Only for Public Consultation. Not for Other Distribution

1 Global guideline for the diagnosis and management of invasive infections caused by emerging, 2 uncommon or rare yeasts: An initiative of the European Confederation of Medical Mycology in 3 cooperation with TBD

5 Sharon C-A Chen*, John Perfect*, Arnaldo L. Colombo*, Oliver A. Cornely*, Andreas H. Groll, 6 Danila Seidel, Kerstin Albus, Joao N. de Almedia Jr., Guilliermo Garcia-Effron, Nicole Gilroy, 7 Cornelia Lass-Florl, Luis Ostrosky-Zeichner, Livio Pagano, Tamas Papp, Riina Rautemaa- 8 Richardson, Jon Salmanton-Garcia, Andrej Spec, Jorg Steinmann, Sevtap Arikan-Akdagli, 9 Dorothee E. Arenz, Rosanne Sprute, Luisa Duran-Graeff, Tomas Freiberger, Corrado Girmenia, 10 Michelle Harris Souha Kanj, Olivier Lortholary, Joseph Meletiadis, Maryam Roudbary, Esther 11 Segal, Felipe Tuon, Nathan Wiederhold, Tihana Bicanic, Jagdish Chander, Yee-chun Chen, Po-ren 12 Hsueh, Margaret Ip, Patricia Munoz, Isabel Spriet, Elivs Temfack, Luis Thompson, Aristea 13 Velegraki, Nelesh P. Govender* 14 *Equal contribution consultation. 15 16 Affiliations distribution. 17 SC-AC: Centre for Infectious Diseases and Microbiology Laboratory Services, Institute of Clinical 18 Pathology and Medical Research,public New South Wales Health Pathology, and Centre for Infectious 19 Diseases and Microbiology, Westmead Hospital, The University of Sydney, Sydney, Australia 20 JP: Duke University Medicalfor Center, Durham,other North Carolina, USA 21 ALC: Division of Infectious Diseases, Escola Paulista de Medicina, Universidade Federal de Sao 22 Paulo, Sao Paulo, Brazil for 23 OAC:Only Department I of Internal Medicine University Hospital of Cologne, German Centre for 24 Infection ResearchNot (DZIF) partner site-Bonn-Cologne, ECMM Excellence Centre, Clinical Trials 25 Centre Cologne, University Hospital of Cologne, CECAD Cluster of Excellence, University of 26 Cologne, Cologne, Germany

27 AHG: Infectious Disease Research Program, Centre for Bone Marrow Transplantation and 28 Department of Paediatric Hematology and Oncology, University Children's Hospital Muenster, 29 Muenster, Germany

30 DS: Department of Internal Medicine University Hospital of Cologne, ECMM Excellence Centre, 31 CECAD Cluster of Excellence, University of Cologne, Cologne, Germany

32 KA: Department of Internal Medicine University Hospital of Cologne, ECMM Excellence Centre, 33 CECAD Cluster of Excellence, University of Cologne, Cologne, Germany

34 JNAJ: Central Laboratory Division, Hospital das Clínicas da Faculdade de Medicina da 35 Universidade de São Paulo, São Paulo, Brazil; Center for Discovery and Innovation, Hackensack 36 Meridian Health, Nutley, New Jersey, USA

37 GGE: Laboratorio de Micología y Diagnóstico Molecular, Cátedra de Parasitología y Micología, 38 Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Santa Fe, 39 Argentina and Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), CCT 40 Santa Fe, Argentina

41 NG: Centre for Infectious Diseases and Microbiology, Westmead Hospital, The University of 42 Sydney, Sydney, Australia 43 CL-F: Institute of Hygiene and Medical Microbiology,consultation. ECMM Excellence Centre, Medical 44 University of Innsbruck, Innsbruck, Austria

45 LO-Z: Division of Infectious Diseases, McGovern Medical School,distribution. Houston, Texas, USA

46 LP: Fondazione Policlinico Universitario A. Gemelli – IRCCS, Università Cattolica del Sacro Cuore, 47 Largo Agostino Gemelli 8, I-00168public Roma, Italy 48 TP: Fungal Pathogenicity Mechanisms Researchother Group, Department of Microbiology, University 49 of Szeged, Szeged, Hungaryfor 50 RR-R: Manchester University NHSfor Foundation Trust, Wythenshawe Hospital, ECMM Excellence 51 Centre and Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, 52 MedicineOnly and Health, University of Manchester, UK 53 JS-G: Department Notof Internal Medicine University Hospital of Cologne, ECMM Excellence Centre, 54 CECAD Cluster of Excellence, University of Cologne, Cologne, Germany

55 AS: Division of Infectious Disease, Washington University in St Louis, School of Medicine, St. Louis, 56 Missouri, USA

57 JS: Institute of Clinical Hygiene, Medical Microbiology and Infectiology, Paracelsus Medical 58 University, Nuremberg, Germany; Institute of Medical Microbiology, University Hospital Essen, 59 Essen, Germany

60 SA-A: Department of Medical Microbiology, Hacettpe University Medical School, Sihhiye Ankara, 61 Turkey

62 DEA: Department of Internal Medicine University Hospital of Cologne, German Centre for 63 Infection research (DZIF) partner site-Bonn-Cologne, ECMM Excellence Centre, University 64 Hospital of Cologne, Cologne, Germany; MediGate, Medical Center Hamburg-Eppendorf (UKE), 65 Hamburg, Germany

66 RS: Department of Internal Medicine University Hospital of Cologne, German Centre for Infection 67 research (DZIF) partner site-Bonn-Cologne, ECMM Excellence Centre, University Hospital of 68 Cologne, Cologne, Germany

69 LD-G: Unidad de Infectología, Departamento de Medicina Interna, Clínica Las Condes, Santiago, 70 Chile consultation. 71 TF: Centre for Cardiovascular Surgery and Transplantation, Brno, and Medical Faculty, Masaryk 72 University, Brno, Czech Republic distribution. 73 CG: Department of Hematology, Umberto I Policlinico di Roma, Roma, Italy 74 MH: Duke University Medical Center,public Durham, North Carolina, USA 75 SK: Department of Internal Medicine, Divisionother of Infectious Diseases, American University of 76 Beirut Medical Centre,for Beirut, Lebanon 77 OL: Service des Maladies Infectieusesfor et Tropicales, Hôpital Necker-Enfants malades, Université 78 Paris V, Paris, France 79 JM: ClinicalOnly Microbiology Laboratory, Attikon University Hospital, Medical School, National and 80 Kapodistrian UniversityNot of Athens, Athens, Greece 81 MR: Department of Mycology and Parasitology, School of Medicine, University of Medical 82 Science, Tehran, Iran

83 ES: Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv 84 University, Tel Aviv, Israel

85 FT: Laboratory of Emerging Infectious Diseases (LEID), Pontifícia Universidade Católica do Paraná, 86 Curitiba, PR, Brazil

87 NW: Fungus Testing Laboratory, University of Texas Health Science Center, San Antonio, Texas, 88 USA

89 TB: Insitute of Infection and Immunity, St George’s Univiersty of London, England, United 90 Kingdom

91 JC: Department of Microbiology, Government Medical College Hospital, Chandigarh, India

92 Y-CC: Division of Infectious Diseases, Department of Medicine, Centre for Infection Control, 93 National Taiwan University, College of Medicine, Taipeh, Taiwan

94 P-RH: Department of Laboratory Medicine, and the Department of Internal Medicine, National 95 Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan

96 MI: Department of Microbiology, The Chinese University of Hong Kong, Shatin, Hong Kong, China 97 PM: Infectious Diseases and Clinical Microbiology Department,consultation. Hospital General Universitario 98 Gregorio Marañón, Servicio de Microbiología-Enfermedades Infecciosas, Madrid, Spain 99 IS: Department of Pharmaceutical and Pharmacological Sciences,distribution. KU Leuven, Leuven, Belgium 100 and Pharmacy Department, University Hospitals Leuven, Leuven, Belgium 101 ET:Internal Medicine Unit, Doualapublic General Hospital, Douala, Cameroon 102 LT: Unidad de Infectologia, Departamento de Medicina, Clinica Alemana-Universidad del 103 Desarrollo, Santiago, forChile other 104 AV: Mycology Research Laboratory and UOA/HCPF Culture Collection, Depatment of 105 Microbiology, Medical School, Nationalfor and Kapodistrian University of Athens, Athens, Greece 106 NPG:Only National Institute for Communicable Diseases (Centre for Healthcare-Associated Infections, 107 Antimicrobial ResistanceNot and Mycoses), a Division of the National Health Laboratory Service and 108 School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 109 South Africa

110 ABSTRACT

111 In these guidelines we examined the epidemiology, diagnosis and management of uncommon, 112 emerging or rare yeast infections excluding those caused by any Candida and Cryptococcus 113 species. It is important to emphasize several points. First, the selection of rare yeasts is arbitrary 114 and does not cover them all but includes the most common clinically encountered genera. 115 Second, by definition, there is reduced clinical experience of rare yeast infections and studies on 116 these diseases were not randomized nor were groups compared. Therefore, most 117 recommendations are not robust in their validations but simply represent insightful guidance 118 using clinical cases/reviews, expert clinician opinions, and in vitro susceptibility testing. Third, 119 these rare yeasts are dynamic in their nomenclature as molecular studies continue to be applied 120 to changing taxonomy. Therefore, the connection with the named genera/species and outcomes 121 can be difficult to follow. Finally, although these yeast infections are uncommon, they are 122 continuing to increase particularly in advanced health care systems with a growing 123 immunocompromised population. It is with these contexts considered that we examined the 124 genera of Trichooporon, Malassezia, Sporobolomyces,consultation. Rhodotorula, Pseudozyma (renamed 125 Moesziomyces), Saccharomyces, Saprochaete, Kodamaea and Geotrichum. In these guidelines, 126 we comprehensively report their epidemiology, microbiology,distribution. detection methods for these 127 infections, in vitro antifungal susceptibility, and outcomes of treatment modalities. We aimed to 128 develop a guideline to help clinicians synthesise current knowledge and opinions about the 129 appropriate antifungal and supportivepublic treatment to manage these infections successfully. This 130 global guideline is an initiative of the Europeanother Confederation of Medical Mycology. 131 for for Only Not

132 INTRODUCTION

133 Although Candida spp. remain the major cause of invasive yeast infections in hospitalised 134 patients, especially among immunocompromised and seriously ill patients, non-candidal yeast 135 pathogens are increasingly recognised.[1-5] Knowledge of the epidemiology and clinical 136 characteristics of infections caused by these ‘rare’ yeasts as they are often referred to however, 137 remains relatively limited. Data on their antifungal susceptibility profiles are also fewer with 138 interpretation of susceptibility results hampered by absence of clinical breakpoints (CBPs).[6, 7] 139 Additionally, systematic comparative clinical trials on treatment efficacy are not feasible. Owing 140 to their low frequency, primary antifungal prophylaxis is not indicated unless local epidemiology 141 suggests otherwise. Specific diagnostic surrogate markers are not available for these pathogens 142 and culture-based methods, including blood culture, remain central to diagnosis. Pathogen 143 identification, though reliant on phenotypic methods in many laboratories is increasingly enabled 144 by proteomic and molecular methods but their availability varies and is resource dependent. 145 Optimising management should encompass (i) recognising pathogen-associated disease patterns 146 and clinical syndromes, (ii) access to diagnostic andconsultation. therapeutic options that differ between 147 geographical regions and (iii) at minimum, a multidisciplinary medical, surgical and laboratory- 148 based team approach. distribution. 149 150 Management recommendationspublic currently hinge upon clinical experience (cohort or case- 151 controlled analytical studies from multiple time series), consensus expert opinion or [7] other 152 extrapolation from animalfor studies. At present available guidelines are either limited to a 153 specific geographic region[8] or require updating given the increasing clinical relevance of 154 uncommon or emerging yeast infections.for The joint European Society of Clinical Microbiology and 155 Infectious Diseases (ESCMID) and European Confederation of Medical Mycology (ECMM) 156 guidelineOnly was published 6-7 years ago.[7] 157 Not

158 To this end, the ECMM has worked with international colleagues together to provide this updated 159 guidance document to facilitate clinical practice in managing rare yeast infections in the modern 160 era, and to discuss areas of uncertainty. This document differs from the previous 161 recommendations in that it has engaged physicians and scientists in multiple disciplines from all

162 parts of the world who are involved in managing uncommon yeast infections and is in alignment 163 with the ECMM’s vision.[9] The recommendations’ target is to reflect the current best practice 164 management for rare yeast infections and the guideline is intended to establish a standard of 165 care.

166

167 The recommendations made in this guideline can be traced to the source references for 168 transparency. Any new information, published after this document, can be placed in context. For 169 consistency, the same methodology was used as in previous guideline.[7] As with any guideline, 170 this document should not replace bedside clinical judgment and management of patients with 171 rare yeast infections should be individualised. Moreover, recommendations do not guarantee 172 availability of specific diagnostics or treatments, or reimbursement by healthcare bodies.

173

174 Pathogens and scope of the guideline 175 This updated guideline is with one major change fromconsultation. the previous guideline[7] in that it does not 176 include recommendations for the basidiomycetous fungus Cryptococcus. This decision was based 177 on acknowledgement of significant differences in the incidence,distribution. epidemiology and management 178 principles between cryptococcosis and other non-candidal ascomycetous or basidiomycetous 179 yeast infections. Whilst the definition of a rare yeast infection is arbitrary, there is a need for 180 pragmatism. This guideline presentspublic the diagnostic and management recommendations for 181 infections caused by (i) basidiomycetousother yeasts of the genera Malassezia, Pseudozyma (now 182 Moesziomyces),[10] Rhodotorulafor , Sporobolomyces, Trichosporon, and (ii) ascomycetous yeasts of 183 the genera Geotrichum, Kodamaeafor, Saccharomyces and Saprochaete. Only known human 184 pathogens were considered. 185 Only 186 This guideline doesNot not consider superficial infections caused by these yeasts,[11, 12] but only 187 systemic or invasive infections which generally occur in immunocompromised hosts or in 188 association with central venous access devices (CVADs). An overview of selected surveillance 189 studies of rare yeast invasive infections is summarised in Table 1. In Denmark, these fungi 190 together comprised only 1.1% of 4000 cases of fungaemia over 8 years[13] whilst a Chinese study 191 reported non-candidal yeasts comprised 1.7% of pathogens causing invasive yeast infections.[14]

192 Rare yeasts caused 1.8% of 767 fungaemia episodes from 2010-2011 in Spain[15] and in a recent 193 25-centre study in Asia analysing 2155 bloodstream yeast isolates over a year, uncommon yeasts 194 were represented as follows: Trichosporon 1.1%, Rhodotorula 0.5%, Kodamaea ohmeri 0.3% and 195 Malassezia spp. 0.2%.[16]

196

197 Table 1. Summary of rare or uncommon yeast pathogens encountered in selected surveillance 198 studies from different geographic regions. Only unique isolates are included in the numbers 199 showna.

Region (reference no.)

Yeast genus or setting Denmark[13] USA[17] ARTEMIS Spain[15] China[14] France[18] study[6]

Fungaemia or invasive 3982 3382 NA 767 NA NA infection (no. isolates or no. cases)

All rare yeasts 30 NA consultation. 7651 14 844 63

Geotrichum spp. 2 2 NA NA NA 11 (Geotrichum distribution. candidum) Kodamaea spp. NA publicNA NA 1 26 3 Malassezia spp. 0 other1 NA NA NA 1 Pseudozyma spp. forNA NA NA NA 2 NA Rhodotorula spp. 4 21 462 2 44 8

Saccharomyces spp. 22 for 8 1321 NA 16 11 Only Saprochaete spp. Not0 NA 101 3 NA 10

Sporobolomyces spp. 0 NA NA NA NA

Trichosporon spp. 2 8 1196 3 74 19

200 NA, not available aData represent numbers of isolates/episodes

201 For each of the above genera examined, evidence and recommendations for clinical practice are 202 stratified, after the epidemiology, by diagnostic modalities, antifungal treatment and 203 management options, with some exceptions. First, as there are no genus- or species-specific 204 serological markers to detect any of the rare yeast pathogens described here, the section on 205 ‘Antigen Detection’ is collectively discussed. Second, as the principles of antifungal therapy and 206 management approach to these infections in children and neonates often mirror those in adults, 207 recommendations on their management are also discussed together. These aspects are 208 described towards the end of the guideline. Lastly, it is essential to note that although this group 209 of yeast pathogens demonstrate yeast-like colonies in vitro, what is seen in vivo i.e. in 210 histopathological sections, may be hyphal forms or yeast forms, or both.

211

212 GUIDELINE DEVELOPMENT

213 The approach applied in the ECMM guideline programme is recently described.[9] For this 214 guideline, ECMM invited experts to participate in February 2018 as determined by their 215 publication activity in the field of medical mycologyconsultation., their personal involvement in patient 216 management, and their geographical location as defined by the United Nations 217 https://unstats.un.org/unsd/methodology/m49/. distribution.

218

219 The guideline follows the structurepublic and definitions of the ESCMID and ECMM Guidelines for 220 diagnosis and management of rare and emergingother fungal diseases[19-21] which are in accordance 221 with the Grading of Recommendationsfor Assessment, Development and Evaluation (GRADE) and 222 Appraisal of Guidelines for Researchfor & Evaluation (AGREE) systems.[22, 23] No randomised 223 treatment trials have been conducted on the topics of this guideline and hence meta-analyses 224 are notOnly applicable. The PICO (population, intervention, comparison, outcome) approach is 225 applied, but in thisNot set of guidelines, PICO is displayed within the tables. Treatment strategies and 226 diagnostic assays may alter patient course and are regarded as interventions. The fixed sequence 227 of columns in the tables is pre-defined and increases transparency. First, a population is defined; 228 then the intention or objective is stated, followed by the intervention. For that logical sequence, 229 strength of recommendation (SoR) and quality of evidence (QoE) are provided, followed by the 230 references on which the recommendation is based, and an index describing the source of level

231 evidence. In the last column, comments are added as appropriate. SoR and QoE are independent 232 evaluations, thus e.g. allowing a strong recommendation even in the absence of the highest 233 quality evidence (Table 2). Additional tables are provided as appropriate by the authors.

234

235 Table 2. Definition of strength of recommendation and quality of evidence

Strength of recommendation Definition

Grade A The guideline group strongly supports a recommendation for use

Grade B The guideline group moderately supports a recommendation for use

Grade C The guideline group marginally supports a recommendation for use

Grade D The guideline group supports a recommendation against use

Quality of evidence Definition

Evidence from at least 1 properly designed randomised, controlled trial (orientated on the primary endpoint of the trial) Level I Note: Poor quality of planning,consultation. inconsistency of results, indirectness of evidence etc. would lower the SoR. Evidence from at least 1 well-designeddistribution. clinical trial (incl. secondary endpoints), without randomisation; from cohort or case-controlled analytic studies (preferably from >1 Level II centre); from multiple time series; or from dramatic results of uncontrolled experiments

Note:public Every Level II evidence must have at least one added index.

Evidence from opinions of respected authorities, based on clinical experience, Level III other fordescriptive case studies, or reports of expert committees Added Index Definingfor the source of level II evidence r Meta-analysis or systematic review of randomised controlled trials

Transferred evidence i.e. results from different patients‘ cohorts, or similar immune- tOnly Notstatus situation h Comparator group: historical control

u Uncontrolled trials

a For published abstract presented at an international symposium or meeting

236

237 Authors and contributors

238 Authors fulfilled the criteria set by the International Committee of Medical Journal Editors 239 (ICMJE). For the purposes of this guideline, further requirements reflecting sufficient author 240 contribution were responsiveness throughout the guideline process, receipt of training on the 241 guideline process, and disclosure of conflicts of interest (Figure 1). Contributors are individuals 242 who did not meet all ICMJE authorship criteria but who have contributed significantly to the 243 work.

244

245 Figure 1. Worldwide distribution of the authors

consultation. distribution. public 246 247 for other 248 Literature search terms

249 Authors used the following searchfor strings: for example for Geotrichum infections: ‘Geotrichosis* 250 OR Geotrichum*’,Only ‘ped Geotrichum* AND child Geotrichum* AND neonate’, ‘epidemiology 251 Geotrichum* ANDNot etiology*’, ‘Geotrichum AND taxonomy*’, ‘Geotrichum* AND susceptibility 252 testing’, ‘Geotrichum* AND diagnosis*’. For the epidemiology section the following string was 253 used ‘Geotrichum* [All Fields]) AND (case[Title/Abstract] OR cases[Title/Abstract] OR 254 patient[Title/Abstract] OR patients[Title/Abstract] OR report[Title/Abstract]) AND 255 ("1999/01/01"[PDat] : "2019/12/31"[PDat])’. Acknowledging the relative infrequent publications

256 on rare yeast infections, a 20-year period was chosen to represent the distribution of worldwide 257 reports. Similar search strings were used for the remaining eight yeast genera.

258

259 Workflow

260 To address the challenge of incorporating members from multiple time zones in the guideline 261 group repeated video conferences on the methodology were convened. A video tutorial 262 https://www.youtube.com/watch?v=1silWTWHwdg was also viewed by all contributors. 263 Assistance to the group was provided by Oliver Cornely (OAC) and the coordinators (SC-AC, AC, 264 NPG, JP), who supervised and reminded contributors of timelines. Documents were shared 265 among the authors on a password-protected OneDrive repository, and were updated several 266 times per day. Updates on PICO tables were written in red font; after coordinators spell-checked 267 and formatted, e.g. for consistent abbreviation use, the font colour was changed to blue for 268 consideration by the group. Once the group agreed on contents, the font colour was changed to 269 black. When all information on a slide had been agreed upon, the slide was flagged ‘final’. A 270 writing group (here with initials: SC-AC, AC, JP, NPG,consultation. OAC, KA, JNAJ, GG-E, JSG, NG, AG, CL-F, LO- 271 Z, LP, TP, RR-R, DS, AS, JS-G) volunteered to contribute to the first draft, which was then circulated 272 to all authors and contributors. distribution.

273

274 Any discrepancies in recommendationspublic were resolved by majority vote. Additional aspects or 275 publications missing in the manuscript couldother be contributed via a survey sent out to all authors. 276 Once the authors andfor contributors agreed on a final draft, a 4-week public consultation phase 277 followed. Comments received werefor evaluated. xx scientific societies from xx countries reviewed 278 and endorsed the guidance document (Figure 2). 279 Only Not

280 Figure 2. National societies endorsing the guideline

281

282 INFECTIONS CAUSED BY GEOTRICHUM CANDIDUM AND GEOTRICHUM SPECIES 283 Taxonomy and epidemiology consultation. 284 Geotrichum candidum rarely causes serious infections. Also known as Galactomyces candidus, 285 Dipodascus geotrichum, or Galactomyces geotrichum, it isdistribution. ubiquitous in soil, decaying organic 286 matter, contaminated foods, and is utilised in manufacture of Brie and Camembert cheeses.[24] 287 Geotrichum spp. are related closelypublic to yeasts of the genus Saprochaete. Based on genetic 288 sequence similarity, Geotrichum clavatum is reassigned as Saprochaete clavata, whilst 289 Geotrichum capitatum is Saprochaete capitatusother.[25] An arthroconidia-producing yeast (note: 290 Candida spp. do not producefor arthroconidia), Geotrichum can easily be confused with members 291 of the genus Trichosporon, exceptfor that Geotrichum does not produce true blastoconidia. In the 292 genus only G. candidum is known to cause infections in humans. 293 Only 294 Since first reportedNot in 1971,[26] fewer than 30 cases of invasive G. candidum infections have been 295 reported in the English literature, mostly from Europe and the USA (Figure 3) but with more cases 296 and small case series reported after 2010. Although there is variation in epidemiology, G. 297 candidum has accounted for only a small proportion of rare yeast infections[27] and in some 298 surveys, none at all.[3, 15]

299 Figure 3. Worldwide distribution of Geotrichum candidum infections (reported cases between 300 1971 and 2019, per million population)

301

302

303

304 Legend: Cases of Geotrichum candidum-related infectionsconsultation. in the medical literature between 2000 305 and 2019 were identified in a PubMed search on January 15, 2020 using the search string 306 ((Geotrich* OR Saprochaet* OR Blastoschizomyc* OR distribution. Magnusiomyc* OR Dipodascus OR 307 Galactomyces) AND (case [Title/Abstract] OR patient OR report [Title/Abstract] OR infection OR 308 invasive OR systemic OR fungemiapublic OR blood)) that yielded 594 publications. Twenty-eight cases 309 reported since 1971 have been identified otherfrom 11 countries. [26-46] Most cases were reported from 310 the United States of for America (N=13), Italy (N=4), Spain and India (each N=2). The two cases 311 reported from Spain were related to intake of contaminated milk.[31] Number of cases reported 312 between 1971 and 2019 are presentedfor as cases per million population per country. The resident [47] 313 populationOnly per country was obtained from www.worldometers.info. 314 Not 315 Patients with underlying haematological diseases including the paediatric population, are at risk 316 but also those with HIV, uncontrolled diabetes mellitus and trauma to soft tissue. In one patient, 317 the infection was linked to eating French cheese after allogeneic stem cell transplantation 318 (SCT).[28] G. candidum-related infections have also been identified in patients with underlying 319 malignancy after itraconazole prophylaxis during an outbreak in a Spanish hospital.[31]

320 Bloodstream infection with or without skin lesions and pulmonary infections are the most 321 common presentations in immunocompromised patients.[28, 34, 38, 39] Localized infections affecting 322 the intestine, eye, heart valves,[29, 48] deep tissue after trauma or surgery and oral mucosa have 323 also been reported.[37, 39] The overall mortality for G. candidum infections is ~55% and is highest 324 in oncological patients (>60%) but lower (<40%) for other patient groups.

325

326 Diagnosis

327 Imaging

328 Evidence - Imaging findings of geotrichosis are few and are non-specific. Abnormalities have been 329 seen in pulmonary disease although chest radiographs are often normal. On computed 330 tomography (CT) scan, findings include peribronchial thickening, fine nodular mottling at the lung 331 bases, air space consolidation or cavitation (which can resemble tuberculosis).[30] Cerebral 332 magnetic resonance imaging (MRI) typically has been suggestive of changes within the 333 cerebrospinal fluid (CSF) consistent with meningealconsultation. inflammation. Echocardiography has 334 detected tricuspid valve vegetations.[48] 335 Recommendations – For all populations, once Geotrichumdistribution. infection has been proven, imaging 336 studies are recommended with at least moderate strength to either exclude, or to determine 337 extent of disease including to the lungs, eye, skin, heart and skeleton.[29, 30, 32, 48] (Table 3). CT 338 scanning is preferred over chestpublic radiography in suspected lung disease. If disease of the eye or 339 brain is suspected, in addition to fundoscopyother by an ophthalmologist, MRI may have better 340 sensitivity for definingfor extent of ocular and extra-ocular disease and is moderately 341 recommended. Endocarditis should be confirmed by transoesophageal echocardiography (TOE) 342 with at least moderate recommendation.for If an IFD is a differential diagnosis, biopsy of affected 343 tissueOnly is strongly recommended even though evidence is sparse. Follow up imaging is also 344 strongly recommendedNot in unstable patients. 345

346 Table 3. Recommendations on imaging studies in rare yeast infections*

Population Intention Intervention SoR QoE Reference Comment

Geotrichum candidum and Geotrichum spp.

Any To detect or X-ray or CT or B III Sfakianakis MedMycol 2017 N=1 exclude MRI or US of [32] involvement or eye Hydy CID 1995 [37] N=1 dissemination Myint MMCR 2015 [29] N=1

Children, To determine Echo- B III Meena JGlobInfectDis 2017 N=1, 1.3 x 11.5 cm immune- extent of cardiography [48] vegetation of tricuspid valve competent Geotrichum infection

Haematological To diagnose Chest CT B III Henrich TID 2009 [30] N=1, multiple lung opacities malignancy with in both lungs pneumonia Kodamaea ohmeri consultation. Any To diagnose Transthoracic B III Sundaram AnnPaedCardiol N=1, tricuspid valve echo 2011 [49]distribution. vegetation Trans- B III Joao HeartVess 2002 [50] N=1, mitral valve vegetation esophageal echopublic Any To determine Transthoracic B III Reina SJID 2002 [51] N=1, mitral valve vegetation extent of echo other for Ni RevEspCard 2018 [52] N=1, aortic valve vegetation infection Lower limb B III Joao HeartVess 2002 [50] N=1, occlusion of popliteal angiographyfor artery

Abdominal CT B III Reina SJID 2002 [51] N=1, splenic infarct Only scan Not Malassezia spp.

Critically il To determine Transthoracic B III Schleman Chest 2000 [53] N=1, adult with septic extent of echo thrombus from superior infection vena cava to right atrium

Haematological To determine Abdominal CT B III de St Maurice N=1, splenic lesions malignancy extent of scan PaediatrTranspl 2014 [54] infection

Pseudozyma spp.

Any To Cerebral CT scan B III Hwang KorJLabMed 2010 N=1, brain abscess diagnose/define [55] site of infection Thoracic CT scan B III Parahym DMID 2013 [56] N=1, pleural empyaema

Joo Mycoses 2016 [57] N=1, lung infection

Rhodotorula spp.

Any To diagnose Transthoracic B III Maeder Infect 2003 [58] N=1 echo Cabral JMMCaseRep 2017 N=1, missed diagnosis in [59] both cases

Trans- B III Cabral JMMCaseRep 2017 N=1, vegetation on aortic esophageal [59] valve echo consultation.Simon JCM 2014 [60] N=1, aortic valve vegetation and root abscess SPECT with C III Simon JCMdistribution. 2014 [60] N=1, increased uptake Indium-111

Haematological To diagnose or Cerebral MRI B III Tsiodras MMCR 2016 [61] N=1, foci of increased signal malignancy to exclude, or to public throughout brain, determine leptomeningeal extent of other enhancement, and on infectionfor repeat imaging, disease progression and ventricular for enlargement

Trauma To diagnose Plain X ray B III Goyal PostgradMed 2008 N=1, needed serial imaging, Only femur [62] non-union and sequestrum Not development

Saccharomyces spp.

Vascular disease To diagnose Abdominal CT B III Smith JCM 2002 [63] N=1, aortic graft infection scan

Chronic kidney To diagnose Abdominal CT B III Pillai SaudiJKidDisTranspl N=1, dilated left ureter, disease and scan and follow 2014 [64] perinephric stranding, diabetes up abdominal hydronephrosis, distal mellitus ultrasound ureteric stone

Saprochaete spp.

Haematology To diagnose and Total body CT B III Del Principe Mycoses 2016 N=3, liver, spleen and lung determine scan [65] disease extent of Favre MMCR 2016 [66] N=1, liver, spleen, GI and infection lung disease

Thoracic CT B III Etienne Mycoses 2008 [67] N=1, bilateral nodular pneumonia

Fianci Infection 2008 [68] N=1, bilateral nodules, infiltrates, consolidation

Haematology, To diagnose Thoracic CT B IIu Pamidumukkala N=1. Consolidation and diabetes, JClinDiagnRes 2017 [69] nodular lesions hepatitis C, consultation. renal transplant Haematology To diagnose Chest X Ray* B IIu Gadea JCMdistribution. 2004 [70] N=4, nodules and infiltrates Haematology To diagnose Abdominal CT B III Schuermans MedMycol N=1, hypodense lesions in 2011 [71] liver

COPD To diagnose Thoracicpublic CT B III Tanabe EpidInfect 2018 [72] N=1, tree-in-bud nodules, other lymph node enlargement Renal To diagnosefor Thoracic CT B III Mandarapu IndJNephrol N=1, nodules and transplantation for 2016 [73] consolidation Sporobolymces spp. – no data for evidence. Recommendation C III TrichosporonOnly spp. Haematology or To diagnoseNot and Chest X-ray* or B III Tashiro Chest 1995 [74] Pulmonary infection is critically ill determine CT scan mainly reported in Mele BoneMarrowTranspl patient with extension of neutropenic and other 2005 [75] fungaemia infection immunocompromised Raza JPakMedAssoc 2006 hosts; lung involvement [76] present in 18% to 58% of

Yang TherClinRiskManag haematology patients. Lung 2014 [77] infiltrate is represented by diffuse alveolar, lobar De Almeida FrontMicrob pneumonia, or mass-like 2016 [78] lesions Fournier EJCMID 2002 [79]

Suzuki EJH 2010 [80]

Haematology To diagnose and Abdominal CT- B III Alegre Sangre 1991 [81] Hepatic and/or splenic patient with determine scan* or lesions have been reported Yong IndDermatol 2017 [82] systemic extension of ultrasound in haematologic patients Alby-Laurent HematolOncol infection infection after neutropenia recovery 2017 [83] (14% of patients) Fournier EJCMID 2002 [79]

Patients with To diagnose and Echocardiogram B III Keay RevInfectDis 1991 [84] Endocarditis may systemic determine complicate fungaemia. Martinez-Lacassa EJCMID infection and extent of Endocarditis after valve 1991 [85] persistent infection replacement have been consultation.Sidarous ClinCardiol 1994 positive blood reported from 3 months to [86] cultures despite 8 years after the surgery targeted Chaumentindistribution. CID 1996 [87] antifungal Izumi therapy public AnnThoracCardiovasSurg 2009 [88] otherDe Almeida FrontMicrob for 2016 [78] SoR, strength of recommendation; QoE,for quality of evidence; N, number of subjects investigated; CT, computerised tomography; GI, gastrointestinal; MRI, magnetic resonance imaging; SPECT, single photon emission computed tomography; US, ultrasound.

*For allOnly genera, in general, plain X rays are useful in resource-limited regions. X rays are also useful in non-resource limited countries but Notare less sensitive in comparison with CT scans which are preferred for defining or excluding infection in a particular body site. In general. Abdominal CT scans are preferred to abdominal ultrasound but ultrasound has good clinical utility as well.

347

348 Histopathology

349 Evidence – Only small numbers of cases of G. candidum skin and soft tissue infection with 350 adequately documented tissue invasion have been reported in haematology patients and those 351 with diabetes mellitus.[30, 32] (Table 4). Disseminated infection involving numerous organs 352 including the gastrointestinal (GI) tract was documented on post mortem examination in one 353 report.[43] Both direct microscopy on histopathological examination of clinical specimens 354 including formalin-fixed paraffin-embedded (FFPE) tissue sections have been useful.[89]

355

356 Table 4. Recommendations on interpretation of histological-based, and direct detection by

357 molecular methods for diagnosis of rare yeast infections.

Population Intention Intervention SoR QoE Reference Comment

Geotrichum candidum and Geotrichum species

Haematological To diagnose Histopathology on fresh A III Kassamali JCM 1987 N=1, skin lesions malignancy and tissue consultation.[43] diabetes mellitus Henrich TID 2009 [30] N=1, skin lesions Sfakianakisdistribution. MedMycol N=1, skin lesions, soft tissue 2007 [32] Irregular septate hyphae (GMS and PASpublic stain); necrosis and thrombosis of blood vessels. Haematology To diagnose Histopathology on A III Kassamali JCM 1987 N=1, Elongated hyphal autopsy materialother and [43] elements, variable in fortissue diameter with infrequent irregular branching and for budding yeasts Sites: heart, lungs, liver, Only spleen, pancreas, lymph Not nodes, bone marrow, kidneys

Kodamaea ohmeri

Any To diagnose Histopathology on fresh C III No reference found or FFPE tissue or autopsy

Any To diagnose Molecular methods in C III No reference found fresh or FFPE tissue or body fluids

Malassezia spp.

Haematological To diagnose Histopathology on fresh B III De St Maurice N=1, splenic lesions, malignancy and tissue PaediatrTranspl 2014 budding yeasts and determine [54] pseudohyphae dissemination N=1, nasopharyngeal tissue, beyond blood budding yeasts

Critically ill Detect 18S rRNA PCR C III Tirodker JPerinatol N=4, blood neonates and Malassezia 2003 [90] N=1/4 PCR-positive children directly from blood culture

Pseudozyma spp.

Haematology To diagnose Histopathology on fresh A III Joo Mycoses 2016 [57] N=1, lung tissue tissue consultation.Chen IntJDerm 2011 N=1, leg/sinus tissue [91] Dichotomous hyphae with septa, with associated necrosis (H&E, GMS),distribution. clustered yeast like cells on PAS Any To diagnose Molecular methods in C III No reference found freshpublic or FFPE tissue or body fluids Rhodotorula spp. for other Any To diagnose Histopathology on fresh A III George ClinExpt N=1, skin and soft tissue tissuefor Dermatol 2016 [92] lesion Goyal JPostgradMed N=1, bone Only 2008 [62] Not Simon JCM 2014 [60] N=1, cardiac valve Tsiodras MMCR 2016 N=1, brain [61]

Round-oval budding yeast forms (GMS, PAS, KOH, Blankophor), necrotising granulomas

Systemic lupus To diagnose Histopathology on post B III Pamidimukkala N=1, brain erythematosus mortem tissue NeurolInd 2007 [93]

Budding yeasts in brain and subarachnoid space (GMS)

Any To diagnose Molecular methods in B III George N=1, skin fresh or FFPE tissue or ClinExpDermatol 2016 body fluids (panfungal [92] PCR)

Saccharamyces spp.

Haematology To diagnose Histopathology on fresh A III Choi BJH 2012 [94] Liver biopsy tissue PAS stain, typical fungal forms on PAS as for other genera

Haemato- To diagnose Real time ITS2-directed C IIu Rahn IJMM 2016 [95] N=17/36 respiratory tract oncology, HSCT PCR on fresh tissue samples

Haematology To diagnose 18S rRNA sequencing B III Choi BJH 2012 [94] N=1, liver biopsy Saprochaete spp. consultation. Any To diagnose Histopathology on pre- A IIu Martino CID 2004 [96] N not specified, utility and establish or post-mortem tissue established for inclusion of epidemiology distribution.proven cases Diabetes To diagnose Histopathology on lung B IIIu Subramanya Supram N=1, lung PAS stain, hyphal mellitus aspiratepublic MedMycol 2016 [97] fragments with yeast cells Any To diagnose Histopathology on pre- A IIu Duran-Graeff Mycoses Total N not specified and establish or post-mortem tissue 2017 [28] other N=11, lungs epidemiologyfor N=5, liver for N=3, spleen N=2, CNS

Only N=2, kidneys Not Haematology To diagnose Histopathology on post A IIu Gadea JCM 2004 [70] N=1, disseminated mycotic and mortem tissue nodules including in CNS determine extent of infection

Any To diagnose 18S/ITS-directed PCR on B IIu Arrieta-Aguirre JCM N=1 sample, FPPE liver FFPE tissue 2017 [98] tissue

Sporobolomyces spp.

No evidence in human infection

Any To diagnose Histopathology on B III Saey VetPathol 2011 N=1, dog with postmortem tissue [99] granulomatous meningoencephalitis

Any To diagnose Molecular methods on B III Saey VetPathol 2011 N=1, dog with fresh or FFPE tissue [99] granulomatous meningoencephalitis

Trichosporon spp.

