godinne, Université Catholique de Louvain, Yvoir, Belgium.
⁹Ecole de Santé Publique, Université Libre de Bruxelles, Brussels, Belgium.
¹⁰Department of Microbiology, Cliniques Universitaires Saint-Luc—Université Catholique de Louvain, Bruxelles, Belgium.
¹¹Centre Hospitalier Universitaire Sour? Sanou, Bobo-Dioulasso, Burkina Faso.

DOI: 10.4236/jbm.2024.121012                

Abstract

Candida auris since it discovery in 2009 is becoming a severe threat to human health due to its very quickly spread, its worldwide high resistance to systemic antifungal drugs. In resource-constrained settings where several conditions are met for its emergence and spread, this worrisome fungus could cause large hospital and/or community-based outbreaks. This review aimed to summarize the available data on C. auris in Africa focusing on its epidemiology and antifungal resistance profile. Major databases were searched for articles on the epidemiology and antifungal resistance profile of C. auris in Africa. Out of 2,521 articles identified 22 met the inclusion criteria. In Africa, nearly 89% of African countries have no published data on C. auris. The prevalence of C. auris in Africa was 8.74%. The case fatality rate of C. auris infection in Africa was 39.46%. The main C. auris risk factors reported in Africa were cardiovascular disease, renal failure, diabetes, HIV, recent intake of antimicrobial drugs, ICU admissions, surgery, hemodialysis, parenteral nutrition and indwelling devices. Four phylogenetic clades were reported in Africa, namely clades I, II, III and IV. Candida auris showed a pan-African very high resistance rate to fluconazole, moderate resistance to amphotericin B, and high susceptibility to echinocandins. Finally, C. auris clade-specific mutations were observed within the ERG2, ERG3, ERG9, ERG11, FKS1, TAC1b and MRR1 genes in Africa. This systematic review showed the presence of C. auris in the African continent and a worrying unavailability of data on this resilient fungus in most African countries.

Keywords

Africa, Antifungal Resistance, Candida auris, Clinical Features, Phylogenetic Clades

1. Introduction

Candida auris is an emerging fungal pathogen recognized as a human colonizer in 2009 [1] and a causative agent of invasive fungal infections in 2011 [2] . Since then, this worrisome yeast has rapidly emerged worldwide as a significant healthcare threat causing outbreaks, especially in intensive care settings [3] [4] [5] . Candida auris infection covers a wide spectrum of clinical diseases, from superficial infections to life-threatening invasive fungal infections [6] . The crude mortality rate of this new fungal pathogen ranges from 30% to 70%, depending on the patient’s underlying conditions and the therapeutic management [7] [8] [9] . The emergence and spread of C. auris raises public global health threat due to its unique characteristics. Indeed, this fungus is characterized by its ability to colonize the human body, and its aptitude to survive in an abiotic environment for weeks [10] . This situation is associated with horizontal transmission, causing outbreaks in health care settings [11] . Furthermore, C. auris is frequently misidentified by standard microbiological techniques [12] . Finally, this fungus displayed a markedly decreased susceptibility to the three major classes of antifungal drugs currently approved for systemic use (azoles, echinocandins, and polyenes) [13] . Some C. auris isolates were reported as multidrug resistant, and others as pan-resistant [13] [14] [15] . The unique characteristics of this fungus prompted the Centers for Disease Control and Prevention (CDC) in the U.S to classify it as an urgent threat to public health, making C. auris one of the only five pathogens, and the single fungal pathogen to be classified as such [16] . In Europe, after the first outbreaks in 2014 and 2015, the European Centre for Disease Prevention and Control (ECDC) alerted healthcare facilities to strengthen control measures in order to prevent further hospital outbreaks [17] . Faced with the urgent need to control this fungus, organizations such as the Public Health England (PHE) or the Infection Prevention and Control (IPC) group of the International Society for Antimicrobial Chemotherapy (ISAC) have also published recommendations for the management and control of this new yeast fungal pathogen [18] [19] . Finally, C. auris has been classified in the critical group of the WHO priority fungal pathogens list due to its ability to cause invasive acute and subacute systemic fungal infections for which there is antifungal drug resistance or other processing and management issues [20] . However, effective and sustainable control of this resilient fungus requires in-depth knowledge of its epidemiology and biology in all parts of the world, global awareness of its threat to public health and the adoption of recommendations on a global scale [21] . Some conditions encountered in many health facilities in resource-constrained countries like those in Africa, namely overwhelmed and overcrowded hospitals; compromised hygiene and infection control measures; overuse of antibiotics; and low awareness of fungal infections could promote the rapid spread of this fungus and undermine its global control efforts [22] . In addition, international travel to and from African countries might also promote the emergence of C. auris in this continent. This review highlights the available literature on C. auris in Africa, with particular insight into its epidemiology, clinical features and antifungal resistance profile.

2. Methods

Search Strategy, Selection Criteria, Data Extraction and Synthesis

The proposal for the present systematic review was registered on PROSPERO (registration number: CRD42023412158). PubMed, ScienceDirect, Google Scholar, and African Journal OnLine (AJOL) were searched for articles published in English. A search strategy was developed based on the epidemiology, clinical features, and antifungal resistance of C. auris in Africa. Studies reporting original data on C. auris in Africa, such as case reports, case series (≥2 cases), and observational studies were eligible for this review. No restriction was imposed on the publication date and the study design. Studies were excluded if they were commentary article and if the study population was outside African countries. Studies were also excluded if the available data did not make it possible to extract the relevant data for this review. After the literature search, the title and abstract of all citations were screened to assess their potential eligibility by two independent reviewers. Following the duplicates removed, the remaining full-text articles were also screened for inclusion by the two independent reviewers. The discrepancies between the two reviewers were resolved by discussion and consensus, if necessary, by involving a third reviewer. The systematic review was conducted as per PRISMA (Preferred Reporting Items for Systematic and Meta-analyses) guidelines [23] . Data extraction was only performed for studies that met all inclusion and exclusion criteria. The following data were extracted: country, authors, study design, prevalence, risk factors, case fatality rate, phylogenetic clades, clinical features, distribution of Candida species, site of C. auris isolation, antifungal resistance profile, and antifungal resistance mechanism of C. auris. For epidemiological purposes, the CDC tentative MIC breakpoints (µg/mL) for determining C. auris resistant isolates were used as follows: fluconazole, ≥32; amphotericin B, ≥2; caspofungin, ≥2; anidulafungin ≥4; micafungin, ≥4 [24] . The MIC breakpoints (µg/mL) for resistance proposed by Lockhart et al. were used for voriconazole (≥2) and flucytosine (≥128) [25] .

