FEMSYeastResearch,16,2016,fov114 doi:10.1093/femsyr/fov114 AdvanceAccessPublicationDate:20December2015 Minireview MINIREVIEW Old and new pathogenic Nakaseomyces species: D o w n epidemiology, biology, identification, pathogenicity loa d e d and antifungal resistance fro m h A. Angoulvant1,2,∗, J. Guitard3,4 and C. Hennequin3,4 ttps://a c a 1LaboratoiredeParasitologie-Mycologie,UniversityHospitalBiceˆtre,APHP,94275LeKremlin-Biceˆtre,France, de m 2CNRSUMR8621,Ge´ne´tiqueQuantitativeetE´volution,UnivParis-Sud,LeMoulon,91190Gif-sur-Yvette, ic .o France,3ServicedeParasitologie-Mycologie,UniversityHospitalStAntoine,APHP,75012Paris,Franceand u p 4Centred’ImmunologieetdesMaladiesInfectieuses(CIMI-Paris),UnivParis06UPMC,SorbonneUniversite´s, .co m CR7,75013Paris,France /fe m ∗Correspondingauthor:LaboratoiredeParasitologie-Mycologie,APHP,78rueduGe´ne´ralLeclerc,94275LeKremlin-Biceˆtre,France.Tel:+33145213394; sy Fax:+33145213319;E-mail:[email protected] r/a Onesentencesummary:Thisreviewprovidesthecurrentstateofknowledgeontheepidemiology,biology,identification,pathogenicityandantifungal rtic resistanceofC.glabrata,C.nivariensisandC.bracarensis. le -a Editor:MoniqueBolotin-Fukuhara b s tra c t/1 ABSTRACT 6/2 /fo Duringthepreviousdecades,asthenumberofimmunocompromisedpatients,theaverageageofWesternpopulationsand v1 1 thewidespreaduseofindwellingmedicaldeviceshaveincreasedconcomitantly,sohastheincidenceofinfectionscaused 4 /2 byCandidaspecies.Candidaalbicansremainsthemostfrequentlyisolatedagentofcandidiasis.However,C.glabratanow 5 7 accountsforasubstantialpartofclinicalisolates,rankingnumbertwoamongtheetiologicagentsofeithersuperficialor 0 1 1 invasivecandidiasisinNorthAmericaandEurope.AlongwithC.glabrataandbelongingtotheNakaseomycesclade,twonew 4 b species,C.nivariensisandCbracarensishaverecentlybeendescribedasemergingpathogens.Thisreviewprovides y g informationonthecurrentstateofknowledgeontheepidemiology,biology,identification,pathogenicityandantifungal u e resistanceofC.glabrata,C.nivariensisandC.bracarensis. st o n Keywords:C.glabrata;C.nivariensis;C.bracarensis:epidemiology;biology;pathogenicity 0 8 A p ril 2 INTRODUCTION 0 changecomprisestheemergenceofC.glabratawhichnowranks 1 9 number two among the Candida species responsible for mu- Theincidenceofinvasivefungalinfections(IFI)hasincreased cosalandinvasivecandidiasisinadultpatientsinWesterncoun- sincetheendofthe1990s.Candidainfectionsremainbyfarthe tries (Trick et al. 2002; Tortorano et al. 2004; Li, Redding and mostfrequentcause,accountingfor43%–75%ofIFI,withanes- Dongari-Bagtzoglou 2007; Diekema et al. 2012; Al-Rawahi and timatedincidenceof36to290permillionpopulationintheUSA Roscoe2013;Bitaretal.2014;Colomboetal.2014).Apartfrom andFrance(PfallerandDiekema2010;Bitaretal.2014).While itsemergence,C.glabratastandsoutbyparticularphenotypic Candidaalbicansremainsthepredominantcausativespeciesof and genetic characteristics. For example, its inability to pro- those infections, there has recently been an increase in the ducepseudohyphae,afeaturesharedbymostofthepathogenic incidence of non-albicans Candida species. This epidemiologic Candida species (Barnett, Payne and Yarrow 1990), correlates Received:18July2015;Accepted:17December2015 (cid:3)C FEMS2015.Allrightsreserved.Forpermissions,pleasee-mail:[email protected] 1 2 FEMSYeastResearch,2016,Vol.16,No.2 with its taxonomic position distant from the clade that in- tractcolonizationbyC.glabrata(Kauretal.2005),itwasfound cludes most of the pathogenic Candida species, and closer to that this genomic feature was in fact shared by all the mem- Saccharomyces cerevisiae. More recent advances in molecular bersoftheNakaseomycesclade.Overall,comparedtoS.cerevisiae, studies have demonstrated that C. glabrata belongs to a phy- genelossesaremostlysharedbythewholeclade,asitisthe logeneticcladethatincludesthreeenvironmentalspeciesand caseforthePAU,SNZ/SNOandPHOfamilies.Moreinteresting, twonewhumanpathogens,C.nivariensisandC.bracarensis(Cor- anexpansionoftheEPAgenefamily,knowntobeinvolvedin reiaetal.2006).Thisdiscovery,alongwiththeabilitytoiden- adhesiontohumanepithelia(Cormack,GhoriandFalkow1999), tifythesecrypticspecieseasily,shouldleadtoare-evaluation was only seen in the three pathogenic Nakaseomyces species of their