Any To diagnose Histopathology A III Chakrabarti MedMycol Yeasts, pseudohyphae 2002 [100] and/or hyphae may be (especially visualized but are not important in Padhye JCM 2003 [101] specific. Less often, skin, pulmonary Colombo CMR 2011 arthroconidia are seen and or other organ consultation. [102] Trichosporon infection is involvement) De Almeida more likely FrontMicrobdistribution. 2016 [78]

Rüchel JCM 1999 [103]

Histological To diagnose In situpublic hybridization B III Shinozaki JCM 2013 Not commercially available, proven cases of with specific peptide [104] requires multicentre yeast infection nucleic acid probesother in validation, not evaluated for forFFPE sections species other than for Trichosporon asahii Histological To diagnose Nested PCR with genus B IIu Sano VirchowArch N=30, 20/30 specimens provenOnly cases of specific primers in FFPE 2007 [105] positive, tissue fixation yeast infection Notsections diminished amplification Histological To diagnose Nested PCR 28S rDNA in B IIu Nagai JCM 1999 [106] N=11 sera; 7/11 positive proven cases of body fluids and serum yeast infection

Confirmed To diagnose Nested PCR in serum B IIu Sugita MicroImm 2001 N=11 sera; 9/11 positive autopsy cases [107]

Any To diagnose Two pan-Trichosporon B IIu Landlinger JCM 2009 4 species detected (T. from various probes (xMAP [108] asahii, T. inkin, T. cutaneum, samples technology, Luminex) T. beigelii)

Any To diagnose LAMP-assay clinical B IIu Zhou BiomedResInt N= 6 samples; positive from positive specimens 2015 [109]

blood cultures

Haematology To diagnose Nested PCR in serum C IIu Sugita MicroImm 2001 N=11 sera; 9/11 positive [107]

Haematology To diagnose Serum PCR C IIu Hosoki JPaedHemOnc Breakthrough infection 2008 [110] DNA detection for over 39 days of follow up

Haematology To diagnose DNA microarray based C IIu Spiess JCM 2007 [111] N=11, blood BAL fluid; T. in serum, BAL asahii

Haematology To diagnose Real Time IGS1 PCR in C IIu Mekha Mycopath 2010 N=21, blood T. asahii serum consultation.[112]

SoR, strength of recommendation; QoE, quality of evidence; BAL, bronchoalveolar lavage; CNS, central nervous system;FFPE, formalin-fixed paraffin-embedded; GMS, Gomori Methenaminedistribution. Silver; IGS1, intergenic spacer 1; KOH; potassium hydroxide; LAMP, loop-mediated isothermal amplification; MAP, multiple analyte profiling; PAS, Periodic acid Schiff; PCR, polymerase chain reaction; qPCR, quantitative PCR

358 public 359 Microscopy should be performed preferablyother with a fluorescent brightener such as Calcofluor 360 White (Sigma Aldrich;for St. Louis, USA) or Blankophor (Tanatax Chemicals; Ede, The Netherlands) 361 and elongated yeast-to-hyphalfor like structures sought. To confirm infection, hyphae must be 362 demonstrated in affected tissue using one or more of haematoxylin-eosin (H&E), periodic acid- 363 SchiffOnly stain (PAS) or Grocott-Gomori’s methenamine-silver stain (GMS).[30, 43, 89] The morphology 364 of G. candidum hyphaeNot is non-specific, but often visualized as long, thin, septate and regularly- 365 shaped hyphae with variable angles of branching.[113] However, the degree of branching in tissue 366 can be difficult to define due to distortion of hyphal or tissue architecture during processing. 367 Hyphae within areas of necrosis and thrombosis of blood vessels may be seen.[32] There are no 368 Geotrichum-specific immunohistochemistry stains to assist diagnosis.

369 Recommendations – Despite few reports, it is strongly recommended that histopathological 370 examination of affected tissue for presence of fungi be undertaken. If present, hyphae of 371 Geotrichum are readily visible as hyaline, long, thin and septate structures. It is also strongly 372 recommended to confirm the diagnosis of geotrichosis by culture of specimens and/or by 373 application of direct molecular detection techniques (below) to enable identification of the 374 pathogen. Diagnosis of geotrichosis exclusively by histopathology is not possible.

375

376 Culture and microscopy

377 Evidence- Direct microscopy of clinical specimens can provide a rapid presumptive diagnosis. 378 Yeast-to-hyphal like structures may be seen on Gram stain of blood cultures (Table 5).[30, 38, 43] 379 There are sparse data on use of fluorescent brighteners. In one report, direct potassium 380 hydroxide (KOH) wet mounts of ocular fluid revealed septate hyphae of G. candidum measuring 381 6–8 μM in width with characteristic fragmentation into arthrospores (also 6-10 µM in width)[29] 382 but generally, the use of KOH is limited to skin, sputum (to decrease viscosity of mucous) and 383 corneal scrapes. Identification to species level by microscopyconsultation. is not possible. 384 distribution. 385 Culture of clinical specimens, and in particular blood, is essential and has the advantage of 386 yielding an isolate for species identification and susceptibility testing. A positive culture from a 387 sterile site in the vast majoritypublic of cases establishes a definite diagnosis whilst that from a 388 nonsterile site including bronchoalveolar lavageother fluid (BALF) must be accompanied by clinical and 389 radiological evidencefor of disease to enable a diagnosis of probable infection. As for all IFD, a 390 negative culture does not excludefor diagnosis. Colonies of G. candidum typically manifest after 48 391 hours on Sabouraud’s dextrose agar (SDA) but will grow on other mycological media, with growth 392 best Onlyat 25oC. At higher temperatures to 36oC, growth is slower and may take beyond 4 days. 393 Colonies are describedNot to be cream-to-white, moist and yeast-like in appearance but may be flat, 394 wrinkled with fimbriate margins.[113] Microscopically, hyphae are long with di- or trichotomous 395 branching, and with segmentation into variably sized, rectangular arthroconidia (Figure 4). 396 Blastoconidia are absent in subcultures. Species identification of G. candidum requires sufficient 397 level of mycological expertise. Characteristic colonial and morphological features of G. candidum 398 are shown in Table 5.

399 Figure 4. Geotrichum candidum microscopy.

400 Lactophenol cotton blue preparation of 401 microscopic characteristics of a culture of 402 Geotrichum candidum showing hyphae that are 403 long with di- or trichotomous branching, and 404 with segmentation into variably sized, 405 rectangular arthroconidia (photograph 406 provided by Dr. Catriona Halliday, Centre for 407 Infectious Diseases and Microbiology, Westmead Hospital, Sydney, Australia).

408

409 Table 5. Recommendations on microscopy and culture in Geotrichum infections

Population Intention Intervention SoR QoE Reference Comment

Any To diagnose Direct microscopy using A III Myint MMCR 2015 [29] N=1 fluorescent brighteners consultation.Kassamali JCM 1987 [43] N=1 (Calcofluor White, Henrich TID 2009 [30] N=1 Blankophor),

KOH wet mounts and Ng MedJMalaydistribution. 1994 [38] N=1 Gram-stain All specimenspublic Allows rapid presumptive diagnosis, long, septate and di- or trichitomous branching hyphae, hyphal diameter 6-10 µm. Characteristic arthroconidafor (6-10 um diameter). Hyphalother elements on Gram stain. No species identification. Any To diagnose Culture A III Duran Graeff Mycoses 2017 N=2, sites not specified [28] All specimensfor Myint MMCR 2015 [29] N=1, vitreous fluid

Only Henrich TID 2009 [30] N=1, blood, skin lesion

Not Sfakianakis MedMycol 2007 N=1, skin lesions [32]

Kassamali JCM 1987 [43] N=1, blood, skin lesion

Hrdy CID 1995 [37] N=1, joint fluid

Meena JGlobID [48] N=1, heart valve

Ng MedJMalay 1994 [38] N=1, blood

Chitasombat JInfect 2012 [17] N=2, blood

Allows species identification and susceptibility testing.

Fast growing flat, white/cream colonies, with dry fimbriate margins or which are moist, are suggestive of G. candidum and Geotrichum spp. Growth is best at 25oC.

Perform supplemental morphological studies using cornmeal Tween 80 agar and slide culture preparation. Hyphae are long and branched and segmented into rectangular arthroconidia

SoR, strength of recommendation; QoE, quality of evidence; N, number of subjects investigated; KOH, potassium hydroxide

410

411 Recommendations – Direct microscopy with fluorescent brighteners for clinical specimens (or 412 KOH mounts for skin, sputum, coranel scrape samples), focusing on septation and arthroconidia 413 formation is strongly recommended for first clues of presence of G. candidum. Culture of 414 specimens with incubation at 25°C and 37°C is strongly recommended for genus and species 415 identification, and for antifungal susceptibility testing.consultation. 416 distribution. 417 Susceptibility testing

418 Evidence – The European Committee on Antimicrobial Susceptibility Testing (EUCAST) and the 419 Clinical and Laboratory Standardspublic Institute (CLSI) have developed standardised reference 420 methodologies for antifungal susceptibilityother testing of Candida and Cryptococcus yeasts.[114, 115] 421 Agreement between forthe two methods are high for Candida spp. but there are no comparative 422 studies involving Geotrichum spp,for where both reference methods have been employed. The 423 EUCAST Edef 7.1 document is intended for testing the susceptibility of yeasts that are able to 424 fermentOnly glucose, and Geotrichum spp. do ferment glucose, but current data are insufficient to 425 recommend one Not ‘reference’ method over the other. The use of the commercial E-test 426 (bioMerieux, Marcy L’Etoile, France) and the CLSI-based Sensititre (Thermofisher) has been 427 uncommonly reported[28, 48] but neither was compared against the reference methods (Table 6).

428

429 Table 6. Recommendations on antifungal susceptibility testing in rare yeast infections

Population Intention Intervention SoR QoE Reference Comment

Geotrichum infections

Any To establish Susceptibility testing A IIu Wildfeuer Mycoses N=23, in house macrobroth dilution epidemiologic 1998 [116] (various methods) knowledge Duran Graeff N=1, E test or Sensititre Mycoses 2017 [28]

Cuenca-Estrella AAC N=12, EUCAST DEF. 7.1 2006 [117]

Cordoba N=1, EUCAST DEF. 7.1 RevArgenMicol 2011 [27]

Diabetes To guide CLSI broth C III Sfakianakis N=1, MICs: AMB 1 mg/L, FLU 1 mg/L, mellitus treatment macrodilution MedMycol 2007 ITC 0.03 mg/L, VRC 0.008 mg/L, CAS consultation.[32] 1 mg/L E test C III Myint MMCR 2015 N=1, MICs: VRC 0.125 mg/L, ITC 6 [29] mg/L, FLU 128 mg/L, AMB 0.047 distribution.mg/L

Haematolo To guide Disk diffusion C III Ng MedJMalay N=1 G. candidum, reported as gy treatment public 1994 [38] susceptible to AMB (100 ug) (paediatric ) other Any To guide forEUCAST / CLSI B III Meena N=1, CLSI M27-A3 document. MICs: treatment reference JGlobInfectDis 2017 VRC, 0.016 mg/L, POS 0.016 mg/L, microdilutionfor [48] CAS 0.032 mg/L, MICA 0.016 mg/L, methods AMB >16 mg/L, ITC > 16 mg/L

KodamaeaOnly ohmeri infections Not Any To establish Susceptibility testing A IIu Bretagne JAC 2017 N=3, EUCAST broth microdilution epidemiologic [18] (various methods) knowledge Chakrabarti CMI N=38, CLSI M27-A3 2013 [118]

Lee JCM 2007 [119] N=13, CLSI M27-A2

Giacobino N=1, CLSI M27-A3 MedMycol 2016 [120]

Fernandez-Ruiz N=1, CLSI 27-A3, EUCAST Edef.7.1 MedMycol 2017 [15]

Yamamoto BMCID N=1, M27-A2 2013 [121]

Xiao InfDrugRes N=26, CLSI M44-S3 disk diffusion for 2018 [5] FLU and VRC

A IIu Eddouzi MedMycol N=2, Senstitre and E test 2013 [122]

Any To guide Susceptibility testing B III de Barros N=1, M27-A2 treatment (reference CLSI or MedMycol 2009 EUCAST, or [123] SensititreTM methods) consultation.Shaaban Mycopath N=1, M27-A3 2010 [124] Distasi JMycolMeddistribution. N=1, Sensititre 2015 [125]

Puerto EJCMID N=1, Sensititre public 2002 [126] Susceptibility testingother C III Taj-Aldeen JMM N=1, E test for(other commercial 2006 [127] methods) Santino Mycoses N=1, E test for 2012 [128]

Otag Mycoses 2005 N=2, E test Only [129] Not Al-Sweih MedMycol N=1, E test 2011 [130]

Yang IJID 2009 N=1, ATB fungus [131]

Shang N=1, ATB fungus JMicrobiolImmunolI nfect 2010 [132]

Kanno N=1, yeast-like fungi FP Eiken JInfectChemother 2017 [133]

Malassezia spp. infections

Any For Modified broth C III Rojas Mycoses. N=30 (M. furfur, clinical non- epidemiological dilution method 2017 [134] invasive), FLZ 0.5-128, AMB 0.25-16, surveillance ITZ 0.03-0.125, VOR 0.03-0.5, TBN 0.125-32

Cafarchia N=78 (M. furfur, clinical invasive), MedMycol 2015 FLZ 8–>128, ITZ 0.032–8, POS 0.016– [135] 8, VOR 0.064–8

Velegraki JCM 2004 N=12 (M. furfur, clinical/ reference), [136] ITZ 0.03-0.06, FLZ 0.5-32, VOR 0.03- consultation.16 (CLSI M27-A2)

Miranda IJAA 2007 N=74 (M. furfur, non-invasive), ITZ [137] distribution.<0.03-0.25, VOR <0.03-0.5, FLZ <0.125-16 public Iatta JMM 2014 N=36 (M. furfur, invasive), AMB 16- [138] >16, FLZ 8->128, ITZ 0.125-2, POS other 0.125-0.5, VOR 0.125-4 forEtest C III Velegraki JCM 2004 N=12 (M. furfur), ITZ 0.03-0.12, FLZ for [136] 0.5-64, VOR 0.03-32 Pseudozyma spp. infections Any Only To guide CLSI broth B III Prakash Mycoses N=1 treatmentNot microdilution 2014 [139] Parahym DMID N=1 2013 [56]

EUCAST B III Orecchini JCM 2015 N=1 [140]

Lin JMM 2008 [141] N=1

Sensititre YeastOne C III Herb MMCR 2015 N=1 [142] Etest

All P. aphidis. Overall, low MICs (mg/L) to AMB, ITC, VRC, POS and isavuconazole. High MICs to FLU (>4), 5FC no activity (MICs >64), High MICs to echinocandins (>4).

Any To establish Eiken Kit C IIu Mekha N=3 (1 each of P. alboameniaca, P. epidemiological MicrobiolImmunol crassa, P. siamensis) knowledge 2014 [143] MIC (mg/L) range: micafungin, >16; AMB, 0.125-0.25; 5FC, >64; FLU, 32- >64, ITC, 4->8; VRC, 2

Sugita N=3 (1 each of P. antarctica, P. MicrobiolImmunol parantarctica, P. thailandica). MIC 2013 [144] range (mg/L): AMB 0.125-0.25; FLU, 0.5->64; ITC, 0.125->8

Rhodotorula infections

Any To establish In-house broth B IIu Wildfeuer Mycoses N=13, in house macrobroth dilution epidemiologic microdilution 1998 [116] consultation.Low MICs to AMB and VRC knowledge CLSI M27-A A IIu Barchiesi AAC 2000 N=7, CLSI M27-A. [145] distribution. High MICs to FLU and ITC, MICs to POS 2-4 mg/L public Zaas JCM 2003 N=10, CLSI M27-A [146] other MICs in mg/L, AMB 0.21-1, 5-FC for 0.125-0.25, FLU 32->64, VRC 4-8, POS 1-2, echinocandins >16 CLSI M27-A3for A IIu Nunes AAC 2013 N=59, CLSI M27-A3, [147] MICs in mg/L, AMB 0.5-1, FLU >/=64, Only VRC 0.25-4, POS 1-8, CAS 4->16 Not Capoor N=14, CLSI M27-A3, MICs in mg/L: IndJMedMicrobiol AMB 0.25-1, FLU 32-356, ITC 32-256, 2014 [148] VRC 32

Alp Mycoses 2020 N=2, CLSI M27-A3, MICs in mgL: [149] AMB 1-2, FLU, 8-64, ITC 0.5-4, VRC 0.25-1, POS 0.5

CLSI M27-A2 and E- A IIu Diekema JCM 2005 N=64, CLSI M27-A2, E test. By CLSI, test [150] low MICs to AMB, 5-FC, higher MICs to azoles, FLU MICs >/= 32 mg/L. By E test wider range AMB MIC, 8/64 had MICs >1–64 mg/L

CLSI M27-A2 A IIu De Almeida N=20, CLSI M27-A2. low MICs to MedMycol 2008 AMB, 5-FC, higher MICs to azoles, [151] FLU MICs >/= 64

Thompson JAC 2009 N=14, CLSI M27-A2, low MICs to [152] AMB, 5-FC; high MICs to azoles including ISAV

CLSI M44-S3 B IIu Xiao InfectDrugRes N=44, CLSI-M44 S3, 2018 [5] 100% resistance to FLU and VRC

EUCAST Edef7.1 A IIu Cuenca-Estrella AAC N=23, EUCAST DEF. 7.1, low MICs to 2006 [117] AMB, high MICs to azoles and consultation.echinocandins Bretagne JAC 2017 N=8, EUCAST DEF. 7.1, low MICs to [18] AMB, high MICs to azoles and distribution.echinocandins

Gomez-Lopez JAC N=29, EUCAST Edef.7.1, MICs in public 2005 [153] mg/LAMB 0.03-8, 5-FC 0.06-64, FLU 8->64, VRC 0.25-8, ITC, 0.06 ->8

Sensititre Yeast Oneother A IIu Falces-Romero N=6, Sensititre Yeast One, low MICs for Mycoses 2018 [154] to AMB and 5-FC, high MICs to for azoles and echinocandins Any To establish CLSI M27-A3 and B IIu Fernandez-Ruiz N=1, EUCAST higher MICs than CLSI; epidemiological EUCAST E Def 7.1) MedMycol 2016 high echinocandin MICs, high azole Onlyknowledge and [15] MICs, low AMB MICs to compareNot methods

Haematolo To guide CLSI broth B III Mori TID 2012 [155] N=1, MICs in mg/L - FLU > 64, VRC 8, gy treatment microdilution AMB 0.25, 5-FC <0.125, MICA>16, ITC 1

CLSI M27-A3 B III Miglietta MMJ 2015 N=1, MICs in mg/L AMB 0.5, [156] echinocandins >8, 5-FC 0.06, POS 4, VRC 4, FLU>/=64

Any To guide Sensititre YeastOne B III Perniola EJCMID N=4, MICs in mg/L - FLU >/= 256, treatment 2006 [157] VRC 2, AMB 0.25, 5-FC 0.125

Fores Mycoses N=1, MICs in mg/L: AMB 0.12, 5-FC 2012 [158] 8, “resistant to azoles and echinocandins, no MICs

Tsiodras MMCR N=1, MICs in mg/L: AMB 0.5, 5FC 2014 [61] 0.06, FLU 32, VRC 0.06, POS, 0.25, echinocandins >8

Savini JCM 2008 N=1, MIC in mg/L: AMB 0.25, 5-FC [159] <0.03, FLU >/=256, VRC 8

E test C III Cabral N=1, MICs in mg/L: AMB 0.,25, 5-FC JMMCaseRep 2017 0,19, FLU >/=256, VRC 0.5 consultation.[59] E test and M27-A B III Hsueh JCM 2003 N=1 but 3 isolates; MICs in mg/L: [160] AMB 0.125, FLU >256, ITC ranged distribution.from 0.5 – 8 with the two methods

E test C III Duggal MedMycol N=2, MICs in mg/L, AMB 0.5-1.5, VRC public 2011 [161] 0.38 -32, FLU >256, CAS >16 Franconieri N=1, MICs in mg/L: AMB 0.19, 5-FC otherPeritDialInt 2018 0.006, FLU >256, VRC 6, POS >32, for [162] CAS >32 ATB Fungusfor 2 C III PamidimukkalaNeur N=1, MICs in mg/L: AMB <0.5, 5FC (BioMerieux) olInd 2007 [93] <0.5, FLU 64 SaccharomyceOnlys spp. infections Any To establishNot EUCAST Edef.7.1 A IIu Lass-Florl AAC 2008 N=3, MIC range mg/L: AMB, 0.5-1; epidemiology [163] CAS 1-2, ITC, 1-4, VRC 0.125-0.5; POS 0.5-1.0

Bretagne JAC 2017 N=35, MIC range mg/L: [18] AMB 0.03-0.25, VRC 0.015-1, FLU 0.25-32, CAS 0.03-2

Cordoba N=2, FLU MIC 8 mg/L RevArgentMicrobiol 2011 [27]

Minea EJCMID 2015 N=11, MIC range mg/L: VRC 0.016- [164] 0.25, FLU 0.125-8, MXP (new drug) 0.016-0.125

CLSI M27-A3 A IIu Chitasombat JInfect N=8, susceptible rates: 2012 [17] AMB 100%, FLU 75%, VRC 100%, ITC 87%, CAS 100%, POS 100%

Roy Mycoses 2017 N=15, MIC90 in mg/L: [165] AMB 0.03, FLU 0.12, VRC 0.12, ITC 0.5, POS 0.03, CAS 0.25, ANIDULA 0.06, MICA 0.03

CLSI M27-A2 A IIu Thompson JAC 2009 N=18. MIC range mg/L: [152] ISAV 0.03-1, VRC 0.03-0.25, POS, consultation.0.125-1, FLU 0.125-16, AMB 0.25-1, 5-FC, 0.125 CLSI M27-A A IIu Barchiesidistribution. AAC 2000 N=15, MIC range mg/L: [145] POS 0.015->4, FLU 0.25->64, ITC public 0.015->4 Salonen JHospInfect N=160, MIC90 mg/L: 2000 [166] for other AMB 1, FLU 128, ITC 16 CLSI M27-A and A IIu Tiballi DMID 1995 N=32, MIC90 mg/L: unstated version of [167] for AMB, <0.02, 5FC 0.2, ITC 0.8, FLU 4 sensititre by CLSI Only For Sensititre: 0.05, 0.5, 1.6 and 8 Not respectively CLSI M44-S3 B IIu Xiao InfectDrugRes N=26, % susceptible: FLU 38.5, VRC 2018 [5] 100

BMD (Pfaller JCM B IIu Sobel CID 1993 N=20 isolates.MIC90 mg/L: AMB 0.2, 1988) [168] 5F 0.31, keto 0.78, clotrimazole 0.2,

Miconazole 0.1, FLU 40, terconazole 0.78, ITC 1.56, saperconazole 1.56

To establish CLSI M27-A3 and E A IIu Guinea AAC 2010 N=20. MIC90 in mg/L epidemiology test [169] CLSI: ISAV 0.5, POS 2, VRC 0.25, FLU and to compare 16 methods E test ISAV 0.5, POS >16, VRC 0.125, FLU 64

CLSI M27-A2 and CLSI A IIu Canton JAC 2008 N=4, POS MICs: M44-A [170] M27-A, range

M44-A, mean zone of inhibition 30 mm

CLSI M27A A IIu Chryssanthou JCM N=9 2002 [171] E test VRC: 0.03-0.25 for all caspofungin: 1 for EUCAST and CLSI, 0.25-0.5 for E EUCAST EDeF7.1 consultation.test Any To guide BMD B III Popiel TID 2015 N=1, MICs in mg/L: AMB 1, 5-FC treatment [172]

NCCLS (specifics not B III Smith JCM 2002 N=1, susceptible to AMB, FLU stated public [63] Sensititre B III Atici MMCR 2017 N=1, susceptible to FLU, POS, VRC, for other[173] MICA, CAS, AMB E test C III Appel-da-Silva N=1, susceptible to AMB, CAS, MICA, for MMCR 2017 [174] VRC Santino N=1, susceptible to CAS, VRC, Only IntJImmunopatholP resistant to FLU, ITC, AMB Not harmacol 2014 [175]

To guide EUCAST EDef 7.1 A IIu Sobel CID 1993 N=4, 3 blood, 1 probiotic treatment and [168] MICs in mg/L: AMB 0.5, 5FC 0.12- establish 0.25, FLU 8, ITC 1-2, VRC 0.12- 0.25 epidemiology

Saprochaete spp. infections

All To establish CLSI M27-A3 A IIu Subramanya N=7 epidemiological Supram MedMycol MICs in mg/L: AMB 2; FLU 2; ITC knowledge and 2016 [97] 0.212-0.5; VRC 0.12-0.5, POS 0.12- guide treatment 0.5; echinocandins 1-4 except for one isolate with CAS MIC of 0.12

CLSI M27-A2, then A3 A IIu Del Principe N=3. MICs in mg/L: AMB 0.25-0.5; Mycoses 2016 [65] VRC, 0.03-0.06; POS 0.125-0.25, ITC 0.12-0.03; ANIDULA, MICA 0.5, CAS 8

CLSI M27-A2 A IIu Gadea JCM 2004 N=5. MICs in mg/L: AMB 0.5-2; 5FC [70] 0.25-0.5; FLU 16-32; ITC 0.12-025; VRC 0.25-0.5

Sensititre and CLSI A IIu Birrenbach EID N=5. MICs in mg/L: AMB 0.5; 5FC disk diffusion (FLU, 2012 [176] 0.03-16; FLU 1-16; ITC 0.06-0.25; VRC) VRC 0.03-0.5; POS 0.06-0.5; CAS 4- consultation.>16 All To establish E test B IIu Duran-Graeff N=16. MICs in mg/L: AMB 0.12-2; epidemiology Mycoses 2016 [28] 5FC (32, knowledge distribution.ANIDULA/MICA 0.25->32, FLU, 1-32, POS

Aslani BMCID 2018 N=1. MICs in mg/L: FLU 1; AMB 4; [178] CAS 0.125; ANIDULA 0.016

CLSI M27-A2 A IIu Cuenca-Estrella AAC N=25. MIC90 in mg/L: AMB 8; 5FC 16; 2006 [117] FLU 16; ITC 0.25; VRC 0.5; POS 0.25; CAS >16

Canton JAC 2008 N=4. MICs v in mg/L: POS GM 0.074; [170] range 0.03-0.25

Ulu-Kilic Mycoses N=18. MICs v in mg/L: AMB 0.125-1; 2015 [179] FLU 0.5-64; VRC 32

Thompson JAC 2009 N=7. MICs in mg/L: AMB 0.25-1; 5FC [152] 0.125-8; ISAV 0.03-0.5; VRC 0.03- 0.25; POS 0.06-0.5; FLU 1-4

CLSI M27-A3 and E A IIu Koc InfDisLond N=20. MIC90s: CAS >32; VRC 0.125, test (caspofungin) 2016 [180] AMB 0.25, FLU 1

NCCLS, version not C IIu Martino CID 2004 N=12 for azoles, N=17 for AMB stated [96] MICs in mg/L:

3/12 FLU >64 (resistant)

consultation.1/6 ITC >1 (resistant) distribution.1/12 5FC >32 (resistant) 2/17 AMB >2 (resistant)

Mini API-ATB, Vitek II C IIu Pamidumukkala N=6. MICs in mg/L: AMB 0.5, FLU 1- YSIT cardpublic JClinDiagnRes 2017 8; ITC 0.125-0.5; VRC 0.063-0.125 other[69] All To guide forSensititre YeastOne B III Schuermans N=1; MICs in mg/L: AMB 1, FLU, 32, treatment MedMycol 2011 VRC 1, ANIDULA 2, CAS >8 for [71] Chittick AAC 2009 N=1. MICs in mg/L: AMB 0.5; 5FC Only [181] 0.06; FLU 4; ITC 0.06; VRC 0.06; POS Not 0.12; micafungin 0.5; caspofungin 8; anidulafungin 0.5

CLSI M27-A2 B III D’Assumpcao N=1. MICs in mg/L: AMB 1; FLU 8; JInvestMedHighImp ITC 1; POS 0.5; VRC 0.25; ISAV 0.25 act Case Rep 2018 [182]

Fianci Infection N=1. MIC in mg/L: VRC 0.12; CAS 2008 [68] 0.25; AMB 0.25

EUCAST Def7.1 B III Favre MMRCR 2016 N=1. MICs in mg/L: CAS/MICA >4; [66] FLU 32; AMB 0.25’ 5FC 0.25; VRC 0.5; POS 0.5

E test C IIIu Etienne Mycoses N=1. MICs in mg/L: AMB 0.38; 5FC 2008 [67] 0.5; FLU 6; VRC 0.19; CAS >/=32; CAS/VRC 0.094

Vitek 2 AST YSO7 C IIIu Mandarapu N=1; Susceptible to AMB, VRC, 5FC IndJNephrol 2016 Resistant to CAS [73]

To correlate Sensititre YeastOne A IIu Arrieta-Aguirre AAC N=5. MICs in mg/L: ANIDULA, 1-2; MICs with 2018 [98] MIC 2->8; CAS >/=8 (all S. capitata) genetic mechanisms of resistance

Sporobolomyces spp. infections consultation.

Any To establish Sensititre YeastOne B IIu Espinel-Ingroff JCM N=2 (S. salmonicolor), MICs not epidemiologic (versus CLSI M27-A) 1999 [183]distribution. specifically reported for these 2 knowledge strains (only noted that MICs read public after 72 hours’ incubation) CLSI broth B IIu Serena JAC 2005 N=5 (S. salmonicolor), MICs in mg/L: microdilution assayother [184] AMB 0.25-16, MFG 64-64, FLZ 8-64, for(M27-A2) ITZ 0.25-0.5, VOR 0.12-1, RVC 0.12-1 Trichosporon spp. infections for Systemic To guide CLSI or EUCAST broth B IIu Rodriguez-Tudela Interpretation of CBP MICs against infection therapy microdilution AAC 2005 [185] Trichosporon species are lacking. Only methods However, consider Trichosporon Lemes Not asahii as a poor target for AMB. In BrazJMicrobiol addition, T. asahii isolates with FLU 2010 [186] MICs above 2 mg/L have been Colombo CMR 2011 frequently reported. T. asahii [102] isolates with VRC and POS MICs

Tsai Mycopath 2012 above 2 mg/L have also been [187] reported. A Trichosporon dermatis isolate with high MICs for all azoles Arabatzis CMI 2014 was reported. [188] A recent publication testing 273 T. Taverna MedMycol asahii isolates suggested the 2014 [189] following ECOFF values – 8 mg/L for De Almeida FLU, –0.125 mg/L for VRC, 0.5 mg/L FrontMicrobiol for POS 2016 [78]

Francisco CMI 2019 [190]

All To establish CLSI M27-A (AMB in A IIu Paphitou AAC 2002 N=39, AMB was tested using RPMI epidemiological RPMI and in AM3) [191] and AM3 media. AM3 gave narrow knowledge ranges of AMB MICs. Non-T. asahii isolates showed lower MICs for all consultation.antifungals CLSI M27-A and Etest A IIu Arikan DMID 2002 N=43, only T asahii. s [192] distribution.AMB MIC50 and MIC90 values were 4 mg/

FLU MIC50 and MIC90 values were 2 public and 8 mg/L, respectively EUCAST otherA IIu Rodriguez-Tudela N=49, 11 species. Multicentre study. for AAC 2005 [185] For all isolates: GM MICs of FLU was ≤0.78 mg/L. T. dermatis had the for highest FLU GM MIC. T. asahii and T. faecale had the highest AMB GM MICs (5.2 and 3.2 mg/L, Only respectively). ITC and VRC were the Not most active drugs against all species

CLSI M27-A2 A IIu Chagas-Neto JCM N=22, 5 species. Five-centre study of 2009 [193] T asahii. Similar GM MICs for AMB and FLU. ITC and VRC the most potent drugs. Caspofungin and 5-FC with very high MICss

Thompson III JAC N=54, 3 species. Multicentre. Good 2009 [152] in vitro activity of triazoles. Similar susceptibility to AMB (GM MIC 0.6 mg/L) for all 3 species: T asahii, T inkin and T mucoides. Limited in vitro activity of 5-FC

ISAV (GM MICs <0.09 mg/L) was the 2nd most potent antifungal after VRC (GM MIC <0.04 mg/L) against all isolates

Mekha Mycopathol N=101, T. asahii. Substantial number 2010 [112] of isolates with high MICs to AMB (GM MIC 0.7 mg/L), FLU (10.35 mg/L) and 5-FC (12.97 mg/L). VRC was the most potent (GM MIC 0.09 v mg/L). Similar susceptibility among consultation.different T. asahii genotypes CLSI M27-A3 A IIu Guo JCM 2011 N=48, 6 species. Multicentre. Wide [194] MIC ranges of AMB (0.125-32 mg/L) distribution.and FLU (0-125-8 mg/L) for T. asahii. T. japonicum (2 isolates) with high AMB MIC (≥4 mg/L). VRC followed by public ITC exhibited highest activity against other all species forCLSI M27-A3 and A IIu Tsai Mycopath 2012 N=35, 8 species. Most Trichosporon EUCAST E DEF3.1 [187] spp. were susceptible to AMB, FLU for and VRC (using CLSI breakpoints for Candida). T. cutaneum had high AMB Only MICs, one T. asahii was multi-drug Not resistant. VRC was the most potent agent

CLSI M27-A3 A IIu Sun JMM 2012 N=23, T. asahii. All urine isolates. [195] VRC was the most potent followed by ITC. No differences in antifungal susceptibility among different T. asahii genotypes

Yang MedMycol N=32, T. asahii. Multicentre. Blood 2013 [196] isolates. Very low VRC MICs. Few strains with AMB MICs ≥2 mg/L (1 isolate). All but 2 isolates had FLU MICs ≤ 4 mg/L. Genotypes did not impact susceptibility

Ruan CID 2009 N=43, 7 species. Various sites. All [197] isolates AMB MICs ≤2 mg/L. FLU

MIC90 8 mg/L. VRC (MIC90 0.125 mg/L) followed by ITC were the most potent drugs. Strains with high FLU MICs showed low VRC MICs

EUCAST compared A IIu Arabatzis CMI 2014 N=42, 5 species. No significant with CLSI M27-A3 [188] differences between methods for MIC ranges. Rare species (T. loubieri and T. mycotoxinivorans) needed 48 hr growth (both methods). Good consultation.VRC and ITC activity against T. asahii, T. coremiiforme and T. dermatis. T. distribution.loubieri and T. mycotoxinivorans showed very high MIC to all azoles

Any To establish EUCAST E DEF7.2 A IIu Taverna MedMycol N=41, 5 species. Non T. asahii (isolate epidemiological public 2014 [189] species had lower AMB and FLU collection) knowledge other MICs than T. asahii. VRC and ITC for were the most potent drugs. Terbinafine showed good activity CLSI M27-A3for A IIu Montoya N=39, T. asahii. Very low FLU GM MedMycol 2015 MICs when compared with other Only [198] series. VRC and ITC were the most Not potent. No differences between T. asahii genotypes except for 5-FC. More than 50% of the isolates showed high AMB MICs

Any To establish CLSI M27-A3 A IIu Hazirolan AAC 2013 N=90, T. asahii. GM MICs of FLU, (isolate epidemiological [199] VRC, POS and ISAV were 1.54 mg/L, collection) knowledge 0.04 mg/L, 0.016 mg/L, and 0.07

mg/L µg/ml, respectively. GM MFCs of FLU, VRC, POS and ISAV were 20.78 mg/L, 0.71 mg/L, 1.68 mg/L and 1.79 mg/L, respectively. VRC was the most potent

To establish CLSI M27-A3 A IIu Iturrieta-Gonzalez N=54, 6 species. T asahii and T.

epidemiological PloSOne 2014 [200] asteroides had MIC50 values ≥ 2 knowledge mg/L. No differences between MIC including impact values among isolation sites (e.g. on biofilm blood and urine). All species had low production VRC MICs (≤0.06 mg/L). Non-T asahii isolates were more susceptible to FLU than T asahii

To establish CLSI M27-A3 B IIu Liao AAC 2014 [201] N=16, T. asahii. All isolates were epidemiological susceptible to VRC (low MICs). All knowledge but one AMB MICs were ≥2 mg/L Any To establish CLSI M27-A3 A IIu consultation. Guo JCM 2019 N=133, 10 species (108 T asahii ). epidemiological [202] Multicentre, various sites. T. asahii

knowledge and isolates had AMB MIC50 and MIC90 to establish distribution.values of 1 and 2 mg/L, and FLU

ECOFFs MIC50 and MIC90 values of 4 and 8 mg/L. Limited in vitro activity of public candins (MICs >8 mg/L). VRC GM other MIC was 0.09 mg/L (MIC90 0.25 for mg/L) To establish CLSI M27-A3 A IIu Francisco CMI 2019 N=358, 5 species (273 T. asahii). T epidemiological for [190] asahii isolates had AMB MIC50 and knowledge and MIC 90 values of 2 and 4 mg/L, and Onlyto establish FLU MIC50 and MIC 90 values of 2 and ECOFFs Not 8 mg/L. All species had VRC MIC50 and MIC90 values ≤0.25 mg/L µg/ml.

AMB MIC50 values ranged 2 - 8 mg/L for all species

SoR, strength of recommendation; QoE, quality of evidence; 5-FC, 5-flucytosine; N, number of strains investigated; CBP, clinical breakpoint MIC, minimum inhibitory concentration; ECOFF, Epidemiological cut off value; EUCAST, European Committee on Antimicrobial Susceptibility Testing; CLSI, Clinical and Laboratory Standards Institute; AMB, amphotericin

B; ANIDULA, aniodulafungin; CAS, caspofungin; FLU, fluconazole; GM, geometric mean; ITC, itraconazole; MICA,

micafungin; POS, posaconazole; VRC, voriconazole. ISAV, isavuconazole; GM, geometric mean; MIC50- MIC value able to

inhibit 50% of isolates tested, MIC90- MIC value able to inhibit 90% of isolates tested

430

431 As neither CBPs or epidemiological cut-off values (ECVs) have been defined for G. candidum, 432 classification of isolates as susceptible or resistant, or as wild type (WT) or non-WT (NWT) should 433 not be made. For all antifungal agents, MICs have varied between studies.

434

435 Overall, voriconazole (MIC range 0.008-4 mg/L), posaconazole (range 0.02-4 mg/L) and 436 micafungin (0.06 mg/L) have been the most active compounds with low MICs against Geotrichum 437 spp. The MIC of isavuconazole was 0.5 mg/L against a single G. candidum strain. Itraconazole 438 MICs are variable but may be as high as >16 mg/L whilst those of fluconazole ranged from 1-128 439 mg/L.[27-29, 32, 48, 116, 117] In one report, the MIC of amphotericin was >16 mg/L[29], otherwise MICs 440 are low. Caspofungin MICs may be high (>8 mg/L).