3. Results

3.1. Search results

A total of 2521 citations were found across four electronic databases (PubMed = 50, ScienceDirect = 203, AJOL = 58, and Google Scholar = 2210) of which 2430 were excluded after reading the titles, abstracts and type of study. Of the 91 screened, 28 duplicate articles were removed. From this screening, 63 papers were eligible for full-text screening. From this last screening process, 40 were excluded based on eligibility criteria and 23 eligible articles were retained (Figure 1). A study whose available data did not allow extracting the number of C. auris cases and the total number of cases was excluded from this study [26] . Thus, finally, 22 articles were considered for data analysis in this review.

Figure 1. Flow chart of articles selected for the systematic review on the epidemiology, clinical features and antifungal resistance profile of C. auris in Africa, adapted from the PRISMA guidelines [23] .

3.2. Epidemiology of C. auris in Africa

3.2.1. Distribution of C. auris in Africa

Data reported in Africa showed that only 6 African countries, namely Algeria, Egypt, Kenya, Nigeria, South Africa and Sudan, have published data on C. auris i.e. 11.11% (6/54) of African countries [27] - [48] . Three countries (Algeria, Egypt and Nigeria) reported fewer than 10 C. auris cases [44] [45] [46] [47] [48] . In Sudan and Kenya, 26 and 86 C. auris cases were reported respectively [41] [42] [43] . The country with the most reported cases of C. auris in Africa was South Africa with over 1000 cases (Figure 2) [27] - [40] .

3.2.2. Prevalence of C. auris in Africa

The prevalence of C. auris in Africa was 8.74%. This prevalence in the specific group of intensive care patients and those with C. auris bloodstream infection (BSI) were 13.56% and 9.38%, respectively (Table 1). It is also important to know that a case report and 4 case series reported 1, 4, 4, 85, and 1692 C. auris isolates in Africa [28] [31] [37] [44] [48] .

Figure 2. Distribution of C. auris across African countries.

Table 1. Prevalence of C. auris in Africa.

n: number of C. auris cases; N: total number of cases; ICU: intensive care unit; HDU: high dependency unit; CSF: cerebrospinal fluid.

3.2.3. Distribution of Candida Species in Africa

Table 2 summarizes the distribution of Candida species in Africa. These data showed that Candida parapsilosis (39.91%) was the most prevalent Candida species in Africa. The second, third and fourth most prevalent Candida species were Candida albicans, C. auris and Nakaseomyces glabrata with 27.58%, 9.40%, and 6.68%, respectively. The other Candida species were Candida tropicalis (1.66%), Pichia kudriavzevii (1.44%), Candida famata (0.03%), Candida lusitaniae (0.01%), and Candida duobushaemolumonii (0.01%).

3.2.4. Factors Associated with C. auris in Africa

The associated factors reported in Africa with C. auris infection can be categorized into comorbidity, “history of antimicrobial use”, and “hospitalization related factors”. The main comorbidity factors associated with C. auris infection in Africa were cardiovascular disease (CVD), renal failure, diabetes (insipidus and mellitus), and tumor diseases (pituitary adenoma, prostate cancer, or malignancy). Other comorbidities such as living with human immunodeficiency virus (HIV), coronavirus disease 2019 (COVID-19), systemic lupus erythematosus (SLE), Wegeners granulomatosis, and dyslipidaemia were also reported. The recent intake of broad-spectrum antibiotics was the most frequent “history of antimicrobial use” factor associated with C. auris infection in Africa. The recent

Table 2. Distribution of Candida species in Africa.

CP: C. parapsilosis; CA: C. albicans; CAU: C. auris; CT: C. tropicalis; NG: Nakaseomyces glabrata; PK: Pichia kudriavzevii; CF: C. famata; CD: C. duobushaemolumonii; CL: C. lusitaniae, CSF: cerebrospinal fluid; *: other yeasts species; n: number of C. auris isolates by Candida species; N: total number of Candida isolates.

intake of antifungal drugs has also been associated with this infection in Africa. Most factors associated with C. auris infection in Africa were related to “hospitalization related factors”. The main “hospitalization related factors” reported were ICU patients, indwelling devices, recent surgery, hemodialysis, and parenteral nutrition. Other “hospitalization related factors” were also reported such as extension of hospital stay, mechanical ventilation, and history of recent hospitalization (Table 3).

3.2.5. Phylogenetic Clade Distributions of C. auris in Africa

Globally 4 phylogenetic clades were reported in Africa: clades I, II, III and IV. The most prevalent clades were clades I and III, with 47.39% each. Clades IV and II accounted for 3.79% and 1.42%, respectively. No cases of clade V have yet been reported in Africa (Table 4).

3.2.6. Case Fatality Rate of C. auris Infection in Africa

The case fatality rate (CFR) of C. auris infection in Africa was 39.46%. This CFR in the specific group of patients with C. auris bloodstream infection (BSI) was 38.97%. Out of 5 case reports of C. auris infection with outcome data reported in Africa, 4 died (Table 5) [44] [48] .

3.3. Clinical Features of C. auris in Africa

3.3.1. Clinical Features

One study evaluated the clinical features of C. auris in Africa (Table 6) [35] . The data reported in this study showed that fever was more frequently observed in C.

Table 3. Factors associated with C. auris infection in Africa.

COVID-19: coronavirus disease 2019; HIV: human immunodeficiency virus; ICU: intensive care unit; SLE: systemic lupus erythematosus; *: the type of malignancy was not specified.

Table 4. Phylogenetic clade distributions of C. auris in Africa.

n: number of isolates by clade; N: total number of isolates.

auris group than C. albicans and N. glabrata groups (p < 0.001). These data also showed that compared to C. albicans group, sepsis was more common in C. auris group (p = 0.04).

Table 5. Case fatality rate of C. auris infection in Africa.

n: number of fatal cases; N: number of C. auris infection cases.

Table 6. Clinical features of C. auris in Africa.

* Statistical significance (p < 0.05); n: number of patients with the clinical sign; N: total number of patients.