epidemiologic features, previously considered as per- (Gabaldon et al. 2013). Indeed, this gene family is completely tainingtoC.glabrata.Indeed,whilethebiologyandpathology absent from C. castelli and K. bacillisporus genomes, and only ofC.glabratahavebeenstudiedforsometime,dataarestillvery representedbyasinglegeneintheclosestnon-pathogenic,N. limitedforthe othertwopathogenicNakaseomyces species. In delphensis(Gabaldonetal.2013).Phylogeneticandgenomeanal- thispaper,wewillfocusonC.glabrataandtheclinicalspectrum ysis reveals that the most likely scenario for the appearance D ofitsinfectionsandcompareitscharacteristicswiththoseavail- of pathogens in this group of species is their fortuitous pre- o w ableforC.nivariensisandC.bracarensis. adaptation to the human host as a clade, and the emergence nlo ofcommensality–pathogenicityindependentlyinthreespecies a d TAXONOMY (Gabaldonetal.2013). ed fro m Candidaglabratawasfirstisolatedin1917asaCryptococcus,by Populationstructure h AndersonH.W.duringastudyonyeastsisolatedfromhuman ttp ssptoeoclises(ATnodruerlosposnis19g1la7b)r.aInta1o93n8,thLoedbdaesrisanodfDitesVinriaebsinlitaymteodpthrois- Timhperaovvaeimlaebniltitoyfomfothleecugleanrotmypeinogf Cm.egtlhaobdrastafoarlstoraacilnlogwsetdratihnes s://ac a duce pseudomycelium and its morphological and physiologi- andinitiatingpopulationgeneticstudies.Indeed,thesequence de calcharacteristicssimilartoyeastsoftheTorulopsisgenusand dataofferedthepossibilitytosetupmultilocussequencetyp- m ic differentfromthoseoftheCryptococcusgenus(LodderandDe ing (MLST) and Multiple Loci VNTR Analysis (MLVA) (Dodgson .o Vries1938).Fromthenon,andformanyyears,C.glabratawas etal.2003;Brisseetal.2009).Authorsfoundanoverallagreement up consideredanon-pathogenicsaprophyteofthehumandiges- betweenclonalcomplexesdefinedwithbothanalyses.(Dodg- .co m tiveflora,untilthe1980swhenitwasshowntoberesponsible sonetal.2005;Enache-Angoulvantetal.2010a;Lott,Fradeand /fe formucosalandinvasivecandidiasis(Odds1988).Atthesame Lockhart2010).Asisthecaseformostofthesestudies,acor- m time, the definition of the Candida genus turned into ‘strains relation between genotype distribution and geographic origin sy oofrswpeelcliedsevoerlovapreide’tileesawdiinthgptoseruednoahmyephTa.eglaabbsraetnat,arsudCi.mgleanbtraartya wsoasfaorbssuersvtaedin.Athltehohuygphoathllepsoispuolfaatiomnogsetnlyetciclosntualdireespproudbulicsthioend r/article (YarrowandMeyer1978).Uptonow,nosexualreproductionhas mode in C. glabrata, Dodgson et al. (2005) all found some ge- -a b brDeeNnAdcelemaorlnysptrlaatceedsfCo.rgtlahbisrastapewciitehsi.nMtohleecAuslcaormaynceatleyssipshoyflutmhe, ntieotnicevinecnotms.pInadtiebeidli,tieevse,nsuifpCp.ogrltainbrgattahehaesxinsotednecmeoonfsrtercaotmedbsinexa-- strac closelyrelatedtothegroupofSaccharomycesandKluyveromyces ual reproduction, its genome contains homologs of all genes t/1 6 (KurtzmanandFell1998).In2003,Kurtzmanproposedtoinclude neededformating-typeswitchingandmating.MLVA(Brisseetal. /2 C. glabrata in a clade that he named Nakaseomyces with three 2009)wasthenappliedtodescribethebiodiversityandgenetic /fo v environmental species, e.g. C. castellii, Nakaseomyces delphen- relationshipofclinicalisolatescollectedfromBCanddigestive 11 sis(syn.Kluyveromycesdelphensis)andNakaseomycesbacillisporus tractofoutpatients.Itwasshownthatthedigestiveisolatesex- 4/2 (syn. Kluyveromyces bacillisporus) (Kurtzman 2003). A few years hibitahighergenotypicdiversityassociatedwithdifferental- 57 0 later, two new species isolated in pathogenic conditions from lelic frequencies, and are preferentially excluded from clonal 1 1 humansamples,wereaddedtothisclade:C.nivariensisfirstiso- complexes(Enache-Angoulvantetal.2010a).Thedemonstration 4 b latedfromabroncho-alveolarlavagefluid,urineandblood,and oftheoccurrenceofmicroevolutionindigestivestrainsisolated y g C.bracarensisisolatedfromvaginaandbloodculture(BC;Alcoba- fromasamesubjectsupportstheideathatC.glabratacanbe ue Florezetal.2005b;Correiaetal.2006). apersistentcommensalofthehumangut(Enache-Angoulvant st o Thus,theNakaseomycescladenowincludes,inalimitedge- et al. 2010a). However, in another study, genotypes of strains n netic distance, six closely related species, three environmen- isolatedfrombloodstreamandthatofnon-invasivestrainsob- 