441 As MICs appear to be strain dependent, susceptibilityconsultation. testing of all clinically significant 442 Geotrichum isolates is reasonable. There are no data on antifungal combinations against these 443 fungi. distribution.

444

445 Recommendations – The use ofpublic reference methods for antifungal susceptibility testing to guide 446 antifungal treatment in Geotrichum infectionsother is moderately supported and may be clinically 447 useful in cases of treatmentfor failure. However, we strongly recommend the use of these methods 448 primarily to establish epidemiological knowledge. Commercial methods are recommended with 449 marginal strength only and usefor of disk diffusion methods advised against (Table 6). 450 Only 451 Molecular methodsNot for direct detection

452 Evidence – Evidence for the direct detection of Geotrichum spp. in clinical specimens is sparse, 453 but the principles are similar to that for detection of any fungus from clinical specimens other 454 than blood, by panfungal PCR. Targeting one or more of the internal transcribed spacer (ITS), 28S 455 or 18S rDNA regions is typical and if followed by DNA sequencing of the amplified PCR product, 456 assays have good specificity (~100%) and a sensitivity that is highest when hyphae or yeast forms

457 are visualized in the specimen.[203, 204] Studies have shown utility in detecting a broad range of 458 fungal species in both fresh and Formalin-Fixed Paraffin-Embedded (FFPE) specimens.[203-206] 459 However in many of these studies, in house techniques were used, some which lacked external 460 validation or standardisation, and utilising a variety of techniques (e.g. PCR +/- sequencing, real- 461 time multiplex PCR, qPCR +/- high resolution melting. The International Society for Human and 462 Animal Mycology (ISHAM) Fungal PCR Initiative (FPCRI) is addressing this issue using simulated 463 tissue specimens (Dr. Rebecca Groton, Trends in Medical Mycology, Nice, 2019). Test 464 performance is improved with fresh specimens rather than FFPE samples.

465

466 Recommendation – From few reports documenting its use to specifically detect Geotrichum spp. 467 (Table 4) and in the absence of a standardised test, the use of molecular methods on fresh clinical 468 material and FFPE sections for the detection of G. candidum is moderately supported. Due to lack 469 of data on the detection of G. candidum DNA in serum and in other body fluids, molecular 470 methods are only weakly supported.

471 consultation. 472 Species identification distribution. 473 Evidence – Identification to the species level is important for understanding of the epidemiology 474 and clinical features of disease. Outbreaks of G. candidum infection have not been reported. 475 Currently there are no data to indicatepublic that identification of causative Geotrichum to species level 476 can guide the choice of the antifungal treatment.other 477 for

478 Colonial and microscopic characteristicsfor (see Culture and Microscopy) of these germ-tube 479 negative yeasts provide important clues for species identification. Importantly, G. candidum is 480 urease-negativeOnly distinguishing it from other rare yeasts, e.g. Trichosporon spp. G. candidum 481 assimilates glucose,Not galactose, and xylose, but not lactose, maltose, sucrose, melibiose or 482 cellobiose[113] and may be identified using commercial biochemical identification systems such as 483 API 20C AUX and Vitek 2 ID-YST (all bioMerieux). These systems have provided accurate 484 identification in small numbers of patients (Table 7).[29, 32, 35, 38, 43, 48]

485

486 Table 7. Recommendations on genus and species identification of Geotrichum candidum and 487 Geotrichum spp.

Population Intention Intervention SoR QoE Reference Comment

Phenotypic identification

Any To identify to Carbon B IIu Farina Mycoses 1999 N=3 species level (carbohydrate) [35] assimilation and Myint MMCR 2015 [29] N=1 urease testing Sfakianakis MedMycol N=1 for species 2007 [32] identification Kassamali JCM 1987 [43] N=1

Ng MedJMalay 1994 N=1 [38]

Meena JGlobID 2017 N=1 [48]

consultation.Lohmann JCM 2013 N=6 [207] Urease-negative; Auxacolor 2 (Bio-Rad), API 20C AUX, API 20A, API ID 32Cdistribution. and VITEK 2 (all bioMerieux) allowed accurate identification MALDI-TOF MS public Any To identify to MALDI-TOF B IIu Fraser MedMycol 2016 N=20 strains, Bruker system species level MSidentificationother [208] v3.0 confirmation by DNA for sequencing, 95% correct species identification; Bruker for database only; full extraction required

Only Mancini JCM 2013 [209] N=4, Bruker and Vitek Not systems; both 100% correct identification to species. Bruker extended database not required

Kolecka JCM 2013 [25] N=16; Bruker system; 68.7% correct identification to

species; Bruker and in house database

Sendid MedMycol 2013 N=14, Bruker system [210] 2 of 2 G. candidum correctly identified. Three of 11 Geotrichum spp. identified as such; Bruker database only

Westblade JCM 2013 N=6 Geotrichum kabahnii [211] Vitek MS v. Vitek 2 v2.0

0% correctly identified

Lohmann JCM 2013 N=6, Bruker and Shimadzu [207] systems with 100% and 66.7% correct identfications although with scores that do not reflect “species” level consultation.identification Molecular Identification Any To identify To confirm or A IIu Moleculardistribution. identification superior to MALDI-TOF MS species supplement or identifications MALDI TOF MS Westblade JCM 2013 N=6 (G. klebahnii), D2 of the identification public [211] 28S rRNA gene otherFraser MedMycol 2016 N=5 for [208] for Kolecka JCM2013 [25] N=11 Sendid MedMycol 2013 N=5 Only [210] Not To supplement A IIu Lohmann JCM 2013 N=6 phenotypic [207] identification

Haematology To identify ITS and D1/D2 A III Henrich TID 2009 [30] N=1, skin infection species sequencing

Any To identify ITS, 18S, 28S A III Meena JGlobInfectDis N=1, endocarditis species rRNA 2017 [48] sequencing

Any To identify ITS sequencing A IIu Duran Graeff Mycoses N=3, molecular identification species and to 2017 [28] superior to MALDI TOF MS establish identification epidemiologic knowledge

SoR, strength of recommendation; QoE, quality of evidence; N, number of subjects investigated; ITS, internal transcribed spacer; MALDI-TOF, matrix assisted laser desorption ionisation time of flight; MS, mass spectrometry

488

489 Matrix assisted laser desorption ionisation time of flight mass spectrometry (MALDI-TOF MS) can 490 accurately identify G. candidum and other Geotrichum species using commercial databases 491 with/without supplementation by in-house spectra, although misidentification of species has 492 been reported.[25] More data are needed to validate MALDI-TOF MS in species identification and 493 because of under-representation of spectra in commercialconsultation. databases, in-house libraries should 494 supplement these databases.

495 distribution.

496 One study using the Bruker system (Bruker Daltoniks, Bremen, Germany) correctly identified 497 19/20 G. candidum and Geotrichumpublic silvicola (teleomorph of G. candidum) strains although not 498 all isolates achieved log scores of >2.00;other full protein extraction involving sequential ethanol, 499 formic acid, and acetonitrilefor precipitations was needed.[208] A French study compared MALDI-TOF 500 MS identification with that of ITS sequencing (see below) and correctly identified 2/2 G. 501 candidum isolates,[210] whilst anotherfor using the Bruker system and Shimadzu systems (Shimadzu- 502 Biotech corp., Kyoto, Japan) correctly identified 6/6 and 4/6 strains, respectively although with 503 log scoresOnly of <2.00 using the Bruker system.[207] Koleckta et al. using an in-house supplemented 504 Bruker database Not correctly identified 11/16 G. candidum isolates.[25] Mancini et al. correctly 505 identified 4/4 G. candidum using both the Bruker and Vitek MS (bioMerieux) systems[209] but 506 another study found 6/6 G. klebahnii strains misidentified as G. candidum.[211]

507

508 The current gold standard method of accurate species identification however is sequence 509 analysis of the universal fungal barcode marker, the ITS rDNA region.[212] For this purpose, the 510 universal primers ITS1 and ITS4 for the whole ITS region and ITS3 and ITS4 for the ITS2 fragment 511 are used. Alternatively, the D1/D2 domains of the large subunit (LSU or 28S) rDNA[213] also can 512 provide successful identification[25, 29] for G. candidum. Data are limited by small numbers of 513 isolates. Molecular identification performs better than morphological approaches and are used 514 to benchmark the accuracy of other tests including MALDI-TOF MS (Table 7). In one study, where 515 MALDI-TOF MS identification was compared with phenotypic identification methods and ITS/28S 516 rDNA sequencing, 5/11 Geotrichum isolates were identified with incorrect genus with others 517 identified to genus only.[25] This is likely due to evolving taxonomy of Geotrichum-like yeasts with 518 possible new species that are undistinguishable morphologically.

519

520 Central to molecular identification is a reliable database such as those developed by CBS 521 (http://www.westerdijkinstitute.nl/Collections/BioloMICSSequences.aspx) or ISHAM 522 (http://its.mycologylab.org) for sequence pairwise alignment.consultation. Whole genome sequencing (WGS) 523 approaches may have utility in epidemiology and outbreak investigations, but there are currently 524 no data on genotyping methods of Geotrichum spp. distribution. 525

526 Recommendation – Identificationpublic to the species level is strongly supported for a better 527 epidemiological understanding of G. candidumother infections. Guiding treatment by identification to 528 the species level isfor supported with moderate strength. Morphological identification is 529 moderately supported to identify G. candidum but molecular identification by ITS sequencing is 530 strongly preferred over morphology.for MALDI-TOF MS identification is moderately supported with 531 a needOnly for more extensive testing against commercial databases (Table 7). 532 Not 533 Diagnostic pathways

534 The capability of diagnosis of Geotrichum infections relies on availability of 535 mycological/histological investigations by skilled personnel. This is summarised in Figure 5. 536 Diagnosis is justified after positive cultures from deep samples combined with demonstration of 537 large numbers of typical fungal elements in tissue or respiratory secretions. Isolation from

538 sputum or faeces of asymptomatic individuals has no diagnostic significance. There are 539 insufficient data on the utility of the serum 1,3-β-D-glucan (BDG) test and this is discussed later. 540 Imaging is relevant where indicated. Throughout this guideline, diagnostic pathways are provided 541 for the genera of rare yeast where there are data to suggest a pathway.

542

consultation. distribution. public for other for Only Not

543 Figure 5. Diagnostic pathway for suspected cases of systemic geotrichosis due to Geotrichum 544 candidum and Geotrichum spp.

consultation. distribution. public for other for Only Not

545

546

547 Treatment approaches to Geotrichum infections

548 Surgical treatment

549 Evidence – Unlike IFDs caused by certain mould pathogens, e.g Mucorales, there are no data to 550 indicate that surgical intervention confers higher cure or survival rates. Many patients may be 551 too sick to undergo surgery. For all patient groups, where there is tissue invasive disease, 552 adjunctive surgical treatment with removal of infected tissue is important for source control. 553 Multiple sites of infection can be present in disseminated infection. Skin and soft tissue infection 554 should be treated by surgical debridement[32] with margins clear of infection, although it is 555 currently unclear how to define such margins for rare yeast infections. After surgery, patients 556 need to be closely followed to identify new areas of infection, which may require repeated 557 debridement. With eye involvement, vitrectomy and enucleation have been central to good 558 outcomes.[29] Vegetectomy and valve replacement assisted with cure of one child with 559 Geotrichum endocarditis.[48] Septic arthritis responded to drainage of pus and joint washout.[37] 560 consultation. 561 Recommendations – We strongly support early surgical treatment for Geotrichum infections 562 where indicated with engagement of surgical colleaguesdistribution. in addition to systemic antifungal 563 therapy (Table 8). Resection or debridement should be repeated as needed. 564 public 565 Table 8. Recommendations on surgical treatmentother for rare yeast infections. Population IntentioforIntervention SoR QoE Reference n Geotrichum infection for Any To cure Surgical A III Myint MMCR 2015 [29] and resection in Only Meena JGlobID 2017 [48] improveNot addition to Sfakianakis MedMycol 2007 [32] outcome any antifungal s treatment Hrdy CID1995 [37]

Kodamaea ohmeri infection

To cure A III Joao HeartVess 2002 [50]

Endocarditis Vegetectomy Reina SJID 2002 [51] with vascular +/- Ni RevEspCardiol 2018 [52] embolism valvuloplasty Yanghua JMedColl 2010 [214] +/- valve replacement

Malassezia infection

Any To cure Source control C III No reference found.

Pseudozyma infection

Bone and To Multiple A III Chen IntJDerm 2011 [91] skin/subcutaneo control debridement us infection local leg mycetoma infection

Rhodotorula infection

Bone To Debridement A III Goyal JPostgradMed 2008 [62] improve of wound and outcome removal of consultation. intramedullary nail distribution. Endophthalmitis To cure Vitrectomy A III Pinna BrJOph 2001 [215] Enucleation Gregory ArchOph 1992 [216]

publicMerkur BrJOph 2002 [217] Endocarditis To cure Vegetectomy A other III Maeder Infection 2003 [58] +/- valve for Cabral JMMCR 2017 [59] replacement for Simon JCM 2014 [60] Saccharomyces infection

VascularOnly graft To cure Graft A III Smith JCM 2002 [63] infection Notreplacement, debridement

Saprochaete infection

Alcoholic liver To cure Repair of A III D’Assumpcao JIMHICR 2018 [182] disease gastrointestin al leak post

pancreatecto my

Sporobolomyces infection

Any To cure Source control C III No reference found

Trichosporon infection

Endocarditis To cure Valve B IIu Reinhart AJM 1988 [218] replacement Keav RevInfectDis 1991 [84]

Martinez-Lacasa EJCMID 1991 [85]

Sidarous ClinCardiol 1994 [86]

Chaumentin CID 1996 [87]

De Almeida FrontMicrob 2016 [78]

Endophthalmitis To cure Vitrectomy B IIu Scofield-Kaplan OphRetina 2018 [219] and local Gonul ArcBrasOph 2015 [220] infusion of antifungal consultation.

SoR, strength of recommendation; QoE, quality of evidence

566 distribution. 567 Antifungal drug treatment public 568 Targeted treatment and salvage therapy 569 Evidence – Treatmentfor is diagnostic drivenother and should be instituted when G. candidum is isolated 570 from sterile body fluids or tissue specimens. However the data on selection of antifungals is 571 limited to in vitro data, case reportsfor and case series.[28, 30, 32, 34, 38, 43, 48] The 2014 ESCMID guideline 572 recommends an amphotericin B formulation with or without 5-flucytosine (SoR B QoE III) where 573 clinicalOnly responses have been noted (Table 9).[7] Since then, good treatment responses have also 574 been noted followingNot therapy with voriconazole.[28, 29, 32] Although MICs to the echinocandins 575 may be low, there is little experience with their use in Geotrichum infections, but they have a 576 favourable safety profile. Where an amphotericin B formulation is used, liposomal amphotericin 577 B has been employed successfully.[28, 32, 48] Conventional amphotericin B can be utilized if lipid 578 preparations are unavailable but their safety profile is expected to be worse.[221] There are no 579 data on salvage therapy where first line therapy has failed.

580

581 Table 9. Recommendations on targeted antifungal therapy for Geotrichum infections

Population Intention Intervention SoR QoE Reference Comment

Any To cure VRC 2 x 6 mg/kg on d1 B III Sfakianakis MedMycol N=1, diabetes mellitus 2007 [32] followed by 2 x 4 mg/kg/d Henrich TID 2009 [30] N=1, haematology

Meena JGlobInfectDis N=1, child [48]

Any To cure VRC 2 x 6 mg/kg on d1 B III Myint MMCR 2015 N=1, cured [29] followed by 2 x 4 mg/kg/d

and

L-AmB 3 mg/kg/day

followed by VRC (dose as above) alone consultation. Haematology To cure c-AmB 1 mg/kg/d B III Kassamali JCM 1987 N=1, formulation and (adults and [43] dose not stated or distribution. children) Ng JMedMalay 1994 N=1, c-AmB, 1 mg/kg/day L-AmB 3 mg/kg/d [38]

SoR, strength of recommendation; QoE,public quality of evidence; N, number of subjects investigated; c-AmB, conventional amphotericin B; L-AmB, liposomal amphotericin B;other VRC, voriconazole 582 for 583 Recommendations - Antifungalfor treatment is moderately supported with either a triazole, 584 preferably voriconazole, or an amphotericin B formulation with or without 5-flucytosine. 585 EchinocandinOnly use as initial therapy is also supported with moderate recommendation. In the 586 event of treatmentNot failure, the guideline recommends with moderate support the use an 587 antifungal agent of a different drug class, supported by susceptibility results. Figure 6 summarises 588 the treatment pathways for Geotrichum infections.

589 Figure 6. Treatment pathway for antifungal therapy and management of infections due to 590 Geotrichum candidum and Geotrichum species.

Suspected and confirmed infections due to Geotrichum spp. are emergencies and require rapid action

Timely, rapid antifungal therapy and managementis required for suspected and confirmed infections

Surgical resection of localised lesions

Amphotericin B Amphotericin B liposomal deoxycholate 3 mg/kg/d 1 mg/kg/d Voriconazole iv/po 2x6 mg/kg/d d1; 2x4 mg/kg/d from d2 ± Flucytosine iv/po consultation. 4x25 mg/kg/d

Response assessment distribution. (weekly, ≥ 14 days after last negative blood culture) public Progressive disease for other

Change the antifungal class (supportedfor by susceptibility results) Only Legend: Not strongly recommended gg moderately recommended gg marginally recommended gg recommended against gg

iv, intravenous; po, per os

591

592 Treatment duration

593 Evidence – Clinical cures have been reported with 3-4 weeks of amphotericin therapy,[38] 594 between 6 weeks to 6 months of monotherapy with voriconazole[29] and with sequential use of 595 liposomal amphotericin B (+/- 5-flucytosine) and voriconazole for beyond 10 weeks.[32] The 596 duration of intravitreal amphotericin B and intravitreal voriconazole (additional to systemic 597 voriconazole beyond 3 months duration) given to a patient with endophthalmitis was not stated. 598 Duration was 6 months for endocarditis[48] and 3-4 months for eye and soft tissue/skin infection.

599 Recommendation – Treatment duration is empirical and should be determined on a case-by-case 600 basis. This is guided by clinical response, site and extent of infection, and current and expected 601 future immune status. If end organ disease is present, the guideline moderately supports a longer 602 period of treatment in conjunction with surgical measures where relevant.

603

604 Antifungal therapy in children 605 The same principles of antifungal therapy and alsoconsultation. of surgical and other therapy as in adults 606 applies to the paediatric population, with similar duration of therapy.[29, 38] Dosing requirements 607 may differ however. These issues are common to treatmentdistribution. of all rare yeast infections in children 608 and are discussed later. 609 public 610 INFECTIONS CAUSED BY KODAMAEA OHMERIother 611 Taxonomy and epidemiologyfor 612 Kodamaea species are ascomycetefor yeasts of the family Saccharomycetaceae and clade Candida 613 mesenterica.[222, 223] The main human pathogen Kodamaea ohmeri (anamorph Candida 614 guilliermondiiOnly var. membranefaciens; previously Pichia ohmeri and Yamadazyma ohmeri)[224] is 615 found in a wide varietyNot of environments including leaves, fruit, brine and fermented foods.[223] 616 The clinical importance of other Kodamaea species (K. anthrophila, K. kakaduensis, K. laetipori 617 and K. nitidulidarum) is not known.

618

619 K. ohmeri is a rare cause of fungaemia but may also manifest as endocarditis, cellulitis and wound 620 infections, funguria, and peritonitis with or without fungemia; infections are described in adults,

621 children, neonates, both immunocompromised and immunocompetent.[50, 51, 118, 120, 123, 124, 126-128, 622 225-227] Fungemia, often associated with indwelling CVADs is the most common manifestation.[118, 623 132, 133] As for other rare yeasts, it may be misidentified by phenotypic methods as a species of 624 Candida or as another ascomycetous yeast.[118, 119]

625

626 There are few reports of K. ohmeri infections. Following the first clinical case of K. ohmeri 627 fungemia in a renal transplant patient,[228] subsequent cases mostly appear to be from Asia, the 628 Americas and Southern Europe (Figure 7).

629

630 Figure 7. Worldwide distribution of Kodamaea infections (reported cases between 2000 and 631 2019 per million population)

consultation. distribution. public other 632 for 633 Legend: Cases of Kodamaea-relatedfor infections reported in the medical literature between 2000 634 and 2019 were identified in a PubMed search on January 15, 2020 using the search string 635 (Kodamae*Only OR Kodameae OR Pichia ohmeri OR Candida ohmeri) that yielded 143 publications. 636 Hundred-thirty nineNot cases have been identified from 19 countries.[15, 49-52, 118-125, 127, 130-133, 225, 227, 637 229-251] The majority of cases were reported from China (N=47) and India (N=40), followed by 638 Taiwan (N=8), Spain, South Korea (each N=6), and Malaysia (N=5). Number of cases reported 639 between 2000 and 2019 are presented as cases per million population per country. The resident 640 population per country was obtained from www.worldometers.info.[47]

641

642 One case series from India reported 38 K. ohmeri fungaemia cases over one year and a smaller 643 study from South Korea involved nine patients. Clonality amongst isolates largely from a neonatal 644 ICU was suggested in the Indian study[118] whilst isolation of K. ohmeri from the hands of a 645 healthcare worker suggested a nosocomial outbreak in a surgical ward in the other series.[119] 646 The propensity for cases to occur in Asia is supported by a recent report where 26/190 (13.7%) 647 of noncandidal yeast isolates (systemic infections) were K. ohmeri[5] compared with none in a US 648 survey[17] and 1/14 (7%) rare yeast fungaemias in Spain.[15] The larger number of publications 649 after 2000 are likely due to wider availability of molecular diagnostic methods.[5, 18, 113, 118]

650

651 Adults with haematological malignancy and diabetes mellitus are particularly at risk but also 652 those in the intensive care unit (ICU)[118, 125, 126, 128, 240] and in the setting of HIV (oral infection),[252] 653 alcoholic liver disease[227] and corticosteroid or antibiotic receipt.[118] Neonates and preterm 654 infants are well represented in K. ohmeri fungaemia reports including case clusters.[127, 129, 130, 244] 655 Risk factors for paediatric fungaemia are underlying immunocompromise, indwelling CVADs, 656 prematurity, low birth weight, ICU admission andconsultation. prolonged hospital stay.[249] The crude 657 mortality for K. ohmeri infection from collective clinical experience was estimated at 31.8- 658 38%.[118] It is uncertain whether mortality is higher in immunocompromiseddistribution. patients compared 659 with other patient groups. 660 public 661 Diagnosis other 662 Imaging for 663 Evidence – For all adult and paediatricfor populations, imaging is helpful to establish involvement of 664 or dissemination to body sites including the heart and abdominal organs. K. ohmeri endocarditis 665 has Only been diagnosed using both transthoracic (TTE)[49-52] and TOE.[50] Embolic phenomena 666 including splenic Not infarcts and vascular emboli have been elucidated by abdominal CT[51] and 667 arterial angiography, respectively.[50]

668 Of endocarditis cases, echocardiography has identified vegetations of 20 mm involving a native 669 mitral valve, of 5 cm involving a mitral valve bioprosthesis, an 11 x 6.4 mm vegetation on the 670 tricuspid valve of a neonate and a 30 X 12mm vegetation on the aortic valve in an adult (Table 671 3).

672 Recommendations – In all patients, positive blood cultures provide the important clue to 673 diagnosis. Once Kodamaea infection is proven, imaging studies to determine the extent of 674 disease are recommended with moderate strength. However, there is strong support to perform 675 a TOE in patients with a strong suspicion of endocarditis, even prior to positive blood cultures 676 (Table 3) Follow up imaging is strongly recommended.

677

678 Histopathology

679 Evidence – In suspected K. ohmeri infection, as for all Geotrichum infections and subsequently 680 for rare yeast IFDs, histopathological examination of clinical specimens (using H&E, PAS or GMS) 681 including FFPE tissue sections can be useful, despite scarce data. There are no known K. ohmeri- 682 specific immunohistochemistry stains to assist diagnosis.

683 Recommendations – no specific recommendations are made; however, we strongly support the 684 examination of all tissue specimens for presence of fungal forms by direct microscopy using 685 standard fluorescent brighteners and histopathologicalconsultation. stains (Table 4). 686

687 Culture and microscopy distribution.

688 Evidence – Gram stain of blood cultures yields budding yeast forms and have provided the first 689 diagnostic clue in multiple case publicreports and series (Table 10). Direct microscopy identified yeasts 690 in urine in one report.[126] There are sparseother descriptions on the utility of microscopic methods on 691 other clinical specimensfor for presumptive diagnosis of K. ohmeri infections. 692 for 693 Table 10. Recommendations on microscopy and culture in Kodamaea ohmeri infections PopulationOnly Intention Intervention SoR QoE Reference Comment Any To diagnoseNot Direct microscopy A III Ni RevEspCardiol 2018 [52] N=1 Gram stain of blood Hitomi JHI 2002 [238] N=1 cultures Biswal JClinDiagnRes2015 [230] N=2

Kanno JIC 2017 [133] N=1

Han EJCMID 2004 [225] N=1

Otag Mycoses 2005 [129] N=1

Poojary IndPaed 2009 [244] N=1

Taj-Aldeen JMM 2006 [127] N=1

Vivas MMCR 2016 [249] N=1

Gram stain shows yeasts, often budding

Any To diagnose Direct microscopy B III Puerto EJCMID 2002 [126] N=1, documented Gram stain of urine urinary tract infection

Any To diagnose Direct microscopy C III No reference found Gram stain of specimens other than urine and blood cultures

Any To diagnose Culture A IIu Chakrabarti CMI 2014 [118] N=38, blood

All specimens Giacobino MedMycol 2016 [120] N=1, peritoneal fluid Xiao consultation.InfDrugRes 2018 [5] N=26, various sites, unspecified Fernandez-Ruizdistribution. MedMycol 2017 [15] N=1, blood Mahfouz Pathology 2008 [240] N=1, blood Fast growing flat, white colonies, roughpublic and ragged on SDA, characteristically radial. On CHROMagar, colonies turn from pink to blue within 48 hours. Grow at 25oC and at 35oC. Morphological studies shouldfor be performed usingother cornmeal Tween 80 agar and slide culture. Any To diagnose Culture A III Distasi JMM 2015 [125] N=1, blood

All specimensfor Al-Sweih MedMycol 2011 [130] N=1, blood Only Shaaban Mycopath 2010 [124] N=1, blood Not Taj-Aldeen JMM 2006 [127] N=1, blood Han EJCMID 2004 [225] N=2, blood, buttock wound

De Barros MedMycol 2009 [123] N=1, blood

Chiu IJAA 2010 [227] N=1, blood

Hitomi JHI 2002 [238] N=1, blood

Biswal JClinDiagnRes 2015 [230] N=2, blood

Ostronoff LeukLymph 2006 [243] N=1, blood

Shang JMicroImmInfect 2010 [132] N=2, blood

Poojary IndPaed 2009 [244] N=1, blood

Vivas MMCR 2016 [249] N=1, blood

Kanno JInfectChemother 2017 [133] N=1, blood

Santino Mycoses 2012 [128] N=2, sputum, oral mucosa

Yang IJID 2009 [131] N=1, blood

Otag Mycoses 2005 [129] N=2, blood

Reina SJIDs 2002 [51] N=1, blood, heart valve

Sundaram AnnPaedCard 2011 [49] N=1, blood

Joao HeartVess 2002 [50] N=1, blood, embolus, consultation.vegetation Ni RevEspCard 2018 [52] N=1, blood Puerto EJCMIDdistribution. 2002 [126] N=1, urine Fast growing flat, white colonies, rough and ragged on SDA, characteristically radial. On CHROMagar, colonies turn from pinkpublic to blue within 48 hours. Grow at 25oC and at 35oC. Morphological studies should be performed using cornmeal Tween 80 agar and slide culture. SoR, strength of recommendation;for QoE, quality ofother evidence; N, number of subjects investigated; SDA, Sabouraud Dextrose agar 694 for 695 Culture of blood and other specimens is essential and yields an isolate for species identification 696 and susceptibilityOnly testing. A positive culture from a sterile site in a consistent clinical scenario e.g. 697 sepsis, establishesNot a definite diagnosis whilst that from a nonsterile site including from the 698 oropharynx and sputum must be accompanied by clinical or radiological evidence of disease to 699 enable a diagnosis of probable infection. Colonies of K. ohmeri grow within 48 hours as flat, white 700 colonies which can be rough and ragged on SDA, and are characteristically radial.[113] On 701 CHROMagar™ Candida (CHROMagar, France) colonies turn from pink to blue within 48 hours, 702 and may be confused with Candida tropicalis (Figure 8). Colonies grow at 25oC and at 37oC where

703 K. ohmeri is the only Kodamaea species capable of growth at 37oC. Supplemental morphological 704 studies should be performed using cornmeal agar and slide culture. True hyphae are not present 705 but pseudohyphae are seen. Blastoconidia are present (see Table 10).

706

707 Figure 8. Blue grey – pink colonies of Kodomaea 708 ohmeri after subculture onto CHROMAgar™ 709 Candida, isolated from a tracheostomy site 710 (courtesy of Riina Richardson, 2019)

711

712

713

714 715 consultation. 716 717 Recommendations – Culture of specimens is strongly recommendeddistribution. for genus and species 718 identification, and for antifungal susceptibility testing as is incubation at 25°C and 37°C. Direct 719 microscopy using Gram stain ofpublic blood cultures is strongly recommended but using fluorescent 720 brighteners or KOH mounts on clinical specimens, weakly recommended as there are no data. 721 for other 722 Susceptibility testing

723 Evidence –Both EUCAST and CLSIfor methodologies recommend 24 hours incubation time prior to 724 reading of MICs.[114, 115] There is only one study comparing MICs obtained by EUCAST with those

Only [15] 725 observed by CLSI methodologiesNot on single K. ohmeri isolate; the EUCAST method gave up to 726 10-fold higher MICs. Other methods including the CLSI M44-S3 disk diffusion method[253] and the 727 E-test (bioMerieux), CLSI-based Sensititre (Thermofisher), ATB Fungus (bioMerieux) and Yeast- 728 like fungi FP Eiken (Eiken Chemical Co. Ltd., Tokyo, Japan) methods have also been used in 729 assessing the antifungal susceptibilities of K. ohmeri (Table 6). However, no comparative 730 evaluation of commercial systems has been performed against reference methods although one

731 study utilized the E-test and Sensititre (Thermofisher), which gave similar MICs for seven 732 antifungal agents.[122] Neither CBPs or ECVs have been defined for K. ohmeri and classification of 733 isolates as susceptible or resistant, or WT or NWT, should not be made.

734

735 Fluconazole MICs (range 2-64 mg/L) are higher than those of voriconazole (0.03-8 mg/L) or

736 posaconazole (0.06-4 mg/L) whilst the MIC90 to itraconazole for 38 isolates in one study was 0.50 737 mg/L.[118] Susceptibility results by the CLSI M44-S3 disk diffusion for 26 isolates showed all were 738 voriconazole-‘susceptible’ though only 38.5% were fluconazole-susceptible.[253] The MIC for 739 isavuconazole for one isolate was 0.06 mg/L.[128] Echinocandin MICs appear to be generally low[15, 740 118, 119, 121, 125] although high MICs for caspofungin (4->16 mg/L) have been reported by all of 741 EUCAST, CLSI and commercial methods.[18, 122, 125] MICs for amphotericin B range from 0.03-1 742 mg/L.

743 As MICs may be strain dependent, susceptibility testing of all clinically significant Kodamaea 744 isolates is advised. There are no data on antifungal combinationsconsultation. against these fungi. 745 746 Recommendations – The use of reference broth microdilutiondistribution. methods inclusive of the CLSI- 747 based Sensititre method (Thermofisher) for antifungal susceptibility testing to guide treatment 748 of K. ohmeri infections is moderately supported and is clinically useful in cases of treatment 749 failure. We strongly recommendpublic the use of these methods to establish epidemiological 750 knowledge. The use of E-test, Vitek 2 AST-YS07other and ATB Fungus (all bioMerieux) methods are 751 supported with marginalfor strength only. 752 for 753 Molecular methods for direct detection

754 EvidenceOnly – Most evidence is indirect from studies that address the detection of fungi from clinical 755 specimens other thanNot blood by panfungal PCR assays (targeting the ITS, 28S or 18S rDNA), which 756 include very small numbers of Kodamaea identifications (see the discussion in the Geotrichum 757 section for specificity and sensitivity studies). Ongoing efforts to standardise PCR procedures 758 using simulated tissue specimens by ISHAM are recognised.

759

760 Recommendation – The use of molecular methods on fresh clinical material and FFPE sections for 761 the diagnosis of K. ohmeri infection is moderately supported even though there are no data, 762 (Table 4) especially where fungal hyphae are visualized. There is only weak recommendation for 763 use of molecular methods to detect K. ohmeri in blood cultures as there are no data to support 764 this.

765

766 Species identification

767 Evidence – Identification to the species level is essential for epidemiological studies, for case 768 clusters which may be healthcare associated[5, 118, 119, 129] and for extending clinical appreciation 769 of disease. However, there are no data to indicate that identification of a Kodamaea pathogen 770 to species level could guide the choice of the antifungal treatment.

771

772 Colonial and microscopic characteristics (see Culture and Microscopy also) of K. ohmeri are 773 summarised in Table 11. These yeasts are germ tubeconsultation. negative, do not have hyphae and do not 774 form ascopsores.[113] K. ohmeri is urease-negative distinguishing it from Trichosporon spp. K. 775 ohmeri has been identified to species using the API 20C AUX,distribution. ATB ID 32C and Vitek 2 ID-YST 776 systems (all bioMerieux) in small numbers of patients in multiple studies and in epidemiological 777 studies.[18, 121] public 778 other 779 Table 11. Recommendationsfor on genus and species identification of Kodamaea ohmeri Population Intention Interventionfor SoR QoE Reference Comment Phenotypic identification

Any To identify to Carbon B III Distari JMycolMed N=1 Onlyspecies level for (carbohydrate) 2015 [125] diagnosisNot assimilation and Sundaram N=1 urease testing) AnnPaedCardiol 2011 [49]

Joao HeartVess 2002 N=1 [50]

Hitomi I HospInfect N=1 2002 [238]

Kanno N=1 JInfectChemother 2017 [133]

Vivas MMCR 2016 N=1 [249]

Ostronoff LeukLymph N=1 2006 [243]

Otag Mycoses 2005 N=2 [129]

Han EJCMID 2004 N=2 [225]

Biswal J ClinDiagnRes N=2 2015 [230]

consultation.Santino Mycoses N=2 2013 [128] distribution.Poojary IndPaed 2009 N=1 [244]

Shaaban N=1 public Mycopathologia 2010 other [124] for Al-Sweih MedMycol N=1 for 2011 [130] Taj-Aldeen JMM 2006 N=1 [127]

Only De Barros MedMycol N=1 Not 2009 [123]

Ni RevEspCard [52] N=1

Puerto EJCMID 2002 N=1 [126]

Preliminary identification is possible by CHROMagar (Urease-negative; Vitek 2 ID-YST, API 20C AUX, ATB ID32 C (all BioMerieux) allow identification. Many case reports used two systems.

Any To identify to Carbon B IIu Yamamoto BMCID N=1, ATB ID 32C species level and (carbohydrate) 2013 [121] for assimilation and Lee JCM 2007 [119] N=, 6(API 20C and Vitek epidemiological urease testing 2 ID-YST study Bretagne JAC 2017 N=3, ID 32C [18]

MALDI-TOF MS

Any To identify to MALDI-TOF MS B IIu Eddouzi MedMycol N=2, Bruker system, species level with Bruker 2013 [122] neither identified, system, Bruker Bruker database database Fraser MedMycol N=5, Bruker system, 2016 [208] 100% correctly identified,

consultation.Bruker database

Full extraction required

distribution.Kanno JIC 2017 [133] N=1, Bruker system, correct identification, public Bruker database MALDI-TOF MS B IIu Ghosh CMI 2015 N=5, Bruker system, with Bruker other [237] 100% correct forsystem, in- identification but in- hoese database house database for required

MALDI-TOF MS B IIu Westblade JCM 2013 N=11, Vitek MS, 91% Only with Vitek MS, [211] correct identification, NotVitek database Vitek data base Distasi JMM 2015 N=1, Vitek MS, correct [125] identification, Vitek database

Molecular Identification

Any To identify To supplement A IIu Ghosh CMI 2015 N=5, ITS2, D1/D2 28S species or confirm [237] rRNA gene Molecular MALDI TOF MS identification superior species to MALDI-TOF MS identification Westblade JCM 2013 N=11, D2 28S rRNA gene [211] Molecular identification confirmed MALDI-TOF MS identification

Fraser MedMycol N=5, pyrosequencing 2016 [208] ITS2, Molecular identification confirmed MALDI-TOF MS identification

Any To identify ITS and D1/D2 A III De Barros MedMycol N=1 (bloodstream) species, to sequencing 2009 [123] diagnose Al-Sweih MedMycol N=1 (bloodstream) consultation.2011 [130]

5.8 S A III Taj-Aldeen JMM 2006 N=1 (bloodstream) sequencing distribution.[127]

Poojary Ind Paed N=1 (bloodstream) public 2009 [244] 18S and ITS A III Shaaban N=1 (bloodstream) sequencing other Mycopathologia 2010 for [124] for Yang IJID 2009 [131] N=1 (bloodstream) 28S rRNA A III Santino Mycoses N=2 (sputum, oral Only 2012 [128] mucosa) Any To identifyNot to ITS sequencing A IIu Fernandez-Ruiz N=1 (bloodstream) species and MedMycol 2017 [15] establish Bretagne JAC 2017 N=3 (bloodstream) epidemiologic [18] knowledge Xiao InfDrugRes 2018 N=26 (bloodstream) [5]

ITS and D1/D2 A IIu Lee JCM 2007 [119] N=6 (bloodstream) 28S rRNA Giacobino MedMycol N=1 (peritoneal fluid) sequencing 2016 [120]

Chakrabarti CMI 2013 N=38 (bloodstream) [118]

SoR, strength of recommendation; QoE, quality of evidence; N, number of isolates investigated; ITS, internal transcribed spacer; MALDI-TOF, matrix assisted laser desorption ionisation time of flight; MS, mass spectrometry; SDA

780

781 Only small numbers of K. ohmeri isolates have been analysed by MALDI-TOF MS and more data 782 are needed to validate this approach for species identification. Both major commercial databases 783 identify strains but there remains a relative under-representation of Kodamaea spectra in these 784 databases.

785

786 In the largest study, the Vitek MS system (bioMerieux) correctly identified 10/11 (91%) isolates 787 to species.[211] The Bruker system (Bruker Daltoniks)consultation. also has been shown to have utility noting 788 full protein extraction was needed for log scores >2.00.[210] An Indian study of 5 isolates found 789 that construction of an in-house database was required as thedistribution. K. ohmeri spectra obtained in their 790 series were novel.[237]

791 public 792 As for Geotrichum species, the gold standardother species identification method and the principles 793 thereof, of K. ohmerifor is sequence analysis of the ITS +/- 28S rRNA gene regions;[213] accurate 794 identification of K. ohmeri hasfor been achieved in multiple case reports (Table 11), in 795 epidemiological studies[18, 118, 119] and to confirm MALDI TOF MS identifications.[208, 211, 237] Data 796 are limitedOnly by small numbers of isolates studied. Molecular identification performs better than 797 morphological approachesNot and has been used for primary diagnosis and to benchmark accuracy 798 of other tests.