3.3.2. Site of C. auris Isolation

A total of 70.71% (2416/3417) of C. auris strains were isolated from sterile sites versus 29.29% (1001/3417) from non-sterile sites (Table 7 and Table 8). Of the strains isolated from sterile sites 81.71% were from blood isolation (Table 7). Urine and respiratory tract fluid were the main non-sterile sites of C. auris isolation with 68.83% and 19.68%, respectively (Table 8).

3.4. Antifungal Resistance of C. auris in Africa

3.4.1. Distribution of Resistant C. auris in Africa

Table A1 (in Annex) summarizes the distribution of C. auris resistant isolates in Africa. Available data in Africa showed that at least 80% of C. auris isolates were resistant to fluconazole regardless of the antifungal susceptibility testing (AFST) method (BMD, E-test or Vitek methods). The proportions of these fluconazole-resistant isolates ranged from 81.44% to 91.3%, depending on the AFST method. MICs values for fluconazole-resistant isolates ranged from 32 to ≥256 mg/L regardless of the method used. According to the BMD method, 29.14% (153/525) of fluconazole-resistant isolates had MICs values ≥ 256 mg/L. Proportions of fluconazole-resistant isolates with MICs values ≥ 256 mg/L were 35.71% (5/14) and 31.64 (25/79) with E-test and Vitek methods, respectively. Candida auris resistance to amphotericin B was 18.60% and 4.82% for BMD and E-test,

Table 7. Repartition of C. auris isolates across sterile sites.

CSF: Cerebrospinal fluid; n: number of isolates per sterile site; N: total number of isolates in sterile site; CSF: cerebrospinal fluid; CVC: central venous catheter.

Table 8. Repartition of C. auris isolates across non-sterile sites.

1: hands of healthcare workers, handwashing basin, bed linen and bed rails, windowsill, curtain, drying rack and on the floor around a bed; CVC: central venous catheter; n: number of isolates per non-sterile site; N: total number of isolates in non-sterile site.

respectively. MICs values for amphotericin B-resistant isolates ranged from 2 to 12 mg/L regardless of the AFST method used, with 2.80% (3/107) and 8.70% (2/23) of these isolates exhibiting MICs values of 8 mg/L with BMD and E-test methods respectively. Resistance to echinocandins (micafungin and anidulafungin), regardless of the AFST method used, was less than 2%. MICs values for micafungin-resistant isolates ranged from 4 to 16 mg/L, with 33.33% (3/9) of these isolates exhibiting MICs values of 8 mg/L with BMD method. According to the E-test method 100% (2/2) of two micafungin-resistant isolates exhibited MICs values of 16 mg/L. Only one C. auris anidulafungin-resistant isolate was reported in Africa with MIC value of 4 mg/L. Available data on C. auris in Africa also showed voriconazole resistance to be 2.26%, 31.25%, and 6.94% with BMD, E-test, and Vitek methods, respectively. MICs values for voriconazole-resistant isolates ranged from 2 to ≥32 mg/L with 7.69% (1/13) of these isolates exhibiting MICs values ≥ 8 mg/L with BMD method. According to E-test method, 40% (2/5) of voriconazole-resistant isolates exhibited MICs values ≥ 12 mg/L. No cases of flucytosine-resistant isolates have yet been reported in Africa.

Table 9 depicts the antifungal susceptibility profile of C. auris isolates across the phylogenetic clades. Of the 105 C. auris isolates with whole genome sequencing (WGS) analysis data, 93 (88.57%) were resistant to at least one antifungal agent, and only 12 isolates (11.42%) were susceptible to all antifungal agents (Table 9). All 17 clade I isolates (100%) were resistant to at least one antifungal agents. Of this clade I, 70.59% (12/17) were resistant to both fluconazole and amphotericin B, and one (5.882%) was pan-resistant (fluconazole, amphotericin B, and micafungin). Among clade III isolates, 91.14% were resistant to at least one antifungal agents, 8.86% to both fluconazole and amphotericin B, and two (2.53%) were pan-resistant (fluconazole, amphotericin B, and micafungin). Of the eight clade IV isolates, 50% (4/8) were resistant to at least one antifungal agent. All four resistant clade IV isolates were fluconazole-resistant, and one isolate was also resistant to caspofungin. The only one clade II C. auris strain reported in Africa was susceptible to all antifungal agents.

3.4.2. Mechanism of C. auris Antifungal Resistance

Table A2 (in Annex) summarizes the mechanism of C. auris antifungal resistance in Africa. Candida auris clade-specific mutations were observed within the ERG2, ERG3, ERG9, ERG11, FKS1, TAC1b and MRR1 genes in Africa. Out of the 30 clade I isolates reported, 14 fluconazole-resistant isolates had Y132F ERG11 substitutions, while 2 fluconazole-resistant isolates had Y132F/L125F ERG11 substitutions. The remaining clade I fluconazole-resistant isolates had uncommon substitutions namely one E39D ERG2, one L148I, R937S, I701V, and I694V FKS1HP1 (FKS1 hot spot1), one A651P TAC1b, and 8 A657V TAC1b substitutions. Three clade I echinocandin (anidulafungin and micafungin)-susceptible isolates had D642Y substitution due to a mutation within the FKS1HP1 region. Among clade III 68 fluconazole-resistant isolates and 8 fluconazole-susceptible isolates had VF125AL ERG11 substitutions. One and 15 clade III fluconazole-

Table 9. Antifungal susceptibility profiles of C. auris isolates across phylogenetic clades.

*: one isolate was also resistant to caspofungin.

resistant isolates had S195G TAC1b and A651P TAC1b substitutions, respectively. Among clade III 68 fluconazole-resistant isolates and 8 fluconazole-susceptible isolates also exhibited uncommon N647T MRR1 substitutions. Two clade III echinocandin-resistant isolates and one clade III echinocandin-susceptible isolate had S639P FKS1HP1 substitutions. One clade III echinocandin-susceptible isolate had uncommon T125I, C1253fs [fs = frameshift], and G1250S substitutions due to a mutation within the FKS1HP1 region. Two clade IV fluconazole-resistant isolates and three clade IV fluconazole-susceptible isolates had uncommon E343D, N335S, and K177A ERG11 substitutions. One clade IV amphotericin B-resistant isolate and one clade IV amphotericin B-susceptible isolate had uncommon M351V and A27T ERG9 substitutions. Two clade IV amphotericin B-susceptible isolates and one clade IV amphotericin B-susceptible isolate also had uncommon S58T ERG3 substitution and within the MRR1 gene (S30T, N70S, E76_P77delnsDS, D80E, N133S, K138E, K167N, L211V, R249K, R280G, R413K, and K534N), respectively.