08 talandthreepathogenic,makingitaveryinterestinggroupfor tainedfromnon-sterilesitesofsubjectswithnoevidenceoffun- Ap comparativestudiesfocusingonadaptationtothehumanhost galdiseasewerefoundtobesimilaroverall(Lott,FradeandLock- ril 2 andthereforevirulence. hart2010).ThismaybeduetoamorehomogenousC.glabrata 01 studiedpopulation(samegeographical area, overlappingtime 9 periods) (Lott, Frade and Lockhart 2010). It could also reflect GENOMEANDGENETICDIVERSITY a lower discriminatory power of MLST analysis compared to MLVA, since a sub-analysis of VNTR genotypes of the French Comparativegenomics strainstakingintoaccountthetimeofisolation,confirmedthe The genome of the type strain of C. glabrata was released in difference in genotype frequencies between BC and digestive 2004 (Dujon et al. 2004) and the sequences of the five other strains (Angoulvant A., unpublished data). Overall, the typing Nakaseomyces species were published in 2013 (Gabaldon et al. methods support the hypothesis that C. glabrata strains caus- 2013). ingbloodstreaminfectionsaregeneticallyclosefromthosenor- Comparativegenomicstudiespointoutsomecharacteristics mallypresentinthecommensalfloraofthehost.Inaddition, potentially linked to virulence. While the deletion of the BNA MLVAtypingwithasetofeightmarkersshowedahighdiscrim- genes involved in the de novo synthesis of nicotinic acid, was inatorypower,calculatedat0.97,makingitsuitablefortracing initiallythoughttobeakeyfeatureassociatedwiththeurinary strains(Chapeland-Leclercetal.2010;Garnaudetal.2015). Angoulvantetal. 3 D o w n lo a d e d fro m h Figure1.OverviewofisolationsitesofC.nivariensisandC.bracarensisstrainsinliterature.NS,notstated.Miscellaneous:oneC.nivariensisisolatefromthroat,two ttp s C20.0b8ra;cLaorceknhsiasritseotlaatle.s20fr0o9m;Cshtoowold.h(Aalrcyoebtaa-lF.l2o0re1z0;ePtaarl.m2e0l0a5nbd;Cetoarrl.e2ia01et2;aGl.o2r0t0o6n;Petagael.e2t0a1l3.;2L0o0p6e;zF-uSjoitraiaeteatla.l2.020071;3B;oSrhmaramnaeteatla.l2.020081;3P;iCnhtoaoeteatla.l2.020081;4W;Laahcyruoinxinetgsailh.2e0t1a4l.; ://ac a Swoboda-Kopecetal.2014;Tayetal.2014).DetaileddataarepresentedinTableS1. d e m Molecular typing of C. nivariensis and C. bracarensis by beennoticedinseveralstudies(Khatibetal.2001;Ribeiroetal. ic.o AFLP, RAPD and PCR finger printing, has been performed by 2001;Qi,HuandZhou2005;Sanchez-Vargasetal.2005).Were- up Wahyuningsihetal.(2008)andshowedthattheC.nivariensisIn- centlyperformedanepidemiologicalstudyonstoolcarriageof .co m donesianisolate(CBS10161)andtheEuropeanisolate(CBS9983) Candidaspeciesin258healthyadultsinvestigatedforparasitic had different molecular patterns from each other and from carriageinthecontextofpreventivemedicine.Theprevalence /fem C.bracarensis(CBS10154)andC.glabrata(CBS138)strains.How- ofC.glabrataisolationwasfoundtobe1.9%,comparedto32.2% sy ever,despitetherecentavailabilityofthegenomeofC.nivariensis for C. albicans. Previous reports showed a prevalence at 11.7% r/a aswellasthatofC.bracarensis(Gabaldonetal.2013),tothebest and0.8%inadultsandchildrenunder10,respectively(Rimek, rtic le ofourknowledge,notypingmethodssuchasMLSTandMLVA Redetzke and Kappe 2006). The prevalence of isolation of -a havebeendevelopedforthesespecies.Suchtechniquesshould C.glabrataismuchmoreimportantinelderlysubjectsinwhom bs beusefultodefinepopulationstructure,geographicaldistribu- itcan reach 58% (Lockhart et al.1999) and inhospitalizedpa- tra c tionwithemphasisonepidemiologyandsusceptibilitytoanti- tients(21,1%)versusoutpatients(9%)(RimekandKappe2007). t/1 6 fungalagentsofthesepoorlyknownpathogens. Theprevalencewasalsofoundtobecorrelatedwiththelength /2 ofhospitalizationandantibiotictherapy(Vazquezetal.1998). /fo v Candidaglabratamayalsobeisolatedfromthevaginalflora 1 Epidemiology 1 ofhealthywomen,withaprevalencerangingfrom4%to50% 4/2 ThereareveryfewstudiesreportingthepresenceofC.glabrata (Ribeiroetal.2001;Danetal.2006;PirottaandGarland2006).In 57 intheenvironmentorcollectedfromanimals.However,itsiso- ourexperience,C.glabratawasisolatedin0.7%ofvaginalsam- 01 1 lationinareasclosetohumanhousingcanbeinterpretedasa plescollectedfrom2885pregnantwomeninvestigatedforStrep- 4 b ‘contamination’oftheenvironmentbyhumans(Brinkmanetal. tococcus B portage (Angoulvant A., unpublished