Invasive Fungal Infections Supplement ESCMID / ECMM Joint Clinical Guideline for the Diagnosis and Management of Rare Invasive Yeast Infections

The mortality associated with invasive fungal infections remains high with that involving rare yeast pathogens other than Candida being no exception. This is in part due to the severe underlying conditions typically predisposing patients to these health-care related infections (most often severe neutropaenia in patients with haematological malignancies), and in part due to the often challenging intrinsic susceptibility pattern of the pathogens that potentially leads to delayed appropriate antifungal treatment. A panel of experts of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Fungal Infection Study Group (EFISG) and the European Confederation of Medical Mycology (ECMM) undertook a data review and compiled guidelines for the diagnostic tests and procedures for detection and management of rare invasive yeast infections. The rare yeast pathogens were defined and limited to the following genus/species: Cryptococcus adeliensis, Cryptococcus albidus, Cryptococcus curvatus, Cryptococcus flavescens, Cryptococcus laurentii and Cryptococcus uniguttulatus (often published under the name Filobasidium uniguttulatum), Malassezia furfur, A cc ep te d A rt ic le This article is protected by copyright. All rights reserved. Malassezia globosa, Malassezia pachydermatis and Malassezia restricta, Pseudozyma spp., Rhodotorula glutinis, Rhodotorula minuta and Rhodotorula mucilaginosa, Sporobolomyces spp., Trichosporon asahii, Trichosporon asteroides, Trichosporon dermatis, Trichosporon inkin, Trichosporon jirovecii, Trichosporon loubieri, Trichosporon mucoides and Trichosporon mycotoxinivorans and ascomycetous ones: Geotrichum candidum, Kodamaea ohmeri, Saccharomyces cerevisiae (incl. S. boulardii) and Saprochaete capitatae (Magnusiomyces (Blastoschizomyces) capitatus formerly named Trichosporon capitatum or Geotrichum (Dipodascus) capitatum) and Saprochaete clavata. Recommendations about the microbiological investigation and detection of invasive infection were made and current knowledge on most appropriate antifungal and supportive treatment reviewed. In addition, remarks about antifungal susceptibility testing were made. INTRODUCTION In 2012 the first official European Society for Clinical Microbiology and Infectious Diseases (ESCMID) guideline on the diagnosis and treatment of a fungal infection was published [1-6]. Mucosal and invasive candidosis were covered and a comprehensive consensus guideline developed with the participation of many experts from the ESCMID Fungal Infection Study Group (EFISG) representing many European countries. Before publication the recommendations were presented for discussion at an ECCMID workshop and the subsequent manuscripts underwent peer-review before publication in the ESCMID journal, Clinical Microbiology and Infection. Following the same rigorous procedure, EFISG continued the ESCMID guideline developing process this time in collaboration with the European Confederation of Medical Mycology (ECMM) and focusing on rare invasive fungal infections. The definition of such pathogens is somewhat pragmatic but yeasts other than Candida, mucorales, hyalohyphomycetous and dematiaceous fungi which are not common causes of invasive infections were included. This guideline presents the diagnostic and management guideline for “rare invasive yeast infections” including several basidiomycetous yeasts: Cryptococcus adeliensis, C. albidus, C. curvatus, C. flavescens, C. laurentii and C. uniguttulatus (often published under the name Filobasidium uniguttulatum), Malassezia furfur, M. globosa, M. pachydermatis and M. restricta, Pseudozyma spp., Rhodotorula glutinis, R. minuta and R. mucilaginosa, Sporobolomyces spp., Trichosporon asahii, T. asteroides, T. dermatis, T. inkin, T. jirovecii, T. loubieri, T. mucoides and T. mycotoxinivorans and ascomycetous ones: Geotrichum candidum, Kodamaea ohmeri, Saccharomyces cerevisiae (incl. S. boulardii) and Saprochaete capitatae (Magnusiomyces (Blastoschizomyces) capitatus formerly named Trichosporon capitatum or Geotrichum (Dipodascus) capitatum) and Saprochaete clavata. The selection of organisms has been based on the following criteria: 1) species were only included if they were documented as cause of human invasive infections and 2) rare Candida species were excluded because we anticipate that readers would probably refer to the ESCMID Candida guidelines rather than an rare invasive yeast infection guideline concerning species like C. palmioleophila etc. A cc ep te d A rt ic le This article is protected by copyright. All rights reserved. although such species fulfil the term of being a rare cause of invasive infections. The species not considered being documented as cause of invasive human disease included Cryptococcus albidosimilis, C. diffluens, C. humicola and C. uzbekistanensis, Trichosporon spp. others than those mentioned above, Blastobotrys proliferans, Millerozyma