799

800 Recommendation – Identification to the species level is strongly supported for epidemiological 801 understanding. Guiding treatment by identification to the genus level is supported with 802 moderate strength. Morphological identification can identify K. ohmeri but molecular

803 identification by ITS sequencing is strongly supported and preferred over morphology. MALDI- 804 TOF MS identification is moderately supported with a need for more extensive testing against 805 commercial databases.

806

807 Diagnostic pathways

808 Figure 9 shows the recommended diagnostic pathway. Culture-based techniques remain central 809 to the diagnosis of K. ohmeri infections and blood cultures are essential to detect fungaemia. As 810 for other genera of rare yeasts, species identification by molecular methods are the current gold 811 standard.

812

consultation. distribution. public for other for Only Not

813 Figure 9. Diagnostic pathway for suspected cases of systemic infections due to Kodamaea 814 ohmeri

Suspected and confirmed infections due to Kodamaea spp. are emergencies and require rapid action

Timely, rapid antifungal therapy and management is required for suspected and confirmed infections

Surgical valve replacement

Amphotericin B Amphotericin B Caspofungin Micafungin Fluconazole iv/po liposomal deoxycholate 70 mg/d d1; 100 mg/d 400 mg/d 3 mg/kg/d 1 mg/kg/d 50 mg/d from d2

Removal of CVAD

Response assessment (weekly, ≥ 14 days after last negative blood culture) Progressive diseaseconsultation. Change the antifungal class (supported by susceptibility results)

Legend: distribution. strongly recommended gg moderately recommended gg marginally recommended gg recommended against gg

CVAD, central vascular access device; iv, intravenous; po, per os 815 public 816 other 817 Treatment approachesfor to Kodamaea infections 818 Surgical treatment for 819 Evidence – There are sparse data for indications for a surgical approach for Kodamaea infections. 820 However,Only if endocarditis is present, then valve replacement has been reported to be associated 821 with better outcomes.Not Of five cases, all four patients that underwent aortic or mitral valve 822 replacement recovered from infection.[50-52, 214] In one patient with a popliteal artery embolus, 823 successful embolectomy was undertaken.[50]

824

825 Recommendations – The guideline strongly supports early vegetectomy and valve replacement 826 where there is evidence of endocarditis. Removal of embolic lesions is also strongly supported 827 where feasible (Table 8).

828

829 Antifungal drug treatment

830 Targeted treatment and salvage therapy

831 Evidence – Data regarding the treatment of Kodamaea infections are few. Treatment is driven 832 upon isolation of K. ohmeri from blood cultures, or other sterile body fluids and tissue. Data on 833 selection of antifungals are limited to in vitro data, predominantly based on sporadic case reports 834 in the adult and paediatric literature (Table 12).[123-125, 127, 131, 133, 227] Based on largely case reports, 835 the 2014 ESCMID guideline for management of rare yeast infections had moderately 836 recommended an amphotericin B formulation as a first line agent with echinocandins as 837 promising alternate candidates.[7] Since then, good treatment responses have also been 838 observed following therapy with either voriconazole,consultation. caspofungin, micafungin, lipid 839 amphotericin B formulations, deoxycholate amphotericin B and micafungin (Table 12). There are 840 insufficient data to recommend one antifungal over another.distribution. Where an amphotericin B 841 formulation is used, liposomal amphotericin B and amphotericin B lipid complex have been 842 employed successfully.[50, 51, 123, 243] Experience with echinocandins is growing although efficacy 843 data are few.[118, 124, 133] Regardingpublic second line treatment, after the failure of a frontline approach, 844 azole and amphotericin B compoundsother are preferred over the echinocandins with weak 845 recommendation.[118]for Figure 10 summaries the treatment pathway if all drug options are 846 available. for 847 848 TableOnly 12. Recommendations on targeted antifungal therapy for Kodamaea ohmeri infections Population IntentionNot Intervention SoR QoE Reference Comment

Neonates To cure c-AmB 0.5-1.5 mg/kg/d B III Al-Sweih MedMycol 2011 N=1, pre-term, fungaemia, [130] cured

Biswal JClinDiagnRes 2015 N=1, term, fungaemia, cured [230]

Vivas MMCR 2016 [249] N=1, fungaemia, cured

c-AmB 1 mg/kg/d B III Taj-Aldeen JMM 2006 [127] N=1, fungaemia, cured

followed by

L-AmB 3 mg/kg/d

Paediatrics To cure L-AmB 3 mg/kg/d B III De Barros MedMycol 2009 N=1, fungaemia, cured [123]

Paediatrics To cure FLU 400 mg/d B III Han EJCMID 2004 [225] N=1, fungaemia, cured

Otag Mycoses 2005 [129] N=1, fungaemia

Paediatrics To cure c-AmB 1 mg/kg/d B III Otag Mycoses 2005 [129] N=1, fungaemia, cured

Adults To cure FLU 400 mg/d B IIu Chakrabarti CMI 2013 [118] N=23, fungaemia, 15 cured

To define Lee JCM 2007 [119] N=1, fungaemia, died epidemiol ogy

Adults To cure CAS 70 mg day 1 B IIu Chakrabarti CMI 2013 [118] N=4, fungaemia, 4 cured followed by 50 mg/d To define consultation. epidemiol ogy distribution. Adults To cure c-AmB 1 mg/kg/d B IIu Lee JCM 2007 [119] N=3, fungaemia, 1 cured To define public epidemiol ogy other Adults To cure c-AmBfor 1 mg/kg/d B IIIu Yang IJID 2009 [131] N=1, cured for Chiu IJAA 2010 [227] N=1, cured Adults To cure c-AmB 1 mg/kg/d B IIIu Reina SJID 2002 [51] N=1, endocarditis, cured after L-AMB Only followed by NotL-AmB 3 mg/kg/d

Adults To cure L-AmB 3 mg/kg/day B IIIu Ostronoff LeukLymph 2006 N=1, cured [243]

Adults To cure L-AmB 3 mg/kg/d B III Joao HeartVess 2002 [50] N=1, fungaemia and endocarditis, and arterial and embolism, cured 5-FC 4 x 25 mg/kg/d

Adults To cure VRC 2 x 6 mg/kg on d1 B III Ni RevEspCard 2018 [52] N=1, cured

followed by 2 x 4 mg/kg/d

Adults To cure FLU 400 mg/d B III Puerto EJCMID 2002 [126] N=1, UTI cured

Adults To cure MICA 100 mg/d B III Kanno JInfectChemother N=1, cured 2017 [133]

Shaaban Mycopathologia N=1, cured 2010 [124]

SoR, strength of recommendation; QoE, quality of evidence; N, number of subjects investigated; 5-FC, 5-flucytosine; c- AmB, conventional amphotericin B; CAS, caspofungin; FLU, fluconazole; L-AmB, liposomal amphotericin B; MICA, micafungin; UTI, urinary tract infection; VRC, voriconazole 849 consultation. distribution. public for other for Only Not

850 Figure 10. Treatment pathway for antifungal therapy and management of infections due to 851 Kodamaea ohmeri

Suspected and confirmed infections due to Kodamaea spp. are emergencies and require rapid action

Timely, rapid antifungal therapy and management is required for suspected and confirmed infections

Surgical valve replacement

Amphotericin B Amphotericin B Caspofungin Micafungin Fluconazole iv/po liposomal deoxycholate 70 mg/d d1; 100 mg/d 400 mg/d 3 mg/kg/d 1 mg/kg/d 50 mg/d from d2

Removal of CVAD

Response assessment (weekly, ≥ 14 days after last negative blood culture)

Progressive disease

Change the antifungal classconsultation. (supported by susceptibility results)

Legend: strongly recommended gg moderately recommended gg distribution. marginally recommended gg recommended against gg

CVAD, central vascular access device; iv, intravenous; po, per os 852 public 853 other 854 Recommendations - Diagnostic-drivenfor antifungal treatment is strongly supported with moderate 855 support for use of either an amphotericin B formulation or a triazole. In the event of failure of 856 first line therapy, the guideline forrecommends with moderate support the use an antifungal agent 857 of a differentOnly drug class, supported by in vitro susceptibility results. 858 Not 859 Other treatments: growth factors and removal of medical devices

860 Evidence – Because the majority of patients with K. ohmeri infections are either 861 immunocompromised with hematological malignancy and neutropenia, and who are very young 862 or elderly the question of white cell support has been asked.[254] However, the indication to use 863 of granulocyte growth factors (i.e. G-CSF) or granulocyte transfusions is not supported by data.[15]

864 It is reported that the removal of all implanted medical devices with particular attention to CVADs 865 be undertaken. Amongst 30 adults and children with Kodamaea infection with an intravenous 866 catheter or vascular implant in situ, removal of the catheter was often successful in resolving 867 infection but some patients died.[133] Hence device removal is indicated but may not always be 868 associated with cure of infection.

869 Recommendations – There are weak recommendations for the use of growth factors in subset of 870 patients who may be neutropenic or in haematological malignancy. Removal of CVADs is 871 supported with moderate recommendation.

872

873 Treatment duration

874 Evidence – Clinical cures have been reported with 2-3 weeks of antifungal therapy although one 875 study reported cure using conventional amphotericin B for 7 days.[131] Of patients with 876 endocarditis who survived, one received 8 weeks total therapy with liposomal amphotericin B 877 and 5-flucytosine, another received amphotericin consultation. B lipid complex for 21 days then lifelong 878 fluconazole suppressive therapy. Duration of therapy should be decided by clinical response, site 879 and extent of disease, and current and expected future immunedistribution. status. 880 881 Recommendation – Treatment durationpublic should be individualised and depends, on the extent of 882 infection, the organs involved, and ongoing immunosuppression. Treatment duration is empirical 883 but has averaged 2-3 weeks. If endocarditisother is present, the guideline moderately supports a longer 884 period of treatment infor conjunction with strong support for surgical measures.

885 for 886 INFECTIONSOnly DUE TO MALASSEZIA SPP. 887 Taxonomy and epidemiologyNot 888 The genus Malassezia includes lipid-dependent basidiomycetous yeasts (except for Malassezia 889 pachydermatis which is not lipid-dependent) in the sub-phylum Ustilaginomycotina, class 890 Exobasidiomycetes, order Malasseziales and family Malasseziaceae, and currently comprises 17 891 recognised species, grouped into four clusters.[255-258] Malassezia are stable, dominant 892 components of the human skin microbiome through both culture-based and culture-

893 independent methods, and have also been identified from other human body sites (including 894 mucosal surfaces), skin of warm-blooded animals and from the environment. Many species have 895 been implicated in skin conditions. However, two species are most commonly described to cause 896 IFD in immunocompromised hosts: Malassezia furfur (cluster A) and Malassezia pachydermatis 897 (cluster B2);[257, 258] Malassezia restricta has caused splenic lesions in a child with neutropenia.[54] 898 Malassezia sympodialis has caused a case of post-appendectomy fungaemia in child on long-term 899 inhaled corticosteroids for asthma and post-gastrectomy CVAD-associated fungaemia in an 900 elderly man.[259, 260] The distribution of systemic Malassezia infections is shown in Figure 11.

901

902 Figure 11. Worldwide distribution of Malassezia infections (reported cases between 2000 and 903 2019 per million population)

904 consultation. distribution. public for other 905

906 Legend: Cases of Malassezia-relatedfor infections n the medical literature between 2000 and 2019 907 wereOnly identified in a PubMed search on January 15, 2020 using the search string ((Malassezia OR 908 Pityrosporum) ANDNot (case [Title/Abstract] OR patient OR report [Title/Abstract] OR infection OR 909 invasive OR systemic OR fungemia OR blood)) that yieled 881 publications. Sixty-six cases have 910 been identified from 17 countries.[16, 17, 53, 54, 138, 259-283] Most cases were reported from Italy 911 (N=19), the United States of America (N=17), Taiwan (N=6), and Japan (N=4). Number of cases 912 reported between 2000 and 2019 are presented as cases per million population per country. The 913 resident population per country was obtained from www.worldometers.info.[47]

914 M. furfur forms biofilms, can colonise devices such as CVADs and also causes infections during 915 continuous ambulatory peritoneal dialysis.[284, 285] Colonisation of skin and CVADs among babies 916 in hospital neonatal units is common where risk factors include prematurity (gestational age <26 917 weeks), increased length of stay in the unit, hyaline membrane disease, long duration of 918 mechanical ventilation, long duration of antimicrobial therapy, and a CVAD in situ where 919 outbreaks have been reported.[286-291] Colonisation of CVADs may be less common among adults 920 receiving parenteral nutrition.[288] Parenteral nutrition and intravenous lipids are important risk 921 factors[290, 292] but not always present.[293] Molecular investigations of outbreaks of fungaemia 922 can be useful: one investigation identified the source of an M. pachydermatis neonatal unit 923 outbreak to be healthcare workers’ pet dogs.[291] Malassezia can also persist on incubator 924 surfaces for months despite standard cleaning.[294] Multiple genotypes can colonise the same 925 neonate where in one outbreak, withdrawal of a lipid-rich staff hand cream was effective in 926 halting the outbreak.[295]

927

928 There is a low prevalence of Malassezia infection consultation.among cases of yeast fungaemia, but with 929 publication bias with more reports from developed countries. Only one Malassezia was cultured 930 from 2984 blood cultures positive for Candida and non-distribution.Candida yeasts (N=94) at one US 931 centre.[17] In a multicentre fungaemia surveillance programme in Asia, Malassezia was cultured 932 from 4/2155 (0.1%) episodes.[16]public The prevalence is probably under-estimated because surveys 933 involved patients with culture-confirmed fungaemia and M. furfur in particular has special 934 growth requirements (see later). An increaseother in M. furfur CVAD colonisation or fungaemia was 935 seen in a neonatal ICUfor over several years; the authors hypothesised a temporal association with 936 use of fluconazole prophylaxis.[296]for 937

938 Only Diagnosis Not 939 It is important to consider Malassezia as a potential pathogen in high-risk patients so that the 940 laboratory can be informed to inoculate clinical specimens onto special lipid-containing media. 941 Microscopy and culture by skilled personnel remain the mainstay of diagnosis although MALDI- 942 TOF MS and molecular techniques are increasingly used for organism identification. Figure 12 943 shows the recommended diagnostic pathway of this guideline.

944 Figure 12. Diagnostic pathway for suspected cases of systemic Malassezia infections

consultation. distribution.

945 946 Imaging public 947 Evidence – Dissemination of Malasezzia fromother blood to other sites (e.g. heart, spleen, brain, lungs) 948 has been described occasionally.for [53, 293, 297, 298] In one premature neonate, skin purpura and black- 949 discoloured toes complicated M. furfur fungaemia; cardiac echocardiogram revealed no valve 950 vegetations/thrombi and the lesionsfor resolved with amphotericin B and removal of a CVAD.[299] In 951 an adult with CVAD-associated fungaemia, TTE revealed a septic thrombus extending from the

Only [53] 952 superior vena cavaNot into the right atrium. Splenic lesions of M. restricta have been visualised 953 on abdominal CT scan in a neutropenia child,[54] and skull base osteomyelitis (M. sympodialis) 954 demonstrated on cerebral CT scan.[300]

955

956 Recommendation – There is insufficient evidence to routinely recommend imaging for every case 957 of Malassezia fungaemia. However, imaging of the heart and great vessels, lungs and abdominal

958 organs is moderately supported to establish or exclude a nidus of infection if the patient does 959 not respond clinically, or where the patient does not have a CVAD in situ, or if blood cultures 960 remain positive despite CVAD removal and antifungal treatment (Table 3). In localised infection, 961 imaging of the affected site is recommended as clinically indicated.[300]

962

963 Histopathology

964 Evidence – Deep-seated Malassezia infections have rarely been reported and histological 965 findings, rarely described (Table 4). In a paediatric case report of M. restricta disseminated 966 infection, histological examination of the spleen revealed pseudohyphae and yeast forms by H&E 967 and GMS staining with associated granulomas, lymphocytes, and neutrophils.[54] In a case of M. 968 sympodialis infection, histological examination of nasopharyneal tissue revealed budding yeast 969 cells.[300]

970 Recommendation – No specific recommendations are made; however, the examination of all 971 tissue specimens for presence of fungal pseudo-hyphaeconsultation. and yeast forms by direct microscopy 972 and standard histopathological stains where an IFD is in the differential diagnosis is strongly 973 supported (see Geotrichum section). The examination of distribution. sites suspected to be affected as a 974 complication of fungaemia is moderately supported (Table 4). 975 public 976 Culture and microscopy other 977 Blood cultures, CVAD fortips 978 Evidence – Direct microscopy of blood cultures has good utility for rapid presumptive diagnosis 979 of Malassezia fungaemia. Monopolar,for broad base budding yeast-like cells may be seen on Gram 980 stain. “Blind” Gram stains may be necessary depending on the automated blood culture system 981 used.Only Standard BacT/Alert (bioMerieux) procedures have not detected M. furfur fungaemia 982 indicating the needNot to supplement blood culture media with lipids. Indeed, failure to detect M. 983 furfur in blood cultures has also been documented with the BACTEC (BD) blood culture 984 system.[301, 302]

985 There are sparse data on the use of fluorescent brighteners.

986

987 In one study, blood was collected from 492 neonates and inoculated into either Isolator 988 (Wampole Laboratories, Cranbury, NJ) or BacT/Alert (bioMerieux) culture bottles; CVAD tips 989 were collected from all.[301] Blood culture aliquots were inoculated onto Dixon’s agar for both 990 culturing systems (immediately for Isolator system and on a positive ’flag’ for the BacT/Alert 991 system), and CVAD tips rolled onto Dixon’s agar. Fifteen M. furfur fungaemias were detected. In 992 the group who had Isolator (Wampole Laboratories) blood cultures, 6 cases were detected by 993 both this system and the CVAD culture method. In the BacT/Alert group, nine cases were 994 detected only by CVAD culture (in 1 case, immediate inoculation on Dixon’s agar yielded a 995 positive culture).

996

997 Clinical specimens are most often inoculated onto SDA (Figure 13) with olive oil overlay or 998 alternatively, a specialised medium such as modified Leeming and Notham or modified Dixon 999 agars.[303] CHROMagar™ Malassezia medium also enables primary isolation and differentiation 1000 of common Malassezia species. Plates are incubated at 35-37oC for up to 1 week, with most 1001 Malassezia isolates detected after 2-4 days. consultation. 1002 distribution. 1003 Figure 13. Malassezia furfur colonies, cultured 1004 on Sabouraud dextrose agar with an olive oil public1005 overlay, after 72 hours of incubation at 30oC 1006other (authors’ own photograph). for 1007 for 1008 1009

1010 RecommendationOnly – Culture of both blood and CVAD tips is strongly recommended for all patient 1011 groups (Table 13Not), and is essential for diagnosis of fungaemia, and to yield an isolate for 1012 susceptibility testing. The laboratory should be notified that a Malassezia infection is suspected 1013 so that appropriate culture methods can be set up. Microscopy of blood drawn from CAVD or 1014 their tips is often diagnostic and is strongly recommended (Table 13).

1015 Table 13. Recommendations on microscopy and culture in Malassezia spp.infections

Population Intention Intervention SoR QoE Reference Comment

Any To diagnose Direct microscopy Gram stain on A IIu Iatta MedMycol 2018 N=7 (Malassezia furfur blood cultures (including those [301] and Malassezia collected through CVAD) pachydermatis)

Any To diagnose Culture A IIu Iatta MedMycol 2018 N=15 (M. furfur and M. [301] pachydermatis) Blood, CVAD tip

Culture is recommended for species identification and susceptibility testing.

Colonies of Malassezia grow within 48-72 hours as cream-colored to yellow smooth and glistening colonies which can become dull and wrinkled with age. Agars containing lipid supplementation are required. Oval-globose budding yeasts with short hyphal forms on microscopy. From culture, budding yests more often seen (but without hyphal forms) about the the same size as Candida spp.

SoR, strength of recommendation; QoE, quality of evidence; N, number of subjects investigated; CVAD, central venous access device

1016 1017 Susceptibility testing consultation. 1018 Evidence – These yeasts exhibit poor growth in standard RPMI medium and hence MICs in 1019 published studies are derived using non-standardised methods.distribution. Tentative ECVs have been 1020 proposed for M. furfur and M. pachydermatis based on a modified CLSI broth microdilution 1021 method.[135] In general, M. furfur appears to be less susceptible to the main antifungal classes 1022 than M. pachydermatis.[6, 257, 258]public In two studies of bloodstream M. furfur isolates, very wide MIC 1023 ranges for amphotericin B, fluconazole andother extended-spectrum triazoles were reported.[135, 138] 1024 High echinocandin andfor 5-flucytosine MICs are reported in general Table 6).[304] 1025 Recommendation – At this point,for routine susceptibility testing to guide treatment is only weakly 1026 recommended. However, susceptibility testing to establish epidemiological knowledge is 1027 moderatelyOnly supported. 1028 Not

1029 Molecular methods for direct detection

1030 Evidence – There is limited evidence for molecular detection of Malassezia directly from clinical 1031 specimens in systemic infection (Table 4). However, PCR assays have enabled detection of 1032 Malassezia from skin specimens (patients with pityriasis versicolor or seborrheic dermatitis[305-

1033 307] or colonised neonates.[308] In one study of 50 skin scrapings, a ITS/5,8S rDNA-directed 1034 multiplex PCR detected Malassezia in all samples; the assay was able to detect and identify 11 1035 species of Malassezia.[307] Using a 18S rRNA PCR assay Malassezia was detected in the blood of 1036 only one of four critically ill neonates/children with Malassezia fungaemia.[90]

1037

1038 Recommendation – There is insufficient evidence to recommend molecular testing of blood for 1039 direct detection of Malassezia (Table 4). As for other rare yeast infections, panfungal PCR assays 1040 followed by DNA sequencing can be expected to have good specificity (approaching 100%) and 1041 sensitivity that is highest when hyphae are visualized in fresh tissue specimens.[204-206] Multiplex 1042 PCR assays for direct detection are moderately supported.

1043

1044 Species identification

1045 Phenotypic methods

1046 Evidence – M. furfur and M. sympodialis are obligatelyconsultation. lipid-dependent while lipids stimulate the 1047 growth of M. pachydermatis but are not absolutely required for growth.[309] M. pachydermatis 1048 may therefore grow as tiny colonies after 2-3 days on SDAdistribution. but an increased incubation time of 1049 up to 10-15 days is recommended.[255] In resource-limited settings, fatty acid-containing olive oil 1050 can be added to the surface ofpublic SDA (less costly than specialised media). Typically, colonies are 1051 cream-coloured, smooth and glistening and become dull and wrinkled with age (Table 14). 1052 Colonies of M. furfur are large, pale pink otherand wrinkled producing no precipitate on CHROMagar 1053 Malassezia medium (CHROMagar).for [303] Microscopically, budding yeast cells are oval-globose. The 1054 common Malassezia species arefor urease-positive on Christensen’s urea slopes within 24 hours 1055 and can be identified to species level with simple biochemical tests as well as growth 1056 characteristicsOnly at 40 oC, and on various Tween-containing media.[113, 309] Malassezia may not grow 1057 or may be misidentifiedNot by commercial identification systems such as API 20C AUX, Vitek 2 YST- 1058 ID (both bioMerieux) and Auxacolor (Bio-Rad).[310]

1059

1060 Table 14. Recommendations on genus and species identification of Malassezia species.

Population Intention Intervention SoR QoE Reference Comment

Phenotypic identification

High-risk Identify Use of specialised A IIu Velegraki PloS To ensure organism will patients with Malassezia as a culture media e.g. add Pathog 2015 [311] grow to enable genus and suspected cause of sepsis oil to SDA plates species identification invasive disease

All To identify to Morphology, carbon B IIu Kaneko JCM 2007 N=43, 9 species. species level for (carbohydrate) [303] Combination of colony epidemiology assimilation, and other colour and morphology biochemical tests, (size, precipitates) on CHROMagar Malassezia CHROMagar Malassezia, utilization of Tween and esculin compounds (Tween- consultation.esculin slants), urease and catalase testing and growth at 40oC separated major distribution.Malassezia species correctly All To identify to Morphology, carbon B IIu Cafarchia Review. Combination of species level and (carbohydrate)public MolCellProb 2011 morphology, differential for assimilation tests, [309] growth on SDA, Cremophor epidemiology CHROMagar Malasseziaother EL, utilization of Tween, fordifferential growth tryptophan, urease and catalase testing separated for Malassezia 14 species MALDI-TOF MS

Any Only To identify to MALDI-TOF MS B IIu Kolecka BrJDermatol N=500; Bruker system species level identification 2014 [312] Not In house library built and then validated against test set. 14 species. All identified

Denis JCM 2016 N=40, Bruker, in house [313] library created first, 6 species

All correct identification (log score >2.00)

Molecular Identification

Any Species ITS sequencing A IIu Kaneko JCM 2007 N=43, 10 species identification as [303] a benchmark for phenotypic tests

Species 28S rRNA-based PCR- B IIu Guillot N=55, 7 species identification for REA LettApplMicrobiol distinguished epidemiology 2000 [314]

Mirhendi JMM 2005 N=13, 11 species [315] distinguished Review of Multiple PCR-based B consultation. IIu Cafarchia Methods include AFLP, tFLP, identification methods +/- DNA MolCellProbes 2011 PCR-REA, PCR-SSCP . methods, ID and sequencing [309] Subject to availbility and genotyping distribution.access directed at the ITS, 28S rRNA, chitin synthase-2 genepublic and RNA polymerase-1 gene

Species ITS-directed otherB IIu Kim Ann ermatol N=11, 11 species, N=83 identificationfor for PCR/pyrosequencing cf. 2013 [316] DNA extracts, all correctly epidemiology 28S rRNA PCR-REA identified. Pyrosequencing for more discriminatory than PCR-REA

OnlySpecies ITS and D1/D2 A IIu Kolecka BrJDermatol N=500, all concordant ID identificationNot as sequencing 2014 [312] benchmark for ITS sequencing A IIu Mancini JCM 2013 N=1 MALDI-TOF MS [209]

Denis JCM 2016 N=40, all concordant [313]

SoR, strength of recommendation; QoE, quality of evidence; AFLP, amplified fragment length polymorphism; N, number of isolates investigated; ID, identification; ITS, internal transcribed spacer; MALDI-TOF, matrix assisted laser desorption ionisation time of flight; MS, mass spectrometry; REA, restriction enzyme analysis, tFLP, terminal fragment length polymorphism; SSCP, single strand conformational polymorphism

1061

1062 Recommendations – Species level identification by phenotypic methods is moderately supported 1063 but should be confirmed by non-phenotypic methods (below). A positive urease test result may 1064 be helpful for identification but is not sufficiently discriminatory by itself, nor are differential 1065 growth characteristics on CHROMagar Malassezia or on lipid-supplemented media (Table 14).

1066

1067 MALDI-TOF MS and molecular methods

1068 Evidence – Direct sequencing of the ITS, intergenic spacer (IGS) regions and the D1/D2 28S rDNA 1069 regions have proved to be reliable for the identification of Malassezia spp.[135, 305, 307, 311, 316] (Table 1070 14). A multiplex PCR method based on the ITS/5.8S rDNA region was able to identify 11 1071 Malassezia species.[306] PCR-RFLP of the 28S rDNA geneconsultation. is a useful method for identification and 1072 to study species epidemiology.[314, 315, 317-319] MALDI-TOF MS has also proved useful in identifying 1073 14 Malassezia species and a Malassezia MS spectrum databasedistribution. was recently developed for the 1074 reliable identification of six species.[312, 313]

1075 public 1076 Recommendation – Species identification otheris strongly recommended for establishing epidemiology 1077 and moderately recommendedfor for guiding therapy. Identification of Malassezia species by 1078 phenotypic methods or by MALDI-TOF MS is moderately supported with molecular methods by 1079 ITS/28S sequencing, strongly recommended.for 1080 TreatmentOnly 1081 Surgery Not

1082 There are no data describing surgical therapy and this practice if undertaken, must be guided by 1083 the clinical context.

1084

1085 Antifungal drug treatment and treatment duration

1086 Evidence – Gaitanis reviewed more than 50 case reports of M. furfur systemic infections in 1087 neonates from 1981 to 2011.[255] In 26 neonates with a favourable outcome, the only intervention 1088 was removal or change of a CVAD. In another 14 cases with a favourable outcome, the CVAD was 1089 removed and neonates were treated with a systemic antifungal agent, usually an amphotericin 1090 B formulation. In 10 cases, the outcome was recorded as fatal: two received amphotericin B with 1091 CVAD removal (one of these deaths was attributed to Pseudomonas sepsis), one was treated with 1092 amphotericin B alone, four received no therapy and therapy was not recorded for three. In five 1093 cases, parenteral lipid administration was also stopped, usually as an adjunctive measure with 1094 either antifungal treatment or CVAD removal. One neonate with a favourable outcome was 1095 treated with combination amphotericin B and 5-flucytosine. This combination was also used in 1096 two patients with CVAD-related fungaemia where CVAD removal was not possible.[320]

1097

1098 Recommendations – Removal of CVADs is strongly recommended. Discontinuation of parenteral 1099 lipids is supported with moderate strength. Systemicconsultation. antifungal agents are also recommended; 1100 there is most experience with amphotericin B formulations hence these are moderately 1101 supported in neonates and other high-risk groups. Indistribution. resource-limited settings, use of 1102 amphotericin B deoxycholate can be considered (Table 15). The duration of antifungal treatment 1103 is empirical but it is reasonable publicto continue for at least 14 days after last negative blood culture 1104 and removal of CVAD, similar to candidaemia.other[321] The practice of prevention of Malassezia 1105 infections by ensuringfor adherence to hand hygiene (M. pachydermatis), ensuring timely removal 1106 of CVADs and by appropriate environmental cleaning of neonatal units including incubators is 1107 strongly supported. A summaryfor of the treatment pathway is shown in Figure 14. 1108 Only Not

1109 Figure 14. Treatment pathway for antifungal therapy and management of infections due to 1110 Malassezia species.

Suspected and confirmed infections due to Malassezia spp. are emergencies and require rapid action

Timely, rapid antifungal therapy and management is required for suspected and confirmed infections

Amphotericin B Amphotericin B liposomal deoxycholate 5 mg/kg/d 1 mg/kg/d

Removal of CVAD

Response assessment (weekly, ≥ 14 days after last negativeconsultation. blood culture)

Legend: distribution. strongly recommended gg moderately recommended gg marginally recommended gg recommended against publicgg CVAD, central vascular access device other 1111 for 1112 Table 15. Recommendations onfor targeted antifungal therapy for Malassezia infections. Population Intention Intervention SoR QoE Reference Comment Fungaemia,Only CVAD-related Haemato- To cureNot Remove CVAD only B III Lautenbach NEJM 1998 N=1, M. pachydermatis, oncology [322] alive

Morrison BMT 2000 [283] N=2, alive

Haemato- To cure c-AmB 1 mg/kg/d B IIu Barber AJM 1993 [323] N=7, 4 cured without CVAD oncology removal

Lautenbach NEJM 1998 N=1 (M. pachydermatis), [322] cured with CVAD removal

Choudhury Pathol 2014 N=1 (M. pachydermatis), [268] cured with CVAD removal

CVAD removal To cure c-AmB (0.5-1.0 B IIu Redline HumPathol 1985 N=7, 4 died, 3 alive not possible mg/kg/d) [320]

and

5-FC 4 x 21-32 mg/kg/d

Post trauma, To cure AmB lock therapy C III Arnow AmJMed 1991 [324] N=1, cured on total 2.5 mg/kg for 12 parenteral hours/d for 21d nutrition

CVAD removal not possible

Intensive care To cure L-AmB 5 mg/kg/d B III Pedrosa JDermatol 2018 N=2, died [261] CVAD removed consultation.

SoR, strength of recommendation; QoE, quality of evidence; N, number of subjects investigated; 5-FC, 5-flucytosine; AmB, amphoteiricn B; c-AmB, conventional amphotericin B; CVAD, centraldistribution. vascular access device

1113

1114 PSEUDOZYMA (MOESZIOMYCES)public INFECTIONS 1115 Taxonomy and epidemiologyfor other 1116 The study of Pseudozyma species is a classic example of botanical mycology and clinical practice 1117 trying to align with new molecular-basedfor taxonomy. Recently, Pseudozyma species that cause 1118 human disease were reassigned to the genus Moesziomyces.[10] For this guideline however, we 1119 continueOnly to use the term ‘Pseudozyma’ as this allows identification with clinical studies but 1120 acknowledge that Notthe nomenclature of this group of fungi is changing. 1121

1122 Pseudozyma species belong to the phylum Basidiomycota, subphylum Ustilaginomycotina, class 1123 Ustilaginomycetes and order Ustilaginales. Both Pseudozyma species and its relative, Ustilago 1124 species, are well-known plant pathogens but rarely cause disease in humans (Figure 15).

1125 However, there have been cases of fungaemia, brain abscesses, pneumonia and mycetomas 1126 caused by these fungi.[3, 55-57, 91, 139-144, 325] Pseudozyma spp. has most often been identified in 1127 cancer patients. Pseudozyma aphidis has been the most common species identified in known 1128 cases, but at least five other species have been isolated from blood cultures.[56, 143] A weak 1129 pathogen, Pseudozyma has been proposed to be directly inoculated into tissue or translocate 1130 across disturbed mucosal barriers. It is important to distinguish contamination and colonization 1131 from true disease.

1132

1133 Figure 15. Worldwide distribution of Pseudozyma infections (reported cases between 2000 and 1134 2019 per million population).

consultation. distribution. public 1135 1136 other Legend: Cases of Pseudozymafor -related infections reported in the medical literature between 2000 1137 and 2019 were identified on January 15, 2020 through PubMed using the search string 1138 (Pseudozyma OR Candida antarctica)for AND (case* [Title/Abstract] OR report [Title/Abstract] OR 1139 patient OR infection OR invasive OR systemic OR fungemia OR blood). Seventeen cases have been 1140 identifiedOnly from nine countries.[3, 55-57, 91, 139-144, 325, 326] Most cases were reported from Thailand 1141 (N=6) and the UnitedNot States of America (N=3). Number of cases reported between 2000 and 2019 1142 are presented as cases per million population per country. The resident population per country 1143 was obtained from www.worldometers.info.[47]

1144 Diagnosis

1145 Imaging, culture and species identification

1146 Evidence – Imaging investigations are performed as required. In a case of Pseudozyma brain 1147 abscess, cerebral CT was useful to define the site of infection,[55] as was thoracic CT scanning in 1148 defining lung infection (Table 3).[56, 57] Examination of tissue for presence of fungi using H&E 1149 and/or GMS and PAS stains has been useful[57, 91] in which dichotomous hyphae with septa, 1150 clustered yeast cells, with associated necrosis may be seen (Table 4). Direct microscopy and 1151 culture have provided the diagnosis in many instances (Table 16).

1152

1153 Table 16. Recommendations on microscopy and culture in Pseudozyma spp. infections

Population Intention Intervention SoR QoE Reference Comment

Any To diagnose Direct microscopy A III Hwang KorJLabMed 2010 N=1 Gram stain on [55] 1-1.5 by 9-10 µm fusiform or spindle- Brain abscess consultation.shaped yeasts with budding on short stalks. Elongated blastoconidia and distribution.branching pseudophyphae Any To diagnose Direct microscopy A III Parahym DMID 2013 [56] N=1

Gram stain on Elongated spindle-shaped pleural fluidpublic blastoconidia Any To diagnose Direct microscopy A other III Herb MMCR 2015 [142] Wet mount: fungal elements with short hyphae, fusiform cells with forGram stain and polar budding. wet mount on blood culturefor Lin JMM 2008 [141] Wet mount: elongated fusiform spindle-shaped blastoconidia that Only are slightly irregular Any To diagnoseNot Culture A III Hwang KorJLabMed 2010 N=1, brain [55] All specimens Lin JMM 2008 [141] N=1, blood

Joo Mycoses 2016 [57] N=1, blood

Orrechini JCM 2015 [140] N=1, blood

Parahym DMID 2013 [56] N=1, pleural fluid

Herb MMCR 2015 [142] N=1, blood

Mekha MicroImm 2014 N=3, blood [143]

Chen IntJDerm 2011 [91] N=1, leg tissue

Colonies are soft, butyrous, and cream-white with fringed wrinkled margins on SDA after 3 to 4 days at 30oC. Colonies are white, glabrous or dry on blood agar, white to pale yellow/cream coloured, slightly raised, folded in the surface with a fringed margin, and butyrous on yeast malt extract agar; and at first blue on chromogenic medium, and then yellow- beige.

SoR, strength of recommendation; QoE, quality of evidence; N, number of subjects investigated; SDA, Sabouraud Dextrose agar

1154

1155 Pseudozyma yeasts are not easily identified by the routine clinical microbiology laboratory and 1156 require a reference laboratory for definitive identification as biochemical identification methods 1157 will not provide reliable information. In addition, theconsultation. identification to species level of this fungus 1158 is not routinely performed. Furthermore, MALDI-TOF-MS still is not robust for identification due 1159 to databases not including spectra for these pathogens.distribution. The clinical utility of Pseudozyma 1160 detection using any culture-independent approach has not yet been reported, however, ITS1, 1161 ITS2 or 28 rRNA gene sequencing has occasionally been used to determine or confirm the fungus 1162 identity to the genus or species publiclevel.[55, 56] 1163 for other 1164 Recommendations - It is important to advance learning of Pseudozyma spp. and hence the 1165 guideline strongly recommendsfor correct identification to genus level which will require DNA 1166 sequencing (Table 17). Species identification is also strongly recommended for epidemiological 1167 knowledge,Only but there are no data which suggest that species knowledge is required to guide 1168 treatment. The guidelineNot recommends with at least moderate strength, imaging tests where 1169 indicated by clinical need. Histopathological examination of tissue for fungi is strongly 1170 recommended where clinical suspicion is high. Culture of specimens is essential to provide an 1171 isolate for characterisation.

