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Review

Emerging Fungal Infections: New Patients, New Patterns, and New Pathogens

Division of Infectious Diseases, Department of Medicine, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB T6G 2G3, Canada
*
Author to whom correspondence should be addressed.
J. Fungi 2019, 5(3), 67; https://doi.org/10.3390/jof5030067
Submission received: 19 June 2019 / Revised: 18 July 2019 / Accepted: 19 July 2019 / Published: 20 July 2019
(This article belongs to the Special Issue Fungal Epidemiology)

Abstract

:
The landscape of clinical mycology is constantly changing. New therapies for malignant and autoimmune diseases have led to new risk factors for unusual mycoses. Invasive candidiasis is increasingly caused by non-albicans Candida spp., including C. auris, a multidrug-resistant yeast with the potential for nosocomial transmission that has rapidly spread globally. The use of mould-active antifungal prophylaxis in patients with cancer or transplantation has decreased the incidence of invasive fungal disease, but shifted the balance of mould disease in these patients to those from non-fumigatus Aspergillus species, Mucorales, and Scedosporium/Lomentospora spp. The agricultural application of triazole pesticides has driven an emergence of azole-resistant A. fumigatus in environmental and clinical isolates. The widespread use of topical antifungals with corticosteroids in India has resulted in Trichophyton mentagrophytes causing recalcitrant dermatophytosis. New dimorphic fungal pathogens have emerged, including Emergomyces, which cause disseminated mycoses globally, primarily in HIV infected patients, and Blastomyces helicus and B. percursus, causes of atypical blastomycosis in western parts of North America and in Africa, respectively. In North America, regions of geographic risk for coccidioidomycosis, histoplasmosis, and blastomycosis have expanded, possibly related to climate change. In Brazil, zoonotic sporotrichosis caused by Sporothrix brasiliensis has emerged as an important disease of felines and people.

1. Introduction

In clinical mycology, as in other facets of healthcare, the only thing constant is change. Medical advances have improved and prolonged lives, but have also increased the pool of individuals vulnerable to fungal disease; among these, new therapies for old diseases—such as monoclonal antibodies for autoimmune disease and small-molecule inhibitors (e.g. receptor tyrosine kinase inhibitors like ibrutinib) for B-cell malignancies—have resulted in reports of atypical and unusually severe fungal infections [1]. At the same time, more sophisticated methods to identify fungi have led to the recognition of genetic and phenotypic diversity among fungal pathogens [2]. Finally, decades of prolonged antifungal and antibacterial use in agriculture and medicine have altered the global microbiome, with a consequence being the emergence of drug-resistant fungal infections of plants, animals, and humans [3]. Within these contexts, changing trends are explored in global epidemiology of human fungal infections.

2. New Patients at Risk for Fungal Disease

Immunotherapy: Medical Progress Begets New Risk Factors for Invasive Fungal Disease

Immunotherapies have revolutionized the treatment of cancers and autoimmune diseases. Their infectious risks, however, are only beginning to be fully appreciated. Invasive fungal infections are important complications of some of these novel immunomodulators. Notably, the Bruton’s tyrosine kinase inhibitor, ibrutinib, used to treat B-cell malignancies, is associated with severe and unusual fungal infections, particularly with Aspergillus and Cryptococcus [4,5]. Fingolimod, a syphingosine-1-phosphate receptor used for the treatment of relapsing-remitting multiple sclerosis, has been identified as a possible risk factor in some patients who developed cryptococcosis and histoplasmosis [6,7,8].
Cell cycle checkpoint inhibitors, such as inhibitors of CTLA4, PD1 and PD-L1, are used for several different cancer types (particularly melanoma, non-small cell lung cancer and hematologic malignancies), and, due to the upregulation of the immune system, are hypothesized to have antifungal properties [9]. However, both invasive aspergillosis and candidiasis have been reported following the use of the checkpoint inhibitor, nivolumab, for the treatment of non-small cell lung cancer [10]. As their use continues to increase, more studies are required to better define the infectious risk, particularly for opportunistic fungal infections, with these novel immunomodulators.

3. Emerging Yeast Infections

3.1. Shift to Non-albicans Candida Species and the Emergence of Antifungal Resistance

Invasive candidiasis is a serious infection that primarily affects critically ill and immunocompromised patients. Candida albicans, usually susceptible to fluconazole, has long been the most prevalent species implicated in both invasive and mucocutaneous infections. However, with increasing use of antifungal agents and new diagnostic techniques, a change in the epidemiology of Candida infections is occurring, with the consequence of increased incidences of infections caused by species with less predictable antifungal susceptibility.
Established in 1997, the SENTRY Antifungal Surveillance Program monitors the global epidemiology of invasive Candida infections with respect to species distribution and resistance to antifungals. Most recently, the program has published its data from the first 20 years, which included over 20,000 clinical isolates collected through passive surveillance from 39 countries worldwide. Although C. albicans remains the most prevalent species causing invasive candidiasis, the total proportion of infections attributable to C. albicans has decreased from 57.4 to 46.4% over the 20-year surveillance period [11]. In the United States, over 30% of cases of candidemia are now caused by C. glabrata, a concerning trend given the increased rates of antifungal resistance associated with this species [12]. In some centers, resistance to echinocandins—mediated by mutations to the FKS1 hot spot—is seen in as many as 10% of C. glabrata isolates, and among these echinocandin-resistant strains, azole co-resistance occurs in 20% [13]. Conversely, in the United Kingdom, C. glabrata isolates were rarely resistant to echinocandins (0.55%) [14]. Also more frequently encountered is C. parapsilosis. This species is attributable for 15% of cases of candidemia in the United States [12], 20% in Russia [15], and rivals C. albicans as the leading cause of invasive disease in South Africa [16]. The rise of C. parapsilosis may be a marker of poor infection control practices, because C. parapsilosis is a commensal of the skin and can be transmitted within healthcare settings. This is worrisome because C. parapsilosis is also commonly resistant to antifungals. As many as 60% of C. parapsilosis isolates were fluconazole-resistant in South Africa [16].
Candida species have undergone a taxonomic reclassification, with the emergence of new clades, genera and species over the last decade. Stavrou et al. systematically reviewed the literature of epidemiology of yeasts species, identified by molecular techniques causing invasive Candida infections [17]. Although in 13 epidemiologic studies from 2013–2018 C. albicans remained the most prevalent agent of candidiasis, newly-reclassified yeasts were recognized, including species of the genera Kluveromyces, Pichia, and Wickerhamiella. This cladisitic analysis resulted in species groupings of similar antifungal susceptibility patterns, emphasizing the importance of proper identification to facilitate appropriate empiric therapy.

3.2. The Global Emergence of Candida auris

One of the most troubling changes in the epidemiology of invasive candidiasis is the worldwide emergence of C. auris, a multidrug resistant organism potential for efficient nosocomial transmission. Since it was described in Japan in 2009 [18], C. auris has been reported from 32 countries from six continents (Figure 1) [19]. In an examination of 54 isolates by whole genome sequencing, Lockhart et al., showed that there are four phylogeographic clades of C. auris from three continents. The average genetic distance between isolates within the clades was <70 single-nucleotide positions (SNPs), whereas between the clades isolates differed by 20,000 to 120,000 SNPs [20]. This suggests that C. auris emerged simultaneously in different corners of the globe, with a subsequent spread through travel. Recently, the emergence of C. auris in Iran identified a fifth genetically distinct clade, albeit with only a single isolate identified to date [21]. The important virulence factors include the ability to form biofilms [22,23], the production of phospholipases and proteinases [24], the propensity to colonize patients and their environments for weeks to months, resulting in efficient transmission in healthcare settings [25,26], and resistance to antifungals. Most isolates studied had high-level fluconazole resistance (minimum inhibitory concentrations, MICs > 64 µg/mL). Additionally, up to 30% of isolates demonstrated reduced susceptibility to amphotericin B. Furthermore, 5% can be resistant to the echinocandins, which are the currently recommended first-line antifungals for candidemia [20,27]. Rudramurthy et al. performed a retrospective study to identify risk factors for acquisition C. auris candidemia in intensive care unit patients compared to other Candida species. Most importantly, prior antifungal use, vascular surgery, admission to a public-sector hospital, underlying pulmonary disease and indwelling urinary catheterization were associated with C. auris infection [28]. Despite being implicated in a minority of candidemia cases, the mortality associated with C. auris has been reported as up to 60% in some studies [29]. Collectively, these epidemiologic shifts restrict the utility of fluconazole as empiric therapy in candidemia.

3.3. Cryptic Speciation in Cryptococcus

For decades, after its description at the end of the 19th century, C. neoformans was a rare cause of human disease. However, the recognition of meningoencephalitis and other infections caused by this opportunistic organism increased in light of the AIDS epidemic in the 1980s and 1990s. Another species, C. gattii, has become an important cause of disease in both immunocompromised and immunocompotent hosts with geographic tropism, notably the Pacific Northwest coast of North America [39].
Based on molecular typing, Hagen et al. proposed that the genus be further subdivided into a number of new species [40]. Cryptococcus neoformans sensu stricto (formerly C. neoformans serotype A) differs in primarily causing meningoencephalitis rather than skin lesions and in geographical distribution [41]. Cryptococcus deneoformans, previously known as C. neoformans serotype D or C. neoformans var. neoformans, has been shown to occur at higher rates in HIV-infected individuals over the age of 60, those with cutaneous manifestations, and those who use intravenous drugs. The rates of infection were lower in Africans [41]. Cryptococcus gattii sensu stricto primarily affects apparently healthy individuals, with rates highest in Australia. Cryptococcus bacillisporus more commonly affects HIV-infected and immunocompromised hosts and the global numbers are too small to propose a geographic distribution. Cryptococcus deuterogattii is associated with the previous outbreak in Vancouver Island and Pacific Northwest of the United States. C. deuterogattii has higher MICs for isavuconazole compared to other species. Cryptococcus tetragattii comprises the majority of cases of infections with C. gattii species complex in Africa. However, little is known of the epidemiology of another species, C. decagattii.