4. Discussion

This systematic review shows that nearly 89% of African countries have no published data on C. auris even though several favourable conditions for its emergence and spread on this continent are met. This lack of data on C. auris in the large majority of African countries could further hide the existence of undiagnosed cases of C. auris infection. These potential undiagnosed cases of C. auris could promote the occurrence of large hospital outbreaks. The management of such outbreaks in many of these African hospitals would be very difficult due to scarcity of infrastructure, overcrowded hospitals, compromised hygiene and infection control measures, [22] unavailability of effective antifungals and because most of patients in these countries are economically deprived. Moreover, the control of accessibility in most of these hospitals not being strict, it cannot be ruled out that this situation could also promote community-based outbreaks of C. auris infection. It is important and very urgent that studies be carried out to map C. auris in all African countries. Medical personnel and national health authorities in African countries must be quickly made aware of the threat posed by this new resilient fungus. Finally, each African country should establish a management protocol for C. auris including preventive measures and diagnosing and treating of this fungal pathogen. The prevalence of C. auris in Africa was 8.74%. This prevalence could be only the tip of the iceberg given the lack of data in most African countries and the difficulty of diagnosing this fungus with routine laboratory methods. This prevalence is consistent with data from a previous study [49] . The prevalence of C. auris BSI in this study (9.38%) was lower than in previous similar studies, with more than 17% [50] [51] . The low prevalence of C. auris in this review could be due to undiagnosed C. auris cases in Africa but may also be due to the currently low spread of this fungus in Africa. A recent study conducted in the United States showed that C. auris BSI was more frequently reported in non-Hispanic Black patients [52] . Studies should be conducted in Africa to understand better the influence of the black race on the occurrence of C. auris BSI. The overall and specific case fatality rate of C. auris in Africa was nearly 39%. This case fatality rate was more or less higher than those reported in previous studies [52] - [57] . Early diagnosis and rapid administration of effective antifungal treatment combined with effective and rapid management of other comorbidities are key factors for patient survival. Candida auris was the third cause of invasive candidiasis in Africa. This crucial data must considered in managing of patients with invasive candidiasis in Africa, given C. auris low sensitivity to systemic antifungal drugs, particularly fluconazole [13] [14] [15] . If the management of C. auris cases isolated from a sterile site seems obvious, particular attention should also be paid in case of colonization (isolation in non-sterile site such as skin or mucosa). Indeed, nearly 10% of patients colonized with C. auris develop invasive candidiasis, especially those subjected to mechanical ventilation and the placement of invasive devices in intensive care settings [58] . Risk factors associated with C. auris infection reported in Africa were consistent with data from previous worldwide studies [59] [60] [61] [62] [63] . One study assessing the clinical features of C. auris in Africa showed that fever and sepsis were more frequently observed in C. auris group than C. albicans and N. glabrata groups [35] . However, this study failed to attribute these differences to the sole fact of C. auris infection. Furthermore, this study did not compare the clinical features of patients with C. auris infection with those of patients with non-fungal infections, particularly bacterial ones. In short, this study failed to provide clinical-based evidence of pathognomonic clinical signs of C. auris infection. The absence of such specific clinical signs with C. auris infection makes its diagnosis very delicate, especially in resource-constrained settings where the lack of qualified human resources and diagnostic methods is glaring. However, some biological parameters accessible in these resource-limited settings, such as C-reactive protein (CRP) and procalcitonin (PCT), could contribute to the discrimination between fungal and bacterial infections. Some studies reported that a substantial elevation of CRP value associated with a low PCT value in immunocompromised patients could indicate an invasive fungal infection rather than a bacterial infection [64] [65] [66] . These combined CRP and PCT data associated with the presence of C. auris risk factors and the ineffectiveness of broad-spectrum antibiotic treatment could play a crucial role in the suspicion of C. auris infection in resource-limited settings. An experimental murine model showed that the highest fungal load of C. auris isolates was detected in the kidney followed by spleen, liver and lung [60] . Clinical studies must be conducted to assess the existence of such a phenomenon in humans and its possible impact on the occurrence or worsening of certain diseases, such as renal failure. In accordance with previous studies, [25] [67] [68] [69] the data in this review showed a pan-African very high resistance rate to fluconazole, moderate resistance to amphotericin B, and high susceptibility to echinocandins. So, identifying all Candida at the species level particularly those isolated from sterile specimens, is important to ensure the better candidiasis management [70] . It is also important in Africa to avoid fluconazole as the first-line empirical treatment in cases of invasive candidiasis, especially those due to Candida non-albicans. No cases of flucytosine-resistant isolates have yet been reported in Africa. In resource-constrained settings a combination of amphotericin B and flucytosine would be potentially useful for treating invasive C. auris infections if studies confirm its efficacy as it has been for the treatment of cryptococcosis [32] . In accordance with previous study the present review confirmed that the resistance to each antifungal is closely linked to the type of clade the isolate belongs to [71] . In Africa, four phylogenetic clades were reported, namely clades I, II, III and IV, with clades I and III being the most widespread clades. The existence of several clades in the same area could lead to an increase in the genetic diversity of C. auris and an increase in its virulence and the exchange of drug resistance alleles [13] . Thus, global efforts to fully understand the biology of C. auris should be continued to provide the most sensitive protocol for detecting potential C. auris hybrids [13] . Candida auris clade-specific mutations were observed within the ERG2, ERG3, ERG9, ERG11, FKS1, TAC1b and MRR1 genes in Africa. In according with previous study, [72] clade I C. auris fluconazole-resistant isolates reported in this review commonly exhibited Y132F ERG11 substitutions. However, no case of other predominant mutations in ERG11, namely F126L and K134R, were observed with clade I fluconazole-resistant isolates in Africa [72] . Other common mutations observed with clade I fluconazole-resistant were A657V TAC1b substitutions. These last mutations are frequently associated in the same isolate with the ERG11 Y132F variant, resulting in a marked increase in MIC values, suggesting an additive effect of resistance to fluconazole [73] . African C. auris clade III appeared to have specific VF125AL ERG11 substitutions [73] . Following previous studies the main mutations reported with echinocandin-resistant isolates in Africa were S639P FKS1HP1 region [74] [75] . The differences in mutations observed between the different clades are probably due to the specificity of the resistance mechanism depending on the clade and the antifungal agents tested. Finally, uncommon mutations observed with African C. auris isolates, particularly those found with susceptible isolates, may be linked to natural evolutionary divergence, rather than antifungal resistance mechanisms [32] .