1172

1173 Table 17. Recommendations on genus and species identification of Pseudozyma spp.

Population Intention Intervention SoR QoE Reference Comment

Phenotypic identification

Pseudozyma spp. - no data and recommendation is CIII

MALDI-TOF MS

Any To identify to MALDI-TOF MS C III Orecchini JCM 2015 N=1, Bruker system, no species level identification [140] identified (score <1.7), Bruker database

Herb MMCR 2015 [142] N=1, Bruker system, no identification (score<1.7)

Bruker database

Molecular Identification

Any To identify ITS sequencing A III Herb MMCR 2015 [142] N=1, bloodstream species and to Siddiqui BMC CR 2014 N=1 bloodstream; identified diagnose consultation.[325] to genus only

Parahym DMID 2013 [56] N=1, pleural fluid

Lin JMMdistribution. 2008 [141] N=1, bloodstream

Chen IntJDerm 2011 [91] N=1, tissue

Paediatric To identify D1/D2public A III Prakash Mycoses 2014 N=1, bloodstream species and to sequencing other[139] diagnosefor Any To identify to ITS and D1/D2 A III Pande TID 2017 [3] N=1, bloodstream. Could only species level and 28Sfor rRNA identify to genus level diagnose sequencing Orecchini JCM 2015 N=1, bloodstream Only [140] Not Hwang KoreanJLabMed N=1, brain 2010 [55]

Joo Mycoses 2016 [57] N=1, bloodstream

A IIu Mekha N=3, bloodstream MicrobiolImmunol 2014 [143]

A IIu Sugita MicrobiolImmunol N=3, bloodstream 2003 [144]

SoR, strength of recommendation; QoE, quality of evidence; N, number of isolates investigated; HSCT, Haemopoetic stem cell transplant; ITS, internal transcribed spacer; MALDI-TOF, matrix assisted laser desorption ionisation time of flight; MS, mass spectrometry

1174

1175 Susceptibility, treatment and management

1176 Evidence – At present, as a pathogen, Pseudozyma species is accepted as an identification for 1177 clinical practice and management. Specifically, it identifies a yeast that will not respond to 1178 echinocandin treatment. When these yeasts are found in the human host, the management 1179 includes: control of the underlying disease, removal of all catheters or other foreign bodies[325] 1180 and treatment with either an amphotericin B formulationconsultation. or extended- spectrum azoles such as 1181 voriconazole, posaconazole and isavuconazole; fluconazole and itraconazole have variable 1182 activity in vitro.[3, 57] The yeasts are resistant to echinocandinsdistribution. and 5-flucytosine in vitro and this 1183 yeast may actually grow in the blood of patients receiving echinocandin therapy. An indication 1184 of the reduced virulence of this group of yeasts is suggested by the fact that despite the small 1185 numbers of reported cases, thepublic outcomes of infections with this yeast have generally been 1186 reported to be good (Table 18, Table 6).[3,other 56, 57, 139, 140, 325] 1187 for 1188 Table 18. Recommendations onfor targeted antifungal therapy for Pseudozyma spp. infections Population Intention Intervention SoR QoE Reference Comment

Any Only To cure L-AmB 3 mg/kg/d B III Joo Mycoses 2016 [57] Isolates had low MICs to Not AmB. or Pande TID 2017 [3] In the reports, all patients ABLC 5 mg/kg/d Orecchini JCM 2015 [140] had clinical improvement Herb MMCR 2015 [142] Duration is empirical but 10- Parahym DMID 2013 [56] 14 days at 3-5 mg/kg/d has been used with good results

Any To cure VRC 2 x 6 mg/kg on d1 B III Pande TID 2017 [3] Low MICs to VRC

followed by 2 x 4 mg/kg/d Siddiqui BMJ CR 2014 [325] Effective as first line therapy

Joo Mycoses 2016 [57] Effective as oral step down therapy after AmB

Any To cure ITC 2 x 200 mg/d C III Joo Mycoses 2016 [57] MICs to ITC vary

Lin JMM 2008 [141]

Any To cure FLU 400 mg/d D III Lin JMM 2008 [141] MICs to FLU high; failure of FLU

Any To cure CAS 70 mg/d1, followed by D III Pande TID 2017 [3] Breakthrough infections on 50 mg/d echinocandins

MICA 100mg/d

SoR, strength of recommendation; QoE, quality of evidence; N, number of subjects investigated; 5-FC, 5-flucytosine; ABLC, amphotericin B lipid complex; AmB, amphoteiricn B; c-AmB, conventional amphotericin B; CAS, caspofungin; FLU, fluconazole; ITC, itraconazole; L-AmB, liposomal amphotericin B; MICA, micafungin; MIC, minimum inhibitory concentration; VRC, voriconazole consultation. 1189 1190 Recommendations - With these fungi, we recommend precisedistribution. determination of disease and at 1191 least genus level identification. Susceptibility testing for guiding therapy is moderately supported 1192 using reference testing methodologypublic (Table 6). There is moderate support for the use of polyenes 1193 and extended-spectrum azoles as they are useful but there are not large studies of outcomes 1194 with these fungi. There is no support for theother use of echinocandins. Control of underlying diseases 1195 and removable of foreignfor bodies where reasonable is strongly recommended and most of these 1196 infections can be successfully managed.for The guideline recommends the treatment pathway as 1197 shown in Figure 16. 1198 Only Not

1199 Figure 16. Treatment pathway for antifungal therapy and management of infections due to 1200 Pseudozyma spp.

Suspected and confirmed infections due to Pseudozyma spp. are emergencies and require rapid action

Timely, rapid antifungal therapy and management is required for suspected and confirmed infections

Surgical resection of localised lesions

Amphotericin B Voriconazole iv/po Amphotericin B liposomal 2x6 mg/kg/d d1; lipid complex Fluconazole Echinocandins 3 mg/kg/d 2x4 mg/kg/d from d2 5 mg/kg/d

Removal of CVAD

Response assessment (weekly, ≥ 14 days after last negative blood culture)

Legend: strongly recommended gg moderately recommended gg marginally recommended gg recommended against gg consultation. CVAD, central vascular access device; iv, intravenous; po, per os 1201

1202 distribution. 1203 RHODOTORULA INFECTIONS public 1204 Taxonomy and epidemiology 1205 Rhodotorula speciesfor are pigmented basidiomycetousother opportunistic yeasts of the family 1206 Soridiobolaceae, clade Rhodosporidium.[327, 328] They are common in the environment in soil, 1207 aquatic ecosystems, fruit juices,for and dairy products as well as fomites such as shower curtains.[151, 1208 329] The genus contains at least 50 species of which three are well described as human pathogens: 1209 RhodotorulaOnly mucilaginosa (formerly R. rubra), R glutinis and R. minuta;[330, 331] R. slooffiae and R. 1210 pilimanae have beenNot rarely isolated from human samples.[60] The clinical relevance of other 1211 Rhodotorula species (e.g. R. calptogenae, R. diffluens) is not known.

1212

1213 Rhodotorula spp. comprised the 4th most common noncandidal yeasts from clinical specimens 1214 (4.2% of 8821 isolates) in one global study[330] and are detailed in several reviews.[331-333] Most

1215 infections are fungemia, often as breakthrough infections[146, 149, 151, 155, 334-337] in association with 1216 indwelling CVADs, but endocarditis, meningitis, endophthalmitis and other eye infections, and 1217 peritonitis complicating peritoneal dialysis are described.[59, 61, 162, 217, 331, 338-340] After fungaemia, 1218 ocular infections are the next most common, ranging from traumatic keratitis to scleritis to 1219 endophthalmitis.[341] Of 128 cases in one review, 79% presented with fungemia, 7% with eye 1220 infections and 5% as peritonitis.[331] Rhodotorula spp. have been isolated from the nails, skin and 1221 hands of health care workers.[342, 343]

1222

1223 Infections occur worldwide but are most often reported from the Asia-Pacific region (17% of all 1224 isolates in one survey vs. 5-14% from other regions.[6] In one review in 2011, 48% of all infections 1225 are ascribed to this region.[2] Figure 17 shows the distribution of cases. Sporadic reports are 1226 numerous and are accompanied by case series.[15, 17, 18, 344] R. mucilaginosa is the commonest 1227 causative species in fungemia (about 75%) followed by R. glutinis (7.7%) and R. minuta (rare).[331] 1228 consultation. 1229 Figure 17. Worldwide distribution of Rhodotorula infections (reported cases between 2000 and 1230 2019 per million population) distribution. public for other for Only Not 1231

1232 Legend: Cases of Rhodotorula-related infections in the medical literature between 2000 and 2019 1233 were identified on January 15, 2020 through PubMed using the search string (Rhodotorula AND 1234 (case [Title/Abstract] OR report [Title/Abstract] OR patient OR infection OR invasive OR fungemia 1235 OR blood OR disseminated OR systemic). In total, 204 cases were identified from 24 countries.[4,

1236 5, 15-17, 58-61, 93, 146-148, 153-158, 160-162, 215, 217, 231, 336, 338, 340, 345-393] Most cases were reported from China 1237 (N=43), Brazil (N=34), Spain (N=30), India (N=16), Italy (N=12), USA (N=13), and Taiwan (N=10).[4, 1238 5, 15-17, 58-61, 93, 146-148, 151, 153-158, 160-162, 215, 217, 231, 336, 338, 340, 346-398] Four cases of R. mucilaginosa- 1239 related infections were associated with an outbreak in an Italian neonate intensive care unit 1240 where the source could not be identified.[157] Number of cases reported between 2000 and 2019 1241 are presented as cases per million population per country. The resident population per country 1242 was obtained from www.worldometers.info.[47]

1243

1244 A recent study from China found Rhodotorula spp. caused 5.2 % (44/844) of invasive yeast 1245 infections[5] whilst a survey in Turkey in 2018 identified Rhodotorula spp. to account for 15.8% of 1246 all non-candidal yeast fungaemias.[149] In comparison, the proportion of yeast fungemia caused 1247 by Rhodotorula spp. was 0.3% (2/767), 2.4% (8/338), and 0.5% (1/201) in Spain, France and 1248 Slovakia, respectively.[15, 18, 344] In the USA, 21/94 (22%) of bloodstream noncandidal yeast cases 1249 (total number of yeast fungaemias not stated) were due to Rhodotorula spp.[17]

1250 consultation. 1251 Adults, children and neonates with underlying haematologicaldistribution. malignancy, HSCT and HIV 1252 infection are at increased risk for infection but ICU patients, those with burns, cirrhosis, 1253 abdominal surgery and those receiving immunosuppressive therapy are also at risk.[4, 17, 18, 61, 149, 1254 151, 154, 217, 334, 370, 399]. CVAD placementpublic is a risk factor for Rhodotorula fungaemia [17, 154, 161, 331-333, 1255 335] in all patients. other 1256 for 1257 One study identifying a cluster forof fungemia in preterm infants in a neonatal ICU.[157] Mortality is 1258 reported to be 15-42%.[56, 334, 399] It is uncertain whether mortality in higher in 1259 immunocompromisedOnly patients compared with other patient groups. Mortality in haematology 1260 patients has rangedNot from 0% in lymphoma patients to 11% in HSCT to 15.7 % in acute 1261 leukemia.[158, 329]

1262

1263 Diagnosis

1264 Imaging

1265 Evidence – Data to support various imaging approaches in the diagnosis of Rhodotorula infections 1266 stem from cases of endocarditis, meningitis and CNS infection, and orthopaedic infections. In 1267 endocarditis, TOE was superior to TTE, the latter of which failed to detect vegetations on the 1268 aortic valve of two separate patients.[58, 59]

1269

1270 Vegetations and a 0.5 X 0.6 cm aortic root abscess was detected by TOE in another patient where 1271 in addition, an Indium-111 labelled leukocyte SPECT scan showed highly-likely infection at the 1272 aortic root.[60] Earlier reports of ‘Rhodotorula endocarditis’ have not incorporated 1273 echocardiography findings and are based on isolation of Rhodotorula spp. from blood 1274 cultures.[400-402] In a patient with meningitis, cerebral infection was diagnosed by MRI which 1275 showed high signal intensity brain lesions and leptomeningeal enhancement that progressed 1276 over 10 days, accompanied by ventricular enlargement;[61]consultation. in another patient also with 1277 meningitis, the cerebral CT scan was normal.[353] Plain X rays in trauma-related orthopaedic 1278 infection have shown sequestra and may assist with diagnosisdistribution. of bone infection.[62] The MRI and 1279 bone scan findings in one case of an infected hip prosthesis were not described (Table 3).[159] 1280 public 1281 Recommendation – Imaging of suspected sites of involvement is recommended with at least 1282 moderate support to diagnose or to excludeother disease. In suspected endocarditis, TOE is preferred 1283 over TTE. In cases of formeningitis, MRI is more sensitive in diagnosing concomitant brain lesions 1284 than CT and is preferred. Plain Xfor rays can assist with diagnosis of orthopaedic infections but may 1285 not be sensitive but are also recommended with moderate strength. Follow up imaging is strongly 1286 recommendedOnly especially when the diagnosis is unclear or in unstable patients (Table 3). 1287 Not

1288 Histopathology

1289 Evidence – Data for direct detection of Rhodotorula organisms in tissue are few and are from case 1290 reports where in suspected non-bloodstream (skin and soft tissue, bone, brain, and heart valve) 1291 infection, direct microscopy of tissue specimens can be useful using standard histological stains.

1292 PAS staining of skin tissue demonstrated numerous budding yeasts within necrotising 1293 granulomas in a combined kidney/liver transplant recipient.[92] Debrided bone tissue from a 1294 fractured femur yielded budding yeasts visible on PAS and GMS.[62] GMS staining showed 3 µm x 1295 3 µm yeast forms within aortic valve tissue in another patient enabling diagnosis of 1296 endocarditis.[60] All of PAS, KOH mounts and Blankophor stains were used to visualise 4-6 µm 1297 yeasts in brain tissue,[61] with GMS providing diagnosis in post mortem brain tissue.[93] Of note, 1298 Rhodotorula may be confused as cryptococci as the two genera cannot be readily differentiated 1299 in tissue sections where the semblance of a faint capsule may be visualiszed [92, 374] and should be 1300 interpreted in clinical context. There are no Rhodotorula-specific immunohistochemistry stains.

1301

1302 Recommendations – Despite few reports, there is strong support for the examination of all tissue 1303 specimens for fungal yeast cells where an IFD is in the differential diagnosis by direct microscopy 1304 using standard fluorescent brighteners and histopathological stains (Table 4). As Rhodotorula 1305 may not be readily distinguished from Cryptococcus in tissue specimens, it is strongly 1306 recommended to confirm the diagnosis by cultureconsultation. of specimens or by application of direct 1307 molecular detection techniques.

1308 distribution.

1309 Culture and microscopy

1310 Evidence – Direct microscopy bypublic Gram stain of blood cultures in multiple case reports has shown 1311 oval-globose, yeasts with narrow bud scarsother with or without pseudohyphae, and provided the first 1312 clue of fungaemia for (Table 19). However, negative Gram stain results do not exclude 1313 fungaemia.[155, 158, 403] Gram stainingfor of CSF, peritoneal dialysis fluid, vitreous fluid and crushed 1314 heart valve were also useful for diagnosis although may not show organisms.[58, 61, 147, 162, 215, 372, 1315 374] TheOnly India ink stain may show yeasts with small capsules which may be resemble 1316 Cryptococcus.[372, 374]Not There are sparse descriptions on the utility of fluorescent brighteners or 1317 KOH mounts. However, in a case of R. mucilaginosa keratitis, confocal microscopy of the cornea 1318 showed round-to-dumbbell shaped budding yeasts with hyphae or pseudohyphae.[341]

1319 Table 19. Recommendations on microscopy and culture in Rhodotorula spp. infections

Population Intention Intervention SoR QoE Reference Comment

Any To diagnose Direct microscopy A IIu Falces-Romero Mycoses 2018 [154] N=8 (R. mucilaginosa)

Gram stain on Perniola EJCMID 2006 [157] N=4 (R. mucilaginosa) blood cultures Duggal MedMycol 2011 [161] N=2 (R. mucilaginosa)

Pamidimukkala NeurolInd 2007 [93] N=1 (R. glutinis)

Simon JCM 2014 [60] N=1 (R. mucilaginosa)

Yeasts are seen; often budding

HIV To diagnose Direct microscopy A III Thakur IndJMedMicrobiol 2007 [374] N=1 (R. rubra)

Gram stain on CSF Shinde IndJMedMicrobiol 2008 [372] N=1 (R. glutinis)

Baradkar AnnIndAcadNeurol 2008 N=1 (R. mucilaginosa) [370]

HIV To diagnose Direct microscopy C III Thakur IndJMed Microbiol 2007 N=1 (R. rubra) [374] India Ink on CSF consultation. Shinde IndJMed Microbiol 2008 N=1 (R. glutinis) [372] distribution. Haematology To diagnose Direct microscopy C III Tsiodras MMCR 2014 [61] N=1 (R. mucilaginosa) malignancy Giemsa on CSF

Renal To diagnose Heart Valvepublic Gram A III Cabral JMMCaseRep 2017 [59] N=1 (R. mucilaginosa) Transplant stain other Trauma To diagnosefor Confocal C III Giovanni CaseRepOphthalmol 2014 N=1 (R. mucilaginosa) microscopy of [341] cornea for

IVDU To diagnose Gram stain of A III Pinna BrJOphthalmol 2001 [215] N=1 (R. minuta) Only vitreous fluid CAPD To diagnoseNot Gram stain of PD A III Raaijmakers PaedNeph 2007 [404] N=1 (R. rubra) fluid Franconieri PeritDialInt 2018 [162] N=1 (R. mucilaginosa)

Any To diagnose Culture all A IIu De Almeida MedMycol 2008 [151] N=25, blood (R. specimens mucilaginosa)

100

Garcia-Suarez Mycoses 2011 [399] N=29, blood (23 R. mucilaginosa, 3 R. glutinis, 3 other species)

Tuon RevIberoamMicol 2008 [331] Review N=128; 103 blood, 9 eye, 6 PD fluid

Perniola EJCMID 2006 [157] N=4 nosocomial cluster, blood

Xiao InfDrugRes 2018 [5] N=44, various sites, unspecified

Fernandez-Ruiz MedMycol 2017 [15] N=2, blood

Krcmery JMedMicrobiol 2002 [388] N=1, blood

Bretagne JAC 2017 [18] N=2, blood Tuonconsultation. MedMycol 2007 [332] N=23, blood Capoor IndJMed Microbiol [148] N-=14, 5 blood, 9 CSF Chitasombatdistribution. JInfect 2012 [17] N=1, blood Potenza Mycoses 2019 [334] N=21, blood

Lunardi CID 2006 [336] N=27, various body public sties otherFalces-Romero Mycoses 2018 [154] N=7, blood for Westblade JCM 2013 [211] N=6, blood for Cuenca-Estrella AAC 2006 [117] N=35, various body sites Only Mancini JCM 2013 [209] N=24, various body Not sites Gomez-Lopez JAC 2005 [153] N=4, various body sites

Lohmann JCM 2013 [207] N=29, various body sites

101

Unal IntUrolNephrol 2011 [405] N=8, various body sites

Raaijmakers Paediatr Nephrol 207 N=1 (R. mucilaginosa) [404]

Eisenberg AmJMed 1983 [339] N=1 (R. rubra)

Franconieri PeritDialInt 2018 [162] N=3, PD fluid

Giovanni CaseRepOphthalmol 2014 N=1, cornea [341]

Gregory ArchOphthalmol 1992 [216] N=1, vitreous fluid

Pinna BrJOphthalmol 2001 [215] N=1, vitreous fluid

Means DermatolSurg 2012 [406] N=1, skin biopsy

Maeder Infection 2003 [58] N=1, heart valve

Simon JCM 2014 [60] N=2, blood Goyalconsultation. JPostgradMed 2008 [62] N=1, bone Savini JCM 2008 [159] N=1, bone fistula

Baradkar AnnIndAcadNeurol 2008 N=1, CSF [370] distribution.

Tsiodras MMCR 2014 [61] N=1, brain tissue

public Nor Mycopathologia 2015 [353] N=1, CSF otherPamidimukkala NeurolInd 2007 [93] N=1, post-mortem for blood, brain tissue Shinde IndJMed Microbiol 2008 N=1, CSF for [372]

Thakur IndJMed Microbiol 2007 N=1, CSF Only [374] Not Lanzafame JCM 2001 [338] N=1, CSF

Duggal Med Mycol 2011 [161] N=2, blood

Wang JMicroImmuInf 2019 [347] N=1, blood

Miglietta MMJ 2015 [156] N=1, blood

102

Pasqualotto JPediatrHemtaolOncol N=3, blood, CVC 2005 [407]

Fores Mycoses 2011 [158] N=1, blood

Mori TID 2011 [155] N=1, blood

Samonis Infection 2001 [390] N=1, blood

Alliot ClinOncol 2000 [403] N=2, blood

Hsueh JCM 2003 [160] N=1, blood

Colonies of Rhodotorula grow within 48 hours as smooth, coral pink-salmon coloured colonies which can be corrugated, smooth or wrinkled on SDA. Budding yeasts (2.5 X 4-6.5 X 10-14 um) are seen. Unlike direct microscopy, pseudohyhpae and hyphae are not typically seen.

SoR, strength of recommendation; QoE, quality of evidence; N, number of subjects investigated; CSF, cerebrospinal fluid; PD, peritoneal dialysis; SDA, Sabouraud Dextrose agar

1320

1321 Given the propensity to confuse Rhodotorula with Cryptococcus by direct microscopy, culture of 1322 specimens is essential and yields an isolate for definitiveconsultation. identification and susceptibility testing. 1323 Rhodotorula grow typically within 48 hours as smooth, coral pink-salmon coloured colonies 1324 (Figure 18) which can be corrugated, smooth or wrinkled distribution.on SDA, with similar morphology on 1325 malt extract agar.[113] Identification to species level requires mycological expertise. Budding 1326 yeasts are typical (measuring 2.5public X 4 - 6.5 X 10-14 um depending on species). Unlike with direct 1327 microscopy, hyphae/pseudohyphae are notother seen (Table 19 ). for 1328 Figure 18. Typical smooth, coral pink-salmon 1329 coloured colonies of Rhodotorula mucilaginosa for 1330 on Sabouraud dextrose agar after 48 hours at Only 1331 28oC (authors’ own photograph). Not 1332 1333

1334

1335

1336

103

1337 Recommendations – Direct microscopy with Gram stain is strongly recommended for 1338 presumptive diagnosis. Staining with India Ink is weakly supported (Table 19). Fluorescent 1339 brighteners or KOH wet mount microscopy is weakly recommended. Culture of all specimens is 1340 strongly recommended for genus and species identification and for susceptibility testing.

1341

1342 Susceptibility testing

1343 Evidence – Although there is no standardised susceptibility testing method, and no Rhodotorula- 1344 specific CBPs or ECVs defined, it is reasonable to expect that the EUCAST and CLSI broth 1345 microdilution methodologies[114, 115] can provide reliable susceptibility results with data to 1346 indicate that it is appropriate to read MICs after 72 hours of incubation.[6, 146, 147, 150] The one 1347 comparative study of EUCAST-, versus CLSI-derived MICs for a number of antifungal agents was 1348 carried out on only one R. mucilaginsoa isolate; the EUCAST method gave higher MICs up to 4- 1349 20-fold.[15] Two reports, each testing a single patient’s isolates, compared the CLSI M27 A-2 1350 method with the E-test (bioMerieux) and in one, also with the Sensititre YeastOneO9 1351 (Thermofisher). Both observed that whilst MICs forconsultation. amphotericin B were similar, MICs for the 1352 azoles were 4–32 fold lower with the E-test (bioMerieux).[60, 160] The CLSI M44-S3 disk diffusion 1353 method was used to establish epidemiological data in onedistribution. study.[4] The E-test, (bioMerieux), 1354 Sensititre (Thermofisher), ATB Fungus (bioMerieux) have been employed to provide 1355 epidemiological data and to guidepublic treatment (Table 6). 1356 other 1357 Data from the few largerfor series indicate that amphotericin B and 5-flucytosine exhibit the lowest 1358 MICs (1 mg/L or lower and <0.5for mg/L, respectively) followed by voriconazole, posaconazole and 1359 isavuconazole;[146, 147, 153, 215, 408, 409] however high MICs up to 32 mg/L to these agents have also 1360 beenOnly observed [60, 146, 154, 408] Isavuconazole MICs in one study ranged from 0.5 to 16 mg/L.[152] 1361 Fluconazole MICsNot are high (MIC90 >64 mg/L) and MICs to all the echinocandins, very high 1362 regardless of methodology (Table 6). Hence Rhodotorula species are regarded as intrinsically 1363 resistant to some azoles and the echinocandins. As MICs may be strain dependent, susceptibility 1364 testing of clinically significant Rhodotorula isolates is recommended.

1365

104

1366 Recommendations – The use of reference methods inclusive of the CLSI-based Sensititre method 1367 (Thermofisher) for antifungal susceptibility testing to guide treatment of Rhodotorula infections 1368 is moderately supported and is clinically useful in cases of treatment failure. We strongly 1369 recommend the use of these methods primarily to establish epidemiological knowledge. The use 1370 of E-test, and ATB Fungus (all bioMerieux) methods is supported with marginal strength only.

1371

1372 Molecular methods for direct detection

1373 Evidence –Evidence is indirect and from studies that address the detection of fungi from a series 1374 of clinical specimens (other than blood) by panfungal PCR targeting the ITS, 28S or 18S rDNA 1375 regions, which include very small numbers of Rhodotorula identifications. There is one case 1376 report documenting the use of panfungal PCR to detect Rhodotorula spp. in tissue from a skin 1377 biopsy in a renal transplant patient.[92] There is no data on the use of molecular methods to detect 1378 Rhodotorula in blood cultures. 1379 Recommendation: The use of molecular methods onconsultation. fresh clinical material and FFPE sections for 1380 the diagnosis of IFD (which includes Rhodotorula infection) is moderately supported especially 1381 where hyphae or yeast forms are visualized (Table 4). distribution. 1382 1383 Species identification public 1384 Evidence – Identification to the species level is essential for epidemiological studies, for other [4, 17, 18, 154, 157, 1385 investigation of case forclusters and for clinical understanding of species delineation. 1386 399] There are no data to indicate that identification of Rhodotorula to species level could guide 1387 the choice of antifungal treatment.for 1388 Only 1389 Morphological characteristicsNot of cultures of Rhodotorula spp. are summarised in Table 20. 1390 Colonies are germ tube negative, coral-red to salmon-pink in colour and exhibit budding yeasts 1391 forms without hyphae and pseudohyphae, including on cornmeal Tween 80 agar. There are no 1392 blastoconidia. Small capsules may be seen.[113] R. mucilaginosa is able to grow at 40oC. Colonies 1393 are urease-positive and have carbon assimilation patterns that have allowed species 1394 identification. On their own, commercial systems including the RapID Yeast Plus (Innovative

105

1395 Diagnostic Systems, Norcross, GA) API ID 32C, API 20C AUX, and Vitek YBC platforms (all 1396 bioMerieux) are limited in accuracy in both species and genus identification[151, 410, 411] but only 1397 after supplementation with manual phenotypic methods, species identification is enabled (Table 1398 20).

1399

1400 Table 20. Recommendations on genus and species identification of Rhodotorula spp.

Population Intention Intervention SoR QoE Reference Comment

Phenotypic identification

Any To identify to Carbon B III Duggal MycolMed N=2 species level for (carbohydrate) 2011 [161] diagnosis assimilation Miglietta MMJ 2015 N=1 nitrate [156] assimilation Mori TID 2012 [155] N=1 (no details) and urease testing for consultation.Samonis Infection 2001 N=1 species [390] identification Alliott ClinOncol 2000 N=2 [403]distribution.

Hseuh JCM 2003 [160] N=1

public Cabral JMMCaseRep N=1 (morphological only) other 2017 [59] for Simon JCM 2014 [60] N=1 Maeder lnfection 2003 N=1 for [58]

Goyal JPostgradMed N=1 (manual conventional Only 2008 [62] only) Not Savini JCM 2008 [159] N=1

Bradkar N=1 AnnIndAcadNeurol 2008 [370]

106

Tsiodras MMCR 2014 N=1 [61]

Nor Mycopathologia N=1 2015 [353]

Pamidimukkala N=1 NeurolInd 2007 [93]

Lanzafame JCM 2001 N=1 [338]

Shinde N=1 IndJMedMicrobiol 2008 [372]

Thakur N=1 (morphology) IndJMedMicrobiol 2007 [374]

Any To identify to Carbon B IIu Cappor IndJMed N=14 (API 20C), all species level and (carbohydrate) consultation.Microbiol 2014 [148] identified correctly for assimilation), Ramani JCM 1998 N=11 (API 20C, ID 32C, epidemiological nitrate [410] identified 6/11 and 3/11, study assimilation distribution. respectively) and urease Kitch JCM 1996 [411] N=6, (rapid Yeast Plus, 2/6 testing for identified) speciespublic identification other Barchiesi AAC 2000 N=7 (not stated), all forplus [145] correct biochemical kits Gomez-Lopez JAC 2005 N=29 (manual phenotypic for [153] tests), all correct ID

Diekema JCM 2005 N=64 (Vitek, API systems Only [150] and supplemented by Not manual tests), all correct Lohmann JCM 2013 N=8, (Auxacolor 2 and ID [207] 32 C), all correct IIU

Nunes AAC 2013 [147] N=59, (ID 32C plus manual methods), all correct ID

107

Zaas JCM 2003 [146] N=10 (API 20C), all correct

Chitasombat JInfect N=21 (Vitek YBC or API 2012 [17] 20C), all correct

Krcmery JMM 2002 N=1 (Mycotube and Vitek [388] Jr system)

De Almeida MedMycol N=23, (Vitek YBC) and API 2008 [151] 20C AUX), all correct

Perniola EJCMID 2006 N=4, (API 32C and Vitek [157] YBC), all correct

Presumptive identification is possible on SDA with coral-red to salmon-pink coloured colonies; round to oval budding yeast cells without rudimentary hyphae; Urease-negative; nitrate-negative; one or more of Vitek YBC, API 20C AUX, ATB ID32 C (all BioMerieux) used, but when in combination with manual methods, allow accurate identification. Commercial systems on their own have also produced errors or “no identification” score.

MALDI-TOF MS

Any To identify to MALDI-TOF MS B IIu Falces-Romero N=6, Bruker database (all species level identification consultation.Mycoses 2018 [154] correct ID, R. mucilaginosa) Fraserdistribution. MedMycol 2016 N=59, Bruker database, all [208] correct ID, full extraction required, R. mucilaginosa

public Westblade JCM 2013 N=35, Vitek MS database, other [211] all correct ID, R. for mucilaginosa Lohmann JCM 2013 N=8, Bruker and AXIMA for [207] systems, all correct identification, R. Only mucilaginosa, scores may Not be <2.00

108

Mancini JCM 2013 N=4, Bruker and Vitek. R. [209] slooffiae,

N=1, Bruker no ID, Vitek ID to genus, R. glutinis,

N=1, Bruker no ID, Vitek, error. R. mucilaginosa,

N=2, Bruker and Vitek, each correct ID 1 of 2

C III Cabral JMM CR 2017 N=1, Database not [59] specified. Correct ID, R. mucilaginosa

B III Franconieri PeritDialInt N=1, Bruker, correct ID, R. 2018 [162] mucilaginosa

Molecular Identification

Any To identify To supplement A IIu Mancini JCM 2013 N=4, ITS1 and ITS2, species or confirm consultation.[209] molecular identification MALDI TOF MS superior to MALDI-TOF MS species Lohmanndistribution. JCM 2013 N=8, ITS (5.8S) sequencing identification [207]

Westblade JCM 2013 N=35, MicroSeq D2 LSU kit, public [211] molecular identification other confirmed MALDI-TOF MS for identification for all 35 Fraser MedMycol 2016 N=59, pyrosequencing ITS2 for [208] +/- D1/D2 sequencing. Sequencing confirmed Only MALDI-TOF MS Not identification for all isolates

Any ITS and D1/D2 A III De Barros MedMycol N=1 (bloodstream) sequencing 2009 [123]

109

To identify Giovanni N=1 (cornea) species to CaseRepOphthalmol diagnose 2014 [341]

ITS sequencing A III Miglietta MMJ 2015 N=1 (bloodstream) [156]

Cabral JMMCR 2017 N=1 (heart valve) [59]

Simon JCM 2014 [60] N=1 (bloodstream)

Tsiodras MMCR 2014 N=1 (brain tissue) [61]

Any To identify to ITS sequencing A IIu Fernandez-Ruiz N=2 (bloodstream) species and MedMycol 2017 [15] establish Xiao InfDrugRes 2018 N=44 (various sites) epidemiologic [5] knowledge ITS and D1/D2 A IIu Lunardi CID 2006 [336] N=7 (bloodstream) rRNA consultation. Nunes AAC 2013 [147] N=44 (clinical and sequencing environmental)

Bretagnedistribution. JAC 2017 [18] N=8 (bloodstream)

SoR, strength of recommendation; QoE, quality of evidence; N, number of isolates investigated; ID, identification; ITS, internal transcribed spacer; MALDI-TOF,public matrix assisted laser desorption ionisation time of flight; MS, mass spectrometry 1401 for other 1402 Several studies have investigated the use of MALDI-TOF MS to identify Rhodotorula spp., using 1403 commercial databases (Table 20for) of the Bruker, Vitek MS and AXIMA systems. In the largest study 1404 of 59 R. mucilaginosa isolates using the Bruker system (Bruker Daltoniks), all were correctly 1405 identifiedOnly to species with full protein extraction.[208] In studies of smaller numbers of isolates, 1406 correct identificationNot was also achieved for all study strains.[154, 207, 211]

1407

1408 There are two case reports of correct assignment of “R. mucilaginosa” as the pathogen (one each) 1409 by MALDI-TOF MS. However, in another study of four Rhodotorula spp. using the Bruker (Bruker 1410 Daltoniks) and Vitek MS (bioMerieux) system, the single isolates each of R. slooffiae and R.

110

1411 glutinis were not identified and only 1/2 R. mucilaginosa was identified.[209] Both major 1412 commercial databases are able to speciate R. mucilaginosa, but under-representation of spectra 1413 of other Rhodotorula spp. should prompt supplementation by in-house libraries.

1414

1415 The gold standard identification method is molecular-based with sequence analysis of the ITS, 1416 D1/D2 domains of the 28S rRNA gene as well as the mitochondrial cytochrome b gene.[213, 328, 412, 1417 413] In particular, ITS sequencing has been used as the confirmatory method to speciate 1418 Rhodotorula in many case reports [59-61, 156, 341] in epidemiological studies[5, 15, 18, 336] and to support 1419 MALDI-TOF MS identifications of various Rhodotorula species.[207, 208, 211]

1420

1421 The usefulness of ITS-directed sequencing using ITS1 and ITS4 universal primers for Rhodotorula 1422 was well demonstrated in the identification of R mucilaginosa, R. dairenensis, R. (Cystobasidium) 1423 minuta, R glutinis, R. (Cystobasidium) slooffiae and R. fluviale amongst a collection of 51 clinical 1424 and 8 environmental strains - when compared withconsultation. the phenotypic ID 32 identification system 1425 coupled with nitrate assimilation tests, there was 90.3% concordance in species identification 1426 with discrepancies mostly related to non-R. mucilaginosa distribution.isolates.[147] Molecular identification 1427 performs better than morphological approaches as well as MALDI-TOF MS and is used for primary 1428 diagnosis, and to benchmark the accuracy of other tests.

1429 public

1430 Recommendation – Identification to the otherspecies level is strongly supported for epidemiological 1431 understanding. Guidingfor treatment by identification to genus level is supported with moderate 1432 strength. Phenotypic identificationfor can identify Rhodotorula spp. and is moderately supported 1433 but molecular identification by ITS sequencing is strongly supported over morphology. MALDI- 1434 TOF OnlyMS identification is moderately supported with more testing required against commercial 1435 databases for non-NotR. mucilaginosa species (Table 20). 1436

1437 Diagnostic Pathway

1438 Figure 19 displays the suggested diagnostic pathway for Rhodotorula spp. infections. Culture 1439 remains the cornerstone of diagnosis; the majority of invasive infections being diagnosed by

111

1440 blood culture. Commercial biochemical tests whilst able to identify most species, should be 1441 coupled with the urease test (a negative result excludes Rhodotorula) and nitrate assimilation 1442 test to improve its identification capability.[414] ITS sequencing should be considered the gold- 1443 standard procedure for genus and species dentification.

1444

consultation. distribution. public for other for Only Not

112

1445 Figure 19. Diagnostic pathway for suspected cases of systemic Rhodotorula infections

consultation. distribution. public for other for Only Not

1446

113

1447 Treatment

1448 A summary of a suggested treatment pathway by this guideline for patients with Rhodotorula 1449 infection is shown in Figure 20.

1450

1451 Figure 20. Treatment pathway for antifungal therapy and management of systemic infections 1452 due to Rhodotorula spp.

Suspected and confirmed infections due to Rhodotorula spp. are emergencies and require rapid action

Timely, rapid antifungal therapy and management is required for suspected and confirmed infections

Surgical resection of localised lesions and valve replacement

Amphotericin B Amphotericin B liposomal deoxycholate 3-5 mg/kg/d 0.7-1 mg/kg/d consultation. Echinocandins Triazoles

± Flucytosine iv/po 4x25 mg/kg/d distribution.

publicRemoval of CVAD

Response assessment for(weekly, ≥ 14 days otherafter last negative blood culture) forProgressive disease

Change the antifungal class Only (supported by susceptibility results) Not Legend: strongly recommended gg moderately recommended gg marginally recommended gg recommended against gg

CVAD, central vascular access device; iv, intravenous; po, per os 1453

1454

114

1455 Surgical treatment

1456 Evidence – Indications for a surgical approach for Rhodotorula infections will depend on the 1457 context where debridement or excision is needed. Data are few. If endocarditis is present, then 1458 valve replacement in conjunction with antifungal therapy has been associated with good 1459 outcomes.[58-60] Amongst four cases of endocarditis, three had aortic valve replacement whilst 1460 the fourth, a 10-year old child, recovered without resection of a mobile lesion on the wall of the 1461 right atrium.[407] In a rare instance of an infected transplanted cardiac allograft, R. glutinis was 1462 grown from a resected vegetation on the atrial appendage.[380] Debridement and early removal 1463 of an intramedullary nail was essential for recovery in one case of femur infection.[62] In three 1464 patients with endophthalmitis, vitrectomy (in two) and enucleation in the remaining was 1465 required for cure of infection.[215-217]

1466 Recommendations – The guideline strongly supports, with early engagement of surgical 1467 colleagues, vegetectomy and valve replacement where there is evidence of endocarditis, 1468 debridement of bone with removal of prosthetic material and surgical removal of infective foci 1469 in the eye (Table 8). consultation. 1470 distribution. 1471 Antifungal drug treatment

1472 Evidence – Data regarding the treatment of Rhodotorula infections shows that treatment is 1473 driven by diagnosis upon isolationpublic of Rhodotorula spp. from blood cultures but also from CSF, 1474 peritoneal dialysis fluid and other body fluidsother or tissue. 1475 for

1476 For fungaemia, data on selectionfor of antifungals are guided by in vitro data and are predominantly 1477 based on case reports and case series both in the adult and in paediatric populations (Table 1478 21).[15,Only 146, 153-158, 161, 332, 336, 399, 403] Many larger case series of uncommon yeast infections did not 1479 separate treatmentNot data specific for Rhodotorula infections from those caused by other 1480 pathogens[17, 18] The 2014 ESCMID guideline strongly recommends any amphotericin B 1481 formulation as the preferred treatment with caution against the use of azoles and echinocandins 1482 to which Rhodotorula species are intrinsically resistant to.[7] Since then, the literature continues 1483 to support this caution even though some Rhodotorula isolates have exhibited low MICs to azoles 1484 (see Susceptibility). There are no data on efficacy of posaconazole or isavuconazole in

115

1485 Rhodotorula infections but MICs to these drugs are often high. Good treatment responses have 1486 been observed following therapy with an amphotericin B formulation, typically alone, but also in 1487 combination with 5-flucytosine (Table 21).[151, 154, 155] Both amphotericin B deoxycholate and 1488 liposomal amphotericin B have been used with good efficacy. Although there are anecdotal 1489 reports of patients recovering without antifungal treatment [332, 390, 403] there are no clinical trials 1490 for treatment of Rhodotorula infections and such practice is strongly discouraged, especially in ill 1491 patients. Salvage treatment options should be guided by in vitro susceptibility results. Table 21 1492 also summarizes the recommendations for Rhodotorula infections other than fungaemia.