4. Emerging Mould Infections

4.1. Emergence of Azole-Resistance in Aspergillus fumigatus

Invasive aspergillosis (IA) carries a high fatality rate in immunocompromised patients. Aspergillus fumigatus, the most common causative species, has been almost universally susceptible to newer generation triazole antifungals, such as itraconazole, voriconazole and posaconazole. Under the pressure of pervasive antifungal use, however, resistance has become an emerging clinical challenge. The primary target of medical triazoles is lanosterol 14α-demethylase, which is essential for ergosterol biosynthesis and fungal cell membrane stability. The mutations in the cyp51A and cyp51B genes, which encode this demethylase, are important mechanisms of azole resistance in Aspergillus species. Among the most common cyp51A mutations conferring azole resistance is TR34/L98H—a 34-bp tandem repeat in the gene’s promoter region with an associated substitution of lysine to histidine at codon 98, which results in an eight-fold upregulation of lanosterol 14α-demethylase [42,43]. Another leading cyp51A mutation associated with azole resistance in A. fumigatus is TR46/Y121F/T289A, which is a 46-bp tandem repeat with substitution of tyrosine to phenylalanine and threonine to alanine at codons 121 and 289, respectively. Recently, Rybak et al. showed that while cyp51A mutations were insufficient on their own to confer azole resistance, a newly described mutation at HMG reductase gene hmg1 can cause pan-azole resistance in clinical isolates [44].
In the late 1990s, several patients were found with itraconazole-resistant A. fumigatus in the United States, which was suspected to have developed as the result of prolonged antimicrobial therapy [45]. In the following decade, multiple European centers described increasing azole resistance in clinical A. fumigatus isolates, including from patients who had not previously been treated with azoles and environmental isolates. In the Netherlands, a nationwide surveillance of A. fumigatus specimens isolated between 1945 and 1998 reported that fewer than 2% of isolates were highly resistant to itraconazole and no isolates were voriconazole resistant [46]. In 2016, the rate of azole resistance increased to 5.3% [47,48]. This increase occurred in parallel with the widespread use of agricultural demethylase inhibitors throughout Europe [49,50,51,52]. Moreover, the repeated exposure of susceptible A. fumigatus strains to azoles used as pesticides can induce genetic mechanisms identical to those observed in patients and that select for resistance to medical azoles [53]. Azole-resistant A. fumigatus is also becoming recognized beyond Europe, and is now reported from six continents [54]. In the United States, the most recent estimate of azole resistance in A. fumigatus isolates was 1.5%. Furthermore, 30% of these isolates did not have an identifiable cyp51A gene mutation, necessitating further characterization of other loci of resistance [55]. The global distribution of countries reporting azole-resistant A. fumigatus is shown in Figure 2.
However, less is known about antifungal resistance mechanisms and patterns in non-fumigatus Aspergillus species. Notably, A. flavus, the second most common cause of aspergillosis [98,99,100], has also shown low rates of azole resistance in small surveillance studies. Some studies from India, the Netherlands, and China quote azole resistance rates of up to 5% [101,102,103,104]. The consequences of A. flavus azole resistance may be dire in tropical and semi-arid climates, such as in India, South America and Saudi Arabia, where absolute rates of A. flavus infections are higher compared to North America and Europe. The mechanisms of azole resistance in A. flavus go beyond that of cyp51 gene mutations, with some studies showing a role of overexpression of several loci generating multidrug efflux pumps [102,105].

4.2. Influenza-Associated Invasive Pulmonary Aspergillosis

Recently, several studies from the Netherlands and Belgium have reported IA to be a common complication of severe influenza [106,107]. From 2015 to 2016, 23 cases of influenza-associated IA were diagnosed in Dutch intensive care units (ICUs) and half of these patients had no other risk factor for invasive fungal diseases [108]. A subsequent retrospective study reviewed 630 admissions of patients to seven ICUs from 2009 to 2016 with severe community acquired pneumonia. Half of the patients had influenza pneumonia, the presence of which increased the risk of developing IA from 5% to 14% [109]. Immunocompetent patients with influenza-associated aspergillosis had almost 50% mortality in the three months following diagnosis, compared to 29% in matched ICU patients with severe influenza but without IA. This study demonstrated influenza infection to be an independent risk factor for IA. Schauwvlieghe et al. hypothesized that the underlying pathophysiology relies on the influenza virus severely damaging the respiratory epithelium and mucociliary clearance function to allow Aspergillus invasion [109]. Further studies are underway to assess the role of antifungal prophylaxis in patients with severe influenza pneumonia.

4.3. Non-Aspergillus Mould Infections

The use of antifungal prophylaxis in immunosuppressed individuals has also led to an increase of invasive mould infections with non-Aspergillus species. In 2012, Auberger et al. studied the breakthrough invasive fungal infections in patients with prolonged neutropenia receiving posaconazole [110]. They noted an increase in breakthrough Mucorales infections. More recent studies from India suggest Apophysomyces species are becoming more prevalent causes of mucormycosis and are associated with hospital-acquired cutaneous infections [111,112].
More recently, increases of infections with Lomentospora prolificans (formerly Scedosporium prolificans) and Fusarium species, which are more often resistant to voriconazole and posaconazole, have also been observed in immunosuppressed hosts [113]. In a single-center study, Dalyan Cilo et al. showed that over the 20-year period of 1995–2014, cases of fusariosis increased from an average of 0.67 cases per year to 4.8 cases per year. This increase was associated with both a rise in locally invasive and disseminated infections. The predominant species implicated was F. proliferatum [114]. A multicenter study from seven European nations identified 76 cases of fusariosis over a five-year period. The MICs of isolates were generally low for amphotericin B, but variable for azoles (with the highest MICs noted for itraconazole) [115]. Seidel et al. reported on 208 cases of scedosporiosis and 56 cases of lomentosporiosis in the literature and Fungiscope®, a 74-nation registry of rare invasive fungal diseases. Almost half of the cases of Scedosporium spp. infections occurred in immunocompetent hosts, whereas 70% of Lomentospora prolificans infections occurred in patients with immunocompromising conditions, mostly malignancy or solid organ transplantation (SOT) [116]. Lomentospora prolificans isolates were pan-resistant to virtually all systemically active antifungals, including azoles, terbinafine and amphotericin B [116].
In SOT and haematopoietic stem cell transplant (HSCT) recipients, non-Aspergillus moulds are an emerging cause of late-onset invasive fungal infection. Between 2001 to 2006, the Transplant Associated Infection Surveillance Network (TRANSNET) identified 56 cases of phaeohyphomycosis [117] and 105 cases of mucormycosis [98,99], and 31 cases of fusariosis [98] in transplantation recipients in the United States. Non-Aspergillus mould infections tended to occur later following transplantation than IA [98,99]. From 2004 to 2007, Neofytos et al. highlighted that up to 15% of invasive mould infections following transplant were non-Aspergillus [118]. Among HSCT recipients, 29 cases of invasive L. prolificans infection have been published and associated with over 80% mortality [119].

4.4. Indian Epidemic of Resistant Dermatophytosis

A shift in the epidemiology and microbiology of dermatophytoses in India has occurred over the last 20 years. Previously, Trichophyton rubrum has been the prevalent pathogen. However, there has now been an emergence of T. mentagrophytes infection throughout the country [120,121]. This change is substantial, with T. mentagrophytes rising from 20% of dermatophytoses to over 90% in less than 15 years [121]. The sequencing of the internal transcribed spacer region of the ribosomal DNA has determined that this strain is genetically distinct from other reference strains worldwide [121]. This epidemic resulted in more efficient human-to-human transmission and lesions that were more inflammatory and eruptive than previous, with a predilection for the face [121,122]. In one study, 78% of skin lesions presenting to an Indian hospital were a dermatophytosis, which was well above the 20–25% worldwide prevalence [123].
The development of resistance among these fungi to terbinafine is troubling. Terbinafine is the oral and topical squalene epoxidase inhibitor that has long been the first line of therapy for superficial dermatophytosis. In Japan, 1% of Trichophyton isolates harbored point mutations in the squalene epoxidase gene (SQLE) conferring terbinafine resistance [124,125]. The increasing rates of dermatophytosis and emerging antifungal resistance is thought to be due to the unregulated use of antifungals, as well as fixed drug combination creams containing steroids, antifungals, and antibacterials, which have been used for many undifferentiated skin lesions in India [120].

5. Emerging Dimorphic Fungal Infections

5.1. Emergence of Distinct, Novel Pathogens in Emergomyces and Blastomyces, and Cryptic Speciation in Histoplasma

Over the past five years, a taxonomic overhaul of medically important, dimorphic fungi in the family Ajellomycetaceae has occurred [126]. In 2013, Kenyon et al. reported disseminated disease in South African patients with advanced HIV caused by a previously unrecognized dimorphic pathogen, which the authors classified as a likely Emmonsia species on the basis of relatedness to Emmonsia pasteuriana, which was then an obscure fungus reported only once previously [127]. Schwartz et al. later reported an additional 39 cases of disseminated disease in immunocompromised patients from around South Africa [128]. Nearly all the patients had skin lesions, and pulmonary disease was also common. The patients were frequently misdiagnosed as tuberculosis, and in a quarter of cases, a diagnosis of fungal disease only was made when ante-mortum blood cultures grew a mould after the patients had died. In total, half of all patients died. After these reports, additional Emmonsia-like isolates were discovered in several global collections [129]. In 2017, several Emmonsia-like fungi were re-classified into the newly formed genus Emergomyces. Currently, five Emergomyces species have been recognized with cases reported from four continents [2] (Figure 3). Emergomyces pasteurianus infections have been reported from Italy, Spain, France, the Netherlands, India, China, South Africa, and Uganda [130]. In North America, Es. canadensis has been implicated in four cases of disseminated mycoses in immunocompromised patients [131]. One case of disseminated Es. orientalis infection has been described in a previously healthy man in China [132]. Emergomyces africanus has been implicated in dozens of cases of disseminated disease in patients with advanced HIV disease [128] and portends a significant mortality [133]. Further, in vitro data suggest resistance to fluconazole is common, but susceptibility to other triazoles and amphotericin B is generally preserved [134,135].
Although Blastomyces was first described over a century ago, a careful observation of mycologists supplemented by advances in molecular characterization of fungi has led to new appreciations of the genetic diversity and in the geographic niches of these fungi [2]. Until recently, the only known agent of blastomycosis in North America was B. dermatitidis, which is endemic to Mid-Eastern Canada and the United States [140]. Over the last decade, taxonomic changes have led to a broadening of the genus, which now includes at least three additional, clinically relevant species that differ in genetics, virulence, and geographic distribution.
From building on the work of others [141], Meece et al. from Wisconsin demonstrated the genetic variation within clinical and environmental isolates of B. dermatitidis from North America. In 2011, these authors recognized the existence of two distinct genetic populations within B. dermatitidis [142]. Soon thereafter, Brown et al. described one of these subpopulations as a cryptic species, B. gilchristii [143]. While phenotypic and clinical distinctions may exist, they have not yet been convincingly shown. There do seem to be geographic differences, though many if not most regions of geographic risk for blastomycosis are sympatric for both B. gilchristii and B. dermatitidis (herein referred to collectively as B. dermatitidis species complex) [143,144,145].
Retrospectively, at least some cases of blastomycosis occurring in Canada and the United States can be attributed to B. helicus (formerly Emmonsia helica). The earliest known case occurred in 1970 but was only recently reclassified. These infections differ from those caused by B. dermatitidis species complex in their more western North American distribution (Figure 4) through their predilection for immunocompromised, rather than immunocompetent hosts, increased incidence of fungemia and systemic dissemination, and possibly higher rates of infection in felines than observed with B. dermatitidis species complex [146].
Blastomycosis has been reported outside of North America, in patients not known to have traveled to areas of geographic risk. Most cases of blastomycosis reportedly acquired outside of North America have been in Africa [147], where locally-acquired infections have been reported from over two-dozen African countries (Schwartz IS, unpublished data). Other cases of blastomycosis have been reported from the Middle East, and as far east as India. At least some of these cases outside of North America are due to one or more distinct species [2,126,147]. Dukik et al. first described B. percursus in 2015 from isolates obtained from patients with extrapulmonary blastomycosis from South Africa and Israel. This species differed from B. dermatitidis species complex not only in geographic distribution, but also in the pattern of conidia production [126].
The phylogenetics of Histoplasma was revisited by Sepúlveda et al. who noted genetically distinct clades with geographic variation. These authors proposed that H. capsulatum sensu stricto should be the name for the taxa located in Panama where histoplasmosis was first described, while H. mississippiense, H. ohiense, and H. suramericanum were proposed for the other three American taxa found mostly around the Mississippi River, Ohio River, and South America, respectively [148]. The clinical relevance of these distinctions has not been established in humans. In mouse models, H. suramericanum produced acute granulomatous necrotizing lung inflammation associated with high mortality, while H. ohiense and H. mississippiense were associated with chronic lung disease [149]. This taxonomic divergence remains controversial and is not yet widely accepted. On the other hand, H. duboisii, which causes histoplasmosis in western Africa, has long been appreciated to differ by the production of larger yeast cells and for causing predominantly cutaneous and osteo-articular manifestations [148,150,151].