5. Conclusion

This systematic review showed the presence of C. auris in Africa and worrying unavailability of data on this resilient fungus in most African countries. The absence of such data could mean undiagnosed cases of C. auris. This situation in the African settings of a scarcity of financial and qualified human resources combined with the weakness of health systems could favour large hospital and/or community-based outbreaks. National, regional and continental health-care authorities must be quickly made aware of the extreme threat posed by this resilient fungus and strategies for its control and management quickly adopted in the African continent.

Funding

This work was supported by the ARES (Académie de Recherche et d’Enseignement Supérieur) Project, Belgium.

Authors’ Contributions

IWY, SND, and SB designed the study. IWY and SND selected, extracted, and synthesized data. IWY and SND wrote the manuscript. All authors revised the final version of the manuscript. All authors read and approved the final manuscript.

Disclaimer

The funder of the study had no role in the design, data collection, data analysis and interpretation or writing of the report.

Annex

Table A1. Distribution of resistant C. auris isolates in Africa.

Tentative breakpoints: amphotericin B ≥ 2 mg/L; anidulafungin/micafungin ≥ 4 mg/L; caspofungin ≥ 2 mg/L; fluconazole ≥ 32 mg/L; flucytosine ≥ 128 mg/L; voriconazole ≥ 2 mg/L; n: sample size for each study; n1: total number of resistant isolates by antifungal agent; N: sample size for each antifungal agent; MIC: minimum inhibitory concentration; BMD: broth microdilution; *: MICs values ranged from 64 to 256.

Table A2. Mechanism of C. auris antifungal resistance in Africa.

Tentative breakpoints: amphotericin B ≥ 2 mg/L; anidulafungin/micafungin ≥ 4 mg/L; caspofungin ≥ 2 mg/L; fluconazole ≥ 32 mg/L; *: one isolate with N335S/E343D and the other with E343D/N335S/K177A; Multiple: S30T/N70S/E76_P77delnsDS/D80E/N133S/K138E/K167N/L211V/R249K/R280G/R413K/K534N; fs = frameshift.

Conflicts of Interest

The authors declare no conflicts of interest regarding the publication of this paper.