data). Higher y g 2003;Ferreiraetal.2010).Moreover,theaccuracyoftheidentifi- prevalence has been reported among asymptomatic women u e caacttieornistoifcsC.caglnabbreatqauienstoilodneerds.tSuudciehs,absaasestduodnyppehrefnoormtyepdicinchtahre- wbehfooreretcheeivseadmapnlitnibgioatnicdtwreoamtmenenotldienrtthheanpr8e0viyoeuasrstw(Doanweeteakls. st on Amazonianforest(awayfromthehumanhabitat)inthe1980s, 2006;PirottaandGarland2006).Prevalencemayalsoincreasein 08 reportedthat12%ofsamplescollectedfromsoil5cmdeep,con- womensufferingofdiabetesmellitusorHIVinfection(Vazquez A p tainedC.glabrata(Moketal.1984). etal.2001;deLeonetal.2002;Merensteinetal.2013). ril 2 Candida glabrata is, overall, rarely isolated from animals, Untilnow,C.nivariensisandC.bracarensishaverarelybeen 0 1 except from cattle, in which C. glabrata proved to be a true reportedascommensalsofhumanflora.However,inhumans, 9 pathogen responsible for diarrhea in calves (Elad et al. 1998). it seems that they have similar niches: digestive (oropharyn- BirdsmayalsoconstituteareservoirofCandidaincludingC.al- geal,stool)andgenital(vagina)tractsandurine;dataaresum- bicansandC.glabrata(Cafarchiaetal.2008).Untilnow,theeco- marizedinFig.1andTableS1(SupportingInformation).Inour logicalnichesofC.bracarensisandC.nivariensisremaintotally study linked to preventive medicine, neither C. nivariensis nor unknown.Thosespecieshaveonlybeenisolatedfromhuman C. bracarensis was isolated, nevertheless we recently isolated sources but one strain of C. nivariensis that has been isolated C.nivariensisfromthestoolofanasymptomaticBurkinabesub- fromfloweringplantsinAustralia(Lachanceetal.2001). ject (Sanata et al. 2014), suggesting both the existence of this As C. albicans, C. glabrata is considered to be part of the speciesontheAfricancontinentanditsabilitytocolonizethe human digestive and vulvo-vaginal flora. The prevalence of gut.OnecannotethatC.nivariensiswasrepeatedlyisolatedfrom C. glabrata oropharyngeal commensalism has been found to urinesfromasamepatientduringseveralmonthssuggesting varybetween0%(Kleineggeretal.1996)and29%intheelderly thatitcouldcolonizetheurinarytract(Gortonetal.2013)(Boug- (Lockhart et al. 1999). An increase in prevalence with age has nouxM.E.,unpublisheddata). 4 FEMSYeastResearch,2016,Vol.16,No.2 D o w n lo a d e d fro m h ttp s ://a c a Figure2.DistributionofC.nivariensisandC.bracarensisisolatesaccordingtotheanatomicsitesinfourFrenchuniversityhospitals(2010–2014).Miscellaneous:one d e C.nivariensisisolatefromapreservationliquidofsolidorgantransplantandoneC.bracarensisisolatefromapleuralliquid. m ic .o Obviously,therealprevalenceofthosepathogenshastobe for prophylaxis and treatment during the past decades, espe- up re-appreciated using reliable tools for identification. Until re- ciallyinpatientswithhematologicalmalignancies. .co cently,phenotypicidentificationusingabiochemicalpanelwas Again, data for C. nivariensis and C. bracarensis are far less m considered the reference. A number of studies reviewed the abundantanddirectlyinfluencedbytheavailabilityofthemost /fem identification of C. glabrata strains using molecular methods. reliableidentificationmethods.Availabledataaresummarized sy TheprevalenceofC.nivariensisandC.bracarensiswithinthese inFigs1and3andTableS1(SupportingInformation). r/a panels of ‘previously identified C. glabrata strains’ were found rtic le between0%and0.06%,and0%and2.2%,respectively(Bishop -a eEtspaol.st2o00e8taa;l.L2o0c1k3h)a.rNteevteartl.he2l0e0s9s;, Mthiirsanstdraa-tZegaypic(roe-eidteanl.ti2fy0i1n1g; Clinicalspectrumofinfection bstra c C. glabrata strains) may underestimate the true prevalence of Overall, the clinicalspectrum of C. glabrata infectionsisquite t/1 C.nivariensisandC.bracarensis,sincetheirbiochemicalprofile similartothatofC.albicans.ClinicalfeaturesofC.nivariensisand 6/2 maybedifferentfromthatofC.glabrataasdetailedin‘Diagnosis’ C.bracarensisarestillpoorlydescribed,probablybecauseoftheir /fo v paragraph. recentdescriptionanddifficultidentification. 