5.2. Shifting Areas of Geographic Risks: Blastomycosis, Coccidioidomycosis, and Histoplasmosis

The three most common geographically restricted, dimorphic fungal infections (endemic mycoses) in North America are coccidioidomycosis, histoplasmosis and blastomycosis. The causative fungi—Coccidioides spp., Histoplasma spp., and Blastomyces spp., respectively—exist as moulds in the environment. The aerosolized spores can become inhaled by mammals, which lead to a temperature-dependant transformation in mammalian tissue to yeast-like cells. The suitable environmental conditions to support the mould phases are required for the risk of autochthonous infection, although the precise environmental factors remain poorly understood [152].
Recent data suggested that the geographic ranges of these fungi have expanded. The region of geographic risk for blastomycosis in North America is generally considered to include states and provinces adjacent to the Great Lakes and the St. Lawrence, Ohio and Mississippi Rivers, but recent case series have suggested that B. dermatitidis species complex can be found as far west as Saskatchewan [153] and as far east as New York [154]. Histoplasmosis, classically most associated in North America with the Ohio River Valley, has been reportedly acquired in Montana [155] and even Alberta [156], areas not previously considered endemic. Coccidioidomycosis, in the United States classically found in south-western states, has been acquired in Washington state, where C. immitis has been isolated from soil [157]. The precise reasons for the apparent expansions of the geographic ranges for these diseases are unknown but may relate to climate change [157,158].

5.3. The Proliferation of Cases of Zoonotic Sporotrichosis in Brazil

Originally described in 1898, sporotrichosis is a chronic granulomatous infection with a worldwide distribution caused by the thermally dimorphic fungus Sporothrix spp. Until the early 2000s, S. schenckii was the only known species implicated in the disease, but genetic analyses have led to the description of additional species, including S. globosa, S. mexicana, S. luriei and S. brasiliensis [159,160]. Sporothrix brasiliensis is a particularly virulent species capable of producing profound inflammatory responses [161,162]. Furthermore, unlike other causes of sporotrichosis, S. brasiliensis is associated with zoonotic (rather than sapronotic) transmission involving cats (Figure 5) [163]. These factors have led to outbreaks of sporotrichosis amongst feline and human populations in Brazil over the last two decades [164]. Over the 12-year period of 1987 to 1998, only 13 cases of human sporotrichosis were described in Brazil [165]. These rates have grown, especially in the state of Rio Grande do Sul, which has seen a four-fold increase of S. brasiliensis infections in humans from 2010 to 2014 [166] and the city Rio de Janeiro, which is hyperendemic, possibly due to overcrowding [167]. Between 2012 and 2017, 101 human cases of zoonotic sporotrichosis were reported [168].

Author Contributions

Both authors contributed to conceptualization. D.Z.P.F. wrote the first draft, and both authors contributed to reviewing and revising the manuscript.

Acknowledgments

The authors acknowledge Rodrigo Menezes, LAPCLIN-DERMZOO, Evandro Chagas National Institute of Infectious Diseases (INI), Oswaldo Cruz Foundation (Fiocruz) for contributing images for Figure 5.

Conflicts of Interest

I.S.S. has consulted for AVIR Pharma Inc. D.Z.P.F. declares no potential conflicts of interest.