1493

1494 Table 21. Recommendations on targeted antifungal therapy for Rhodotorula infections

Population Intention Intervention SoR QoE Reference Comment

Fungemia

Haemato- To cure c-AmB 1 mg/kg/d B IIu Garcia-Suarez Mycoses 2011 N=22 oncology [399] To define or (adults and consultation. epidemiology Potenza Mycoses 201 9 [334] N=15 L-AmB 3 mg/kg/d paediatrics) with or without Lunardidistribution. CID 2006 [336] N=4 5-FC 4 x 25 mg/kg/d Mori TID 2012 [155] N=1, cured Haematology/ To cure c-AmBpublic (doses not B IIu Capoor IndJMedMycol 2014 N=9, all cured Neurology specified) [148] Haemato- To cure L-AmB 3 mg/kg/dother B IIu Potenza Mycoses 2019 [334] N=2 oncology for To define and (adults and epidemiology VRC 2 x 6 mg/kg on d1 paediatrics) for followed by

Only 2 x 4 mg/kg/d Not CAS 70 mg/d1, followed B IIu Potenza Mycoses 2019 [334] N=1 by 50 mg/d

and

FLU 400 mg/d

FLU 400 mg/d B IIu Lunardi CID 2006 [336] N=1

116

Any (adults To cure c-AmB 1 mg/kg/d B IIu Zaas JCM 2003 [146] N=6 and pediatrics) To define or De Almeida MedMycol 2008 N=15 epidemiology [151] L-AmB 3 mg/kg/d Falces-Romero Mycoses 2018 N=5 [154]

Fernandez-Ruiz MedMycol N=2 2017 [15]

FLU 400 mg/d B IIu Zaas JCM 2003 [146] N=3

De Almeida MedMycol 2008 N=1 [151]

Neonates To define AmB (formulations and B IIu Perniola EJCMID 2006 [157] N=4, cured epidemiology doses not specified)

To investigate outbreak Haematology To cure L-AmB 4 mg/kg/d B consultation. III Fores Mycoses 2012 [158] N=1, cured (HSCT) L-AmB (dose not B III Migleitta MMJ 2015 [156] N=1, cured specified) distribution. Cancer To cure FLU (dose not specified) D III Hsueh JCM 2003 [160] N=1, cured

Trauma To cure c-AmB 1 mg/kg/d B III Duggal MedMycol 2011 [161] N=1, cured

CNS infections public Haematology To cure L-AmB 5 mg/kg/dother B III Tsiodras MMCR 2014 [61] N=1, died forand 5-FCfor 4 x 2 g/d HIV+ve To cure c-AmB 0.7 mg/kg/d B III Shinde IndJMedMicrobiol 2008 N=1 Only [372] Not Nor Mycopathologia 2015 [353] N=1, cured

c-AmB 1 mg/kg/d B III Baradkar AnnIndAcadNeurol N=1, cured 2008 [370]

c-AmB 0.7 mg/kg/d B III Thakur IndJMedMicrobiol 2007 N=1, died [374] and

117

5-FC 4 x 25 mg/kg/d

5-FC 4 x 2 g/d D III Gyargieva JMedVetMycol 1996 N=1, relapsed [415]

HIV+ve To continue ITC 2 x 200 mg/d D III Nor Mycopathologia 2015 [353] N=1, cured therapy after Baradkar AnnIndAcadNeurol N=1, cured 1st line 2008 [370] treatment Gyargieva JMedVetMycol 1996 N=1, cured [415]

Immuno- To cure c-AmB 1 mg/kg/d B III Lanzafame JCM 2001 [338] N=1, cured competent

Skin/ soft tissue infection

Renal To cure c-AmB B III George ClinExpDermatol 2016 N=1, two episodes transplant [92] of infection, cured and

5-FC

(doses not specified) consultation.

To continue VRC (dose not specified) B III George ClinExpDermatol 2016 N=1, two episodes therapy after [92]distribution. of infection, cured 1st line treatment

Endocarditis public Prosthetic To cure L-AmB 5 mg/kg/dother B III Simon JCM 2014 [60] N=1, cured cardiac valve To continuefor VRC 2 x 6 mg/kg on d1 B III Simon JCM 2014 [60] N=1, cured therapy after suppressive followed by 2 x 4 1st line for treatment mg/kg/d treatment

PaediatricOnly To cure c-AmB 1 mg/kg/d B III Pasqualotto N=1, cured haematology Not JPaediatrHematolOncol 2005 and [407] Native 5-FC 4 x 2 g/d structure endocarditis

118

Kidney To cure L-AmB (dose not B III Cabral JMMCaseRep 2017 [59] N=1, cured transplant specified) recipient

Native valve endocarditis

Immuno- To cure c-AmB 1 mg/kg/d B III Maeder Infection 2003 [58] N=1, cured competent To continue ITC 2 x 200 mg/d B III Maeder Infection 2003 [58] N=1, cured Aortic therapy after homograft 1st line endocarditis treatment

Bone infection

Trauma and To cure L-AmB (dose not B III Savini JCM 2008 [159] N=1, implied cure HIV specified)

Trauma To cure c-AmB 0.5 mg/kg/d B III Goyal JPostgradMed 2008 [62] N=1, cured Ocular infection consultation. Injecting drug To cure AmB C III Pinna BrJOph 2002 [215] N=1, cured user 5 ug intravitreal distribution. KTZ D III Pinna BrJOph 2002 [215] N=1, cured

Post-cataract To cure KTZ D III Gregory ArchOphthalmol 1992 N=1, cured surgery public [216] HIV-infected To cure c-AmB 0.5 mg/kg/dother B III Merkur BrJOphthalmol 2002 N=1, cured for [217] AmB C III Merkur BrJOphthalmol 2002 N=1, cured [217] 5 ugfor intravitreal PeritonealOnly infections CAPD patients To cureNot L-AmB B III Franconieri PeritDialInt 2018 N=1, cured [162] 3 mg/kg/d

c-AmB B III Eisenberg AmJMed 1983 [339] N=2, cured

3-5 mg/litre of dialysate q6h intraperitoneally

119

KTZ D III Eisenberg AmJMed 1983 [339] N=1, died

c-AmB C III Flanigan AmJMed 1984 [416] N=1, cured

5 g single dose intraperitoneally

Paediatric To cure c-AmB B III Wong JInfect 1988 [417] N=1, cured

1 mg/litre dialysate intraperitoneally

c-AmB (dose not B III Pennington DelMedJ 1995 N=1, cured sepcified) [418]

c-AmB 0.5 mg/kg/d B III Soylu PediatrNephrol 2004 N=1, cured [382]

c-AmB 1 mg/kg/d B III Unal IntUrolNephrol 2011 [405] N=1, cured

SoR, strength of recommendation; QoE, quality of evidence; N, number of subjects investigated; 5-FC, 5-flucytosine; ABLC, amphotericin B lipid complex; AmB, amphoteiricn B; c-AmB, conventional amphotericin B; CAS, caspofungin; CAPD, continuous ambulatory peritoneal dialysis; CNS, central nervous system; FLU, fluconazole; HSCT, hematopoietic stem cell transplantation; ITC, itraconazole; KTZ, ketoconazole;consultation. L-AmB, liposomal amphotericin B; MICA, micafungin; VRC, voriconazole

1495 distribution.

1496 Similar data describe good outcomes with amphotericin B-based therapy for Rhodotorula 1497 endocarditis (Table 21). In onepublic report, 5-flucytosine was co-administered for the duration of 1498 therapy.[407] Simon et al. reported a patientother where the initial course of liposomal amphotericin B 1499 was followed by a year’sfor duration of voriconazole); the rationale behind selection of an azole was 1500 not described.[60] In endophthalmitis, one patient received intravitreal amphotericin B in addition 1501 to vitrectomy followed by ketoconazole;for [215] another received ketoconazole without intravitreal 1502 therapy.[216] A third received both systemic and intravitreal amphotericin B.[217] In patients with 1503 meningitis,Only the commonest regimen employed was an amphotericin B formulation with/without 1504 5-flucytosine. In someNot patients, itraconazole was used to follow on amphotericin B therapy with 1505 cure.[353, 370] Of 13 cases of Rhodotorula CNS infection, seven patients received an amphotericin 1506 B-based regimen and three died (two had haematological malignancy and one HIV/AIDS).[61] 1507 There are no studies to support the use or any azole in Rhodotorula meningitis. In Rhodotorula 1508 CAPD peritonitis, antifungal treatment has been predominantly amphotericin B-based, used 1509 systemically and intraperitoneal. The absence of comparative clinical trial data indicates that

120

1510 amphotericin B regimens are preferred.

1511

1512 Recommendations – For fungaemia, antifungal treatment after diagnosis is made is strongly 1513 recommended. The use of either any amphotericin B formulation with or without 5-flucytosine 1514 is supported with moderate strength. In the event of failure of first line therapy, the guideline 1515 recommends with moderate support the use an alternate antifungal agent advised by in vitro 1516 susceptibility results. Recommendations are similar for non-bloodstream infections (Table 21). 1517 The use of azoles and echinocandin are strongly discouraged because of intrinsic resistance.

1518

1519 Other treatments: growth factors and removal of medical devices

1520 Evidence – As with other rare yeast infections, in immunocompromised patients with 1521 hematological malignancy and neutropenia, and who may also be very young or very elderly, the 1522 question of white cell support has been asked.[254] Data to support the use of granulocyte growth 1523 factors or granulocyte transfusions in Rhodotorula infectionsconsultation. are scarce. 1524

1525 If present, the removal of CVADs has been associated with distribution.cure of fungemia in case reports and 1526 case series.[155, 156, 158, 331, 332, 336, 399] CVAD removal has been reported to cure infection without 1527 accompanying antifungal therapy.public[52, 335] Conversely, there are reports of patients improving or 1528 being cured without catheter removal.[155,other 336, 337, 407] Hence device removal is indicated but may 1529 not always be associatedfor with cure of infection. 1530 for 1531 A retrospective study of seven patients with fungemia from Brazil all had their CVADs removed; 1532 threeOnly died and two were cured with CVAD removal alone.[336] Of 20 cases of fungemia in another 1533 study, all patientsNot had a CVAD in situ 17 of whom had their catheters removed - three of these 1534 patients died.[151] In a more recent study of 27 patients with fungemia, the mortality amongst 1535 patients treated without CVAD removal was 50% (4/8 cases) compared with a mortality of 19% 1536 (3/16) who had CVAD removal.[334]

1537

1538 The benefits of removal of other implanted medical devices, with particular attention on CAPD

121

1539 catheters [162, 331, 389, 405, 406, 419, 420] has also been reported. In a review of 10 cases,[162] 9 patients 1540 had their dialysis catheter removed with cure. Others have reported in patients without catheter 1541 removed mixed outcomes.[339, 389] The updated International Society for Peritoneal Dialysis (ISPD) 1542 guideline for adults recommend catheter removal immediately after a diagnosis of any fungal 1543 peritonitis.[419] A large deep cutaneous lesion on the scalp failed to respond to azole antifungals 1544 but was cured by a month’s duration of topical salicylic acid, and modified photodynamic therapy 1545 (blue light, and 595 nm pulsed laser) with debridement.[406]

1546

1547 Recommendations –There are no data and hence little to support the use of growth factors in 1548 subset of patients who may be neutropenic or in haematological malignancy. Removal of CVADs 1549 is recommended with strong support as is removal of other medical devices and dialysis 1550 catheters.

1551 1552 Treatment duration consultation. 1553 Evidence –Duration varies according to site and extent of infection. For fungaemia, clinical cures 1554 have been reported with 8-41 days of antifungal therapydistribution. but with most reports describing 1555 between 9-16 days.[15, 151, 154, 156-158, 161, 332] In one series, the average duration of therapy was 13.4 1556 days[151] whilst in another, average duration of amphotericin B treatment was 10-37 days 1557 (average total dose 1254 mg).[399]public In the review by Tuon et al. the range of duration of therapy 1558 was 14-41 days (mean total dose 1368 g).other[332] 1559 for

1560 Of five patients with endocarditisfor who survived, two received approximately 40 days of antifungal 1561 (amphotericin B formulation with/without 5-flucytosine) therapy,[59, 407] one patient with 1562 prostheticOnly valve infection received six weeks of liposomal amphotericin B therapy followed by >1 1563 year of suppressiveNot voriconazole therapy[60] and the last patient, 28 days of amphotericin B 1564 therapy followed by 28 days of itraconazole.[58] Duration of therapy for endophthalmitis was 3, 1565 and 4 weeks for two patients.[215, 216] The single case of bone infection for which duration of 1566 therapy was specified was 4 weeks[62] whilst skin/soft tissue lesions required 3-6 months of 1567 therapy.[92] Treatment duration of Rhodotorula meningitis has ranged from 14 days to 2 1568 months,[61, 338, 353, 370, 372, 374] whilst duration of treatment for CAPD-associated infection has

122

1569 ranged from 2 to 4 weeks,[162] though in general, antifungal therapy is continued for 4-6 weeks 1570 for fungal peritonitis.[420]

1571

1572 Recommendation – Treatment duration should be guided by clinical response, the extent of 1573 infection, the organs involved, and ongoing immunosuppression. For fungaemia, treatment 1574 duration is empirical, but the guideline strongly supports a duration of 2-3 weeks. For 1575 endocarditis, a longer period of treatment (at least 6-8 weeks and for prosthetic valve infection 1576 up to 1 year) is moderately supported, in conjunction with strong support for surgical measures. 1577 In peritonitis, there is also moderate support for a longer period of treatment (4-6 weeks).

1578

1579 INFECTIONS DUE TO SACCHAROMYCES SPECIES

1580 Taxonomy and epidemiology

1581 Saccharomyces cerevisiae represents the classic baker or brewer’s yeast, with Saccharomyces 1582 cerevisiae var. boulardii (sometimes referred to as ‘S.consultation. boulardii’) being the specific strain which is 1583 used as a probiotic for the prevention or treatment of diarrheal illnesses. Both species of the S. 1584 cerevisiae species complex have low but definite human pathogenicity.distribution. S. boulardii when used as 1585 a probiotic in large amounts has been shown to translocate across luminal surfaces of the 1586 gastrointestinal tract in severelypublic immunosuppressed patients and produce fungaemia.[64, 173, 421] 1587 The global distribution of reported cases of systemic infection is shown in Figure 21. 1588 Saccharomyces species are phylogeneticallyother close to Candida glabrata and although less common 1589 as a human pathogenfor than C. glabrata, their clinical and microbiological characteristics may be 1590 similar. for 1591 Only Not

123

1592 Figure 21. Worldwide distribution of Saccharomyces infections (reported cases between 2000 1593 and 2019 per million population)

1594

1595 Legend: Cases of Saccharomyces-related infections reported in the medical literature between 1596 2000 and 2019 were identified on January 15, 2020 primarily through PubMed using the search 1597 string (Saccharomyces AND (infection OR invasive ORconsultation. fungemia OR blood OR isolate) AND (case 1598 [Title/Abstract] OR patient [Title/Abstract] OR report [Title/Abstract])) that yielded 712 1599 publications. In total, 107 cases were identified from 21 countriesdistribution.[3, 5, 17, 63, 64, 165, 172, 174, 175, 422-468]. 1600 Most cases were reported from India and Spain (each N=16), United States of America and China 1601 (each N=15), Italy (N=8) and Brazilpublic (N=7). Three cases of S. cerevisiae-related infections were from 1602 an outbreak in an Italian intensive care unit [460]. Number of cases reported between 2000 and 1603 2019 are presented as cases per millionother population per country. The resident population per 1604 country was obtainedfor from www.worldometers.info. [47] 1605 for 1606 Clinical manifestations of Saccharomyces species range from asymptomatic colonization in 1607 humansOnly to fungaemia and disseminated disease.[441, 453, 469, 470] Like many environmental low- 1608 grade fungal pathogens,Not it is the host that critically determines the presence of disease with these 1609 fungi. Systemic infection with fungemia and disseminated disease mostly occurs in those with 1610 underlying immunocompromised states and can be specifically increased when S. boulardii 1611 probiotic is used in certain high-risk patients. Thus, yeast probiotics should be avoided in 1612 debilitated, immunocompromised patients, those in ICUs,[453] neutropenic patients [94, 421] or 1613 preterm newborns.[470] Since Saccharomyces species can produce biofilms, they have the

124

1614 potential to colonize CVADs and other foreign bodies and this fact can become a management 1615 issue for disease. Although of low pathogenicity Saccharomyces spp. are used as probiotics and 1616 in certain hosts can produce disease that must be treated.

1617

1618 Diagnosis

1619 All modalities of culture, MALDI-TOF MS, antigen detection and molecular approaches to 1620 diagnosis are considered (see Figure 22). The few data reported on the use of imaging, 1621 histopathology and direct detection in clinical specimens by molecular methods are summarised 1622 in Table 3 and Table 4. Direct microscopy, culture and species identification are discussed 1623 together below.

1624

1625 Figure 22. Diagnostic pathway for suspected cases of systemic Saccharomyces infections consultation. distribution. public for other for Only Not 1626

1627 Table 22. Recommendations on microscopy and culture in Saccharomyces spp. infections

Population Intention Intervention SoR QoE Reference Comment

Any To diagnose Culture A III Popiel TID 2015 [172] N=1, blood

125

All Cassone JCM 2003 [460] N=4, blood specimens Appel-da-Silva MMCR 2017 [174] N=1, blood

Santino IntJImmPathPharm 2014 N=1, blood [175]

Fadhel MMCR 2019 [425] N=1, blood

Thygesen BMJ CR 2012 [440] N=1, blood

Cesaro SCC 2000 [466] N=1, blood

Smith JCM 2002 [63] N=1, blood, periaortic fluid

Lolis CritCare 2008 [447] N=1, blood

Atici MMCR 2017 [173] N=1, blood

Shiakh IndPed 2016 [471] N=1, blood (S. kluyveri)

Tiballi DMID 1995 [167] N=3, peritoneal fluid, abscess, ECMO circuit Belet PIDJconsultation. 2005 [472] N=1, blood, CVAD tip Henry ActaClinBelg 2004 [456] N=1 blood Cimolai DMID 1987distribution. [473] N=1, blood Roy Mycoses 2017 [165] N=10, 7 blood, 3 probiotics publicMunoz CID 2005 [453] N=4, 3, blood, 1 probiotic Pillai SaudJKidDisTrans 2014 [64] N=1, blood, urine, stool, for other vaginal swab No probiotic use Haematology To establish Culturefor A IIu Olver JHospInfect 2002 [421] N=3 patients, N=4 surveillance epidemiology culture All (outbreak) Only specimens Various sites including lymph Not node No probiotic use

S. cerevisiae: cream coloured smooth moist colonies on SDA or SDA with chloramphenicol

SoR, strength of recommendation; QoE, quality of evidence; N, number of subjects investigated; CVAD, central venous access device; ECMO, extracorporeal membrane oxygenation

1628

126

1629 Evidence – Culture of S. cerevisiae from a sterile body site is a definitive diagnosis (Table 22). 1630 These urease-negative yeasts are slightly larger than C. glabrata on Gram stain and may produce 1631 small pseudohyphae. They can be identified by biochemical studies and the colonies are dark 1632 pink on CHROMagar Candida (CHROMagar). MALDI-TOF MS is increasingly used for identification 1633 to both genus and species level with reference to a reliable database, either commercial alone 1634 or that supplemented by in-house spectra (Table 23).

1635

1636 Table 23. Recommendations on genus and species identification of Saccharomyces spp.

Population Intention Intervention SoR QoE Reference Comment

Phenotypic identification

Any To identify to Colonial B III Popiel TID 2015 [172] N=1, API 20C AUX species level morphology (bioMeiruex) Yeast Carbohydrate cells are oval, 4-8 by (carbon) 5-10 um; ascopores assimilation consultation.on sodium acetate and medium biochemical B III Santino N=1, API ID32C, Vitek tests distribution. IntJImmunopatholPharmacol 2 ID-YST (bioMerieux) 2014 [175]

publicB III Cesaro SuppCareCanc 2000 N=1, API 32C other [466] (bioMerieux) for B III Smith JCM 2002 [63] N=1, API 20C AUX (bioMerieux) , Uni- for Yeast TEK (Remel), ascopres Only B III Atici MMCR 2017 [173] N=1, API ID 32C Not (bioMeireux) C IIu Kellogg JCM 1999 [474] N=12, MIS (Microbial ID)

B III Cimolai DMID 1987 [473] N=1, API 20C, Vitek Yeast I (bioMerieux)

127

Any To identify to Colour on B IIu Ghelardi CMI 2008 [475] N=28, distinct violet genus Chromogenic colour, requires Candida agar incubation for 48h at (Oxoid) 37°C. Small pinpoint colonies

Any To identify to Colonial D III Cassone JCM 2003 [460] N=4, API Italia. No species level morphology, details on how and to carbohydrate accurate the ID was establish (carbon) B IIu Sobel CID 1993 [168] N=20, 9 patients. epidemiology assimilation Germ tube, API tests and (bioMerieux) biochemical Chitasombat JInfect 2012 N=8, Vitek Yeast +/- tests [17] API 20C Aux, (bioMerieux) supplemental morphological studies consultation.using cornmeal Tween 80 and slide distribution.cultures Munoz CID 2005 [453] N=4, morphological and biochemical public methods (not specified). other Hennequin EJCMID 2000 N=4, API ID32C, for [476] ApiZym, (bioMerieux) for ascospores Lherm ICM 2002 [477] N=7, phenotypic, Only ascopores Not Barchiesi AAC 2000 [145] N=15, conventional methods but not specified

Salonen JHospInfect 2000 N=168, morphological [166] and biochemical methods, not specified

128

Olver JHospInfect 2002 [421] N=7, germ tube test, API 20C AUX (bioMerieux)

Minea EJCMID 2015 [164] N=11, API ID 32C (bioMerieux) (supplemented by MALDI TOF MS and DNA sequencing)

Lohmann JCM 2013 [207] N=20, Auxacolor 2 (Biorad) and API 32C (bioMerieux). No misidentifications

Whilst most studies indicate accurate ID, biochemical systems should always be accompanied by morphological studies using slide culture technique

MALDI TOF MS

Any To identify to MALDI-TOF B IIu Appel-da-Silva MMCR 2017 N=1, correct ID, species level MS consultation.[174] system not stated identification Fadhel MMCR 2019 [425] N=1, correct ID, distribution.system not stated

Atici MMCR 2017 [173] N=1, no system public stated Kolecka JCM 2013 [25] N=3, Bruker system other (Bruker Daltoniks), for Bruker database and in house. All three for non-clavata species not identified

Only Xiao InfectDrugRes 2018 [5] N=16, Vitek MS (Vitek Not database) (bioMerieux)

Mancini JCM 2013 [209] N=5, S. cerevisiae; all identified by Bruker (Bruker Daltoniks)

129

and Vitek systems (bioMerieux)

Westblade JCM 2013 [211] N=70, 68 identified correctly by Vitek MS system (bioMerieux)

Minea EJCMID 2015 [164] N=11, Bruker system (Bruker Daltoniks)

Lohmann JCM 2013 [207] N=20, Bruker (Bruker Daltoniks) and AXIMA -Saramis (Shimadzu), both 100% ID

Molecular Identification

Any To identify 18S rRNA A III Santino IntJImmPharm 2014 N=1 (blood) species and to sequencing [175] diagnose A IIu Leaw JCM 2006 [478] N=8, various sites

A III consultation. Smith JCM 2002 [63] N=1 (blood, periaortic fluid) Any To identify to ITS A IIu Leawdistribution. JCM 2006 [478] N=8, various sites species level sequencing Xiao InfectDrugRes 2018 [5] N=16, various sites Any To establish ITS, 28Spublic rRNA A IIu Mancini JCM 2013 [209] N=5, S. cerevisiae epidemiology D1/D2 Minea EJCMID 2015 [164] N=11, S. cerevisiae and identify to sequencing other species level forITS, 28S rRNA A IIu Bretagne JAC 2017 [18] N=35 D1/D2 for sequencing

28S rRNA A IIu Westblade JCM 2013 [211] N=70 Only D1/D2 Notsequencing

28S rRNA A IIu Roy Mycoses 2017 [165] N=10, 7 blood, 3 D1/D2 probiotic sequencing

130

Restriction C IIu Lherm ICM 2002 [477] N=7 enzyme analysis

1637

1638 Limited data are available on Saccharomyces molecular detection and identification. Real-time 1639 PCR targeting ITS2, or 28S, rRNA gene regions, or ITS2 PCR-based fluorescent capillary 1640 electrophoresis were successfully used to detect Saccharomyces species in clinical material 1641 including biofilm formation on urinary catheters. Identification of cultured isolates to species 1642 level can be achieved by ITS2, 28S rRNA or 18S rRNA sequencing.

1643

1644 Recommendation – Imaging tests to determine site of infection is moderately-to-strongly 1645 supported as indicated. We strongly support the examinationconsultation. of all tissue specimens for presence 1646 of fungal pseudo-hyphae and yeast forms by direct microscopy using standard histopathological 1647 stains in tissue specimens where an IFD is in the differential distribution.diagnosis. All Saccharomyces species 1648 from sterile sites should be identified to species level with either MALDI-TOF-MS and/or DNA 1649 sequencing for accuracy. Serological tests are less precise and used for unique screening (see 1650 later). public 1651 for other 1652 Susceptibility testing

1653 Evidence – In many respects, Saccharomycesfor species in vitro susceptibility results for antifungal 1654 drugsOnly are similar to C. glabrata, although it should be appreciated that the CBPs applied to C. 1655 glabrata cannot beNot used for Saccharomyces species. At times, azoles such as fluconazole may 1656 have high MICs in some isolates, but the majority of isolates possess low MICs for fluconazole 1657 and the other extended-spectrum azoles. There are low MICs to amphotericin B, the 1658 echinocandins and 5-flucytosine (Table 6).

1659 Recommendation – The guideline recommends with moderate strength to perform MICs on all 1660 isolates from sterile body sites requiring treatment using a reference broth microdilution

131

1661 method. Susceptibility testing by reference methods for epidemiological studies is strongly 1662 supported.

1663

1664 Antifungal treatment and other management

1665 For treatment of Saccharomyces fungaemia and disseminated disease, the use of extended- 1666 spectrum azoles, echinocandins or amphotericin B should be successful. However, there can be 1667 failures associated with all three drug classes[166] so it is reasonable to perform MIC testing with 1668 these classes of antifungal agents with a particular emphasis on fluconazole susceptibility.[152, 167, 1669 479] Also, with Saccharomyces biofilm capacity, we recommend to remove intravascular catheters 1670 and replace them if possible after bloodstream has been cleared of yeasts with antifungal 1671 therapy.

1672

1673 Recommendation – The choice of antifungal class will depend on MICs and the clinician’s choice 1674 for the specific clinical condition, but all the majorconsultation. antifungal classes may be empirically 1675 considered with moderate support (Table 24). Similar to most fungal infections, source control 1676 and removal of catheter may be important for cure anddistribution. are strongly recommended. The 1677 suggested treatment pathway for use of antifungal drugs is summarised in Figure 23. 1678 public 1679 Table 24. Recommendations on targeted otherantifungal therapy for Saccharomyces infections Population Intentionfor Intervention SoR QoE Reference Comment S. cerevisiae Fungaemia for Liver To cure CAS 70 mg/d1 B III Popiel TID 2015 [344] N=1, cured transplant Only followed by 50 mg/d Any To cureNot FLU 400 mg/d B IIu Cassone JCM 2003 [370] N=3, cured Outbreak, probiotic use

Munoz CID 2005 [363] N=2, died

Hennequin EJCMID 2000 N=2, cured [792]

132

Hamoud IMAJ 2011 [351] N=1, also Bone marrow infection

2/4 episodes

Fadhel MMCR 2019 [331] N=1, plus cessation of probiotic, cured

Any To cure c-AmB 1 mg/kg/d B IIu Hennequin EJCMID 2000 N=1, cured [792]

Hamoud IMAJ 2011 [351] N=1, also Bone marrow infection

1/4 episodes

Any To cure c-AmB B III Hamoud IMAJ 2011 [351] N=1, also Bone marrow infection and 1/4 episodes 5-FC

4 x 1.5 g/d

Any To cure AmB B consultation. III Thygesen BMJCR 2012 [350] N=1, cured, post probiotic use, (formulation not specified) distribution.S. cerevisiae var. boulardii

Cesaro SuppCareCancer N=1, cured, post public 2000 [377] probiotic use other S. cerevisiae var. for boulardii Any To cure MICA 100 mg/d B III Appel-da-Silva MMCR 2017 N=1, cured, post for [336] probiotic use

S. cerevisiae var. Only boulardii Not Fadhel MMCR 2019 [331] N=1, cured, post probiotic use

S. cerevisiae var. boulardii

1 of 2 episodes

133

CAS 70 mg/d1 B III Santino N=1, cured, post IntJImmunopatholPharmac probiotic use followed by 50 mg/d ol 2014 [347] S. cerevisiae var. (or dose not specified) boulardii

Lolis CritCare2008 [357] N=1, cured, post probiotic use

S. cerevisiae var. boulardii

Paediatrics To cure c-AmB 1 mg/kg/d B III Belet PIDJ 2005 [781] N=1, cured

Chronic kidney To cure MICA B III Pillai Saudi JKidDisTranspl N=1, also renal tract disease and 2014 [326] infection, cured (dose not specified) diabetes mellitus

Chronic kidney To cure c-AmB (dose not specified) B III Cimolai DMID 1987 [782] N=1, died, probably disease, on not from dialysis consultation.Saccharomyces Vascular graft To cure AmB (formulation and dose B III Smith JCM 2002 [375] N=1, also aortic graft not specified) distribution.infection, died Vascular graft To cure CAS 70 mg/d1 B IIu Atici MMCR 2017 [327] N=1, probiotic had been stopped followed bypublic 50 mg/d Vascular graft To cure L-AmB B III Atici MMCR 2017 [327] N=1, probiotic had been stopped for3 mg/kg/d other Vascular graft To cure FLU 400 mg/d B IIu Lherm IntCareMed 2002 N=3 [793] and for c-AmB 1 mg/kg/d

Any Only To cure ABCD 0.75mg/kg/d B IIu Roy Mycoses 2017 [339] N=1, cleared fungus Not Followed by

MICA 2mg/kg/d

Any To cure MICA 2mg/kg/d B III Roy Mycoses 2017 [339] N=1, cured

Any To cure VRC (dose not specified) B III Roy Mycoses 2017 [339] N=1, cured

134

Followed by CAS (dose not specified)

Any To cure CAS (dose not specified) B III Roy Mycoses 2017 [339] N=1, cured

Followed by

VRC (dose not specified)

Any To cure MICA 100mg/d B III Roy Mycoses 2017 [339] N=1, cured

Followed by

FLU 400 mg bd

Any To cure CAS (dose not specified) B III Roy Mycoses 2017 [339] N=1, cured

S. kluyveri To cure L-AMB (dose not specified) C III Shaikh IndPaed 2016 [780] N=1, no outcome fungemia stated

S. kluyveri To cure CAS (dose not specified) C III Shaikh IndPaed 2016 [780] N=1, no outcome fungemia stated

S. kluyveri Non-fungemia

Haematology To cure CAS 70 mg/d1 B consultation. III Choi BJH 2012 [382] N=1, cured followed by 50 mg/d distribution. SoR, strength of recommendation; QoE, quality of evidence; N, number of subjects investigated; 5-FC, 5-flucytosine; ABCD, amphotericin B colloidal dispersion; AmB, amphoteiricn B; c-AmB, conventional amphotericin B; CAS, caspofungin; FLU, fluconazole; ITC, itraconazole;public L-AmB, liposomal amphotericin B; MICA, micafungin; VRC, voriconazole 1680 for other for Only Not

135

1681 Figure 23. Treatment pathway for antifungal therapy and management of systemic infections 1682 due to Saccharomyces spp.

Suspected and confirmed infections due to Saccharomyces spp. are emergencies and require rapid action

Timely, rapid antifungal therapy and management is required for suspected and confirmed infections

Surgical valve replacement

Amphotericin B Caspofungin Micafungin Fluconazole liposomal 70 mg/d d1; 100 mg/d 200-400 mg/d 3 mg/kg/d 50 mg/d from d2

Removal of CVAD

Response assessment (weekly, ≥ 14 days after last negativeconsultation. blood culture) Progressive disease distribution.

Change the antifungal class public(supported by susceptibility results) Legend: strongly recommended gg moderately recommended gg marginally recommended gg other recommended against forgg CVAD, central vascular access device; iv, intravenous; po, per os 1683 for 1684 SAPROCHAETEOnly INFECTIONS 1685 Taxonomy and epidemiologyNot 1686 Members of the genus Saprochaete were previously placed under the genera Geotrichum or 1687 Blastoschizomyces hence previous clinical data may be found under the names of these genera. 1688 Saprochaete capitata and S. clavata (previously of the genera Geotrichum or Blastoschizomyces) 1689 are non-fermentative, urease-negative environmental yeasts that occasionally are found as 1690 colonizers of human skin, sputum and GI tracts. S. capitata rarely causes disease but is a more

136

1691 common cause of infection than S. clavata (Figure 24).[69, 72, 97, 149, 176, 480-482] It is not yet clear 1692 whether S. clavata is less pathogenic and thus generally related to cluster outbreaks of 1693 infections[483] or if its rarity is due to confusion in identification.

1694

1695 Figure 24. Worldwide distribution of Saprochaete infections (reported cases between 2000 and 1696 2019 per million population)

consultation. 1697 distribution. 1698 Legend: Cases of Saprochaete capitata and S. clavata-related infections in the medical literature 1699 between 2000 and 2019 were identified in a PubMed search on January 15, 2020 using the search 1700 string ((Geotrich* OR Saprochaet*public OR Blastoschizomyc* OR Magnusiomyc* OR Dipodascus OR 1701 Galactomyces) AND (case [Title/Abstract]other OR patient OR report [Title/Abstract] OR infection OR 1702 invasive OR systemic forOR fungemia OR blood)) that yielded 594 publications of 205 cases from 30 1703 countries.[5, 15, 18, 28, 31, 65-73, 96, 97, 176, 181, 182, 345, 388, 480, 483-566] Most cases were reported from Italy 1704 (N=38), Spain (N=34), France, Turkeyfor (each N=22), Tunisia (N=11), China and Czech Republic (each 1705 N=10).Only Number of cases reported between 2000 and 2019 are presented as cases per million 1706 population per Not country. The resident population per country was obtained from 1707 www.worldometers.info.[47]

1708

1709 These yeasts most commonly cause fungaemia and disseminated diseases within the hemato- 1710 oncology settings and may present in clusters or outbreaks of nosocomial disease [65, 70, 96, 149, 179, 1711 567] but may also produce disease in immunocompetent individuals.[72] In severely

137

1712 immunocompromised patients, infection will commonly present with deep organ involvement 1713 such as hepatosplenic abscesses, metastatic skin lesions, brain abscesses and osteomyelitis. 1714 Infection can occasionally occur outside the hemato-oncology setting.[72, 178] and has been 1715 described to cause prosthetic valve endocarditis, pneumonia, fungemia and meningitis in the 1716 non-haemato-oncology setting. These yeasts must be considered a part of the fungal invaders in 1717 the management of hemato-oncology patients but in general, low virulent yeasts are a rare cause 1718 of human yeast disease.

1719

1720 Diagnosis and species identification

1721 All modalities of imaging, histopathology, culture, direct detection by molecular approaches 1722 should be considered as appropriate and are discussed together. The principles and methods are 1723 as for other uncommon yeasts and there is nothing routine for specific diagnosis.

1724 1725 Evidence – Primarily, this yeast’s appearance in diseaseconsultation. is from blood cultures or sterile body 1726 sites. Isolates grown on plates can produce hyphae, pseudohyphae and conidia. It can be 1727 identified by classical biochemical methods but with a largerdistribution. database, the use of MALDI-TOF MS 1728 has become more reliable.[25, 178] Molecular tests may prove definitive.[177] Molecular diagnosis 1729 through direct sequencing of blood and tissue specimens has been successful.[98] (Table 4, Table 1730 25, Table 26). public 1731 for other 1732 Table 25. Recommendations on microscopy and culture in Saprochaete spp. infections

Population Intention Interventionfor SoR QoE Reference Comment

Any To diagnose Direct A III Favre MMCR 2016 [66] N=1, blood cultures; septate Only microscopy hyphae Not Gram stain Tanabe EpidInfect 2018 [72] N=1, sputum, yeast cells with on blood pseudohyphae cultures

Other case reports or series of fungaemia do not specifically describe gram stain findings on blood culture, or other body fluids

138

Diabetes To diagnose Direct A III Subramanya Supram N=1, ETT, Sputum, bronchial mellitus Microscopy MedMycol 2016 [97] aspirate, pus

Gram stain Gram stain: Gram positive septate and 10% hyphae and yeast cells KOH wet KOH mount: thin, septate, hyaline mount hyphae with narrow angle branching and pleomorphic yeast- like cells

Diabetes To diagnose Direct A III Hazirolan JMM 2017 [568] N=1, yeast forms in urine mellitus, microscopy chronic Urine kidney disease

Any To diagnose and Culture A IIu Duran-Graeff Mycoses 2016 N=19, various sites establish [28] All epidemiology specimens Birrenbach EID 2012 [176] N=5, blood, skin, urine, peritoneal consultation.fluid, tissue, tracheal aspirate

De Principe Mycoses 2016 N=3, blood [65] distribution.