1 1 In order to evaluate these prevalences, we performed for Candida glabrata is responsible for mucosal candidiasis, 4/2 this paper a small retrospective study in four French univer- mostlyoropharyngeal,esophagealandvaginal.LikeC.albicans, 57 sityhospitals(2010–2014),whereallisolatedstrainswereiden- C.glabratainducesoropharyngealcandidiasis(OPC)withinflam- 01 1 tifiedwithMALDITOFsystemsthatareabletodistinguishthe matory pseudomembranous and erythematous lesions result- 4 b threespecies.Duringthisperiod,55464yeaststrainswereiso- inginsignificantmorbiditywithburns,pain,dysphagia,dysgue- y g lated from clinical samples from 45 633 patients. Candida ni- sia and nutritional compromise. The prevalence of C. glabrata u e vaanrdie0n.s0i1s1a%ndofCt.hberapcaarteiennsitssw,reerpereressepneticntigve0l.y12i%deanntidfie0d.0i1n%0o.0f3t7h%e O(HPaCmiznaHetIVal.i2n0f0e8ct;eMdupluateiteanlt.s20v1a3r)i.eHsibgehtewreperneva5.l8e%nceanhdas2b2e.5e%n st on strains(Fig.2).Thisisinaccordancewithcumulateddatafrom reportedinpatientswithahistoryofantifungaltreatmentuse, 08 theliteratureshowinganoveralllowprevalenceforbothspecies especiallyazolederivatives(Pateletal.2012;Muluetal.2013). A p andhigherprevalenceofC.nivariensiscomparedtoC.bracarensis CandidaglabrataOPChasalsobeendescribedinpatientsreceiv- ril 2 (Fig.3;andTableS1,SupportingInformation). ingimmunosuppressivetherapyorchemotherapy,withapar- 0 1 Finally, it is now well established that the prevalence of ticularmentionforpatientswithradiationtherapyforheadand 9 C. glabrata among the etiologic agents of invasive infection is neckcancerinwhomtheprevalenceofC.glabrataseemstobe higherinNorthernEuropeandNorthernAmericathaninSouth- higher (Oude Lashof et al. 2004; Redding et al. 2004; Dongari- ernpartsoftheworld,notablyinBrazilandKuwait(4.9%and Bagtzoglouetal.2009;Gligorovetal.2011).Similarly,C.glabrata 5.6%,respectively)(Falagas,RoussosandVardakas2010;Pfaller hasbeenshowntobeafrequentpathogeninelderlypatients, etal.2013).Nevertheless,theprevalenceofC.glabratainasame notablydenturewearers,withaprevalenceofC.glabrataamong countryorgeographicalregionvariesdependingonthesetting theagentsofOPCupto31%(Li,ReddingandDongari-Bagtzoglou and/orstudydesignwithvaluesof2.2%inpediatricpopulation, 2007;Pintoetal.2008).Incontrast,localextensiontotheesoph- and24%inadultsintheUSAandhighervaluesinJapan(17.9%) agusislessfrequentlyreportedthanforwithC.albicans.Never- among Asian countries (Falagas, Roussos and Vardakas 2010). theless,arecentstudyshowedthatC.glabratawasimplicatedin Thereasonsforthisunequalrepartitionarenotfullyunderstood 24%ofCandidaesophagitis,aloneorassociatedwithC.albicans, butonecouldhypothesizethatitmaybepartiallylinkedtoclin- suggestingthattheimportanceofC.glabratainthisclinicalform icalpractice,asaresultoftheextensiveuseoffluconazoleboth mightbeunderestimated(Wilson,DelportandPonich2014). Angoulvantetal. 5 D o w n lo a d e d fro m h ttp s ://a c a d e m ic .o u p .c o m /fe m s y r/a rtic le -a b s tra c t/1 6 /2 /fo v 1 1 4 /2 5 7 0 1 1 4 b y g u e s t o n 0 8 A p ril 2 0 1 9 Figure3.GeographicregionswhereC.nivariensis(greysquares)andC.bracarensis(whitesquares)wereisolated.(A)World;(B)Europe.Datacompiledfromtheliterature (detaileddatainTableS1,SupportingInformation)andtheFrenchstudy. Candidaglabratacanalsobethecauseofvulvo-vaginalcan- However,themainconcernwithC.glabratainfectionislife- didiasis(VVC)witharelativefrequencyestimatedat10%–20% threatening invasive forms. Candidemia (the isolation of Can- ofthecases(Corselloetal.2003).Higherfrequency(61.3%)has didafromBC)andintra-abdominalinfectionsarethemostcom- beenreportedinpatientswithtypeIIdiabetesmellitus(deLeon mon.Incaseofbloodstreamdissemination,Candidamayeven- etal.2002)andinelderlypatients(Vermitskyetal.2008).Candida tually spread intodeep organs, mostlyliver, spleenor kidney. glabrataVVCdiffersfromthatduetoC.albicansbyareducedmu- Candidaalbicanscurrentlyremainstheleadingcauseofthesein- cosalinflammation,butitismoreoftenassociatedwithdifficult fections,butC.glabratahassignificantlyemergedinanumberof totreatand/orrecurrentforms(Sobel2007). institutionsforadultpatients(Hornetal.2009;Lortholaryetal. 