References

  1. Clark, C.; Drummond, R. The hidden cost of modern medical interventions: How medical advances have shaped the prevalence of human fungal disease. Pathogens 2019, 8, 45. [Google Scholar] [CrossRef] [PubMed]
  2. Jiang, Y.; Dukik, K.; Muñoz, J.F.; Sigler, L.; Schwartz, I.S.; Govender, N.P.; Kenyon, C.; Feng, P.; van den Ende, B.G.; Stielow, J.B.; et al. Phylogeny, ecology and taxonomy of systemic pathogens and their relatives in Ajellomycetaceae (Onygenales): Blastomyces, Emergomyces, Emmonsia, Emmonsiellopsis. Fungal Divers. 2018, 90, 245–291. [Google Scholar] [CrossRef]
  3. Fisher, M.C.; Hawkins, N.J.; Sanglard, D.; Gurr, S.J. Worldwide emergence of resistance to antifungal drugs challenges human health and food security. Science 2018, 360, 739–742. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Baron, M.; Zini, J.M.; Challan Belval, T.; Vignon, M.; Denis, B.; Alanio, A.; Malphettes, M. Fungal infections in patients treated with ibrutinib: Two unusual cases of invasive aspergillosis and cryptococcal meningoencephalitis. Leuk. Lymphoma 2017, 58, 2981–2982. [Google Scholar] [CrossRef] [PubMed]
  5. Ghez, D.; Calleja, A.; Protin, C.; Baron, M.; Ledoux, M.-P.; Damaj, G.; Dupont, M.; Dreyfus, B.; Ferrant, E.; Herbaux, C.; et al. Early-onset invasive aspergillosis and other fungal infections in patients treated with ibrutinib. Blood 2018, 131, 1955–1959. [Google Scholar] [CrossRef] [PubMed]
  6. Achtnichts, L.; Obreja, O.; Conen, A.; Fux, C.A.; Nedeltchev, K. Cryptococcal meningoencephalitis in a patient with multiple sclerosis treated With Fingolimod. JAMA Neurol. 2015, 72, 1203–1205. [Google Scholar] [CrossRef] [PubMed]
  7. Grebenciucova, E.; Reder, A.T.; Bernard, J.T. Immunologic mechanisms of fingolimod and the role of immunosenescence in the risk of cryptococcal infection: A case report and review of literature. Mult. Scler. Relat. Disord. 2016, 9, 158–162. [Google Scholar] [CrossRef] [PubMed]
  8. Veillet-Lemay, G.M.; Sawchuk, M.A.; Kanigsberg, N.D. Primary Cutaneous Histoplasma capsulatum Infection in a Patient Treated with Fingolimod: A Case Report. J. Cutan. Med. Surg. 2017, 21, 553–555. [Google Scholar] [CrossRef]
  9. Daver, N.; Kontoyiannis, D.P. Checkpoint inhibitors and aspergillosis in AML: The double hit hypothesis. Lancet Oncol. 2017, 18, 1571–1573. [Google Scholar] [CrossRef]
  10. Fujita, K.; Kim, Y.H.; Kanai, O.; Yoshida, H.; Mio, T.; Hirai, T. Emerging concerns of infectious diseases in lung cancer patients receiving immune checkpoint inhibitor therapy. Respir. Med. 2019, 146, 66–70. [Google Scholar] [CrossRef]
  11. Pfaller, M.A.; Diekema, D.J.; Turnidge, J.D.; Castanheira, M.; Jones, R.N. Twenty years of the SENTRY Antifungal Surveillance Program: Results for Candida Species from 1997–2016. In Open Forum Infectious Diseases; Oxford University Press: Oxford, UK, 2019. [Google Scholar]
  12. Lamoth, F.; Lockhart, S.R.; Berkow, E.L.; Calandra, T. Changes in the epidemiological landscape of invasive candidiasis. J. Antimicrob. Chemother. 2018, 1, i4–i13. [Google Scholar] [CrossRef] [PubMed]
  13. Alexander, B.D.; Johnson, M.D.; Pfeiffer, C.D.; Jiménez-Ortigosa, C.; Catania, J.; Booker, R.; Castanheira, M.; Messer, S.A.; Perlin, D.S.; Pfaller, M.A. Increasing echinocandin resistance in Candida glabrata: Clinical failure correlates with presence of FKS mutations and elevated minimum inhibitory concentrations. Clin. Infect. Dis. 2013, 56, 1724–1732. [Google Scholar] [CrossRef] [PubMed]
  14. Fraser, M.; Borman, A.M.; Thorn, R.; Lawrance, L.M. Resistance to echinocandin antifungal agents in the United Kingdom in clinical isolates of Candida glabrata: Fifteen years of interpretation and assessment. Med. Mycol. 2019. [Google Scholar] [CrossRef] [PubMed]
  15. Vasilyeva, N.V.; Raush, E.R.; Rudneva, M.V.; Bogomolova, T.S.; Taraskina, A.E.; Fang, Y.; Zhang, F.; Klimko, N.N. Etiology of invasive candidosis agents in Russia: A multicenter epidemiological survey. Front. Med. 2018, 12, 84–91. [Google Scholar] [CrossRef] [PubMed]
  16. Govender, N.P.; Patel, J.; Magobo, R.E.; Naicker, S.; Wadula, J.; Whitelaw, A.; Coovadia, Y.; Kularatne, R.; Govind, C.; Lockhart, S.R.; et al. Emergence of azole-resistant Candida parapsilosis causing bloodstream infection: Results from laboratory-based sentinel surveillance in South Africa. J. Antimicrob. Chemother. 2016, 71, 1994–2004. [Google Scholar] [CrossRef] [PubMed]
  17. Stavrou, A.A.; Lackner, M.; Lass-Flörl, C.; Boekhout, T. The changing spectrum of Saccharomycotina yeasts causing candidemia: Phylogeny mirrors antifungal susceptibility patterns for azole drugs and amphothericin B. FEMS Yeast Res. 2019, 19, foz037. [Google Scholar] [CrossRef] [PubMed]
  18. Satoh, K.; Makimura, K.; Hasumi, Y.; Nishiyama, Y.; Uchida, K.; Yamaguchi, H. Candida auris sp. nov, a novel ascomycetous yeast isolated from the external ear canal of an inpatient in a Japanese hospital. Microbiol. Immunol. 2009, 53, 41–44. [Google Scholar] [CrossRef] [PubMed]
  19. Tracking Candida auris|Candida auris|Fungal Diseases|CDC. Available online: https://www.cdc.gov/fungal/candida-auris/tracking-c-auris.html (accessed on 13 May 2019).
  20. Lockhart, S.R.; Etienne, K.A.; Vallabhaneni, S.; Farooqi, J.; Chowdhary, A.; Govender, N.P.; Colombo, A.L.; Calvo, B.; Cuomo, C.A.; Desjardins, C.A.; et al. Simultaneous emergence of multidrug-resistant Candida auris on 3 continents confirmed by whole-genome sequencing and epidemiological analyses. Clin. Infect. Dis. 2017, 64, 134–140. [Google Scholar] [CrossRef]
  21. Chow, N.A.; de Groot, T.; Badali, H.; Abastabar, M.; Chiller, T.M.; Meis, J.F. Potential fifth clade of Candida auris, Iran, 2018. Emerg. Infect. Dis. 2019, 25, 190686. [Google Scholar] [CrossRef]
  22. Sherry, L.; Ramage, G.; Kean, R.; Borman, A.; Johnson, E.M.; Richardson, M.D.; Rautemaa-Richardson, R. Biofilm-forming capability of highly virulent, multidrug-resistant Candida auris. Emerg. Infect. Dis. 2017, 23, 328–331. [Google Scholar] [CrossRef]
  23. Oh, B.J.; Shin, J.H.; Kim, M.-N.; Sung, H.; Lee, K.; Joo, M.Y.; Shin, M.G.; Suh, S.P.; Ryang, D.W. Biofilm formation and genotyping of Candida haemulonii, Candida pseudohaemulonii, and a proposed new species (Candida auris) isolates from Korea. Med. Mycol. 2011, 49, 98–102. [Google Scholar] [CrossRef]
  24. Larkin, E.; Hager, C.; Chandra, J.; Mukherjee, P.K.; Retuerto, M.; Salem, I.; Long, L.; Isham, N.; Kovanda, L.; Borroto-Esoda, K.; et al. The emerging pathogen Candida auris: Growth phenotype, virulence factors, activity of antifungals, and effect of SCY-078, a novel glucan synthesis inhibitor, on growth morphology and biofilm formation. Antimicrob. Agents Chemother. 2017, 61, e02396-16. [Google Scholar] [CrossRef]
  25. Jeffery-Smith, A.; Taori, S.K.; Schelenz, S.; Jeffery, K.; Johnson, E.M.; Borman, A.; Manuel, R.; Brown, C.S. Candida auris: A review of the literature. Clin. Microbiol. Rev. 2017, 31, e00029-17. [Google Scholar] [CrossRef]
  26. Cadnum, J.L.; Shaikh, A.A.; Piedrahita, C.T.; Sankar, T.; Jencson, A.L.; Larkin, E.L.; Ghannoum, M.A.; Donskey, C.J. Effectiveness of disinfectants against Candida auris and other Candida species. Infect. Control Hosp. Epidemiol. 2017, 38, 1240–1243. [Google Scholar] [CrossRef]
  27. Colombo, A.L.; de Júnior, J.N.A.; Guinea, J. Emerging multidrug-resistant Candida species. Curr. Opin. Infect. Dis. 2017, 30, 528–538. [Google Scholar] [CrossRef]
  28. Rudramurthy, S.M.; Chakrabarti, A.; Paul, R.A.; Sood, P.; Kaur, H.; Capoor, M.R.; Kindo, A.J.; Marak, R.S.K.; Arora, A.; Sardana, R.; et al. Candida auris candidaemia in Indian ICUs: Analysis of risk factors. J. Antimicrob. Chemother. 2017, 72, 1794–1801. [Google Scholar] [CrossRef]
  29. Spivak, E.S.; Hanson, K.E. Candida auris: An Emerging Fungal Pathogen. J. Clin. Microbiol. 2017, 56, e01588-17. [Google Scholar] [CrossRef]
  30. Barantsevich, N.E.; Orlova, O.E.; Shlyakhto, E.V.; Johnson, E.M.; Woodford, N.; Lass-Floerl, C.; Churkina, I.V.; Mitrokhin, S.D.; Shkoda, A.S.; Barantsevich, E.P. Emergence of Candida auris in Russia. J. Hosp. Infect. 2019, 102, 445–448. [Google Scholar] [CrossRef]
  31. Belkin, A.; Gazit, Z.; Keller, N.; Ben-Ami, R.; Wieder-Finesod, A.; Novikov, A.; Rahav, G.; Brosh-Nissimov, T. Candida auris infection leading to nosocomial transmission, Israel, 2017. Emerg. Infect. Dis. 2018, 24, 801–804. [Google Scholar] [CrossRef]
  32. Kohlenberg, A.; Struelens, M.J.; Monnet, D.L.; Plachouras, D.; The Candida Auris Survey Collaborative Group. Candida auris: Epidemiological situation, laboratory capacity and preparedness in European Union and European Economic Area countries, 2013 to 2017. Eurosurveillance 2018, 23, 18–0013. [Google Scholar]
  33. Lone, S.A.; Ahmad, A. Candida auris—The growing menace to global health. Mycoses 2019, 62, 620–637. [Google Scholar] [CrossRef]
  34. Riat, A.; Neofytos, D.; Coste, A.T.; Harbarth, S.; Bizzini, A.; Grandbastien, B.; Pugin, J.; Lamoth, F. First case of Candida auris in Switzerland: Discussion about preventive strategies. Swiss Med. Wkly. 2018, 148, w14622. [Google Scholar]
  35. Chew, S.M.; Sweeney, N.; Kidd, S.E.; Reed, C. Candida auris arriving on our shores: An Australian microbiology laboratory’s experience. Pathology 2019, 51, 431–433. [Google Scholar] [CrossRef]
  36. Khan, Z.; Ahmad, S.; Al-Sweih, N.; Joseph, L.; Alfouzan, W.; Asadzadeh, M. Increasing prevalence, molecular characterization and antifungal drug susceptibility of serial Candida auris isolates in Kuwait. PLoS ONE 2018, 13, e0195743. [Google Scholar] [CrossRef]
  37. Osei Sekyere, J. Candida auris: A systematic review and meta-analysis of current updates on an emerging multidrug-resistant pathogen. Microbiologyopen 2018, 7, e00578. [Google Scholar] [CrossRef]
  38. Schwartz, I.; Smith, S.; Dingle, T. Something wicked this way comes: What health care providers need to know about Candida auris. Can. Commun. Dis. Rep. 2018, 44, 271–276. [Google Scholar] [CrossRef]