farinosa, Ogataea polymorpha and Guehomyces pullulans. Finally, the guideline was limited to true yeasts and hence the unicellular algae Prototheca wickerhamii and P. zopfii var. zopfii were excluded although we realise they have been misidentified as yeast on occasion. For the uncommon Candida species we kindly refer to the general recommendations regarding diagnosis and treatment as described in the ESCMID Candida guideline [1-6]. However, as some of these species are characterised by unique intrinsic susceptibility patterns, which are not specifically addressed in the Candida guidelines, a table summarising this information has been elaborated and included here (Table 1, [7-19]). This table also includes names used in the anamorphic and teleomorphic states, despite that this distinction has been made superfluous recently [20]. General recommendations regarding collection, transport and storage of clinical specimens, direct examination, isolation and identification procedures which are valid for all yeasts-associated human infections can be found in appropriate textbooks (as for example Barnett et al. [21]) and are not mentioned here. Only specific features regarding genus identifications for the specific yeasts discussed herein were considered. The methods to evaluate the quality of evidence and to reach consensus recommendations were described previously [1]. Strength of recommendations quality of evidence was graded according to the criteria outlined in table 2. Rare invasive yeast infections It is important to underscore that the fungal organisms covered in this guideline are not rare per se. A number of the “rare yeasts” are encountered as frequent colonisers of human skin, mucosal surfaces, in food items or in the environment. In the normal host, infections are typically limited to various superficial infections like pityriasis versicolor, white piedra and occasionally onychomycosis the management of which are dealt with in dermatology guidelines [22-25]. However, in the immunosuppressed or otherwise compromised host, invasive infections may occur, some being related to the presence of a central venous catheter and few reported as nosocomial clusters which require molecular approaches to be properly documented. As predicted from their low pathogenicity, invasive infections are still reported at low numbers in severely immunocompromised hosts (Table 3) [26-30]. For example, these organisms together constituted 1.1% of the almost 4,000 fungaemia isolates in an eight year national surveillance programme in Denmark [26,27]. In Paris, they represented 5.1% of the 3,668 fungaemia isolates in a prospective surveillance program from 2002 to 2012 (YEASTS Network, National Reference Centre for Invasive Mycoses and Antifungals, Paris, France (unpublished data), Table 3). S. cerevisiae is a biotechnologically highly important A cc ep te d A rt ic le This article is protected by copyright. All rights reserved. fungus with a broad use in the production of food and alcoholic beverages etc. Phylogenetically, the species is relatively closely related to C. glabrata [31]. As most of these rare invasive yeast infections occur in the haematology and ICU settings, clinicians should be aware that all of the responsible fungal species, presumably except Saccharomyces spp. and Kodamaea ohmeri, are regarded intrinsically resistant to echinocandins. Due to the rare nature of these pathogens controlled prospective and comparative clinical trials are not feasible and therefore solid data on treatment efficacy cannot be compiled. Moreover, clinical susceptibility breakpoints have not been established. Hence, management recommendations derive from clinical experience (cohort or case-controlled analytic studies, from multiple time series), pragmatic interpretations of susceptibility data and limited animal studies when available. Also due to the rare incidence, primary prophylaxis is not indicated unless specific local epidemiology suggests otherwise. As specific diagnostic surrogate markers have not been developed for these organisms (apart from the antigen test for Cryptococcus but mainly evaluated for C. neoformans), blood culture remains an essential investigation for the detection of invasive infection and the general recommendations concerning volume and sampling frequency should be followed [32-34]. Emerging evidence has highlighted the additional yield obtained for candidaemia when a fungal blood culture bottle is included in order to specifically support the growth of fungi and at the same time avoid suppression by concomitant faster growing microorganisms [35-38]. It remains to be demonstrated if this applies to the detection of fungaemia due to the yeasts described herein. In the following sections the general characteristics for the different pathogens will be reviewed (in alphabetic order). Specific characteristics concerning the epidemiology and species identification are summarised in tables 2 and 3. In most cases, identification to the species level requires the adoption of n