6 FEMSYeastResearch,2016,Vol.16,No.2 2011;Diekemaetal.2012;Al-RawahiandRoscoe2013;Arendrup diabetes,rheumatoid,arthritisleukemia.Systemiccandidiasis et al.2013; Montagna et al. 2014). WhileC. glabrata represents otherthancandidemiaduetoC.nivariensisorC.bracarensisare 16%–29%ofisolatedspeciesinadultpatients,itsfrequencyis alsorarelyreported,pelvicabscessesbeingthemorecommon significantlylowerinpediatricpopulations,neonatesandchil- (Fig.1;andTableS1,SupportingInformation). dren,accountingforonly3%–14%ofthecausativeagentsofcan- didemia(SinghiandDeep2009;Zaoutisetal.2010;Tragiannidis etal.2012). DIAGNOSIS Among the predisposing factors of candidemia, age (>60 years), an underlying solid cancer, a recent abdomino-pelvic The diagnosis of Candida infections relies on data collected surgery,previousantibiotictherapy,notablybasedonwiththird fromthedirectexaminationofpathologicspecimensandiso- generationcephalosporins,tazocilline,vancomycinandaprior lation/identification of Candida in culture, completed with the treatment with fluconazole or echinocandins appear as more detectionofbiomarkersforinvasiveinfections. specificallyassociatedwithC.glabratainfection(Linetal.2005; With very few exceptions (Vandeputte et al. 2007), D Malanietal.2005;PfallerandDiekema2007;Tumbarelloetal. (Angoulvant A., PhD thesis), and contrary to the majority o w 2007;Cohenetal.2010;Lortholaryetal.2011;Guinea2014).Asis of Candida species involved in human infections, C. glabrata nlo thecaseforC.albicans,themainportalofentryofC.glabratais usually does not produce pseudohyphae even in pathogenic a d consideredtobethedigestivetract. conditions. This may represent a limitation for diagnosis ed However,urinecolonization(candiduriawithoutsymptoms) since,andcontrarytomostCandidapathogenicspecies,heavy fro m inhospitalizedpatientsiscommon,C.glabratabeingthesecond colonizationandinfectioncannotbedifferentiatedonthesole h isolatedCandidaspeciesafterC.albicans.PrevalenceofC.glabrata result of direct examination and culture. This characteristic ttp caannddridenuarilatvraanrisepdlafnrotmun5i%tst(oSa8f.4d%arinetianlt.e2n0s0iv5e; Bcaoruegnuonuitxs(eItCaUl). ssepeemciessto(Albceobcao-mFlomreoznettoaal.ll2t0h0r5ebe; CpaotrhreoigaeneticalN.a2k0a0s6e)o.mIytceiss s://ac a 2008;Chenetal.2008;Magilletal.2009;Gortonetal.2013).Thus, noteworthy that one C. nivariensis strain with the ability to d e theurinarytractmayalsorepresentasourcefordissemination producehyphaehasbeenreported(Tayetal.2014). m (Clerckxetal.2012;Pierallietal.2014)thatdeservestobeinves- OnSabourauddextroseagarincubatedat37◦C,C.glabrata, ic.o tigatedanddocumentedwithmolecularmethodsabletotrace C. nivariensis and C. bracarensis grow in the form of white or up strains. creamy butyrous colonies similar to most of the other Can- .co m In contrast, deep-seated infections (renal, liver...), other dida species. Candida glabrata and the two other pathogenic /fe than intra-abdominal, associated or not with candidemia, Nakaseomyces species reproduce by budding; cells are small m appear less frequent as compared to C. albicans (Enache- (3–4.5μm), subglobose to ovoidal. On ChromAgar medium, sy Angoulvant, PhD thesis 2011). Intra-abdominal infections due C.glabratacanusuallybedifferentiatedfromC.nivariensisand r/a toC.glabrataarecommon,probablylinkedwithdigestivecom- C.bracarensis,theformerproducingpinkcolonieswhilethetwo rtic le mensalism. Prevalence of isolation of C. glabrata from peri- othersremainwhite(Bishopetal.2008a;Lockhartetal.2009). -a b tonealfluidhasbeenreportedat17%and20%inFrenchICUs AnotherpeculiarityofC.glabrataisitsslowgrowthinconven- s (Dupontetal.2002;Montraversetal.2011).Consideringtheother tionalBCaerobicflasksbutalsoinanaerobicconditions(Foster tra c deep-seatedinfections,osteo-articular(Slenker,KeithandHorn etal.2007;Paugametal.2014).TwocasereportsofC.nivariensis t/1 6 2012; Neofytos et al. 2014), thoracic empyema (Ko et al. 2000; candidemiareportedtimeofpositivationofBContheBactAlert /2 Ishiguroetal.2010),endocarditis(Ellisetal.2001;Lyeetal.2005; systemat7daysandat24hoursforonesampledfromacentral /fo v Williams and Lye 2007), renal and perirenal infections (Pier- venouscatheterandonesampledfromperipheralblood,respec- 1 1 allietal.2014)(unpublisheddata)andparotiditisarethemost tively(Fujitaetal.2007;Lopez-Soriaetal.2013). 