  39. Centers for Disease Control and Prevention. Emergence of Cryptococcus gattii—Pacific Northwest, 2004–2010. MMWR Morb. Mortal. Wkly. Rep. 2010, 59, 865–868. [Google Scholar]
  40. Hagen, F.; Khayhan, K.; Theelen, B.; Kolecka, A.; Polacheck, I.; Sionov, E.; Falk, R.; Parnmen, S.; Lumbsch, H.T.; Boekhout, T. Recognition of seven species in the Cryptococcus gattii/Cryptococcus neoformans species complex. Fungal Genet. Biol. 2015, 78, 16–48. [Google Scholar] [CrossRef] [Green Version]
  41. Dromer, F.; Mathoulin, S.; Dupont, B.; Letenneur, L.; Ronin, O.; French Cryptococcosis Study Group. Individual and Environmental Factors Associated with Infection Due to Cryptococcus neoformans Serotype D. Clin. Infect. Dis. 1996, 23, 91–96. [Google Scholar] [CrossRef]
  42. Berger, S.; El Chazli, Y.; Babu, A.F.; Coste, A.T. Azole resistance in Aspergillus fumigatus: A consequence of antifungal use in agriculture? Front. Microbiol. 2017, 8, 1024. [Google Scholar] [CrossRef]
  43. Arikan-Akdagli, S.; Ghannoum, M.; Meis, J.F. Antifungal resistance: Specific focus on multidrug resistance in Candida auris and secondary azole resistance in Aspergillus fumigatus. J. Fungi 2018, 4, 129. [Google Scholar] [CrossRef]
  44. Rybak, J.M.; Ge, W.; Wiederhold, N.P.; Parker, J.E.; Kelly, S.L.; Rogers, P.D.; Fortwendel, J.R. Mutations in hmg1, challenging the paradigm of clinical triazole resistance in Aspergillus fumigatus. mBio 2019, 10, e00437-19. [Google Scholar] [CrossRef]
  45. Denning, D.W.; Venkateswarlu, K.; Oakley, K.L.; Anderson, M.J.; Manning, N.J.; Stevens, D.A.; Warnock, D.W.; Kelly, S.L. Itraconazole resistance in Aspergillus fumigatus. Antimicrob. Agents Chemother. 1997, 41, 1364–1368. [Google Scholar] [CrossRef]
  46. Verweij, P.E.; Te Dorsthorst, D.T.A.; Rijs, A.J.M.M.; De Vries-Hospers, H.G.; Meis, J.F.G.M. Nationwide Survey of In Vitro Activities of Itraconazole and Voriconazole against Clinical Aspergillus fumigatus Isolates Cultured between 1945 and 1998. J. Clin. Microbiol. 2002, 40, 2648–2650. [Google Scholar] [CrossRef]
  47. Buil, J.B.; Snelders, E.; Denardi, L.B.; Melchers, W.J.G.; Verweij, P.E. Trends in azole resistance in Aspergillus fumigatus, the Netherlands, 1994–2016. Emerg. Infect. Dis. 2019, 25, 176–178. [Google Scholar] [CrossRef]
  48. Engel, T.G.P.; Slabbers, L.; de Jong, C.; Melchers, W.J.G.; Hagen, F.; Verweij, P.E.; Merkus, P.; Meis, J.F.; Dutch Cystic Fibrosis Fungal Collection Consortium. Prevalence and diversity of filamentous fungi in the airways of cystic fibrosis patients—A Dutch, multicentre study. J. Cyst. Fibros. 2019, 18, 221–226. [Google Scholar] [CrossRef]
  49. Snelders, E.; van der Lee, H.A.L.; Kuijpers, J.; Rijs, A.J.M.M.; Varga, J.; Samson, R.A.; Mellado, E.; Donders, A.R.T.; Melchers, W.J.G.; Verweij, P.E. Emergence of Azole Resistance in Aspergillus fumigatus and Spread of a Single Resistance Mechanism. PLoS Med. 2008, 5, e219. [Google Scholar] [CrossRef]
  50. Lelièvre, L.; Groh, M.; Angebault, C.; Maherault, A.-C.; Didier, E.; Bougnoux, M.-E. Azole resistant Aspergillus fumigatus: An emerging problem. Méd. Mal. Infect. 2013, 43, 139–145. [Google Scholar] [CrossRef]
  51. Cui, N.; He, Y.; Yao, S.; Zhang, H.; Ren, J.; Fang, H.; Yu, Y. Tebuconazole induces triazole-resistance in Aspergillus fumigatus in liquid medium and soil. Sci. Total Environ. 2019, 648, 1237–1243. [Google Scholar] [CrossRef]
  52. Trovato, L.; Scalia, G.; Domina, M.; Oliveri, S. Environmental Isolates of Multi-Azole-Resistant Aspergillus spp. in Southern Italy. J. Fungi 2018, 4, 131. [Google Scholar] [CrossRef]
  53. Snelders, E.; Camps, S.M.T.; Karawajczyk, A.; Schaftenaar, G.; Kema, G.H.J.; van der Lee, H.A.; Klaassen, C.H.; Melchers, W.J.G.; Verweij, P.E. Triazole Fungicides Can Induce Cross-Resistance to Medical Triazoles in Aspergillus fumigatus. PLoS ONE 2012, 7, e31801. [Google Scholar] [CrossRef]
  54. Resendiz Sharpe, A.; Lagrou, K.; Meis, J.F.; Chowdhary, A.; Lockhart, S.R.; Verweij, P.E. Triazole resistance surveillance in Aspergillus fumigatus. Med. Mycol. 2018, 1, 83–92. [Google Scholar] [CrossRef]
  55. Berkow, E.L.; Nunnally, N.S.; Bandea, A.; Kuykendall, R.; Beer, K.; Lockhart, S.R. Detection of TR34/L98H CYP51A mutation through passive surveillance for azole-resistant Aspergillus fumigatus in the United States from 2015 to 2017. Antimicrob. Agents Chemother. 2018, 62, e02240-17. [Google Scholar] [CrossRef]
  56. Abdolrasouli, A.; Scourfield, A.; Rhodes, J.; Shah, A.; Elborn, J.S.; Fisher, M.C.; Schelenz, S.; Armstrong-James, D. High prevalence of triazole resistance in clinical Aspergillus fumigatus isolates in a specialist cardiothoracic centre. Int. J. Antimicrob. Agents 2018, 52, 637–642. [Google Scholar] [CrossRef]
  57. Ahmad, S.; Khan, Z.; Hagen, F.; Meis, J.F. Occurrence of triazole-resistant Aspergillus fumigatus with TR34/L98H mutations in outdoor and hospital environment in Kuwait. Environ. Res. 2014, 133, 20–26. [Google Scholar] [CrossRef]
  58. Alastruey-Izquierdo, A.; Alcazar-Fuoli, L.; Rivero-Menendez, O.; Ayats, J.; Castro, C.; Garcia-Rodriguez, J.; Goterris-Bonet, L.; Ibanez-Martinez, E.; Linares-Sicilia, M.J.; Martin-Gomez, M.T.; et al. Molecular Identification and Susceptibility Testing of Molds Isolated in a Prospective Surveillance of Triazole Resistance in Spain (FILPOP2 Study). Antimicrob. Agents Chemother. 2018, 62, e00358-18. [Google Scholar] [CrossRef]
  59. Alvarez-Moreno, C.; Lavergne, R.-A.; Hagen, F.; Morio, F.; Meis, J.F.; Le Pape, P. Azole-resistant Aspergillus fumigatus harboring TR34/L98H, TR46/Y121F/T289A and TR53 mutations related to flower fields in Colombia. Sci. Rep. 2017, 7, 45631. [Google Scholar] [CrossRef]
  60. Arabatzis, M.; Kambouris, M.; Kyprianou, M.; Chrysaki, A.; Foustoukou, M.; Kanellopoulou, M.; Kondyli, L.; Kouppari, G.; Koutsia-Karouzou, C.; Lebessi, E.; et al. Polyphasic identification and susceptibility to seven antifungals of 102 Aspergillus isolates recovered from immunocompromised hosts in Greece. Antimicrob. Agents Chemother. 2011, 55, 3025–3030. [Google Scholar] [CrossRef]
  61. Bader, O.; Tünnermann, J.; Dudakova, A.; Tangwattanachuleeporn, M.; Weig, M.; Groß, U. Environmental isolates of azole-resistant Aspergillus fumigatus in Germany. Antimicrob. Agents Chemother. 2015, 59, 4356–4359. [Google Scholar] [CrossRef]
  62. Bader, O.; Weig, M.; Reichard, U.; Lugert, R.; Kuhns, M.; Christner, M.; Held, J.; Peter, S.; Schumacher, U.; Buchheidt, D.; et al. cyp51A-based mechanisms of Aspergillus fumigatus azole drug resistance present in clinical samples from Germany. Antimicrob. Agents Chemother. 2013, 57, 3513–3517. [Google Scholar] [CrossRef]
  63. Bedin Denardi, L.; Hoch Dalla-Lana, B.; de Pantella, F.K.J.; Bittencourt Severo, C.; Morais Santurio, J.; Zanette, R.A.; Hartz Alves, S. In vitro antifungal susceptibility of clinical and environmental isolates of Aspergillus fumigatus and Aspergillus flavus in Brazil. Braz. J. Infect. Dis. 2018, 22, 30–36. [Google Scholar] [CrossRef]
  64. Chen, Y.; Lu, Z.; Zhao, J.; Zou, Z.; Gong, Y.; Qu, F.; Bao, Z.; Qiu, G.; Song, M.; Zhang, Q.; et al. Epidemiology and molecular characterizations of azole resistance in clinical and environmental Aspergillus fumigatus isolates from China. Antimicrob. Agents Chemother. 2016, 60, 5878–5884. [Google Scholar] [CrossRef]
  65. Choukri, F.; Botterel, F.; Sitterlé, E.; Bassinet, L.; Foulet, F.; Guillot, J.; Costa, J.M.; Fauchet, N.; Dannaoui, E. Prospective evaluation of azole resistance in Aspergillus fumigatus clinical isolates in France. Med. Mycol. 2015, 53, 593–596. [Google Scholar] [CrossRef]
  66. Chowdhary, A.; Sharma, C.; Kathuria, S.; Hagen, F.; Meis, J.F. Prevalence and mechanism of triazole resistance in Aspergillus fumigatus in a referral chest hospital in Delhi, India and an update of the situation in Asia. Front. Microbiol. 2015, 06, 428. [Google Scholar] [CrossRef]
  67. Chowdhary, A.; Sharma, C.; van den Boom, M.; Yntema, J.B.; Hagen, F.; Verweij, P.E.; Meis, J.F. Multi-azole-resistant Aspergillus fumigatus in the environment in Tanzania. J. Antimicrob. Chemother. 2014, 69, 2979–2983. [Google Scholar] [CrossRef]
  68. Escribano, P.; Peláez, T.; Muñoz, P.; Bouza, E.; Guinea, J. Is azole resistance in Aspergillus fumigatus a problem in Spain? Antimicrob. Agents Chemother. 2013, 57, 2815–2820. [Google Scholar] [CrossRef]
  69. Gungor, O.; Sampaio-Maia, B.; Amorim, A.; Araujo, R.; Erturan, Z. Determination of azole resistance and TR34/L98H mutations in Isolates of Aspergillus Section Fumigati from Turkish cystic fibrosis patients. Mycopathologia 2018, 183, 913–920. [Google Scholar] [CrossRef]
  70. Hurst, S.F.; Berkow, E.L.; Stevenson, K.L.; Litvintseva, A.P.; Lockhart, S.R. Isolation of azole-resistant Aspergillus fumigatus from the environment in the south-eastern USA. J. Antimicrob. Chemother. 2017, 72, 2443–2446. [Google Scholar] [CrossRef]
  71. Jensen, R.H.; Hagen, F.; Astvad, K.M.T.; Tyron, A.; Meis, J.F.; Arendrup, M.C. Azole-resistant Aspergillus fumigatus in Denmark: A laboratory-based study on resistance mechanisms and genotypes. Clin. Microbiol. Infect. 2016, 22, 570. [Google Scholar] [CrossRef]
  72. Lass-Florl, C.; Mayr, A.; Aigner, M.; Lackner, M.; Orth-Holler, D. A nationwide passive surveillance on fungal infections shows a low burden of azole resistance in molds and yeasts in Tyrol, Austria. Infection 2018, 46, 701–704. [Google Scholar] [CrossRef] [Green Version]
  73. Lazzarini, C.; Esposto, M.C.; Prigitano, A.; Cogliati, M.; De Lorenzis, G.; Tortorano, A.M. Azole resistance in Aspergillus fumigatus clinical isolates from an Italian culture collection. Antimicrob. Agents Chemother. 2016, 60, 682–685. [Google Scholar] [CrossRef]
  74. Loeffert, S.T.; Hénaff, L.; Dupont, D.; Bienvenu, A.-L.; Dananché, C.; Cassier, P.; Bénet, T.; Wallon, M.; Gustin, M.-P.; Vanhems, P. Prospective survey of azole drug resistance among environmental and clinical isolates of Aspergillus fumigatus in a French University hospital during major demolition works. J. Mycol. Med. 2018, 28, 469–472. [Google Scholar] [CrossRef]