References

[1]	Satoh, K., Makimura, K., Hasumi, Y., Nishiyama, Y., Uchida, K. and Yamaguchi, H. (2009) Candida auris sp. nov., a Novel Ascomycetous Yeast Isolated from the External Ear Canal of an Inpatient in a Japanese Hospital. Microbiology and Immunology, 53, 41-44. [CrossRef] [PubMed]
[2]	Lee, W.G., Shin, J.H., Uh, Y., Kang, M.G., Kim, S.H., Park, K.H., et al. (2011) First Three Reported Cases of Nosocomial Fungemia Caused by Candida auris. Journal of Clinical Microbiology, 49, 3139-3142. [CrossRef]
[3]	Chybowska, A.D., Childers, D.S. and Farrer, R.A. (2020) Nine Things Genomics Can Tell Us about Candida auris. Frontiers in Genetics, 11, Article 526662. [CrossRef] [PubMed]
[4]	Rhodes, J. and Fisher, M.C. (2019) Global Epidemiology of Emerging Candida auris. Current Opinion in Microbiology, 52, 84-89. [CrossRef] [PubMed]
[5]	Sabino, R., Veríssimo, C., Pereira, á.A. and Antunes, F. (2020) Candida auris, an Agent of Hospital-Associated Outbreaks: Which Challenging Issues Do We Need to Have in Mind? Microorganisms, 8, Article 181. [CrossRef] [PubMed]
[6]	Chatterjee, S., Alampalli, S.V., Nageshan, R.K., Chettiar, S.T., Joshi, S. and Tatu, U.S. (2015) Draft Genome of a Commonly Misdiagnosed Multidrug Resistant Pathogen Candida auris. BMC Genomics, 16, Article No. 686. [CrossRef] [PubMed]
[7]	Bravo Ruiz, G. and Lorenz, A. (2021) What Do We Know about the Biology of the Emerging Fungal Pathogen of Humans Candida auris? Microbiological Research, 242, Article ID: 126621. [CrossRef] [PubMed]
[8]	Eggimann, P., Garbino, J. and Pittetd, D. (2003) Epidemiology of Candida species Infections in Critically Ill Nonimmunosuppressed Patients. The Lancet Infectious Diseases, 3, 685-702. [CrossRef]
[9]	Fasciana, T., Cortegiani, A., Ippolito, M., Giarratano, A., Di Quattro, O., Lipari, D., et al. (2020) Candida auris: An Overview of How to Screen, Detect, Test and Control This Emerging Pathogen. Antibiotics, 9, Article 778. [CrossRef] [PubMed]
[10]	Welsh, R.M., Bentz, M.L., Shams, A., Houston, H., Lyons, A., Rose, L.J., et al. (2017) Survival, Persistence, and Isolation of the Emerging Multidrug-Resistant Pathogenic Yeast Candida auris on a Plastic Health Care Surface. Journal of Clinical Microbiology, 55, 2996-3005. [CrossRef]
[11]	Fayemiwo, S. and Makanjuola, O.B. (2017) Candida auris Infection: How prepaRed Is Nigeria for This Emerging Fungal Agent? African Journal of Clinical and Experimental Microbiology, 19, 58. [CrossRef]
[12]	Chowdhary, A., Sharma, C. and Meis, J.F. (2017) Candida auris: A Rapidly Emerging Cause of Hospital-Acquired Multidrug-Resistant Fungal Infections Globally. PLOS Pathogens, 13, e1006290. [CrossRef] [PubMed]
[13]	Chow, N.A., Munoz, J.F., Gade, L., Berkow, E.L., Li, X., Welsh, R.M., et al. (2020) Tracing the Evolutionary History and Global Expansion of Candida auris Using Population Genomic Analyses. mBio, 11, e03364-19. [CrossRef]
[14]	Kean, R. and Ramage, G. (2019) Combined Antifungal Resistance and Biofilm Tolerance: the Global Threat of Candida auris. mSphere, 4, e00458-19. [CrossRef]
[15]	Kean, R., Delaney, C., Sherry, L., Borman, A., Johnson, E.M., Richardson, M.D., et al. (2018) Transcriptome Assembly and Profiling of Candida auris Reveals Novel Insights into Biofilm-Mediated Resistance. mSphere, 3, e00334-18. [CrossRef]
[16]	CDC: Centers for Disease Control and Prevention (2019) Antibiotic Resistance Threats in the United States. Atlanta. [CrossRef]
[17]	European Centre for Disease Prevention and Control (2018) Candida auris in Healthcare Settings—Europe. Stock ECDC.
[18]	Kenters, N., Kiernan, M., Chowdhary, A., Denning, D.W., Pemán, J., Saris, K., et al. (2019) Control of Candida auris in Healthcare Institutions: Outcome of an International Society for Antimicrobial Chemotherapy Expert Meeting. International Journal of Antimicrobial Agents, 54, 400-406. [CrossRef] [PubMed]
[19]	Bishop (2016) Guidance for the Laboratory Investigation, Management and infEction Prevention and Control for Cases of Candida auris. https://www.gov.uk/government/publications/candida-auris-laboratory-investigation-management-and-infection-prevention-and-control
[20]	World Health Organization (2022) WHO Fungal Priority Pathogens List to Guide Research, Development and Public Health Action. Geneva. https://www.who.int/publications/i/item/9789240060241
[21]	CDC: Centers for Disease Control and Prevention (2022) Antibiotic/Antimicrobial Resistance (AR/AMR) C. auris: CDC’s Response to a Global Emerging Threat. CDC Works to Contain the Global Emerging Threat. https://www.cdc.gov/drugresistance/solutions-initiative/stories/cdc-response-to-global-threat.html
[22]	Kaur, H. and Chakrabarti, A. (2017) Strategies to Reduce Mortality in Adult and Neonatal Candidemia in Developing Countries. Journal of Fungi, 3, Article 41. [CrossRef] [PubMed]
[23]	Liberati, A., Altman, D.G., Tetzlaff, J., Mulrow, C., Gotzsche, P.C., Ioannidis, J.P.A., et al. (2009) The PRISMA Statement for Reporting Systematic Reviews and Meta-Analyses of Studies That Evaluate Healthcare Interventions: Explanation and Elaboration. BMJ, 339, b2700. [CrossRef] [PubMed]
[24]	Ostrowsky, B., Greenko, J., Adams, E., Quinn, M., O’Brien, B., Chaturvedi, V., et al. (2020) Candida auris Isolates Resistant to Three Classes of Antifungal Medications—New York, 2019. Morbidity and Mortality Weekly Report, 69, 6-9. [CrossRef] [PubMed]
[25]	Lockhart, S.R., Etienne, K.A., Vallabhaneni, S., Farooqi, J., Chowdhary, A., Govender, N.P., et al. (2017) Simultaneous Emergence of Multidrug-Resistant Candida auris on 3 Continents Confirmed by Whole-Genome Sequencing and Epidemiological Analyses. Clinical Infectious Diseases, 64, 134-140. [CrossRef] [PubMed]
[26]	Ramdin, T.D., Chibabhai, V., Saggers, R.T., Bandini, R.M. and Ballot, D.E. (2023) Epidemiology, Risk Factors and Outcomes Associated with Candidaemia in Very Low Birth Weight Infants at a Tertiary South African Hospital over a 7-Year Period (2013-2019). Clinical Epidemiology and Global Health, 20, Article ID: 101247. [Google Scholar] [CrossRef]