Fernandez-Ruiz MedMycol N=3, blood public2017 [15] otherKoc InfDisLond 2016 [180] N=20, blood, BAL fluid, wound for Ulu-KIlic Mycoses 2015 [179] N=18, blood Xiao InfDrugRes 2018 [5] N=7, various sites

for Bretagne JAC 2017 [18] N=21, blood Only Pamidumukkala JClinDiagnRes N=6, blood, sputum, BAL fluid Not 2017 [69] Schuermans MedMycol 2011 N=1, sputum, BAL fluid [71]

Any To diagnose Culture A III Fianci Infection 2018 [68] N=1, blood

All Gadea JCM 2011 [70] N=, blood specimens Chittick AAC 2009 [181] N=1, sputum

139

Favre MMCR 2016 [66] N=1, blood

Tanabe EpidInfect 2018 [72] N=1, sputum

Almeida MedMycol 2016 N=1, blood [509]

Etienne Mycoses 2008 [67] N=1, blood, throat, stool, skin biopsy, BAL fluid

Subramanya Supram N=1, blood, sputum, ETT, bronchial MedMycol 2016 [97] aspirate

Hazirolan JMycolMed 2017 N=1, urine [568]

Mandarapu IndJNephrol 2016 N=1, BAL fluid [73]

Colonies on blood agar and SDA are white to cream-coloured, after 10 days at 30°C, with a frosted glass, dry, funiculose appearance with a smooth expanding zone, for both species. SoR, strength of recommendation; QoE, quality of evidence; N,consultation. number of subjects investigated; BAL, bronchoalveolar lavage; ETT, endotracheal aspirate; KOH, potassium hydroxide 1733 distribution. 1734 Table 26. Recommendations on genus and species identification of Saprochete spp. Population Intention Interventionpublic SoR QoE Reference Comment Phenotypic identification Any To identifyfor to Conidial Bother IIu Martino CID 2004 [96] N=25. Three conidial species level morphology types of arthroconida, and for blastoconidia and carbohydrate anneloconidia (carbon) B III Koc InfDisLond 2016 [180] N=20. Anneloconidia. assimilation Only API 20C AUX and Not (bioMerieux). biochemical B III Schuermans MedMycol 2011 [71] N=1. API ID32 tests (bioMerieux), negative urease. Typical bamboo- like conidiophores on corn meal agar with

140

elongated conidia flattened at base

C III Del Principe Mycoses 2016 [65] N=3. Vitek 2 YST-ID (bioMeriex) (low discrimination)

D IIu Ulu-Kilic Mycoses 2015 [179] N=15. No details on how accurate the ID was

B IIu Subramanya Supram MedMycol 2016 N=7. Gram stain and [97] lactophenol cotton blue mount showed hyphae, pseudohyphae and annelloconidia resembling arthroconidia. Grew at

45◦C Assimilated consultation.glucose and galactose but did not hydrolyse distribution.urea B III D’Assumpcao J N=1, morphology using InvestMedHighImpactCase Rep 2018 lactophenol cotton blue public[182] B IIu Pamidumukkala JClinDiagnRes 2017 N=6. Colony for other[69] Morphology, API 1D32C, Vitek 2 ID-YSTI (both for bioMerieux) B III Mandarapu IndJNephrol 2016 [73] N=1, Vitek 2 ID-YST Only (bioMerieux) MALDI TOF MS Not Any To identify to MALDI-TOF MS B III Del Principe Mycoses 2016 [65] N=3, Bruker system, species level identification score >2.0, Bruker database

B IIu Duran-Graeff Mycoses 2017 [28] N=19, Bruker system, Bruker database

141

B III Favre MMCR 2016 [66] N=1, Bruker system, Bruker database

B IIu Kolecka JCM 2013 [25] N=3, Bruker system, Bruker database and in house. All three non- clavata species not identified.

B IIu Fraser MedMycol 2016 [208] N=21. Bruker (Bruker Daltoniks) with Bruker database. Full extraction. Mean log score 1.90

B IIu Aslani BMCID 2018 [178] N=1. Correct identification

C III Hazirolan JMM 2017 [568] N=1, Correct identification

consultation.System not specified.

B IIu Lohmann JCM 2013 [207] N=6. S. capitata. None distribution.identified by Bruker (Bruker Daltoniks) and Axima systems public (Shimadzu) Bother IIu Westblade JCM 2013 [211] N=32. 30 identified for correctly by Vitek MS system (bioMerieux)

Molecular Identification for

Any To identify ITS sequencing A III Birrenbach EID 2012 [176] N=5 (various sites) Onlyspecies and to A IIu Koc InfDisLond 2016 [180] N=20 (blood, wound diagnoseNot BAL, tissue)

A IIu Duran-Graeff Mycoses 2016 [28] N=19 (various sites)

A IIu Subramanya Supram MedMycol 2016 N=7 (various sites) [97]

A IIu Fernandez-Ruiz Med Mycol 2017 [15] N=3 (blood)

142

A III Hazirolan JMM 2017 [568] N=1 (urine)

A III D’Assumpcao N=1 (peritoneum fluid) JInvestMedHighImpactCaseRep 2018 [182]

Any To identify to ITS and 28S A IIu Subramanya Supram MedMycol 2016 N=7 (various sites). species level rRNA [97] and diagnose sequencing Kolecka JCM 2013 [25] N=3 (various sites)

Any To identify to ITS, 28S rRNA, A IIu Kaplan JCM 2018 [177] N=34. M. capitus and S. species level Rbp2, Act and clavata. The Tef1a interspecific similarity ITS and large subunit regions was in the range of 96 to 99%, whereas that using the loci Rbp2, Act, and Tef1a was 89.4 to 95.2%

SoR, strength of recommendation; QoE, quality of evidence; N,consultation. number of isolates investigated; HSCT, Haemopoetic stem cell transplant; ITS, internal transcribed spacer; MALDI-TOF, matrix assisted laser desorption ionisation time of flight; MS, mass spectrometry distribution. 1735 1736 Recommendation- In neutropenicpublic patients induced with chemotherapy, disease may 1737 radiographically look like hepatosplenal othercandidiasis. Culture is essential for epidemiology and 1738 antifungal susceptibilityfor and is strongly recommended. Species identification by molecular 1739 approaches is strongly supported, with phenotypic and MALDI-TOF MS methods, moderately 1740 supported (Table 26). for 1741 Only 1742 Susceptibility Not 1743 Evidence – S. capitata has low MICs to extended-spectrum azoles - itraconazole (MIC range 0.03- 1744 0.5 mg/L), posaconazole (0.016-1 mg/L), voriconazole (0.03-0.5mg/L), and isavuconazole) (0.016- 1745 0.5 mg/L). In contrast, fluconazole MICs are high (MIC 16-32 mg/L). However, in animal models, 1746 high doses of fluconazole are superior to low dose fluconazole, amphotericin B, voriconazole and 1747 5-flucytosine in prolonging survival time and decreasing fungal burden of disease. MICs for

143

1748 amphotericin B tend to be in the moderate range but MICs can be high (MIC 0.5-2 mg/L). 1749 Importantly, S. capitata is considered intrinsically resistant to echinocandins in vitro and in vivo. 1750 These yeasts have low MICs to 5-flucytosine (MIC 0.125-0.5 mg/L) (Table 6).

1751

1752 Recommendation – There are no breakpoint guidelines for in vitro susceptibility testing, and it 1753 remains most important to obtain correct identification of the Saprochaete spp. to help predict 1754 treatment. However, there is some variability of susceptibility of individual strains to azoles and 1755 it is reasonable to obtain MICs to assist with best treatment strategy. MIC determination for 1756 epidemiological knowledge using a reference method is strongly recommended.

1757

1758 Antifungal treatment and other management

1759 Evidence – No optimal treatment regimen for S. capitata has been established as there are no 1760 clinical trials comparing the different antifungal agents. However, the in vitro susceptibility data 1761 are relevant and do influence choice of antifungalsconsultation. agents.[70, 149, 180] Current guidelines 1762 recommend an amphotericin B formulation +/- 5-flucytosine or voriconazole for the initial 1763 treatment of these infections and this is mainly based on in vitrodistribution. susceptibility studies and limited 1764 clinical data from case series and case reports. Breakthrough S. capitata infections were seen 1765 predominantly in immunocompromised patients receiving echinocandin prophylaxis,[71] 1766 however, breakthrough infectionspublic with posaconazole, amphotericin B, caspofungin and 1767 fluconazole have also been reported. Theother echinocandins should not be used as monotherapy[71, 1768 98, 181, 568] as they werefor associated with increased mortality but case reports have used them in 1769 combination regimens especiallyfor with voriconazole due to a potential in vitro synergistic 1770 effect.[66-68] Despite low MICs to 5-flucytosine, during neutropenia there is some hesitancy to use 1771 this drugOnly due to direct bone marrow toxicity. In this case, an extended- spectrum azole with or 1772 without a lipid formulationNot of amphotericin B can be used. High dose fluconazole may be used as 1773 an alternative to extended-spectrum azoles in selected patients with susceptible strains. Despite 1774 treatment with antifungals with good in vitro activity against S. capitata, outcomes can remain 1775 poor.[65, 480]

1776

144

1777 There are not enough data to direct the precise management of CVADs in patients with invasive 1778 S. capitata infections, but early catheter removal had a positive impact on survival in one study. 1779 Adjunctive colony stimulating factor or interferon gamma (IFN-g) infusions and neutrophil 1780 transfusions in addition to antifungal therapy may be helpful and should be considered in select 1781 patients.[66] There are also insufficient data to recommend surgery for managing S. capitata 1782 infection however, surgery (e.g. splenectomy for splenic abscess or lesions) might be beneficial 1783 and should be considered in selected cases that are refractory to antifungal therapy.

1784

1785 Recommendations – The guideline supports with moderate strength that this IFD should be 1786 managed with an extended-spectrum azole (voriconazole, posaconazole or isavuconazole) with 1787 or without addition of a polyene (Table 27). The guideline further strongly recommends that the 1788 underlying disease including neutropenia is controlled and/or resolved and ideally, all CVADs and 1789 other foreign bodies are removed. The guidline recommends the treatment pathway shown in 1790 Figure 25. consultation. distribution. public for other for Only Not

145

1791 Figure 25. Treatment pathway for antifungal therapy and management of systemic infections 1792 due to Saprochaete spp.

Suspected and confirmed infections due to Saprochaete spp. are emergencies and require rapid action

Timely, rapid antifungal therapy and management is required for suspected and confirmed infections

Amphotericin B Amphotericin B liposomal deoxycholate 3 mg/kg/d 1 mg/kg/d Posaconazole Voriconazole iv/po suspension 2x6 mg/kg/d d1; Echinocandins ± 4x200 mg/d 2x4 mg/kg/d from d2 Voriconazole iv/po 2x6 mg/kg/d d1; 2x4 mg/kg/d from d2

Removal of CVAD

Response assessment (weekly, ≥ 14 days after last negative blood culture)

Legend: strongly recommended gg moderately recommended gg marginally recommended gg recommended against gg consultation.

CVAD, central vascular access device; iv, intravenous; po, per os 1793 distribution. 1794 Table 27. Recommendations on targeted antifungal therapy for Saprocheate infections

Populatio Intention Intervention SoR QoE Reference Comment n public Any To cure AmB (formulation and dosesother B IIu Birrenbach EID 2012 [176] N=5, 2 survived varied or not specified) for Del Principe Mycoses 2016 N=3 with or withoutfor [65] 5-FC 4 x 25 mg/kg/d Koc InfDisLond 2016 [180] N=15, 8 survived Only Ulu-Kilic Mycoses 2015 N=9 cured by these Not [179] regimens Favre MMCR 2016 [66] N=1, survived. 88 days treatment

Fianci Infection 2008 [68] N=1, survived. Total duration > 35 days

146

Mandarapu IndJNephrol N=1, total 6 weeks 2016 [73]

Fernandez-Ruiz MedMycol N=3, 2 died 2017 [15]

Pamidumukkala N=3, 1 cured JClinDiagnRes 2017 [69]

Martino CID 2004 [96] N=18

Gadea JCM 2004 [70] N=7

Duran-Graeff Mycoses 2017 Lower mortality than with [28] use of echinocandins

Any To cure VRC 2 x 6 mg/kg/d1 B IIu Birrenbach EID 2012 [176] N=5, 2 survived

followed by Del Principe Mycoses 2016 N=3 [65] 2 x 4 mg/kg/d Koc InfDisLond 2016 [180] N=15, 8 survived (or dose not specified) consultation.Ulu-Kilic Mycoses 2015 N=9, cured [179] Favre MMCRdistribution. 2016 [66] N=1, survived. 88 days treatment

Fianci Infection 2008 [68] N=1, survived. Total public duration > 35 days otherMandarapu IndJNephrol N=1, total 6 weeks for 2016 [73] Fernandez-Ruiz MedMycol N=3, 2 died for 2017 [15]

Martino CID 2004 [96] N=25. Most (N=18) received Only an amphotericin B Not formulation; 5 died

Etienne Mycoses 2008 [67] N=1, cured

Combination therapy was for 35 days

147

Duran-Graeff Mycoses 2017 Lower mortality than with [28] use of echinocandins

Any To cure Adjuvant granulocyte B III Favre MMCR 2016 [66] N=1 infusions

Any To cure CAS 70 mg/d1 B IIu Fianci Infection 2008 [68] N=1, survived. Total duration > 35 days followed by 50 mg/d Etienne Mycoses 2008 [67] N=1, cured (or dose not specified) Combination therapy was for 35 days

Any To cure ITC 400 mg/d or C III Tanabe EpidInfect 2018 [72] N=1, cured after 4 months. No long term follow up. dose not specified Martino CID 2004 [96] N=2, cured

Duran-Graeff Mycoses 2017 Lower mortality than with [28] use of echinocandins Any To cure FLU 200-600 mg/d B IIu consultation. Martino CID 2004 [96] N=2, one cured (or dose not specified) Duran-Graeff Mycoses 2017 Lower mortality than with [28] distribution.use of echinocandins Chronic To cure Echinocandins D III Hazirolan JMM 2017 [568] N=1, failure disease (substances and doses not Duran-Graeff Mycoses 2017 N=8, 7/8 died specified) public [28] MICA (dose not specified) other D III Chittick AAC 2009 [181] N=1, 17 days, died CASfor (dose not specified) D IIu Martino CID 2004 [96] N=1, 6 days, died for Koc InfDisLond 2016 [180] N=1, died Ulu-Kilic Mycoses 2015 N=6, died Only [179] Not Schuermans MedMycol N=1, died 2011 [71]

COPD, To cure FLU (dose not specified) D III Subramanya Supram N=1, alive Diabetes MedMycol 2016 [97] mellitus

Various combinations of treatments given.

148

1795

1796 SPOROBOLOMYCES INFECTIONS

1797 Taxonomy and epidemiology

1798 Like Rhodotorula, Sporobolomyces belongs within the Order Sporidiobolales and Family 1799 Sporidiobolaceae.[113] Sporobolomyces comprises at least 15 recognised species. The type 1800 species, Sporobolomyces roseus and another species, Sporobolomyces salmonicolor have been 1801 implicated in the few published cases of human and animal disease.

1802

1803 Sporobolomyces species are common in the environment including in soil, water, leaf surfaces, 1804 fruit and plants. Their natural habitat includes humans, mammals and birds. Patients at risk for 1805 invasive Sporobolomyces infections include thoseconsultation. with haematological malignancies and 1806 HIV/AIDS. Very uncommon, the following confirmed or possible invasive infections have been 1807 reported: CVAD-associated bloodstream infection in a womandistribution. with advanced breast cancer and 1808 poorly-controlled diabetes mellitus, endophthalmitis in an immunocompetent person, 1809 lymphadenitis in a person with AIDS, pseudo-meningitis (S. salmonicolor); meningitis in an 1810 immunocompetent adult, meningoencephalitispublic in a dog (S. roseus); bone marrow infection and 1811 prosthetic cranioplasty infection (speciesother not specified). [99, 569-574] The global distribution of 1812 invasive sporobolomycosisfor is shown in Figure 26. for Only Not

149

1813 Figure 26. Worldwide distribution of Sporobolomyces infections (reported cases between 1976 1814 and 2019 per million population).

1815

1816 Legend: Cases of Sporobolomyces-related infections in the medical literature between 2000 and 1817 2019 were identified in a PubMed search on Januaryconsultation. 15, 2020 using the search string 1818 (Sporobolomyces OR Amphiernia OR Prosporobolomyces OR Ballistosporomyces) that yielded 1819 271 publications. Between 1976 and 2019, 14 cases were reported from nine countries[569-580]. 1820 Six cases were reported from the United States of America.distribution. Number of cases reported between 1821 1976 and 2019 are presented as cases per million population per country. The resident 1822 population per country was obtainedpublic from www.worldometers.info. [47] 1823 other 1824 Diagnosis for 1825 Histology and direct detection forin clinical specimens 1826 Evidence – In the case of a dog with granulomatous meningoencephalitis, branching septate 1827 pseudo-hyphae,Only 2-4 mm in diameter and up to 15 mm long, were detected in the granulomas in 1828 FFPE sections of theNot brain.[99] (Table 4). Subsequent sequencing of the fungal ITS region yielded 1829 a sequence with 96% homology to S. roseus.

1830 Recommendation – Examination of histological specimens by standard fungal stains is 1831 recommended strongly as is the case for all yeast genera. Although there is insufficient evidence 1832 for routine use of direct molecular detection of Sporobolomyces from clinical specimens,

150

1833 panfungal PCR combined with DNA sequencing is strongly recommended where an IFD is in the 1834 differential diagnosis especially if fungal forms are seen in the specimen.

1835

1836 Culture and species identification

1837 Evidence – Once cultured from clinical specimens, Sporobolomyces colonies grow rapidly are 1838 usually salmon-pink to red with butyrous (butter-like) texture on standard media and can 1839 resemble Rhodotorula species (Table 28).

1840

1841 Table 28. Recommendations on microscopy and culture in Sporobolomyces spp. infections

Population Intention Intervention SoR QoE Reference Comment

Sporobolomyces spp.

Adults To diagnose Culture A IIu Espinel-Ingroff JCM Inoculation of specimen into SDA broth 1999 [581] or onto SDA agar. Sterile samples, e.g. CSF, blood, consultation.Colonies have a pink/red/orange colour. tissue Ballistoconidia are seen and colonies are distribution.urease-positive SoR, strength of recommendation; QoE, quality of evidence; N, number of subjects investigated; CSF, cerebrospinal fluid; SDA, Sabouraud Dextrose agar public 1842 other 1843 They differ from the forlatter by the formation of kidney-shaped ballistoconidia that are actively 1844 discharged, which lead to the formation of many small satellite colonies and mirror-image 1845 colonies on the lids of petri dishesfor (Figure 27). Ballistoconidia are characteristic but not unique 1846 to this genus (Table 29). Microscopic examination of smears from cultured colonies may show 1847 yeast-likeOnly cells, pseudo-hyphae and hyphae. The optimal growth temperature is 25–30°C. Some 1848 isolates grow poorlyNot at 35–37°C. The API 20C AUX (bioMerieux) and RapiID yeast plus system may 1849 misidentify the yeast.[582]

151

1850 Figure 27. Colonies of Sporobolomyces 1851 salmonicolor on Sabouraud dextrose agar after 1852 72 hours of incubation. Note – mirror image 1853 colonies on the lid of the Petri dish (authors’ 1854 own photograph)

1855

1856 Identification of Sporobolomyces with MALDI-TOF MS is not reliable using the standard Bruker 1857 Biotyper (Bruker Daltoniks) or Vitek MS (bioMerieux) databases.[583] In the case of an 1858 immunocompetent man with meningitis, Sporobolomyces was identified directly from CSF by 1859 PCR assay; however, the clinical significance of this test result was not clear.[572] (Table 29).

1860

1861 Table 29. Recommendations on genus and species identification of Sporobolomyces spp.

Population Intention Intervention SoR QoE Reference Comment Phenotypic identification consultation. All including To identify to Colony B IIu Espinel-Ingroff JCM N=4; colonies with those with species level morphology 1998 [582]distribution. pink/red/orange colour; neutropenia; and ballistoconidia are haematological carbohydrate characteristic, urease-positive. malignancies assimilationpublic and API 20C (bioMerieux) and RapID biochemical Yeast Plus (Innovative tests other Diagnostic Systems) have been for used but article does not specify if correctly identified. However, for initial identification is possible by API 20C and RapID Yeast Plus Only System (Innovative Diagnostic Not Systems) but need to confirm ID by MALDI-TOF MS or DNA sequencing

MALDI-TOFMS

Any To identify to MALDI-TOF MS C III Chao PlosOne 2014 N=2; S. salmonicolor species level identification [583] Bruker and Vitek MS.

152

Bruker 2/2 correct ID

Vitek MS 0/2 identified (but 2/2 identified if supplemented by RUO database)

Molecular Identification

Any To identify to ITS sequencing A IIu Chao PlosOne 2014 N=2, S. salmonicolor species level as [583] benchmark for MALDI TOF MS and phenotypic identification

To identify to 18S and D1/D2 A IIu Cobban N=6, environment. All clade of species and for domain of 28S MicrobiolOpen 2016 S. roseus, S. patagonicus, S. phylogenetic sequencing [584] salmoneus, S. pararoseus, S. relation ships ruberrimus, S. phaffii, S. japonicus, S. carnicolor, S. consultation.blumeae, S. salmonicolor, and S. johnsonii SoR, strength of recommendation; QoE, quality of evidence; N, numberdistribution. of isolates investigated; ID, identification; ITS, internal transcribed spacer; MALDI-TOF, matrix assisted laser desorption ionisation time of flight; MS, mass spectrometry; RUO, research use only

1862 public 1863 Recommendations – We strongly recommendother fungal culture of clinical specimens. Isolation of 1864 pink-orange-red yeast-likefor colonies, a positive urease test and production of ballistoconidia in 1865 some but not all isolates providefor supportive evidence for this identification. However, genus/ 1866 species-level identification should be confirmed using ITS sequencing (this may be possible in 1867 resource-richOnly settings only). Identification of Sporobolomyces by MALDI-TOF MS is weakly 1868 supported. Not 1869

1870 Antifungal susceptibility testing

1871 Evidence – The CLSI broth microdilution method and Sensititre (Thermofisher) commercial 1872 method have been used to determine MICs for a few clinical isolates of S. salmonicolor

153

1873 (N=12).[183, 184] Fluconazole and echinocandin MICs were relatively high (ranges, 64–256 mg/L and 1874 ≥128 mg/L for fluconazole and micafungin, respectively) while voriconazole and terbinafine MICs 1875 were lower (0.06–1, and 0.06–0.12 mg/L, respectively). The MIC ranges of amphotericin B and 1876 itraconazole were 1–8, and 0.03–4 mg/L, respectively (Table 6).

1877

1878 Recommendations – There are no clinical breakpoints for any antifungal agent. Susceptibility 1879 testing is moderately recommended for epidemiological purposes but is not routinely 1880 recommended to guide clinical treatment in individual cases.

1881

1882 Treatment

1883 Evidence and recommendations - Although available MIC and clinical outcome data are too 1884 sparse to provide specific treatment recommendations, first-line options may include 1885 voriconazole whereas echinocandins and fluconazole should be avoided based on in vitro data, 1886 and intrinsic resistance of Sporobolomyces to the echinocandins.consultation. Based on a few case reports and 1887 extrapolation from invasive Candida infections, it is reasonable to remove indwelling CVADs and 1888 other devices. Systemic antifungal agents are recommendeddistribution. with strong support: either 1889 liposomal amphotericin B or voriconazole.[569, 570, 572] (Table 30). Optimal duration of antifungal 1890 treatment is uncertain. A recommendedpublic treatment pathway is summarised in Figure 28. 1891 for other for Only Not

154

1892 Figure 28. Treatment pathway for antifungal therapy and management of systemic infections 1893 due to Saprochaete spp.

Suspected and confirmed infections due to Sporobolomyces spp. are emergencies and require rapid action

Timely, rapid antifungal therapy and management is required for suspected and confirmed infections

Liposomal Amphotericin B Voriconazole iv/po 3 mg/kg/d; 2x200 mg/d from d3 5 mg/kg/d

Removal of CVAD consultation. Response assessment (weekly, ≥ 14 days after last negative blooddistribution. culture)

Legend: strongly recommended publicgg moderately recommended gg marginally recommended gg recommended againstfor ggother CVAD, central vascular access device; iv, intravenous; po, per os

1894 for 1895 TableOnly 30. Recommendations on targeted antifungal therapy for Sporobolomyces infections Population IntentionNot Intervention SoR QoE Reference Comment Meningitis in To cure L-AmB 3-5 mg/kg/d B III McNicholas JMM 2012 N=1, Sporobolomyces immunocompe [572] roseus meningitis tent host alive

Endogenous To cure VRC 2 x 6 mg/kg/d1 B III Sharma Eye 2006 [570] N=1, S. salmonicolor, endophthalmiti alive followed by 2 x 4 mg/kg/d

155

s in and immunocompe AmB tent host 5 mcg intravitreal

Malignancy To cure VRC 2 x 6 mg/kg/d1 B III Tang ICHE 2015 [569] N=1, S. salmonicolor and diabetes fungaemia and CVAD followed by 2 x 4 mg/kg/d mellitus, infection; fever abated fungaemia and with antifungal a CVAD infection CVAD removal

SoR, strength of recommendation; QoE, quality of evidence; N, number of subjects investigated; AmB, amphoteiricn B; CVAD, central vascular access device; L-AmB, liposomal amphotericin B; VRC, voriconazole

1896

1897 TRICHOSPORON INFECTIONS

1898 Taxonomy and epidemiology

1899 Trichosporon species are basidiomycetous yeast-like fungi that are urease-positive and exhibit 1900 on microscopy, blastoconidia, arthroconidia, pseudohyphaeconsultation. and hyphae. The genus is distributed 1901 worldwide in nature and has been cultured from soil, decomposing wood, rivers, lakes and 1902 seawater, air, foods such as cheese, as well as from scarab beetles,distribution. bird droppings, bats, pigeons 1903 and cattle. Trichosporon spp. may be part of the normal microbiota of human skin, GI and 1904 respiratory tract.[102, 585, 586] public 1905 other 1906 In light of recent taxonomicfor revision, the genus now encompasses 12 species as identified by 1907 sequencing of the intergenic 1 (IGS1) rDNA gene region. As a result, a number of clinically relevant 1908 species were transferred to otherfor genera such as Cutaneotrichosporon (no longer Trichosporon) 1909 dermatis, Apiotrichum mycotoxinivorans and Cutaneotrichosporon cutaneum.[587] Trichosporon 1910 asahiiOnly is the most common pathogenic species, followed by T. inkin, T. faecale, T. asteroides and 1911 T. coremiiforme. PrevalenceNot rates of non-T. asahii species from sterile site cultures vary with 1912 geographical region including diversities in the distribution of T. asahii and T. faecale 1913 genotypes.[190, 202] The geographic distribution of invasive trichosporonosis is illustrated in Figure 1914 29.

1915

156

1916 Figure 29. Worldwide distribution of Trichosporon infections (reported cases between 2000 and 1917 2019 per million population)

1918

1919

1920 Legend: Cases of severe Trichosporon-related infections reported in the medical literature 1921 between 2000 and 2019 were identified in a PubMedconsultation. search on January 15, 2020 using the 1922 search string “(Trichosporo*) AND (infection OR invasive OR fungemia OR blood OR isolate)” 1923 yielding 794 publications. In total, 744 cases of Trichosporondistribution. spp. infections reported from 43 1924 countries were selected. Most cases were reported from China (N=151), India and Brazil (each 1925 N=114), USA (N=73), Japan (N=72),public Taiwan Province (N=37), France (N=31), and Argentina 1926 (N=24) [3, 15-17, 27, 75, 76, 79, 82, 83, 88, 100, 101, 105, 110, 121, 188-190, 197, 198, 202, 203, 220, 233, 250, 365, 388, 457, 480, 516, 1927 533, 557, 588-779]. Publicationsfor reporting the sameother cases were identified through personal 1928 communication with the authors, where possible. References were included for completeness. 1929 Number of cases reported betweenfor 2000 and 2019 are presented as cases per million 1930 population per country. The resident population per country was obtained from 1931 www.worldometers.infoOnly . [47] *Greece, Qatar, Taiwan and Singapore are countries with 1 – 2 1932 reported cases perNot million population between 2000 and 2019; §Argentina, Brazil, Japan and 1933 Kuwait with 0.5 – 0.9 cases accordingly.

1934

1935 Initially recognized as a pathogen causing superficial infections of skin, nails and hair, 1936 Trichosporon spp. are increasing recognised as causes of fungaemia, endocarditis, CNS infections,

157

1937 peritonitis esophagitis, urinary tract infections and other infections.[102, 780] Invasive disease has 1938 most often been diagnosed in immunocompromised patients, especially in haematologic 1939 patients with prolonged neutropenia, indwelling CVADs and with previous exposure to antifungal 1940 drugs.[78, 82, 83, 87, 113, 774, 781] Haematology patients with fungaemia often present with metastatic 1941 skin lesions (18-43%), pneumonia (18-53%) and splenic and liver abscesses.[78-80, 82, 83, 782] Other 1942 high risk patients include critically ill children and adults with prolonged hospital admissions and 1943 use of multiple invasive medical procedures, corticosteroids and antibiotics. Mortality ranges 1944 from 30-90%, depending on age, co-morbidities and presence of neutropenia.[78, 80, 193, 780]

1945

1946 Diagnosis

1947 As for other rare yeasts, diagnosis is reliant on a combination of diagnostic modalities involving 1948 imaging, detection of the organism in histopathological specimens, culture and molecular 1949 approaches. Notably, fungaemia is the main laboratory finding with invasive disease. 1950 consultation. 1951 Imaging

1952 Evidence Pulmonary lesions have been frequently reporteddistribution. in disseminated Trichosporon 1953 infections mainly in neutropenic patients.[78, 102] Chest CT scans may reveal diffuse alveolar or 1954 interstitial infiltrates, consolidationpublic or mass-like lesions.[74] Abdominal CT or ultrasound scans 1955 have diagnosed hepatic and splenic lesions in haematologic patients with fungaemia during the 1956 phase of neutrophil recovery.for [78, 79, 83] other 1957 Recommendation – Imaging of suspected sites of involvement in all patient groups (Table 3) is at 1958 least moderately recommendedfor to diagnose or to exclude disease. Chest CT is more sensitive in 1959 diagnosing concomitant pulmonary lesions than chest X ray and is preferred. Echocardiography 1960 is moderatelyOnly supported in patients with suspected endocarditis. Follow up imaging is strongly 1961 recommended especiallyNot when the diagnosis is unclear or in unstable patients. Patients with 1962 acute leukemias who develop Trichosporon fungemia should be investigated with abdominal CT 1963 scan in case they develop persistent fever after neutrophil recovery.

1964

158

1965 Histopathology and direct detection in clinical specimens

1966 Evidence – Skin lesions and pneumonia may be often found in patients with Trichosporon 1967 fiungaemia (as above), and conventional histopathology of biopsies using standard fungal stains 1968 may be helpful for the diagnosis of invasive Trichosporon infection; however, arthroconidia are 1969 rarely reported and the procedure requires experienced pathologists.[78, 102] Inferring species is 1970 not possible and even determining genus, may be problematic.

1971

1972 In-house molecular methods have been successfully applied for the diagnosis of deep-seated 1973 Trichosporon infections in both fresh and FFPE sections using panfungal PCR assays[203-205] nested- 1974 PCR with genus specific primers[105] and in situ hybridization with Trichosporon-specific 1975 probes.[104] In addition, despite the fact that more data are required, direct identification of 1976 Trichosporon from positive blood cultures has been reported as a rapid diagnostic test[509] (Table 1977 4). Different molecular techniques such as PCR-based methods, Luminex xMAP technology, and 1978 proteomics performed on various clinical samples have been studied with varying success but 1979 their more widespread use is limited by the small numbersconsultation. of patients studied, as well as the lack 1980 of validation of these tools in multicentre studies.[106-112, 585,distribution. 586] 1981

1982 Recommendation –The guideline strongly recommends the histological examination of affected 1983 tissue by standard fungal stainspublic to visualize the pathogen where an IFD is in the differential 1984 diganosis. Direct detection and identificationother of Trichosporon in clinical specimens by ITS-directed 1985 panfungal PCR methodsfor is moderately recommended and there is weak support for other 1986 molecular methods to detectfor these pathogens in tissue or blood samples. Culture of all 1987 specimens should be undertaken. 1988 Only 1989 Direct MicroscopyNot and Culture

1990 Evidence – Direct microscopy including Gram stain of clinical samples and blood cultures provides 1991 rapid and useful diagnostic information.[102] The presence of hyphae, blastoconidia and 1992 arthroconidia may be seen (Table 31). Culture is the mainstay of diagnosis of both fungaemia and 1993 of deep-seated trichosporonosis. A substantial number of critically ill patients under prolonged 1994 urinary catheterization may present with funguria. This is related to episodes of colonization of 159

1995 the urinary tract system and/or medical device. Trichosporon spp. grow on SDA in 24-48 h and 1996 colonies are creamy white, dry and wrinkled; on CHROMagar, colonies are pale blue in colour 1997 and are dry.[102] Blastoconidia and arthroconidia, plus a positive urease test make the 1998 presumptive identification of Trichosporon and other closely related genera, such as 1999 Cutaneotrichosporon and Apiotrichum.[78, 102, 587]

2000

2001 Table 31. Recommendations on microscopy and culture in Trichosopron spp. infections

Population Intention Intervention SoR QoE Reference Comment

Any To diagnose Direct microscopy A III Colombo CMR Presence of hyphae, arthroconidia 2011 [102] and blastoconidia are suggestive of Gram stain of blood Trichosporon infection cultures, abscess, sterile fluids

Any To diagnose Culture A IIu Baron CID 2013 Adequate volume of blood cultured [783] is essential to yield growth: adults: Blood cultures 40–60 mL. consultation.Lamy FrontMicrob Incubation of cultures under 2016distribution. [784] aerobic conditions preferred over anaerobic conditions

Haematology To diagnose Culture A III Colombo CMR Presence of hyphae, arthroconidia patients with public 2011 [102] and blastoconidia are suggestive of BAL fluid systemic infection other Trichosporon infection. Final and lung lesions for diagnosis requires culture result. SoR, strength of recommendation; QoE, quality of evidence; N, number of subjects investigated; BAL, bronchoalveolar lavage for 2002 Only 2003 Recommendation Not– Useful information is obtained from direct microscopy of specimens obtained 2004 from affected organs and is strongly recommended. Cultures from sterile fluids are also strongly 2005 recommended to yield an isolate for susceptibility testing and is useful for validating newer 2006 detection methods.

2007

160

2008 Species identification

2009 Evidence – For species identification, biochemical assimilation panels such as API 20C AUX ID32C 2010 (bioMerieux), and automated methods such as Vitek 2 YST-ID (bioMérieux) identify a limited 2011 number of but usually provides good identification for T. asahii. Ability to identify most non-T 2012 asahii isolates is limited; species may also be misidentified as ‘T. asahii’ (eg. T. asteroides) or even 2013 as Cryptococcus spp. or simply not be able to be identified.[185, 410, 411, 582, 735, 785] The germ tube 2014 test is negative (Table 32).

2015

2016 Table 32. Recommendations on genus and species identification of Trichosporon spp.

Population Intention Intervention SoR QoE Reference Comment

Phenotypic identification

Any To identify to Colony B IIu Colombo CMI 2011 [102] Genus ID is mandatory for species morphology clinical management. Species De Almeida and ID remains difficult by consultation.FrontMicrobiol 2016 [78] carbohydrate conventional phenotypic Girmenia JCM 2005 [557] assimilation methods if the databases are and non- Marine distribution.Virulence 2015 limited and inconclusive or automated [786] misidentification may occur biochemical Chagas-Neto JCM 2009 tests public [193] otherRuan CID 2009 [197] for Rodriguez-Tudela AAC for 2005 [185] Kalkancı MedMycol Only 2010[787] Not Guo JCM 2019 [202] Any To identify to Commercial B IIu Rodriguez-Tudela AAC Species identification has species non- 2005 [185] been provided fort he five automated most common species, but Ahmad JMM 2005 [735] biochemical limited data on their Ramani JCM 1998 [410] tests (API 20C accuracy. Accurate

161

AUX, ID32C, Espinel-Ingroff JCM 1998 identification of T. asahii has RapID Yeast [582] been provided but other Plus) and species may be erroneously Kitch JCM 1996 [411] automated identified as T. asahii. Dooley JCM 1994 [785] systems (VITEK-2 YST ID, Baxter Microscan)

MALDI TOF MS

Any To identify to MALDI-TOF B IIu Kolecka JCM 2013 [25] Good discriminatory power species MS and high accuracy for majority

of the species when an in comparison (A if extended database is used with DNA extended (e.g. coverage of 65 mass sequencing as de Almeida JCM 2017 database spectra). Vitek MS benchmark [788] used) (bioMerieux) and Bruker Microflex (Bruker Daltoniks) consultation.de Almeida CMI 2014 have similar accuracy when [655] using an extended database. distribution.Lack of inclusion of MSP of all Guo JCM 2019 [202] species of clinical relevance into the library may generate public misidentification of isolates. De Almeida et al tested 93 for other Trichosporon isolates of 16 species. By using their for extended database they correctly identified 98% of isolates. De Almeida et al. [5- Only 7] tested a total of 76 Not Trichosporon isolates, including 8 species. Good performance was obtained with extended database. Guo et al. correctly identified 10

162

species of Trichosporon (133 isolates)

Molecular Identification

Any To identify to IGS1 rDNA A IIu Sugita JCM 2002 [789] N=43, 24 species. IGS1 species sequencin sequence analysis was superior to ITS sequencing and defined as the reference method

Any To identify to IGS1 rDNA A IIu Chagas-Neto JCM 2009 N=22, 4 species. IGS1 DNA species and to sequencing [193] sequencing achieved species establish identification epidemiological knowledge consultation. Any To identify to IGS1 rDNA A IIu Xiao MedMycol 2013 N=48, 8 species. IGS1 DNA species sequencing [790] sequencing achieved for distribution.species identification

Any To identify to ITS and IGS1 A IIu Taverna MedMycol 2014 N=38, 12 blood and 10 urine species and to rDNA public [189] isolates. All identified to establish sequencing specie epidemiological other knowledgefor Any To identify to IGS1 rDNA A IIu Guo JCM 2019 [202] N=133, blood and other species and to sequencingfor sterile fluids. Species establish identification achieved Onlyepidemiological knowledgeNot Any To identify to IGS1 rDNA A IIu Francisco CMI 2019 [190] N=358, 5 species; blood and species and to sequencing other sterile fluids. IGS1 DNA establish sequencing generated good epidemiological results in species knowledge identification

163

SoR, strength of recommendation; QoE, quality of evidence; N, number of isolates investigated; ID, identification; IGS, intergenic spacer, ITS, internal transcribed spacer; MALDI-TOF, matrix assisted laser desorption ionisation time of flight; MS, mass spectrometry; MSP, mass spectral profile; RUO, research use only

2017

2018 MALDI-TOF MS equipped with robust and/or extended in-house libraries has been a useful tool 2019 for species identification for Trichosporon isolates. As such, it has shown good discrimination and 2020 high accuracy for identification of at least 10 species of clinical relevance.[25, 78] Molecular 2021 methods have been increasingly used to identify Trichosporon isolates to species level, 2022 preferentially be carried out by IGS1 sequencing.[189, 190, 202, 789, 790]

2023

2024 Recommendations - Accurate identification of isolates from clinically important specimens is 2025 strongly recommended. However, the significance of species identification[587, 788, 791] in guidance 2026 of therapy remains uncertain. Identification by phenotypic methods (accuracy mostly for T. 2027 asahii) and by MALDI-TOF MS (species identification) are both moderately supported. 2028 Identification by molecular methods provides greatestconsultation. accuracy and is strongly recomemnded 2029 (Table 32).