  75. Mohammadi, F.; Hashemi, S.J.; Seyedmousavi, S.M.; Akbarzade, D. Isolation and characterization of clinical triazole resistance Aspergillus fumigatus in Iran. Iran. J. Public Health 2018, 47, 994–1000. [Google Scholar]
  76. Monteiro, C.; Pinheiro, D.; Maia, M.; Faria, M.A.; Lameiras, C.; Pinto, E. Aspergillus species collected from environmental air samples in Portugal-molecular identification, antifungal susceptibility and sequencing of cyp51A gene on A. fumigatus sensu stricto itraconazole-resistant. J. Antimicrob. Chemother. 2019, 126, 1140–1148. [Google Scholar] [CrossRef]
  77. Mortensen, K.L.; Mellado, E.; Lass-Florl, C.; Rodriguez-Tudela, J.L.; Johansen, H.K.; Arendrup, M.C. Environmental Study of Azole-Resistant Aspergillus fumigatus and Other Aspergilli in Austria, Denmark, and Spain. Antimicrob. Agents Chemother. 2010, 54, 4545–4549. [Google Scholar] [CrossRef]
  78. Mushi, M.F.; Buname, G.; Bader, O.; Groß, U.; Mshana, S.E. Aspergillus fumigatus carrying TR34/L98H resistance allele causing complicated suppurative otitis media in Tanzania: Call for improved diagnosis of fungi in sub-Saharan Africa. BMC Infect. Dis. 2016, 16, 464. [Google Scholar] [CrossRef]
  79. Nawrot, U.; Kurzyk, E.; Arendrup, M.C.; Mroczynska, M.; Wlodarczyk, K.; Sulik-Tyszka, B.; Wroblewska, M.; Ussowicz, M.; Zdziarski, P.; Niewinska, K.; et al. Detection of Polish clinical Aspergillus fumigatus isolates resistant to triazoles. Med. Mycol. 2018, 56, 121–124. [Google Scholar] [CrossRef]
  80. Özmerdiven, G.E.; Ak, S.; Ener, B.; Ağca, H.; Cilo, B.D.; Tunca, B.; Akalın, H. First determination of azole resistance in Aspergillus fumigatus strains carrying the TR34/L98H mutations in Turkey. J. Infect. Chemother. 2015, 21, 581–586. [Google Scholar] [CrossRef]
  81. Pham, C.D.; Reiss, E.; Hagen, F.; Meis, J.F.; Lockhart, S.R. Passive surveillance for azole-resistant Aspergillus fumigatus, United States, 2011–2013. Emerg. Infect. Dis. 2014, 20, 1498–1503. [Google Scholar] [CrossRef]
  82. Prigitano, A.; Esposto, M.C.; Romano, L.; Auxilia, F.; Tortorano, A.M. Azole-resistant Aspergillus fumigatus in the Italian environment. J. Glob. Antimicrob. Resist. 2018, 16, 220–224. [Google Scholar] [CrossRef]
  83. Reichert-Lima, F.; Lyra, L.; Pontes, L.; Moretti, M.L.; Pham, C.D.; Lockhart, S.R.; Schreiber, A.Z. Surveillance for azoles resistance in Aspergillus spp. highlights a high number of amphotericin B-resistant isolates. Mycoses 2018, 61, 360–365. [Google Scholar] [CrossRef]
  84. Riat, A.; Plojoux, J.; Gindro, K.; Schrenzel, J.; Sanglard, D. Azole resistance of environmental and clinical Aspergillus fumigatus isolates from Switzerland. Antimicrob. Agents Chemother. 2018, 62, e02088-17. [Google Scholar] [CrossRef]
  85. Seufert, R.; Sedlacek, L.; Kahl, B.; Hogardt, M.; Hamprecht, A.; Haase, G.; Gunzer, F.; Haas, A.; Grauling-Halama, S.; MacKenzie, C.R.; et al. Prevalence and characterization of azole-resistant Aspergillus fumigatus in patients with cystic fibrosis: A prospective multicentre study in Germany. J. Antimicrob. Chemother. 2018, 73, 2047–2053. [Google Scholar] [CrossRef]
  86. Seyedmousavi, S.; Hashemi, S.J.; Zibafar, E.; Zoll, J.; Hedayati, M.T.; Mouton, J.W.; Melchers, W.J.G.; Verweij, P.E. Azole-resistant Aspergillus fumigatus, Iran. Emerg. Infect. Dis. 2013, 19, 832–834. [Google Scholar] [CrossRef]
  87. Sharma, C.; Hagen, F.; Moroti, R.; Meis, J.F.; Chowdhary, A. Triazole-resistant Aspergillus fumigatus harbouring G54 mutation: Is it de novo or environmentally acquired? J. Glob. Antimicrob. Resist. 2015, 3, 69–74. [Google Scholar] [CrossRef]
  88. Talbot, J.J.; Subedi, S.; Halliday, C.L.; Hibbs, D.E.; Lai, F.; Lopez-Ruiz, F.J.; Harper, L.; Park, R.F.; Cuddy, W.S.; Biswas, C.; et al. Surveillance for azole resistance in clinical and environmental isolates of Aspergillus fumigatus in Australia and cyp51A homology modelling of azole-resistant isolates. J. Antimicrob. Chemother. 2018, 73, 2347–2351. [Google Scholar] [CrossRef]
  89. Tangwattanachuleeporn, M.; Minarin, N.; Saichan, S.; Sermsri, P.; Mitkornburee, R.; Groß, U.; Chindamporn, A.; Bader, O. Prevalence of azole-resistant Aspergillus fumigatus in the environment of Thailand. Med. Mycol. 2017, 55, 429–435. [Google Scholar]
  90. Tsuchido, Y.; Tanaka, M.; Nakano, S.; Yamamoto, M.; Matsumura, Y.; Nagao, M. Prospective multicenter surveillance of clinically isolated Aspergillus species revealed azole-resistant Aspergillus fumigatus isolates with TR34/L98H mutation in the Kyoto and Shiga regions of Japan. Med. Mycol. 2019. [Google Scholar] [CrossRef]
  91. Vermeulen, E.; Maertens, J.; De Bel, A.; Nulens, E.; Boelens, J.; Surmont, I.; Mertens, A.; Boel, A.; Lagrou, K. Nationwide surveillance of azole resistance in Aspergillus diseases. Antimicrob. Agents Chemother. 2015, 59, 4569–4576. [Google Scholar] [CrossRef]
  92. Wirmann, L.; Ross, B.; Reimann, O.; Steinmann, J.; Rath, P.-M. Airborne Aspergillus fumigatus spore concentration during demolition of a building on a hospital site, and patient risk determination for invasive aspergillosis including azole resistance. J. Hosp. Infect. 2018, 100, e91–e97. [Google Scholar] [CrossRef]
  93. Wu, C.-J.; Wang, H.-C.; Lee, J.-C.; Lo, H.-J.; Dai, C.-T.; Chou, P.-H.; Ko, W.-C.; Chen, Y.-C. Azole-resistant Aspergillus fumigatus isolates carrying TR34/L98H mutations in Taiwan. Mycoses 2015, 58, 544–549. [Google Scholar] [CrossRef]
  94. Isla, G.; Leonardelli, F.; Tiraboschi, I.N.; Refojo, N.; Hevia, A.; Vivot, W.; Szusz, W.; Cordoba, S.B.; Garcia-Effron, G. First clinical isolation of an azole-resistant Aspergillus fumigatus harboring a TR46 Y121F T289A mutation in South America. Antimicrob. Agents Chemother. 2018, 62, e00872-18. [Google Scholar] [CrossRef]
  95. Dunne, K.; Hagen, F.; Pomeroy, N.; Meis, J.F.; Rogers, T.R. Intercountry transfer of triazole-resistant Aspergillus fumigatus on plant bulbs. Clin. Infect. Dis. 2017, 65, 147–149. [Google Scholar] [CrossRef]
  96. Lee, H.-J.; Cho, S.-Y.; Lee, D.-G.; Park, C.; Chun, H.-S.; Park, Y.-J. TR34/L98H mutation in CYP51A gene in Aspergillus fumigatus clinical isolates during posaconazole prophylaxis: First case in Korea. Mycopathologia 2018, 183, 731–736. [Google Scholar] [CrossRef]
  97. Fuller, J.; Bull, A.; Shokoples, S.; Dingle, T.C.; Adam, H.; Baxter, M.; Hoban, D.J.; Zhanel, G.G. Antifungal Susceptibility of Aspergillus Isolates from the Respiratory Tract of Patients in Canadian Hospitals: Results of the CANWARD 2016 Study. In Proceedings of the Oral Presentation at: AMMI Canada—Canadian Association for Clinical Microbiology and Infectious Diseases Annual Conference, Vancouver, BC, Canada, 2–5 May 2018. [Google Scholar]
  98. Kontoyiannis, D.P.; Marr, K.A.; Park, B.J.; Alexander, B.D.; Anaissie, E.J.; Walsh, T.J.; Ito, J.; Andes, D.R.; Baddley, J.W.; Brown, J.M.; et al. Prospective Surveillance for Invasive Fungal Infections in Hematopoietic Stem Cell Transplant Recipients, 2001–2006: Overview of the Transplant-Associated Infection Surveillance Network (TRANSNET) Database. Clin. Infect. Dis. 2010, 50, 1091–1100. [Google Scholar] [CrossRef]
  99. Pappas, P.G.; Alexander, B.D.; Andes, D.R.; Hadley, S.; Kauffman, C.A.; Freifeld, A.; Anaissie, E.J.; Brumble, L.M.; Herwaldt, L.; Ito, J.; et al. Invasive Fungal Infections among Organ Transplant Recipients: Results of the Transplant-Associated Infection Surveillance Network (TRANSNET). Clin. Infect. Dis. 2010, 50, 1101–1111. [Google Scholar] [CrossRef]
  100. Pasqualotto, A.C. Differences in pathogenicity and clinical syndromes due to Aspergillus fumigatus and Aspergillus flavus. Med. Mycol. 2009, 47, S261–S270. [Google Scholar] [CrossRef]
  101. Sharma, C.; Kumar, R.; Kumar, N.; Masih, A.; Gupta, D.; Chowdhary, A. Investigation of Multiple Resistance Mechanisms in Voriconazole-Resistant Aspergillus flavus Clinical Isolates from a Chest Hospital Surveillance in Delhi, India. Antimicrob. Agents Chemother. 2018, 62, e01928-17. [Google Scholar] [CrossRef]
  102. Paul, R.A.; Rudramurthy, S.M.; Dhaliwal, M.; Singh, P.; Ghosh, A.K.; Kaur, H.; Varma, S.; Agarwal, R.; Chakrabarti, A. Magnitude of Voriconazole Resistance in Clinical and Environmental Isolates of Aspergillus flavus and Investigation into the Role of Multidrug Efflux Pumps. Antimicrob. Agents Chemother. 2018, 62, e01022-18. [Google Scholar] [CrossRef]
  103. Rudramurthy, S.M.; Chakrabarti, A.; Geertsen, E.; Mouton, J.W.; Meis, J.F. In vitro activity of isavuconazole against 208 Aspergillus flavus isolates in comparison with 7 other antifungal agents: Assessment according to the methodology of the European Committee on Antimicrobial Susceptibility Testing. Diagn. Microbiol. Infect. Dis. 2011, 71, 370–377. [Google Scholar] [CrossRef]
  104. Pfaller, M.A.; Castanheira, M.; Messer, S.A.; Jones, R.N. In vitro antifungal susceptibilities of isolates of Candida spp. and Aspergillus spp. from China to nine systemically active antifungal agents: Data from the SENTRY antifungal surveillance program, 2010 through 2012. Mycoses 2015, 58, 209–214. [Google Scholar] [CrossRef]
  105. Choi, M.J.; Won, E.J.; Joo, M.Y.; Park, Y.-J.; Kim, S.H.; Shin, M.G.; Shin, J.H. Microsatellite Typing and Resistance Mechanism Analysis of Voriconazole-Resistant Aspergillus flavus Isolates in South Korean Hospitals. Antimicrob. Agents Chemother. 2019, 63, e01610-18. [Google Scholar] [CrossRef]
  106. Garcia-Vidal, C.; Barba, P.; Arnan, M.; Moreno, A.; Ruiz-Camps, I.; Gudiol, C.; Ayats, J.; Orti, G.; Carratala, J. Invasive aspergillosis complicating pandemic influenza A (H1N1) infection in severely immunocompromised patients. Clin. Infect. Dis. 2011, 53, e16–e19. [Google Scholar] [CrossRef]
  107. Wauters, J.; Baar, I.; Meersseman, P.; Meersseman, W.; Dams, K.; De Paep, R.; Lagrou, K.; Wilmer, A.; Jorens, P.; Hermans, G. Invasive pulmonary aspergillosis is a frequent complication of critically ill H1N1 patients: A retrospective study. Intensive Care Med. 2012, 38, 1761–1768. [Google Scholar] [CrossRef]