4/2 commonlyreported(Enache-Angoulvantetal.2010b;Leibowitz, Biochemichalprofileusedinauxanogrampanelshasbeen, 57 0 MontoneandBasu2010). for a long time, the routine method for Candida species iden- 1 1 Untilnow,probablyduetoabiasofpublication,C.nivariensis tification. C. glabrata as well as the two other pathogenic 4 b andC.bracarensishavefirstofallbeenreportedasagentsofcan- Nakaseomyces species usually only assimilate glucose and tre- y g didemia,andmostoftenbasedonretrospectivestudiesapplying halose; although some C. glabrata strains may also assimilate u e molecularidentificationonbloodstreamisolatesincollections lactose(Table1)(Barnett,PayneandYarrow1990;Alcoba-Florez st o (Alcoba-Florezetal.2005a;Correiaetal.2006;Bormanetal.2008; et al. 2005b; Correia et al. 2006). However, none of the panels n Lockhartetal.2009;Warrenetal.2010;Cuenca-Estrellaetal.2011; currently available include the new pathogenic Nakaseomyces 08 Lopez-Soriaetal.2012;Parmelandetal.2012;Lopez-Soriaetal. species in their database. This has led to erroneous identifi- A p 2013).Nevertheless,afewcasesofC.nivariensisandC.bracarensis cation as underlined in several recent studies (Borman et al. ril 2 OPChavenowbeenreportedwithoutnoticeableclinicaldiffer- 2008; Lockhart et al. 2009; Warren et al. 2010; Cuenca-Estrella 0 1 enceswiththoseduetootherCandidaspecies(Fujitaetal.2007; et al. 2011; Lopez-Soria et al. 2012, 2013; Li et al. 2014). Speci- 9 Bishopetal.2008b;Bormanetal.2008). ficitymaybeanissuesincemisidentificationofC.nivariensisas CandidanivariensisandC.bracarensishavealsobeenshown Zygosaccharomyces sp. may occur with the ID 32C system toberesponsibleofVVC(Lietal.2014;Tayetal.2014),witha (bioMe´rieux,Marcyl’Etoile,France)(Grenouilletetal.2009)and clinicalpresentationsimilartothatofC.glabrataVVC.Recently, as C. inconspicua with the Auxacolor2 colorimetric sugar as- re-identificationofC.glabratastrainsisolatedfromVVCinChina similationtest(Bio-Rad,Marnes-la-Coquette,France)(Wahyun- showedthatC.nivariensisandC.bracarensisrepresented2.33% ingsih et al. 2008). It should be mentioned that the rapid and0.33%ofstrains,respectively(Lietal.2014). reduction of trehalose as tested by the RTT test (Fumouze Until now, only nine and two cases of C. nivariensis and Diagnostics,Levallois-Perret,France)wasreportedtobespecific C.bracarensiscandidemia,respectively,havebeenreported.Data to C. glabrata (Freydiere et al. 2003; Wahyuningsih et al. 2008). aretooscarcetoestablishspecificpatientprofilesthatmaylead However,wehaverecentlyisolatedaC.nivariensisstrainwitha totheseinfections.Theyoccurredinpatientswithdigestivein- positiveRTTtest(FumouzeDiagnostics,Levallois-Perret,France) jury (pancreatitis, digestive fistula) or underlying diseases as (positive signal for trehalase combined with negative maltose Angoulvantetal. 7 Table1.MainphysiologicalfeaturesofpathogenicspeciesoftheNakaseomycesclade(Barnett,PayneandYarrow1990;Alcoba-Florezetal.2005b; Correiaetal.2006). Candidaglabrata Candidanivariensis Candidabracarensis Feature ATCC2001=CBS138 CBS9983=CECT11998 CBS10154=CECT12000 Growth Surfacegrowth(37◦C) – – – SDAcycloheximide(25◦C) – – + SDA(37◦C) + + + YPD(30◦C) + + + YPD(45◦C) – – – TurbidityYPD(37◦C) + – – Assimilation D Dextrose – – – o w Maltose – – – n lo Sucrose – – – a d Lactose – – – e d Galactose – – – fro Melibiose – – – m Cellobiose – – – h Inositol – – – ttps Xylose – – – ://a Raffinose – – – ca Trehalose + + + de m Dulcitol – – – ic KNO3 – – – .o u 2-Keto-gluconate – – – p Glycerol + + + .co m FDeerxmtreonsteation + + + /fem s Maltose – – – y Sucrose – – – r/a Lactose – – – rtic le Galactose – – – -a Trehalose + + + bs Cellobiose – – – tra c Othercharacteristics t/1 Germtubes – – – 6 Urease(25◦C) – – – /2/fo Ascospores – – – v1 Chlamydospores – – – 14 Esculinhydrolysis – – – /2 5 Pseudohyphae – – – 70 1 1 4 b y g u e utilization (Angoulvant A., unpublished data) suggesting that ufacturers of MALDI-TOF spectrometers and can be identified st o this biochemical test also might lack specificity for differenti- securely(Ferronietal.2010;Baderetal.2011;Pintoetal.2011; n ationbetweenC.glabrataandC.nivariensis. Lacroixetal.2014). 