[27]	Chibabhai, V. (2022) Incidence of Candidemia and Prevalence of Azole-Resistant Candidemia at a Tertiary South African Hospital—A Retrospective Laboratory Analysis 2016-2020. Southern African Journal of Infectious Diseases, 37, a326. [CrossRef] [PubMed]
[28]	Govender, N.P., Magobo, R.E., Mpembe, R., Mhlanga, M., Matlapeng, P., Corcoran, C., et al. (2018) Candida auris in South Africa, 2012-2016. Emerging Infectious Diseases, 24, 2036-2040. [CrossRef] [PubMed]
[29]	Hussain, M., Whitelaw, A. and Parker, A. (2022) A Five-Year Retrospective Descriptive Study on the Clinical Characteristics and Outcomes of Candidaemia at a Tertiary Hospital in South Africa. IJID Regions, 3, 79-83. [CrossRef] [PubMed]
[30]	Law, T., Chibabhai, V. and Nana, T. (2020) Analysis and Comparison of Cumulative Antibiograms for the Charlotte Maxeke Johannesburg Academic Hospital Adult Intensive Care and High-Care Units, 2013 and 2017. South African Medical Journal, 110, 55-64. [CrossRef]
[31]	Magobo, R.E., Mhlanga, M., Corcoran, C. and Govender, N.P. (2020) Multilocus Sequence Typing of Azole-Resistant Candida auris Strains, South Africa. South African Journal of Infectious Diseases, 35, a116. [CrossRef] [PubMed]
[32]	Maphanga, T.G., Naicker, S.D., Kwenda, S., Munoz, J.F., Schalkwyk, E., van Wadula, J., et al. (2021) In Vitro Antifungal Resistance of Candida auris Isolates from Bloodstream Infections, South Africa. Antimicrobial Agents and Chemotherapy, 65, e0051721. [CrossRef]
[33]	Mashau, R.C., Meiring, S.T., Dramowski, A., Magobo, R.E., Quan, V.C., Perovic, O., et al. (2022) Culture-Confirmed Neonatal Bloodstream Infections and Meningitis in South Africa, 2014-19: A Cross-Sectional Study. The Lancet Global Health, 10, e1170-e1178. [CrossRef]
[34]	Naicker, S.D., Maphanga, T.G., Chow, N.A., Allam, M., Kwenda, S., Ismail, A., et al. (2021) Clade Distribution of Candida auris in South Africa Using Whole Genome Sequencing of Clinical and Environmental Isolates. Emerging Microbes & Infections, 10, 1300-1308. [CrossRef] [PubMed]
[35]	Parak, A., Stacey, S.L. and Chibabhai, V. (2022) Clinical and Laboratory Features of Patients with Candida auris Cultures, Compared to Other Candida, at a South African Hospital. The Journal of Infection in Developing Countries, 16, 213-221. [CrossRef] [PubMed]
[36]	Shuping, L., Mpembe, R., Mhlanga, M., Naicker, S.D., Maphanga, T.G., Tsotetsi, E., et al. (2021) Epidemiology of Culture-Confirmed Candidemia among Hospitalized Children in South Africa, 2012-2017. The Pediatric Infectious Disease Journal, 40, 730-737. [CrossRef]
[37]	Magobo, R.E., Corcoran, C., Seetharam, S. and Govender, N.P. (2014) Candida auris-Associated Candidemia, South Africa. Emerging Infectious Diseases, 20, 1250-1251. [CrossRef] [PubMed]
[38]	Van Schalkwyk, E., Mpembe, R.S., Thomas, J., Shuping, L., Ismail, H., Lowman, W., et al. (2019) Epidemiologic Shift in Candidemia Driven by Candida auris, South Africa, 2016-2017. Emerging Infectious Diseases, 25, 1698-1707. [CrossRef] [PubMed]
[39]	Von Knorring, N., Nana, T. and Chibabhai, V. (2019) Cumulative Antimicrobial Susceptibility Data for a Tertiary-Level Paediatric Oncology Unit in Johannesburg, South Africa. South African Journal of Oncology, 3, a65. [CrossRef]
[40]	Withers, A., Cronin, K., Mabaso, M., Brisighelli, G., Gabler, T., Harrison, D., et al. (2021) Neonatal Surgical Outcomes: A Prospective Observational Study at a Tertiary Academic Hospital in Johannesburg, South Africa. Pediatric Surgery International, 37, 1061-1068. [CrossRef] [PubMed]
[41]	Adam, R.D., Revathi, G., Okinda, N., Fontaine, M., Shah, J., Kagotho, E., et al. (2019) Analysis of Candida auris Fungemia at a Single Facility in Kenya. International Journal of Infectious Diseases, 85, 182-187. [CrossRef] [PubMed]
[42]	Solomon, D.A., Nyerere, A.K., Kanyua, A. and Ngugi, C.W. (2021) Prevalence, Species Distribution and Antifungal Susceptibility Profile of Candida Species Isolated from Bloodstream of Critical Care Unit Patients in a Tertiary Care Hospital in Kenya. Open Journal of Medical Microbiology, 11, 32-46. [CrossRef]
[43]	Badri, A.M. and Sherfi, S.A. (2019) First Detection of Emergent Fungal Pathogen Candida auris in Khartoum State, Sudan. American Journal of Biomedical Science & Research, 6, 4-7. [CrossRef]
[44]	Oladele, R., Uwanibe, J.N., Olawoye, I.B., Ettu, A.W.O., Meis, J.F. and Happi, C.T. (2022) Emergence and Genomic Characterization of Multidrug Resistant Candida auris in Nigeria, West Africa. Journal of Fungi, 8, Article 787. [CrossRef] [PubMed]
[45]	Zerrouki, H., Ibrahim, A., Rebiahi, S.A., Elhabiri, Y., Benhaddouche, D.E., de Groot, T., et al. (2022) Emergence of Candida auris in Intensive Care Units in Algeria. Mycoses, 65, 753-759. [CrossRef] [PubMed]
[46]	Khairat, S.M., Anany, M.G., Ashmawy, M.M. and Hussein, A.F.A. (2021) Setting a Protocol for Identification and Detecting the Prevalence of Candida auris in Tertiary Egyptian Hospitals Using the CDC Steps. Open Access Macedonian Journal of Medical Sciences, 9, 397-402. [CrossRef]
[47]	Maxwell, S. and Abd-Elmonsef, M. (2022) Investigation of Candida auris in Tanta University Hospitals, Egypt. Egyptian Journal of Medical Microbiology, 31, 83-88. [CrossRef]
[48]	El-Kholy, M., Shawky, S., Fayed, A. and Meis, J. (2019) Candida auris Bloodstream Infection in Egypt. 9th Trends in Medical Mycology Held on 11-14 October 2019, Nice, France. Journal of Fungi, 5, 310-311.
[49]	Garcia-Jeldes, H.F., Mitchell, R., McGeer, A., Rudnick, W., Amaratunga, K., Vallabhaneni, S., et al. (2020) Prevalence of Candida auris in Canadian Acute Care Hospitals among At-Risk Patients, 2018. Antimicrobial Resistance & Infection Control, 9, Article No. 82. [CrossRef] [PubMed]
[50]	Briano, F., Magnasco, L., Sepulcri, C., Dettori, S., Dentone, C., Mikulska, M., et al. (2022) Candida auris Candidemia in Critically Ill, Colonized Patients: Cumulative Incidence and Risk Factors. Infectious Diseases and Therapy, 11, 1149-1160. [CrossRef] [PubMed]
[51]	Garcia-Bustos, V., Salavert, M., Ruiz-Gaitán, A.C., Cabanero-Navalon, M.D., Sigona-Giangreco, I.A. and Pemán, J. (2020) A Clinical Predictive Model of Candidaemia by Candida auris in Previously Colonized Critically Ill Patients. Clinical Microbiology and Infection, 26, 1507-1513. [CrossRef] [PubMed]