  108. van de Veerdonk, F.L.; Kolwijck, E.; Lestrade, P.P.A.; Hodiamont, C.J.; Rijnders, B.J.A.; van Paassen, J.; Haas, P.-J.; Oliveira dos Santos, C.; Kampinga, G.A.; Bergmans, D.C.J.J.; et al. Influenza-associated Aspergillosis in Critically Ill Patients. Am. J. Respir. Crit. Care Med. 2017, 196, 524–527. [Google Scholar] [CrossRef]
  109. Schauwvlieghe, A.F.A.D.; Rijnders, B.J.A.; Philips, N.; Verwijs, R.; Vanderbeke, L.; Van Tienen, C.; Lagrou, K.; Verweij, P.E.; Van de Veerdonk, F.L.; Gommers, D.; et al. Invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: A retrospective cohort study. Lancet Respir. Med. 2018, 6, 782–792. [Google Scholar] [CrossRef]
  110. Auberger, J.; Lass-Florl, C.; Aigner, M.; Clausen, J.; Gastl, G.; Nachbaur, D. Invasive fungal breakthrough infections, fungal colonization and emergence of resistant strains in high-risk patients receiving antifungal prophylaxis with posaconazole: Real-life data from a single-centre institutional retrospective observational study. J. Antimicrob. Chemother. 2012, 67, 2268–2273. [Google Scholar] [CrossRef]
  111. Chakrabarti, A.; Singh, R. Mucormycosis in India: Unique features. Mycoses 2014, 57, 85–90. [Google Scholar] [CrossRef]
  112. Bala, K.; Chander, J.; Handa, U.; Punia, R.S.; Attri, A.K. A prospective study of mucormycosis in north India: Experience from a tertiary care hospital. Med. Mycol. 2015, 53, 248–257. [Google Scholar] [CrossRef] [Green Version]
  113. Jenks, J.D.; Reed, S.L.; Seidel, D.; Koehler, P.; Cornely, O.A.; Mehta, S.R.; Hoenigl, M. Rare mould infections caused by Mucorales, Lomentospora prolificans and Fusarium, in San Diego, CA: The role of antifungal combination therapy. Int. J. Antimicrob. Agents 2018, 52, 706–712. [Google Scholar] [CrossRef]
  114. Dalyan Cilo, B.; Al-Hatmi, A.M.S.; Seyedmousavi, S.; Rijs, A.J.M.M.; Verweij, P.E.; Ener, B.; de Hoog, G.S.; van Diepeningen, A.D. Emergence of fusarioses in a university hospital in Turkey during a 20-year period. Eur. J. Clin. Microbiol. Infect. Dis. 2015, 34, 1683–1691. [Google Scholar] [CrossRef] [Green Version]
  115. Tortorano, A.M.; Prigitano, A.; Arsic Arsenijevic, V.; Kolarovic, J.; Ivanovic, D.; Paripovic, L.; Klingspor, L.; Nordøy, I.; Hamal, P.; Arikan Akdagli, S.; et al. European Confederation of Medical Mycology (ECMM) epidemiological survey on invasive infections due to Fusarium species in Europe. Eur. J. Clin. Microbiol. Infect. Dis. 2014, 33, 1623–1630. [Google Scholar] [CrossRef]
  116. Seidel, D.; Meißner, A.; Lackner, M.; Piepenbrock, E.; Salmanton-García, J.; Stecher, M.; Mellinghoff, S.; Hamprecht, A.; Durán Graeff, L.; Köhler, P.; et al. Prognostic factors in 264 adults with invasive Scedosporium spp. and Lomentospora prolificans infection reported in the literature and FungiScope®. Crit. Rev. Microbiol. 2019, 45, 1–21. [Google Scholar] [CrossRef]
  117. McCarty, T.P.; Baddley, J.W.; Walsh, T.J.; Alexander, B.D.; Kontoyiannis, D.P.; Perl, T.M.; Walker, R.; Patterson, T.F.; Schuster, M.G.; Lyon, G.M.; et al. Phaeohyphomycosis in transplant recipients: Results from the Transplant Associated Infection Surveillance Network (TRANSNET). Med. Mycol. 2015, 53, 440–446. [Google Scholar] [CrossRef] [Green Version]
  118. Neofytos, D.; Fishman, J.A.; Horn, D.; Anaissie, E.; Chang, C.-H.; Olyaei, A.; Pfaller, M.; Steinbach, W.J.; Webster, K.M.; Marr, K.A. Epidemiology and outcome of invasive fungal infections in solid organ transplant recipients. Transpl. Infect. Dis. 2010, 12, 220–229. [Google Scholar] [CrossRef]
  119. Penteado, F.D.; Litvinov, N.; Sztajnbok, J.; Thomaz, D.Y.; dos Santos, A.M.; Vasconcelos, D.M.; Motta, A.L.; Rossi, F.; Fernandes, J.F.; Marques, H.H.S.; et al. Lomentospora prolificans fungemia in hematopoietic stem cell transplant patients: First report in South America and literature review. Transpl. Infect. Dis. 2018, 20, e12908. [Google Scholar] [CrossRef]
  120. Verma, S.; Madhu, R. The Great Indian Epidemic of Superficial Dermatophytosis: An Appraisal. Indian J. Dermatol. 2017, 62, 227. [Google Scholar]
  121. Nenoff, P.; Verma, S.B.; Vasani, R.; Burmester, A.; Hipler, U.-C.; Wittig, F.; Krüger, C.; Nenoff, K.; Wiegand, C.; Saraswat, A.; et al. The current Indian epidemic of superficial dermatophytosis due to Trichophyton mentagrophytes—A molecular study. Mycoses 2019, 62, 336–356. [Google Scholar] [CrossRef]
  122. Panda, S.; Verma, S. The menace of dermatophytosis in India: The evidence that we need. Indian J. Dermatol. Venereol. Leprol. 2017, 83, 281–284. [Google Scholar] [CrossRef]
  123. Upadhyay, V.; Kumar, A.; Singh, A.K.; Pandey, J. Epidemiological characterization of dermatophytes at a tertiary care hospital in Eastern Uttar Pradesh, India. Curr. Med. Mycol. 2019, 5, 1. [Google Scholar]
  124. Yamada, T.; Maeda, M.; Alshahni, M.M.; Tanaka, R.; Yaguchi, T.; Bontems, O.; Salamin, K.; Fratti, M.; Monod, M. Terbinafine Resistance of Trichophyton Clinical Isolates Caused by Specific Point Mutations in the Squalene Epoxidase Gene. Antimicrob. Agents Chemother. 2017, 61, e00115-17. [Google Scholar] [CrossRef] [Green Version]
  125. Suzuki, S.; Mano, Y.; Furuya, N.; Fujitani, K. Discovery of Terbinafine Low Susceptibility Trichophyton rubrum strain in Japan. Biocontrol. Sci. 2018, 23, 151–154. [Google Scholar] [CrossRef]
  126. Dukik, K.; Muñoz, J.F.; Jiang, Y.; Feng, P.; Sigler, L.; Stielow, J.B.; Freeke, J.; Jamalian, A.; van den Ende, B.G.; McEwen, J.G.; et al. Novel taxa of thermally dimorphic systemic pathogens in the Ajellomycetaceae (Onygenales). Mycose 2017, 60, 296–309. [Google Scholar] [CrossRef]
  127. Kenyon, C.; Bonorchis, K.; Corcoran, C.; Meintjes, G.; Locketz, M.; Lehloenya, R.; Vismer, H.F.; Naicker, P.; Prozesky, H.; van Wyk, M.; et al. A dimorphic fungus causing disseminated infection in South Africa. N. Engl. J. Med. 2013, 369, 1416–1424. [Google Scholar] [CrossRef]
  128. Schwartz, I.S.; Govender, N.P.; Corcoran, C.; Dlamini, S.; Prozesky, H.; Burton, R.; Mendelson, M.; Taljaard, J.; Lehloenya, R.; Calligaro, G.; et al. Clinical Characteristics, Diagnosis, Management, and Outcomes of Disseminated Emmonsiosis: A Retrospective Case Series. Clin. Infect. Dis. 2015, 61, 1004–1012. [Google Scholar] [CrossRef] [Green Version]
  129. Schwartz, I.S.; Kenyon, C.; Feng, P.; Govender, N.P.; Dukik, K.; Sigler, L.; Jiang, Y.; Stielow, J.B.; Muñoz, J.F.; Cuomo, C.A.; et al. 50 years of Emmonsia disease in Humans: The dramatic emergence of a cluster of novel fungal pathogens. PLoS Pathog. 2015, 11, e1005198. [Google Scholar] [CrossRef]
  130. Schwartz, I.S.; Maphanga, T.G.; Govender, N.P. Emergomyces: A new genus of dimorphic fungal pathogens causing disseminated disease among immunocomprised persons globally. Curr. Fungal Infect. Rep. 2018, 12, 44–50. [Google Scholar] [CrossRef]
  131. Schwartz, I.S.; Sanche, S.; Wiederhold, N.P.; Patterson, T.F.; Sigler, L. Emergomyces canadensis, a dimorphic fungus causing fatal systemic human disease in North America. Emerg. Infect. Dis. 2018, 24, 758–761. [Google Scholar] [CrossRef]
  132. Wang, P.; Kenyon, C.; de Hoog, S.; Guo, L.; Fan, H.; Liu, H.; Li, Z.; Sheng, R.; Yang, Y.; Jiang, Y.; et al. A novel dimorphic pathogen, Emergomyces orientalis (Onygenales), agent of disseminated infection. Mycoses 2017, 60, 310–319. [Google Scholar] [CrossRef]
  133. Schwartz, I.S.; Kenyon, C.; Lehloenya, R.; Claasens, S.; Spengane, Z.; Prozesky, H.; Burton, R.; Parker, A.; Wasserman, S.; Meintjes, G.; et al. AIDS-related endemic mycoses in Western Cape, South Africa, and clinical mimics: A cross-sectional study of adults with advanced HIV and recent-onset, widespread skin lesions. Open Forum Infect. Dis. 2017, 4, ofx186. [Google Scholar] [CrossRef]
  134. Dukik, K.; Al-Hatmi, A.M.S.; Curfs-Breuker, I.; Faro, D.; de Hoog, S.; Meis, J.F. Antifungal susceptibility of emerging dimorphic pathogens in the family Ajellomycetaceae. Antimicrob. Agents Chemother. 2017, 62, e01886-17. [Google Scholar] [CrossRef]
  135. Maphanga, T.G.; Britz, E.; Zulu, T.G.; Mpembe, R.S.; Naicker, S.D.; Schwartz, I.S.; Govender, N.P. In Vitro antifungal susceptibility of yeast and mold phases of isolates of dimorphic fungal pathogen Emergomyces africanus (formerly Emmonsia sp.) from HIV-infected South African patients. J. Clin. Microbiol. 2017, 55, 1812–1820. [Google Scholar] [CrossRef]
  136. Gast, K.B.; van der Hoeven, A.; de Boer, M.G.J.; van Esser, J.W.J.; Kuijper, E.J.; Verweij, J.J.; van Keulen, P.H.J.; van der Beek, M.T. Two cases of Emergomyces pasteurianus infection in immunocompromised patients in the Netherlands. Med. Mycol. Case Rep. 2019, 24, 5–8. [Google Scholar] [CrossRef]
  137. Schwartz, I.S.; McLoud, J.D.; Berman, D.; Botha, A.; Lerm, B.; Colebunders, R.; Levetin, E.; Kenyon, C. Molecular detection of airborne Emergomyces africanus, a thermally dimorphic fungal pathogen, in Cape Town, South Africa. PLoS Negl. Trop. Dis. 2018, 12, e0006174. [Google Scholar] [CrossRef]
  138. Schwartz, I.S.; Lerm, B.; Hoving, J.C.; Kenyon, C.; Horsnell, W.G.; Basson, W.J.; Otieno-Odhiambo, P.; Govender, N.P.; Colebunders, R.; Botha, A. Emergomyces africanus in soil, South Africa. Emerg. Infect. Dis. 2018, 24, 377–380. [Google Scholar] [CrossRef]
  139. Rooms, I.; Mugisha, P.; Hadaschik, E.; Esser, S.; Rath, P.-M.; Haase, G.; Wilmes, D.; McCormick-Smith, I.; Rickerts, V. Disseminated emergomycosis in a person with HIV infection from Uganda: Molecular identification of Emergomyces pasteurianus or a close relative from a pathology block. Emerg. Infect. Dis. 2019, 25. [Google Scholar] [CrossRef]
  140. Centers for Disease Control and Prevention. Sources of Blastomycosis. Available online: https://www.cdc.gov/fungal/diseases/blastomycosis/causes.html (accessed on 25 March 2019).
  141. McCullough, M.J.; DiSalvo, A.F.; Clemons, K.V.; Park, P.; Stevens, D.A. Molecular Epidemiology of Blastomyces dermatitidis. Clin. Infect. Dis. 2000, 30, 328–335. [Google Scholar] [CrossRef]