2030 distribution. 2031 Diagnostic pathway public 2032 Figure 30 shows the diagnostic pathway. The microbiological diagnosis of invasive 2033 trichosporonosis relies on visualization other of fungal elements (arthroconidia) compatible with 2034 Trichosporon spp. as for well as culture, being essential to place the findings in relevant clinical 2035 context. Trichosporon spp. growfor readily on SDA as white to cream-colored, cerebriforme, dry 2036 colonies; the germ tube test is negative. Urease positive colonies inform a presumptive 2037 identificationOnly of Trichosporon spp. Confirmation of species identification is recommended using 2038 MALDI-TOF MS orNot IGS1 sequencing.

164

2039 Figure 30. Diagnostic pathway for suspected cases of systemic Trichsoporon infections

consultation. distribution. public for other for Only Not

2040

165

2041 Susceptibility testing and susceptibility-driven treatment

2042 Evidence – Whilst susceptibility testing may be helpful to guide antifungal therapy and to monitor 2043 for drug resistance, Trichosporon-specific CBPs and ECVs for all drugs are lacking.[102, 190, 198] 2044 Moreover commercial methods require more extensive evaluation to determine clinical utility.

2045

2046 Antifungal susceptibility testing of Trichosporon spp. has been performed mostly for 2047 epidemiological purposes and to compare different methods. Good agreement has been found 2048 between EUCAST and CLSI standards[149, 187, 188] and between these, and the E test 2049 (bioMerieux).[192, 792] Data presented in most studies were obtained using the CLSI M27-A3/S4 2050 method[78, 190, 194, 195, 198-201] or older CLSI document versions.[112, 193, 197] Little differences were 2051 observed between the results presented using the newer and older protocols with most authors 2052 providing in vitro data based on reading results at certain temperatures.[112, 185, 187, 188, 190] The 2053 newest EUCAST protocol (E-def 7.3.1) has uncommonly been used.[189] 2054 Cumulative data provides evidence of both genus-,consultation. as well as species-specific susceptibility 2055 profiles. Trichosporon spp. are intrinsically resistant to echinocandins.[730, 793] Conversely, most 2056 Trichosporon spp. showed low voriconazole MICs (independentdistribution. of method) with the second most 2057 potent azole invitro being itraconazole.[149, 189, 192-195, 197, 199-201, 792] The relatively few data on 2058 isavuconazole has revealed promising activity against Trichosporon spp.[152] Fluconazole has 2059 showed the widest range of MICpublic values of all azoles (especially for T. asahii) and has species- and 2060 strain-dependent activity (Table 6). Mostother Trichosporon spp. have shown high amphotericin B [189, 192-195, 197, 199-201, 730, 792, 793] 2061 MICs (MIC90 ≥ 1 mg/L).for 2062 Overall, no significant differencesfor in MIC values were seen between the different T. asahii 2063 genotypes.[195, 196] Similarly, no differences in MIC values were observed in strains isolated from 2064 differentOnly clinical samples. [200] From the relatively few data available, the less common 2065 Trichosporon speciesNot (T. asteroides , T. cutaneum, T. faecale, T. japonicum and T. dermatis) have 2066 tested resistant to most antifungals.[185, 188, 200, 746]

2067

2068 Recommendation – Despite several studies reporting species- and strain-dependent variability in 2069 susceptibility to fluconazole and amphotericin B, overall, there are limited data to support the 2070 notion that susceptibility can drive antifungal therapy. Susceptibility testing is strongly

166

2071 recommended to monitor for emergence of non-wild type isolates and for epidemiological 2072 knowledge.

2073 Management

2074 Antifungal therapy

2075 Evidence – Owing to lack of randomized clinical trials, recommendations for antifungal treatment 2076 of Trichosporon infections come largely from animal studies,[794, 795] in vitro susceptibility data[112, 2077 149, 185, 190, 192, 197, 199, 200, 202] and recently published case series of which the vast majority of clinical 2078 information is derived from the haemato-oncological population.

2079

2080 In general, clinical data have shown that extended spectrum triazole-based regimens are superior 2081 to those based on amphotericin B preparations for all forms of infection including CNS disease, 2082 supported by in vitro and animal model data (Table 33).[78, 80, 149, 597, 666, 781, 795, 796] Data on 2083 isavuconazole are limited, but early experience supports its use as well.[152] Fluconazole MICs may 2084 be low (see above). Combination therapy with azolesconsultation. and polyenes has not shown to offer 2085 advantages in the first line therapy setting.[78, 102, 796, 797] Therefore the recommendation is to 2086 reserve such combinations for salvage therapy where distribution. there is failure to initial triazole 2087 monotherapy. Combination therapies with echinocandins and triazoles have not shown to be 2088 beneficial and are discouraged.[78, 102, 797] Cases of Trichosporon infections that present as 2089 breakthrough infections while public patients are receiving echinocandin or polyene treatment for 2090 another fungal infection can be successfullyother treated with voriconazole monotherapy.[78, 102, 185, 2091 192, 197, 199, 200] Finally, basedfor on outcome data from case reports and case series, for patients with 2092 CVAD -related infections or endocarditis,for CVAD removal and valve replacement may be required 2093 for source control (Table 8 and Table 33). 2094 Only 2095 Table 33. RecommendationsNot on targeted antifungal therapy for Trichosporon infections

Population Intention Intervention SoR QoE Reference Comment

Haematology- To cure FLU 400-800 mg/d B IIu Suzuki EJH 2010 [80] N=22 azole-based, 14 oncology died, fungaemia

167

Haematology- To cure VRC 2 x 6 mg/kg/d1 B IIu Suzuki EJH 2010 [80] N=22 azole-based, 14 oncology died, fungaemia followed by 2 x 4 mg/kg/d

Haematology- To cure c-AmB 1 mg/kg/d B IIu Suzuki EJH 2010 [80] N=6 AmB alone, died, oncology fungaemia

Haematology- To cure L-AmB 3-5 mg/kg/d B IIu Suzuki EJH 2010 [80] N=6 AmB alone, died, oncology fungaemia

Haematology- To cure ABLC 5 mg/kg/d B IIu Suzuki EJH 2010 [80] N=6 AmB alone, died, oncology fungaemia

Any To cure FLU 400-800 mg/d B IIu Liao OFID 2015 [796] N=81, azole-based, 47 with positive outcome

De Almeida FrontMicrobiol N=101 azole-based, 2016 [78] 29% with unfavorable outcome

Any To cure VRC 2 x 6 mg/kg/d1 B IIu Liao OFID 2015 [796] N=81, azole-based, 47 with positive outcome followed by 2 x 4 mg/kg/d consultation. De Almeida FrontMicrobiol N=101 azole-based, 2016 [78] 29% with distribution.unfavourable outcome Any To cure c-AmB 1 mg/kg/d B IIu Liao OFID 2015 [796] N=91 AmB alone, public 28 with positive outcome

other De Almeida FrontMicrobiol N=112 AmB alone, for 2016 [78] 49% with for unfavourable outcome Any To cure L-AmB 3-5 mg/kg/d B IIu Liao OFID 2015 [796] N=91 AmB alone, Only 28 with positive Not outcome De Almeida FrontMicrobiol N=112 AmB alone, 2016 [78] 49% with unfavourable outcome

Any To cure ABLC 5 mg/kg/d B IIu Liao OFID 2015 [796] N=91 AmB alone,

168

28 with positive outcome

De Almeida FrontMicrobiol N=112 AmB alone, 2016 [78] 49% with unfavourable outcome

Any To cure Combination therapy C III Colombo CMR 2011 [102] Few clinical data involving azoles, polyenes, available to support De Almeida FrontMicrobiol echinocandins this strategy; 2016 [78] Controversial results Liao OFID 2015 [796] provided by in vitro and in vivo assays

Any To cure Echinocandins D III Colombo CMR 2011 [102] Lack of in vitro activity and few data to and De Almeida FrontMicrobiol support use of this 2016 [78] 5-FC combination Liao OFID 2015 [796]

consultation.Foster JPID 2017 [797][797][798][798][798][7 98][798][797]distribution. Meningitis To cure FLU 400-800 mg/d B IIu Milan BMCID 2018 [781] N=6; 2 died Meningitis To cure VRC 2 x 6 mg/kg/d1public B IIu Milan BMCID 2018 [781] N=6; 2 died followed by 2 x 4 mg/kg/dother Hematology To cure forVRC 2 x 6 mg/kg/d1 C III Colombo CMR 2011 [102] Few clinical data critically ill, and available to support followed by 2 x 4 mg/kg/d De Almeida FrontMicrobiol elderly patients this strategy; 2016 [78] and for failing azole Controversial results Liao OFID 2015 [796] therapy L-AmB 3-5 mg/kg/d Only provided by in vitro Not and in vivo assays Breakthrough To cure VRC 2 x 6 mg/kg/d1 B IIu Hazirolan AAC 2013 [199] Few series available to infection under support this strategy. followed by 2 x 4 mg/kg/d Mekha Mycopathol 2010 echinocandins In vitro data suggest [112] or AmB that VRC is more Guo JCM 2019 [202] effective than AmB

169

Francisco CMI 2019 [190] formulations and the echinocandins. Colombo CMR 2011 [102]

De Almeida FrontMicrobiol 2016 [78]

2096

2097 Recommendation – The use of an extended spectrum azole is at least moderately recommended 2098 for initial antifungal therapy of Trichosporon infections, with that data being most robust for 2099 voriconazole (Table 33). Should an extended spectrum azole not be available, then fluconazole 2100 use is also moderately supported contingent on the MIC result. There is weak support for 2101 combination antifungal therapy, and the echninocandins are not recommended. CVAD removal 2102 and cardiac valve surgery is moderately supported forconsultation. source control. The benefits of removal of 2103 other infected medical devices, as urinary catheter and catheters for peritoneal dialysis, have 2104 also been documented. Figure 31 shows the treatment pathwaydistribution. for suggested use of antifungal 2105 drugs to treat invasive trichoporonosis. public for other for Only Not

170

2106 Figure 31. Treatment pathway for antifungal therapy and management of systemic 2107 trichosporonosis

Suspected and confirmed infections due to Trichosporon spp. are emergencies and require rapid action

Timely, rapid antifungal therapy and management is required for suspected and confirmed infections

Surgical resection of localised lesions and valve replacement

Breakthrough IFI No breakthrough IFI after administration of

Posaconazole Voriconazole

Voriconazole iv/po Posaconazole 2x6 mg/kg/d d1; suspension 2x4 mg/kg/d from d2 2x400 mg/d consultation.Echinocandins + Liposomal Amphotericin B 3-5 mg/kg/d distribution. If not available

Fluconazole iv/po publicAmphotericin B deoxycholate 1-2x400 mg/kg/d 1 mg/kg/d for other Removal of CVAD for Response assessment Only (weekly, ≥ 14 days after last negative blood culture) Not Legend: strongly recommended gg moderately recommended gg marginally recommended gg recommended against gg

CVAD, central vascular access device; IFI, invasive fungal infection; iv, intravenous; po, per os

2108

171

2109 Duration of therapy

2110 Evidence – Data on duration of therapy are lacking. As with other rare yeast fungaemias, expert 2111 consensus favour two weeks in the absence of deep-seated infection and 4-6 weeks of therapy 2112 or until radiological resolution for deep or organ involvement.[78, 102, 796]

2113 Recommendation – Duration should be individualised. We support with moderate strength 2114 recommendation a longer duration of therapy if there is dissemination from fungaemia with 2115 organ involvement, and 2 weeks if there is only fungaemia. Patients with endocarditis, central 2116 nervous infections or hepatosplenic involvement (mostly haematologic patients) may require 2117 prolonged therapy that should be individualized.

2118

2119 ANTIGEN BIOMARKERS

2120 There are no data for antigen detection or other serological tests to specifically detect the rare 2121 yeasts presented in this guideline. It is feasible however, that the serum BDG may have broad 2122 diagnostic utility as a panfungal marker. For G.consultation. candidum, K. ohmeri, Pseudozyma and 2123 Sporobolomyces infections, there are no data to indicate its utility either in vitro or through 2124 clinical results. Serum levels have been elevated in at least onedistribution. case of S. capitatum infection.[496] 2125 In a study of critically-ill neonates with Malassezia infection who had serum BDG tests, blood 2126 cultures and screens for colonisation, 2/6 with a proven infection had M. pachydermatis 2127 fungaemia and 7/20 with a probablepublic infection were colonised with M. pachydermatis.[798] 2128 However, BDG levels were not different amongother control patients and seven patients with either 2129 M. pachydermatis colonisation/fungaemia.for Of note, the median level among babies with invasive 2130 Malassezia infection was 95 pg/mlfor compared with 251 pg/ml in those with invasive candidiasis. 2131 Serum BDG levels have been imprecise in proven Saccharomyces infections. Yet BDG as well as 2132 mannanOnly antigen have been detected in blood of a small number of patients with Saccharomyces 2133 fungaemia but withNot uncertain diagnostic performance. BDG can consistently be measured from 2134 broth culture supernatants of Saccharomyces[799] and has been detected in the supernatants of 2135 Saprochaete spp. and of three R. mucilagninosa isolates at concentrations two thirds that for 2136 Candida spp.[800] For Trichosporon infections, a limited number of studies have investigated the 2137 use of serum BDG with moderate clinical utility, when the serum BDGs may be positive in 48-82% 2138 of patients.[78, 80]

172

2139 Rare yeast pathogens do not routinely yield positive Aspergillus galactomannan (GM) results 2140 whereby GM testing in blood or BALF may be used to assist their exclusion but the clinical value 2141 of this practice is not documented. Limited data from studies investigating the use of blood GM 2142 testing in patients with trichosporonosis indicates that the GM may return positive.[730, 745, 801]

2143

2144 Of note, there has been a single report where the cryptoccocal latex agglutination test (LAT) gave 2145 a positive result in CSF in a patient with Rhodotorula meningitis.[374] The presence of 2146 polysaccharide capsule in this genus may explain this result. Similarly, one isolate of 2147 Sporobolomyces weakly cross reacted with the cryptococcal LAT (titre of 4).[583] Trichosporon 2148 infections also are well known to cause false-positive cryptococcal LATs as well as the 2149 cryptococcal lateral flow assay (LFA).[78, 801-803]

2150

2151 Recommendation- Specific serological markers to detect the rare yeast pathogens are not 2152 available. There are insufficient data to make a recommendationconsultation. of the use of the serum BDG 2153 test for diagnosis of these infections; however, as fungal infections are probably in the 2154 differential diagnosis of serum BDG positivity in hemato-oncologydistribution. patients, the test is weakly 2155 moderately supported as a screening test but a negative assay result does not exclude diagnosis 2156 (CIII recommendation). Use of GM to exclude aspergillosis is weakly supported (CIII 2157 recommendation). Caution is requiredpublic when interpreting the cryptococcal LAT or LFA tests in CSF 2158 or blood in the setting of Rhodotorula other or Trichosporon infection. Culture of CSF and clinical 2159 specimens is stronglyfor recommended (AII recommendation). 2160 for 2161 SPECIFIC CONSIDERATIONS FOR TREATMENT OF RARE YEAST DISEASE IN CHILDREN AND 2162 NEONATESOnly 2163 Because our knowledgeNot on the epidemiology, presentation, diagnosis clinical course, treatment 2164 and outcome of invasive diseases by rare yeasts is derived from case reports and case series, no 2165 stringent discrimination can be made between paediatric patients and adults for these conditions 2166 and recommendations for diagnosis and management will necessarily not be different for 2167 children and adults. For the selection of antifungal therapies, however, the guideline group 2168 considered four components based on concepts of European Medicines Agency (EMA) paediatric

173

2169 drug development[804, 805] that have been incorporated into previously developed paediatric 2170 guidelines.[806-808] These are: (1) evidence for efficacy from studies in adults; (2) existence and 2171 quality of pediatric pharmacokinetic data and dosing recommendations; (3) pediatric safety and 2172 supportive efficacy data, where available; and (4) regulatory approval for use in pediatric age 2173 groups. While treatment recommendations for children are not different from those for adults, 2174 selection of antifungal drug(s) should be guided by points 2 to 4 above if there is more than one 2175 option available.

2176

2177 Despite substantial progress towards their realisation, not all licensed antifungal agents are 2178 approved for pediatric patients, and for those agents with a pediatric label, appropriate dosages 2179 may not have been studied and established for all age groups and indications. Table 34 and Table 2180 35 provide systematic information on the pharmacokinetics and dosing, safety and drug approval 2181 in both the EU and the USA for all antifungal agents recommended for treatment of rare yeast 2182 infections in this guideline.

2183 consultation. 2184 Table 34. Dosing recommendations of antifungal agents useddistribution. for treatment of rare yeast 2185 infections paediatric patients beyond the neonatal age

Population Agent and Reference Comment dosing public Paediatric L-AmB Lestner AAC 2016other [809] Paediatric PK (N=47, 1-17 years) patients 3-5mg/kg/dfor IV in Seibel AAC 2017 [810] beyond the one single dose Hong AAC 2006 [811] Paediatric PK, N=39 (0.2-17 y) neonatal age for Prentice BJH 1997 [812] Paedtric safety (N=204) Only Kolve JAC 2009 [813] Paediatric safety (N=84) Not Groll JID 2000 [814] Experimental PK/PD CNS infections

L-AmB UK Label [815] Approved in paediatric subjects by both EMA and FDA L-AmB US Label [816]

L-AmB Lestner AAC 2016 [809] Paediatric PK and safety (N=12)

Seibel AAC 2017 [810]

174

10 mg/kg/d IV in L-AmB UK Label [310] Approved in paediatric subjects by both EMA and one single dose FDA L-AmB US Label [311]

Paediatric ABLC Walsh AAC 1997 [817] Paediatric PK (N=6; 21 d-16 y) patients 5 mg/kg/d IV in Walsh PIDJ 1999 [818] Paediatric safety (N=111 pediatric pts) beyond the one single dose Wiley PIDJ 2005 [819] Paediatric safety (N=548 pediatric pts) neonatal age ABLC UK Label [820] No formal paediatric label in countries of the EU and the US ABLC US Label [821]

Paediatric c-AmB Starke JID 1987 [822] Paediatric PK and safety, N=5 children patients 0.7 to 1.0 (max. Koren JPaediatr 1988 [823] Paediatric PK and safety, N=13 children beyond the 1.5) mg/kg once Benson AAC 1989 [824] Paediatric PK and safety, N=12 children neonatal age daily Nath AAC 1999 [825] Paediatric PK and safety, N=20 children

Nath Chemother 2007 [826] Paediatric PK and safety, N=83 children

Electronic Med Comp AmB B No formal paediatric label in countries of the EU and [827] consultation.the US Paediatric 5-FC No formal PK study Paediatric PK patients 100-150 mg/kg/d Pasqualotto JAC 2007 [828] Paediatricdistribution. TDM / safety (N=233 adults and children) beyond the IV in 3-4 divided Pasqualotto JAC 2007 [828] Dosing target (N=233 adults and children) neonatal age doses + TDM Francispublic CID 1992 [829] Dosing target (N=17 adults) Petersen Chemotherapy 1994 Dosing target (N=60 adults) for [830] other Goodwin JAC 2008 [831] TDM strongly advised; target for Candida infections and cryptococcosis: 30-40 mg/L pre-dose and and Pasqualottofor JAC 2007 [828] 70-80 mg/L post dose (30 minutes after a 2-hour Soltani IJAA 2006 [832] Only infusion or 2 hours after oral administration) Not Day NEJM 2013 [833] Utility of 5FC in combination with AmB for yeast meningoencephalitis

Electronic Med Comp [834] 200 mg/kg/day maximum approved dose for children beyond the neonatal age in countries of the EU

FLU Lee JPaediatr 1992 [835] Paediatric PK (N=26, 5-15 years)

175

Paediatric 12 mg/kg IV / PO Brammer EJCMID 1994 [836] Paediatric PK (N=> 100; ≤ 17 years patients in one single Van der Elst CID 2014 [837] Paediatric PK (N=99, ≤ 17 years) beyond the daily dose Novelli AAC 1999 [838] Paediatric safety (N=562, ≤ 17 years in clinical trials) neonatal age Egunsola EJCP 2013 [839] Paediatric safety (systematic review, N=4902 ≤ 17 yrs)

Van der Elst CID 2014 [837] Dosing target (N=99 pediatric pts ≤17 yrs) of 12 mg/kg for invasive Candida infections

Fluconazole EU Label [840] 12 mg/kg and day maximum approved pediatric dosage beyond the neonatal age and corresponds to Fluconazole US Label [841] 400 mg dose in adults

Paediatric ITC oral Repentigny AAC 1998 [842] Paediatric PK and safety, N=26, 6 mths-12 yrs patients suspension Groll AAC 2002 [843] Paediatric PK and safety, N=26; 5-18 yrs beyond the 2.5 mg/kg twice Foot BMT 1999 [844] Paediatric safety, N=103; 0-14 yrs, no concerns neonatal age daily plus TDM Kobayashi PediatrInt 2010 [845] Paediatric safety and TDM, N=22; 0-14 yrs

Allegra consultation.Paediatric safety and TDM, N=290, median age 9.0 ClinExpPharmacolPhysiol 2017 yrs, high varibility, TDM required [846] distribution. Grigull PediatrTranspl 2007 Pediatric safety, IV and oral , N=53; 0.4-18yrs [847]public ITC IV Abdel-Rahman AAC 2007 [848] Single dose PK and safety, 2.5 mg/kg, N=33, 7 mo-17 yrs 2.5 mg/kg or 5 other mg/kg oncefor daily Kim ClinDrugInvest 2015 [849] Safety and TDM, 5 mg/kg once daily (d1: twice daily) plus TDM for for empirical therapy; PK N=6, safety N=159 Ashbee JAC 2014 [850] Dosing target for treatment of invasive aspergillosis: ITC trough by HPLC between 1 and 4 mg/L Only Ullmann CMI 2018 [851] Not ITC UK Label [852] ITC not approved for children ITC US Label [853]

Paediatric VRC Walsh AAC 2004 [854] Paediatric PK and safety (N=39; 2-<12 yrs) patients ≥ 2 2- <12 yrs /12-14 Walsh AAC 2010 [855] Paediatric PK and safety (N=48 2-<12 yrs) years of age yrs and <50kg: 16 Karlsson AAC 2009 [856] Paediatric Pop-PK (N=82 2-<12 yrs)

176

mg/kg/d IV in Michael AAC 2010 [857] Paediatric PK and safety (N=12; 2-<12 yrs) two doses (day 1: Driscoll AAC 2011 [858] Paediatric PK and safety ( N=40; 2-<12 yrs) 18) IV and 18 Driscoll AAC 2011 [859] Paediatric PK and safety (N=26; 12-<17 yrs) mg/kg/d PO in two doses Friberg AAC 2012 [860] Paediatric Pop-PK (N=112 2-<12, 26 12-17)

Gastine AAC 2018 [861] Paediatric Pop-PK (N=24, 2- <12 yrs)

VRC Pieper JAC 2012 [862] Exposure and paediatric safety (N=74, 0.2-18 yrs)

≥15 yrs and 12- Mori AAC 2015 [863] Exposure and paediatric safety (N=21, 2-<15 yrs) 14 yrs and ≥50kg: Martin PIDJ 2017 [864] Paediatric safety (N=53, 2-<18 yrs) 8 mg/kg/d IV in two doses (day 1: Soler-Palacin JAC 2012 [865] Pediatric safety (N=30, median age 10 yrs)

12); 400 mg PO Ashbee JAC 2014 [850] TDM strongly advised; target in adults and children in two doses between ≥1-2 and 6 mg/L at trough Ullmann CMI 2018 [851] +TDM (all) Voriconazole EU Label [866] Approved in children 2 - 18 yrs

Voricoanzole US Label [867]

Paediatric POS Krishna AAC 2007 [868] consultation. Paediatric PK and safety (oral solution; N=12, 12-18 patients ≥ 13 y) 300 mg IV once years of age daily (300 mg Welzen PIDJ 2011 [869] Paediatricdistribution. PK and safety (oral solution; CGD twice daily on patients) day 1); Arrietapublic Plos ONE 2019 [870] Paediatric PK and safety (oral solution; N=43, 2-18 y) Oral delayed Lehrnbecher EJCMID 2010 [871] Paediatric safety (suspension; N=15; < 18 y) release tablet Döring BMCIDother 2012 [872] Paediatric safety (suspension; N=60; < 12 y) formulationfor preferred; 300 Heinz MedMycol 2016 [873] Paediatric safety (suspension; N=27; <17 y) mg once daily Walshfor CID 2007 [874] TDM rationale for inv. aspergillosis (≥1 mg/L) (300 mg twice Onlydaily on day 1) Ashbee JAC 2014 [850] TDM recommended if oral suspension used Alternative:Not oral Ullmann CMI 2018 [851] TDM recommended if oral suspension is used solution at 4x200 or 2x400 mg and day +TDM

POS Groll et al. ECCMID 2019 [875] Paediatric PK and safety

177

Paediatric <13 y/o: oral https://www.eccmidlive.org/#!r N=118, 2-17 yrs, exposures for both IV and podosign patients 2-17 solution with esources/safety-tolerability- within the dosign target esatsblished in adults, years of age dosing based on and-pharmacokinetics -of- safety profile similar to that of adults body-weight + posaconazole-intravenous- TDM solution-and-oral-powder-for- suspension-in-children-with-

neutropenia POSe 6mg/kg Posaconazole EU Label [876] Not approved in children (max. 300 mg) once daily IV (day 1: 6 mg/kg (max. 300 mg) IV twice Posaconazole US Label [877] Approved in children ≥ 13 years daily), followed by novel investigational delayed release suspension at similar daily doses consultation.

Paediatric ISV Arrieta ECCMID 2019 [878] N=29, 1-18 yrs patients ≥1 to 10 mg/kg IV with ISV US Label [879] Notdistribution. approved in children 18 years a maximum dose of 372 mg ISVpublic US Label [880] isavuconazonium sulfate once daily other (days 1 andfor 2: every 8 hours)

Paediatric ANID Benjaminfor AAC 2006 [881] Paediatric PK and safety, N=24, 2-17 yrs patients 3 mg/kg loading Roilides PIDJ 2019 [882] Paediatric safety, N=49, 2-18 yrs beyond the Onlydose, 1.5 mg/kg Anidulafungin EU Label [883] Approved in paediatric subjects ≤ 18 yrs neonatal age maintenance,Not given IV once Anidulafungin US Label [884] daily

Paediatric CAS Walsh AAC 2005 [885] Paediatric PK and safety, N=39, 2 to 17 yrs patients Neely AAC 2009 [886] Paediatric PK and safety, N=9, 10-22 mo

178

beyond the 50 mg/msqu IV Li AAC 2011 [887] Paediatric population PK, N=125, 2-17 yrs neonatal age (day 1 70 Zaoutis PIDJ 2009 [888] Safety in clinical trials, N=171, 1 wk-17 yrs mg/msqu), max. Caspofungin EU Label [889] Approved in paediatric subjects by both EMA and 70 mg, in one FDA single daily dose Caspofungin US Label [890]

Paediatric MICA Seibel AAC 2005 [891] Paediatric PK and safety, N=77, 2-17 yrs patients < 40 kg 2-4 Hope AAC 2007 [892] Paediatric population PK, N=77, 2-17 yrs beyond the mg/kg IV in one Arrieta PIDJ 2011 [893] Safety in clinical trials, N=296, <1-17 yrs neonatal age single daily dose Micafungin EU Label [894] Approved in paediatric subjects by both EMA and > 40 kg 100-200 FDA mg IV in one Micafungin US Label [895] single daily dose

5-FC, 5-flucytosine; ABLC, amphotericin B lipid complex; AmB, amphoteiricn B; c-AmB, conventional amphotericin B; CAS, caspofungin; CVAD, central vascular access device; EMA, European Medicines Agency, EU, European Union, FDA, FLU, fluconazole; ITC, itraconazole;IP, intraperiotoneally; KTZ, ketoconazole; ISAV, isavuconazole; L-AmB, liposomal amphotericin B; MICA, micafungin; PK, pharmacokinetics; VRC, voriconazole; N, number of subjects investigated

2186 consultation. 2187 Table 35. Dosing recommendations of antifungal agents useddistribution. for treatment of rare yeast 2188 infections in neonates Population Agent and dosing publicReference Comment Neonates c-AmB Starke JID 1987 [822] Neonatal PK and safety, N=10

1-1.5mg/kg IV in one single Baley JPaediatrother 1990 [896] Neonatal PK and safety, N=13 daily dose for Driessen PIDJ 1996 [897] Neonatal safety, N=11 forJeon YonseiMedJ 2007 [898] Neonatal safety, N=20

Neonates L-AmB Scarcella PIDJ 1998 [899] No neonatal PK available

Only3-5mg/kg/d IV in one Neonatal safety. N=40 single doseNot Juster-Reicher EJCMID 2003 [900] Neonatal safety, N=37

Manzoni EarlyHumDev 2012 [901] Neonatal safety, N=71, weight ≤1500 g

Neonates ABLC Würthwein AAC 2005 [902] Neonatal PK and safety, N=30

5mg/kg/d IV in one single Wiley PIDJ 2005 [819] Neonatal safety, N=44 aged ≤3 mo) dose

179

Neonates 5-FC Baley JPaediatr 1990 [896] Neonatal PK and safety, N=13

100 mg/kg IV in 3-4 Pasqualotto JAC 2007 [828] Neonatal PK and safety, N=33 divided doses + TDM Pasqualotto JAC 2007 [828] Dosing target, neonates, N=33

Soltani IJAA 2006 [832] Dosing target, neonates, N=167

Target for invasive Candida infections and cryptococcosis: 30-40 mg/L pre- dose and 70-80 mg/L post dose (30 minutes after a 2-hour infusion or 2 hours after oral administration)

Neonates FLU Wade AAC 2008 [903] Neonatal PK, N=55 ≤40 wks of gestation/postnatal age ≤ 12.6weeks 12 mg/kg/d IV in one single dose (day 1: 25 Piper PIDJ 2011 [904] Neonatal PK, N=10 aged ≤38 weeks, mg/kg loading dose

Egunsola EJCP 2013 [839] Pediatric safety – systematic review, consultation.N=4902 aged ≤ 17 years Wade AAC 2008 [903] Dosing target, invasive candidiasis in neonates

Neonates ANID Cohen-Wolkowiez ClinPharmTherdistribution. Neonatal PK and safety, N=15 infants 2011 [905] and neonates 1.5 mg/kg IV in one single daily dose public Neonates CAS Saez-Llorens AAC 2009 [906] Neonatal PK and safety, N=18 aged < 3 other mo of age 25 mg/msqufor IV in one single daily dose Odio PIDJ 2004 [907] Neonatal safety, N=10, 1 term and 9 for preterm patients Neonates MICA Heresi PIDJ 2006 [908] Neonatal PK and safety, N=23 premature infants Only4-10 mg/kg IV in one single daily doseNot Hope AAC 2007 [892] Neonatal population PK, N=47 Benjamin ClinPharmaTher 2010 [909] Neonatal PK and safety, N=13

5-FC, 5-flucytosine; ABLC, amphotericin B lipid complex; AmB, amphoteiricn B; c-AmB, conventional amphotericin B; CAS, caspofungin, FLU, fluconazole; IV, intravenous L-AmB, liposomal amphotericin B; MICA, micafungin; PK, pharmacokinetics;; N, number of subjects investigated; TDM, therapeutic drug monitoring

180

2189 Order of compounds according to drug class (polyens, nucleic acid analogues, azoles, 2190 echinocandins)

2191 While caspofungin and micafungin are approved for use in neonates by the EMA (but not the 2192 FDA); anidulafungin is not approved for pediatric subjects by both agencies. All other listed 2193 agents have variable approval status in neonates in countries of the European Union and the 2194 U.S.

2195

2196 Children and adolescents

2197 Liposomal amphotericin B and amphotericin B lipid complex are well studied and safe in children 2198 beyond the neonatal period, with similar pharmacokinetics and dosing to that in adults. There is 2199 a relative preference for liposomal amphotericin B as it has approved first-line indications, fewer 2200 infusion-related reactions and more favorable pharmacokinetic/pharmacodynamic relationships 2201 in CNS involvement.[814] Amphotericin B deoxycholate is an alternative choice for treatment with 2202 amphotericin B, if liposomal amphotericin B or amphotericinconsultation. B lipid complex are not available. 2203 For 5-flucytosine, no published pharmacokinetic and safety data exist for infants and children 2204 and therapeutic drug monitoring (TDM) is recommended;distribution. robust efficacy data exists for 2205 cryptococcal meningoencephalitis in combination with amphotericin B.[833]

2206 Pharmacokinetics and safety of fluconazole are well established; based on pharmacokinetic and 2207 pharmacodynamic considerationspublic for invasive candidiasis and exposure studies in children, the 2208 maximum approved dosage of 12 mg/kg/dother may be the preferred dose also for infections by 2209 susceptible rare yeast.for[837] Itraconazole is not approved in pediatric age groups, but it is widely 2210 used in middle and low-incomefor countries and solid pharmacokinetic and safety data exist for the 2211 oral suspension; TDM where available is recommended to monitor exposure.[850] Voriconazole is 2212 approvedOnly for children >2 years of age but exhibits high inter- and intra-individual variability in 2213 exposure with a strongNot recommendation for TDM; adequate exposure may be uncertain in the 2214 first few days of treatment or never be reached. There also is a high potential for drug-drug 2215 interactions.[850] Posaconazole is not yet approved for children < 13 years of age; the tablet 2216 formulation provides adequate exposure, and a new delayed release oral suspension and the 2217 intravenous formulation are in late stages of pediatric development.[870, 875] For the new triazole 2218 isavuconazole, dose finding studies are under way in the pediatric population.[878]

181

2219 The echinocandins caspofungin and micafungin are approved in children of all age groups for 2220 treatment of invasive candidiasis; they exhibit favorable pharmacokinetics and an excellent 2221 safety record; anidulafungin is not being developed for children and may not be used because of 2222 approved alternatives (Table 5 and Table 6).

2223

2224 Neonates

2225 Options for neonates include amphotericin B products, flucytosine, fluconazole, caspofungin and 2226 micafungin. While caspofungin and micafungin are approved for use in neonates by the EMA (but 2227 not the FDA), anidulafungin is not approved for pediatric subjects by both agencies. All other 2228 agents have variable approval status in neonates in countries of the European Union and the US. 2229 Of note, amphotericin B deoxycholate is better tolerated in neonates and may be an appropriate 2230 choice if amphotericin B treatment is considered. Robust dosing recommendations and safety 2231 data exist for fluconazole and micafungin, and, to a lesser extent, flucytosine and caspofungin 2232 (Table 6). consultation. 2233 2234 FUTURE DIRECTIONS distribution. 2235 Unmet needs 2236 Unmet needs in rare yeast infectionspublic may differ between regions or even between institutions. 2237 For all however, a multidisciplinary approachother is essential, with early cross-consultation between 2238 specialists from the treatingfor team, radiologists, infectious diseases specialists, microbiologists, 2239 pathologists, and surgeons especially where there is end organ involvement e.g. endocarditis. 2240 This can be challenging as clinicalfor manifestations vary, patients present to diverse “first contact 2241 of care” and access to multidisciplinary care may be limited by logistical difficulties or at times, 2242 geographicalOnly isolation.

2243 Not

2244 Appropriate algorithms for the diagnosis of rare yeast infections with good specificity in early 2245 stages of infection are also essential. Newer MALDI-TOF MS or molecular-based approaches 2246 including the direct detection of rare yeasts in tissue specimens requires larger scale clinical

182

2247 validation. Enabling access to these tests particularly in geographically remote areas should be a 2248 priority.

2249

2250 Increasing awareness amongst physicians and laboratory scientists will enable clinical 2251 management pathways that are currently not sufficiently mature in many institutions, although 2252 reference to guideline documents such as this one can be made. Management pathways are 2253 reliant on understanding of the epidemiology of rare yeasts infections. Hence, multicentre and 2254 multinational experiences to better characterise the epidemiology of these pathogens and 2255 systematic surveys involving reliable diagnostics are another priority. Because there are few data 2256 to inform best practice antifungal therapy, well-designed studies evaluating various treatments 2257 and their efficacy (and disadvantages) are required. Disease due to these pathogens is 2258 uncommon and render randomised clinical trials very unlikely.

2259 2260 Constraints in optimising management consultation. 2261 In resource-limited settings, diagnosis and management of these invasive yeast infections may 2262 be sub-optimal. In the clinic or at the bedside, there are no simple,distribution. rapid antigen tests (analogous 2263 to the blood cryptococcal antigen lateral flow assay) for direct detection from clinical samples. In 2264 the laboratory, these unusual or emerging fungal pathogens may be fastidious and difficult to 2265 culture (Malassezia, for instance),public may be unfamiliar to many laboratory personnel because they 2266 are infrequently isolated and finally, mayother be misidentified because they require advanced 2267 laboratory techniquesfor such as MALDI-TOF MS or DNA sequencing for accurate genus/species- 2268 level identification. Managementfor is likely to be compromised by delayed correct laboratory- 2269 based identification and by a lack of availability of reference antifungal susceptibility testing to 2270 guideOnly the choice of appropriate antifungal treatment. In addition, a very limited armamentarium 2271 of systemic antifungalNot agents (national essential medicines lists are often restricted to 2272 fluconazole, and sometimes include amphotericin B deoxycholate) means that most potent 2273 agents may not be available to treat these infections. Therapeutic drug monitoring is unavailable 2274 in most resource-limited settings.

2275

183

2276 Priority research questions

2277 For rare yeasts, the five most immediate next research questions are focused around diagnosis 2278 and management. First, it will be important to have a stable, molecularly driven naming of the 2279 genus/species. Second, molecular studies must identify specific outbreaks and provide some 2280 insights into the ranking of the pathogenicity of strains/isolates. Third, it will be important to 2281 create worldwide clinical databases so that collections of strains and curation of outcome data 2282 can occur. We must be able to amplify the clinical experience with these yeasts. Fourth, we must 2283 be able to provide robust in vitro susceptibility data with epidemiologic breakpoints using large 2284 numbers of isolates for both old and new antifungal agents. Fifth, we must encourage 2285 development of new classes of antifungal agents but then we need to be aggressive in enrolling 2286 in open clinical trials to obtain the clinical experience in treatment with new agents against rare 2287 yeasts.

2288 2289 ACKNOWLEDGMENTS consultation. 2290 The authors are indebted to Susann Blossfeld and Christina Többen for invaluable technical 2291 support with this manuscript. We also thank catriona Hallidaydistribution. for the providing Figure 4. public for other for Only Not

184

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