[52]	Benedict, K., Forsberg, K., Gold, J.A.W., Baggs, J. and Lyman, M. (2023) Candida auris-Associated Hospitalizations, United States, 2017-2022. Emerging Infectious Diseases, 29, 1485-1487. [CrossRef] [PubMed]
[53]	Pfaller, M.A. and Diekema, D.J. (2007) Epidemiology of Invasive Candidiasis: A Persistent Public Health Problem. Clinical Microbiology Reviews, 20, 133-163. [CrossRef]
[54]	Taori, S.K., Khonyongwa, K., Hayden, I., Athukorala, G.D.A, Letters, A., Fife, A., et al. (2019) Candida auris Outbreak: Mortality, Interventions and Cost of Sustaining Control. Journal of Infection, 79, 601-611. [CrossRef] [PubMed]
[55]	Vallabhaneni, S., Kallen, A., Tsay, S., Chow, N., Welsh, R., Kerins, J., et al. (2017) Investigation of the First Seven Reported Cases of Candida auris, a Globally Emerging Invasive, Multidrug-Resistant Fungus—United States, May 2013-August 2016. American Journal of Transplantation, 17, 296-299. [CrossRef] [PubMed]
[56]	Adams, E., Quinn, M., Tsay, S., Poirot, E., Chaturvedi, S., Southwick, K., et al. (2018) Candida auris in Healthcare Facilities, New York, USA, 2013-2017. Emerging Infectious Diseases, 24, 1816-1824. [CrossRef] [PubMed]
[57]	Teoh, W.H.L. and Kristensen, M.S. (2015) Management of Patients with Angioedema. Cases in Emergency Airway Management, 25, 28-33. [CrossRef]
[58]	Ahmad, S. and Alfouzan, W. (2021) Candida auris: Epidemiology, Diagnosis, Pathogenesis, Antifungal Susceptibility, and Infection Control Measures to Combat the Spread of Infections in Healthcare Facilities. Microorganisms, 9, Article 807. [CrossRef] [PubMed]
[59]	Al-Siyabi, T., Al Busaidi, I., Balkhair, A., Al-Muharrmi, Z., Al-Salti, M. and Al’Adawi, B. (2017) First Report of Candida auris in Oman: Clinical and Microbiological Description of Five Candidemia Cases. Journal of Infection, 75, 373-376. [CrossRef] [PubMed]
[60]	Ben-Ami, R., Berman, J., Novikov, A., Bash, E., Shachor-meyouhas, Y., Zakin, S., et al. (2017) Multidrug-Resistant Candida haemulonii and C. auris, Tel Aviv, Israel. Emerging Infectious Disease, 23, 195-203. [CrossRef] [PubMed]
[61]	Calvo, B., Melo, A.S.A., Perozo-Mena, A., Hernandez, M., Francisco, E.C., Hagen, F., et al. (2016) First Report of Candida auris in America: Clinical and Microbiological Aspects of 18 Episodes of Candidemia. Journal of Infection, 73, 369-374. [CrossRef] [PubMed]
[62]	Chowdhary, A., Sharma, C., Duggal, S., Agarwal, K., Prakash, A., Singh, P.K., et al. (2013) New Clonal Strain of Candida auris, Delhi, India. Emerging Infectious Disease, 19, 1670-1673. [CrossRef] [PubMed]
[63]	Rudramurthy, S.M., Chakrabarti, A., Paul, R.A., Sood, P., Kaur, H., Capoor, M.R., et al. (2017) Candida auris Candidaemia in Indian ICUs: Analysis of Risk Factors. Journal of Antimicrobial Chemotherapy, 72, 1794-1801. [CrossRef] [PubMed]
[64]	Marková, M., Brodská, H., Malícková, K., Válková, V., Cetkovsky, P., Kolár, M., et al. (2013) Substantially Elevated C-Reactive Protein (CRP), Together with Low Levels of Procalcitonin (PCT), Contributes to Diagnosis Of Fungal Infection in Immunocompromised Patients. Supportive Care in Cancer, 21, 2733-2742. [CrossRef] [PubMed]
[65]	Liu, Y., Zhang, X., Yue, T., Tang, Y., Ke, Z., Li, Y., et al. (2022) Combination of C-Reactive Protein and Procalcitonin in Distinguishing Fungal from Bacterial Infections Early in Immunocompromised Children. Antibiotics, 11, Article 730. [CrossRef] [PubMed]
[66]	Stoma, I., Karpov, I., Uss, A., Krivenko, S., Iskrov, I., Milanovich, N., et al. (2019) Combination of Sepsis Biomarkers May Indicate an Invasive Fungal Infection in Haematological Patients. Biomarkers, 24, 401-406. [CrossRef]
[67]	Arendrup, M.C., Prakash, A., Metetiadis, J., Sharma, C. and Chowdhary, A. (2017) Comparison of EUCAST and CLSI Reference Microdilution MICs of Eight and Associated Tentative. Antimicrobial Agents and Chemotherapy, 61, e00485-17. [CrossRef]
[68]	Tsay, S., Welsh, R.M., Adams, E.H., Chow, N.A., Gade, L., Berkow, E.L., et al. (2017) Notes from the Field: Ongoing Transmission of Candida auris in Health Care Facilities—United States, June 2016-May 2017. Morbidity and Mortality Weekly Report, 66, 514-515. [CrossRef] [PubMed]
[69]	Rhodes, J., Abdolrasouli, A., Farrer, R.A., Cuomo, C.A., Aanensen, D.M., Armstrong-James, D., et al. (2018) Genomic Epidemiology of the UK Outbreak of the Emerging Human Fungal Pathogen Candida auris. Emerging Microbes & Infections, 7, 1-12. [CrossRef] [PubMed]
[70]	Driemeyer, C., Falci, D.R., Oladele, R.O., Bongomin, F., Ocansey, B.K., Govender, N.P., et al. (2022) The Current State of Clinical Mycology in Africa: A European Confederation of Medical Mycology and International Society for Human and Animal Mycology survey. The Lancet Microbe, 3, e464-e470. [CrossRef]
[71]	Frías-De-león, M.G., Hernández-Castro, R., Vite-Garín, T., Arenas, R., Bonifaz, A., Castanón-Olivares, L., et al. (2020) Antifungal Resistance in Candida auris: Molecular Determinants. Antibiotics, 9, Article 568. [CrossRef] [PubMed]
[72]	Rybak, J.M., Sharma, C., Doorley, L.A., Barker, K.S., Palmer, G.E. and Rogers, P.D. (2021) Delineation of the Direct Contribution of Candida auris ERG11 Mutations to Clinical Triazole Resistance. Microbiology Spectrum, 9, e0158521. [CrossRef]
[73]	Rybak, J.M., Munoz, J.F., Barker, K.S., Parker, J.E., Esquivel, B.D., Berkow, E.L., et al. (2020) Mutations in TAC1B: A Novel Genetic Determinant of Clinical Fluconazole Resistance in Candida auris. mBio, 11, e00365-20. [CrossRef]
[74]	Chaabane, F., Graf, A., Jequier, L. and Coste, A.T. (2019) Review on Antifungal Resistance Mechanisms in the Emerging Pathogen Candida auris. Frontiers in Microbiology, 10, Article 499266. [CrossRef] [PubMed]
[75]	Biagi, M.J., Wiederhold, N.P., Gibas, C., Wickes, B.L., Lozano, V., Bleasdale, S.C., et al. (2019) Development of High-Level Echinocandin Resistance in a Patient with Recurrent Candida auris Candidemia Secondary to Chronic Candiduria. Open Forum Infectious Diseases, 6, ofz262. [CrossRef] [PubMed]