  142. Meece, J.K.; Anderson, J.L.; Fisher, M.C.; Henk, D.A.; Sloss, B.L.; Reed, K.D. Population genetic structure of clinical and environmental isolates of Blastomyces dermatitidis, based on 27 polymorphic microsatellite markers. Appl. Environ. Microbiol. 2011, 77, 5123–5131. [Google Scholar] [CrossRef]
  143. Brown, E.M.; McTaggart, L.R.; Zhang, S.X.; Low, D.E.; Stevens, D.A.; Richardson, S.E. Phylogenetic analysis reveals a cryptic species Blastomyces gilchristii, sp. nov. within the human pathogenic fungus Blastomyces dermatitidis. PLoS ONE 2013, 8, e59237. [Google Scholar] [CrossRef]
  144. Dalcin, D.; Ahmed, S.Z. Blastomycosis in northwestern Ontario, 2004 to 2014. Can. J. Infect. Dis. Med. Microbiol. 2015, 26, 259–262. [Google Scholar] [CrossRef]
  145. Dalcin, D.; Rothstein, A.; Spinato, J.; Escott, N.; Kus, J.V. Blastomyces gilchristii as cause of fatal acute respiratory distress syndrome. Emerg. Infect. Dis. 2016, 22, 306–308. [Google Scholar] [CrossRef]
  146. Schwartz, I.S.; Wiederhold, N.P.; Hanson, K.E.; Patterson, T.F.; Sigler, L. Blastomyces helicus, a new dimorphic fungus causing fatal pulmonary and systemic disease in humans and animals in Western Canada and the United States. Clin. Infect. Dis. 2019, 68, 188–195. [Google Scholar] [CrossRef]
  147. Frean, A.; Carman, W.; Crewe-Brown, H.; Culligan, G.; Young, C. Blastomyces dermatitidis infections in the RSA. S. Afr. Med. J. 1989, 76, 13–16. [Google Scholar]
  148. Sepúlveda, V.E.; Márquez, R.; Turissini, D.A.; Goldman, W.E.; Matute, D.R. Genome Sequences Reveal Cryptic Speciation in the Human Pathogen Histoplasma capsulatum. mBio 2017, 8, e01339-17. [Google Scholar] [CrossRef]
  149. Durkin, M.M.; Connolly, P.A.; Karimi, K.; Wheat, E.; Schnizlein-Bick, C.; Allen, S.D.; Alves, K.; Tewari, R.P.; Keath, E. Pathogenic Differences between North American and Latin American Strains of Histoplasma capsulatum var. capsulatum in Experimentally Infected Mice. J. Clin. Microbiol. 2004, 42, 4370–4373. [Google Scholar] [CrossRef]
  150. Dubois, A.; Janssens, P.; Brutsaert, P.; Vanbreuseghem, R. A case of African histoplasmosis; with a mycological note on Histoplasma duboisii n.sp. Ann. Soc. Belg. Med. Trop. 1952, 32, 569–584. [Google Scholar]
  151. Pakasa, N.; Biber, A.; Nsiangana, S.; Imposo, D.; Sumaili, E.; Muhindo, H.; Buitrago, M.J.; Barshack, I.; Schwartz, E. African Histoplasmosis in HIV-Negative Patients, Kimpese, Democratic Republic of the Congo. Emerg. Infect. Dis. 2018, 24, 2068–2070. [Google Scholar] [CrossRef]
  152. Gauthier, G.M. Dimorphism in fungal pathogens of mammals, plants, and insects. PLoS Pathog. 2015, 11, e1004608. [Google Scholar] [CrossRef]
  153. Lohrenz, S.; Minion, J.; Pandey, M.; Karunakaran, K. Blastomycosis in Southern Saskatchewan 2000–2015: Unique presentations and disease characteristics. Med. Mycol. 2018, 56, 787–795. [Google Scholar] [CrossRef]
  154. McDonald, R.; Dufort, E.; Jackson, B.R.; Tobin, E.H.; Newman, A.; Benedict, K.; Blog, D. Blastomycosis cases occurring outside of regions with known endemicity—New York, 2007–2017. MMWR Morb. Mortal. Wkly. Rep 2018, 67, 1077–1078. [Google Scholar] [CrossRef]
  155. Nett, R.J.; Skillman, D.; Riek, L.; Davis, B.; Blue, S.R.; Sundberg, E.E.; Merriman, J.R.; Hahn, C.G.; Park, B.J. Histoplasmosis in Idaho and Montana, USA, 2012–2013. Emerg. Infect. Dis. 2015, 21, 1071–1072. [Google Scholar] [CrossRef]
  156. Anderson, H.; Honish, L.; Taylor, G.; Johnson, M.; Tovstiuk, C.; Fanning, A.; Tyrrell, G.; Rennie, R.; Jaipaul, J.; Sand, C.; et al. Histoplasmosis cluster, golf course, Canada. Emerg. Infect. Dis. 2006, 12, 163–165. [Google Scholar] [CrossRef]
  157. Litvintseva, A.P.; Marsden-Haug, N.; Hurst, S.; Hill, H.; Gade, L.; Driebe, E.M.; Ralston, C.; Roe, C.; Barker, B.M.; Goldoft, M.; et al. Valley Fever: Finding new places for an old disease: Coccidioides immitis found in Washington State soil associated with recent human infection. Clin. Infect. Dis. 2015, 60, e1–e3. [Google Scholar] [CrossRef]
  158. Maiga, A.W.; Deppen, S.; Scaffidi, B.K.; Baddley, J.; Aldrich, M.C.; Dittus, R.S.; Grogan, E.L. Mapping Histoplasma capsulatum exposure, United States. Emerg. Infect. Dis. 2018, 24, 1835–1839. [Google Scholar] [CrossRef]
  159. Marimon, R.; Cano, J.; Gene, J.; Sutton, D.A.; Kawasaki, M.; Guarro, J. Sporothrix brasiliensis, S. globosa, and S. mexicana, three new Sporothrix species of clinical interest. J. Clin. Microbiol 2007, 45, 3198–3206. [Google Scholar] [CrossRef]
  160. Marimon, R.; Gené, J.; Cano, J.; Guarro, J. Sporothrix luriei: A rare fungus from clinical origin. Med. Mycol. 2008, 46, 621–625. [Google Scholar] [CrossRef]
  161. Batista-Duharte, A.; Téllez-Martínez, D.; de Roberto Andrade, C.; Portuondo, D.L.; Jellmayer, J.A.; Polesi, M.C.; Carlos, I.Z. Sporothrix brasiliensis induces a more severe disease associated with sustained Th17 and regulatory T cells responses than Sporothrix schenckii sensu stricto in mice. Fungal Biol. 2018, 122, 1163–1170. [Google Scholar] [CrossRef]
  162. Arrillaga-Moncrieff, I.; Capilla, J.; Mayayo, E.; Marimon, R.; Marine, M.; Genis, J.; Cano, J.; Guarro, J. Different virulence levels of the species of Sporothrix in a murine model. Clin. Microbiol. Infect. 2009, 15, 651–655. [Google Scholar] [CrossRef]
  163. Montenegro, H.; Rodrigues, A.M.; Dias, M.A.G.; da Silva, E.A.; Bernardi, F.; de Camargo, Z.P. Feline sporotrichosis due to Sporothrix brasiliensis: An emerging animal infection in São Paulo, Brazil. BMC Vet. Res. 2014, 10, 269. [Google Scholar] [CrossRef]
  164. Schubach, A.; de Barros, M.B.L.; Wanke, B. Epidemic sporotrichosis. Curr. Opin. Infect. Dis. 2008, 21, 129. [Google Scholar] [CrossRef]
  165. de Barros, M.B.L.; Schubach, T.M.P.; Gutierrez Galhardo, M.C.; de Schubach, A.O.; Monteiro, P.C.F.; Reis, R.S.; Zancopé-Oliveira, R.M.; Lazéra, M.; dos, S.; Cuzzi-Maya, T.; et al. Sporotrichosis: An emergent zoonosis in Rio de Janeiro. Mem. Inst. Oswaldo Cruz 2001, 96, 777–779. [Google Scholar] [CrossRef]
  166. Sanchotene, K.O.; Madrid, I.M.; Klafke, G.B.; Bergamashi, M.; Terra, P.P.D.; Rodrigues, A.M.; de Camargo, Z.P.; Xavier, M.O. Sporothrix brasiliensis outbreaks and the rapid emergence of feline sporotrichosis. Mycoses 2015, 58, 652–658. [Google Scholar] [CrossRef]
  167. Almeida-Paes, R.; de Oliveira, M.M.E.; Freitas, D.F.S.; do Valle, A.C.F.; Zancopé-Oliveira, R.M.; Gutierrez-Galhardo, M.C. Sporotrichosis in Rio de Janeiro, Brazil: Sporothrix brasiliensis is associated with atypical clinical presentations. PLoS Negl. Trop. Dis. 2014, 8, e3094. [Google Scholar] [CrossRef]
  168. Brandolt, T.M.; Madrid, I.M.; Poester, V.R.; Sanchotene, K.O.; Basso, R.P.; Klafke, G.B.; de Rodrigues, M.L.; Xavier, M.O. Human sporotrichosis: A zoonotic outbreak in southern Brazil, 2012–2017. Med. Mycol. 2018, 57, 527–533. [Google Scholar] [CrossRef]
Figure 1. Countries reporting cases of Candida auris through June 15, 2019 [19,30,31,32,33,34,35,36,37,38].
Figure 1. Countries reporting cases of Candida auris through June 15, 2019 [19,30,31,32,33,34,35,36,37,38].
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Figure 2. Countries reporting the presence of azole-resistant Aspergillus fumigatus and mechanisms of resistance in surveyed isolates [47,48,49,52,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97].
Figure 2. Countries reporting the presence of azole-resistant Aspergillus fumigatus and mechanisms of resistance in surveyed isolates [47,48,49,52,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97].
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Figure 3. Global distribution of reported cases of emergomycosis [2,130,131,132,136,137,138,139].
Figure 3. Global distribution of reported cases of emergomycosis [2,130,131,132,136,137,138,139].
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Figure 4. The distribution of human and veterinary cases of disease caused by Blastomyces helicus in relation to the classic region of geographic risk for B. dermatitidis species complex. Reproduced with permission from [146].
Figure 4. The distribution of human and veterinary cases of disease caused by Blastomyces helicus in relation to the classic region of geographic risk for B. dermatitidis species complex. Reproduced with permission from [146].
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Figure 5. Zoonotic sporotrichosis caused by Sporothrix brasiliensis. (A) Ulcerative tumour-like lesion on an infected cat; (B) lymphocutaneous zoonotic sporotrichosis in a human patient acquired from a cat; (C) yeast-like cells of S. brasiliensis (arrow) seen in an impression smear of a feline skin ulcer on a glass slide, Quick Panoptic stain (Instant Prov Kit; Newprov, Pinhais, Brazil). Images courtesy of Rodrigo Menezes, LAPCLIN-DERMZOO, Evandro Chagas National Institute of Infectious Diseases (INI), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, Brazil.
Figure 5. Zoonotic sporotrichosis caused by Sporothrix brasiliensis. (A) Ulcerative tumour-like lesion on an infected cat; (B) lymphocutaneous zoonotic sporotrichosis in a human patient acquired from a cat; (C) yeast-like cells of S. brasiliensis (arrow) seen in an impression smear of a feline skin ulcer on a glass slide, Quick Panoptic stain (Instant Prov Kit; Newprov, Pinhais, Brazil). Images courtesy of Rodrigo Menezes, LAPCLIN-DERMZOO, Evandro Chagas National Institute of Infectious Diseases (INI), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, Brazil.
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Friedman, D.Z.P.; Schwartz, I.S. Emerging Fungal Infections: New Patients, New Patterns, and New Pathogens. J. Fungi 2019, 5, 67. https://doi.org/10.3390/jof5030067

AMA Style

Friedman DZP, Schwartz IS. Emerging Fungal Infections: New Patients, New Patterns, and New Pathogens. Journal of Fungi. 2019; 5(3):67. https://doi.org/10.3390/jof5030067

Chicago/Turabian Style

Friedman, Daniel Z.P., and Ilan S. Schwartz. 2019. "Emerging Fungal Infections: New Patients, New Patterns, and New Pathogens" Journal of Fungi 5, no. 3: 67. https://doi.org/10.3390/jof5030067

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