08 Tocircumventtheselimitations,severaltoolshavebeende- Thedetectionofbiomarkersmaybeofinterestforthediag- A p veloped,suchasPeptideNucleicAcidFluorescenceInSituHy- nosisofinvasiveCandidainfection(LerouxandUllmann2013). ril 2 bridizationwithspecificprobesforC.nivariensisandC.bracaren- Mostofthestudiesfocusedonantigens,mainlymannan,and 0 1 sis(Bishopetal.2008b)ormolecularidentification,usingdirect antimannanantibodies.Inarecentpublication,expertsofthe 9 sequencing of the ITS locus or D1/D2 region of the ribosomal ESCMID recommend the use of such assays for the diagnosis DNA(Alcoba-Florezetal.2005a;Bishopetal.2008a;Bormanetal. of candidemia and chronic disseminated candidiasis without 2008;Lockhartetal.2009;Romeoetal.2009;Cornetetal.2011).A anyrestrictionaccordingtospecies.Thedetectionofß-Dglu- rapidmethodusinglengthpolymorphismofanamplifiedfrag- can,acell-wallcomponentofallascomycetesmustbeadded mentencodingtheRPL31genehasalsobeenproposedtodistin- to this panel. Positive tests have been reported in the case of guish the three pathogenic Nakaseomyces (Enache-Angoulvant C.glabratainfectionsbutnonehasbeenevaluatedspecifically etal.2011). for the diagnosis of invasive candidiasis due to C. glabrata or Duringthelastdecade,MALDI-TOFhasemergedasapow- due the other 2 pathogenic Nakaseomyces species. Fujita et al. erfultoolfortheidentificationoffungalclinicalisolates,even (2007) report positive results for both ß-D glucan (153.7μg/L) closely related ones, sometimes included within the same andCandidaantigen(UnimediCandidamonotest,UniticaLtd, species complex. C. glabrata, and now C. bracarensis and C. ni- Tokyo, Japan) detection in a patient serum with C. nivariensis variensis are included in the databases of the different man- candidemia. 8 FEMSYeastResearch,2016,Vol.16,No.2 D o w n lo a d e d fro m h ttp s ://a c a d e m ic .o u p .c o m /fe m s y r/a Figure4.Overviewof(A)azoles,(B)flucytosineamphote´ricineBandcaspofunginandMICsforC.nivariensisandC.bracarensis.(Fujitaetal.2007;Bishopetal.2008b; rticle Bormanetal.2008;Wahyuningsihetal.2008;Lockhartetal.2009;Chowdharyetal.2010;Lopez-Soriaetal.2013;Tayetal.2014)andpersonalunpublisheddata.(Detailed -a b dataarepresentedinTableS2,SupportingInformation) s tra c Antifungaltherapy fungaldrugsagainstC.glabratawithMIC90≤0.12μg/ml(Pfaller t/16 etal.2002).Candidaglabrataflucytosine-resistantstrains(MIC> /2 Fourclassesofantifungalsareavailableforthetreatmentofin- 16μg/ml) have rarely been described (Chapeland-Leclerc et al. /fov vasivecandidiasis:polyeneswithamphotericinBasthemain 1 2010;EdlindandKatiyar2010).AsshowninFig.4andTableS2 1 representative, azole derivatives, echinocandins and flucyto- (SupportingInformation),flucytosineMICsofC.nivariensisvary 4/2 sine.GuidelinesfromtheESCMIDandtheIDSAforthetreatment from0.094to2μg/mlandMICsofC.bracarensisvaryfrom0.03to 57 0 ofinvasivecandidiasishavebeenproposedtodrivethechoiceof 0.125μg/ml. 11 antifungaltherapydependingonthepatientsubsetandtheiso- 4 Azole derivatives, fluconazole, itraconazole and the more b latedpathogen(Pappasetal.2009;Cornelyetal.2012;Ullmann y recent triazoles such as voriconazole and posaconazole, exert g etal.2012). u theiractivitythroughtheinhibitionoftheC14-alphalanosterol e AmphotericinBhasbeenconsideredforalongtimethegold s swfutiandngedaaslprmdeecomtfrubtmrhaenoeafnhatoicfmtuivneiogtyastlalitsnryek,aebtdumtteoanptt.hoeIotrditsioslceehqraaurnialcicbetrepiurrimozfiedloefbthtyhaaet dtneeermtoiclebpthirooyslfiaylsneetvheaenrsycisoa.dcTecdohrebdiyrinstghpeteocEttRrhuGem1m1gooeflneacecu,tilinevsivt.oylvaenddinphtahmeearcgooksi-- t on 08 A Candida glabrata’s reduced susceptibility to fluconazole has p has led to the development of lipid-based formulations. It is beenreportedsincethe1990s(vandenBosscheetal.1992;Rex, ril 2 commontoisolateC.glabratastrainswithareducedsuscepti- 0 RinaldiandPfaller1995).Pfalleretal.(2010c)showedthat31.3% 1 bilitytoamphotericinB.Inalargestudyincluding1993strains, 9 of 28 939 C. glabrata strains collected from 1997 to 2007 had up to 24.8% of the C. glabrata stains had an MIC > 1μg/ml decreased susceptibility (MIC ≥ 16μg/ml) to fluconazole. This (Pfaller et al. 2004). Mutations in the ERG6 gene involved in prevalenceofstrainswithdecreasedsusceptibilityvarieswith the ergosterol biosynthesis have been associated with lower geographicalorigin,beingthehighestinNorthernEuropeand sensitivity to amphotericin B in C. glabrata (Vandeputte et al. America(Pfalleretal.2010b),andinmedicaldepartments.One 2007,2008).Similarly,itcanbenotedthatMICsofC.nivarien- can note that the prevalence of C. glabrata strains resistant sisaremoreoften≥0.5μg/ml.Figure4andTableS2(Support- tofluconazolemaybedecreasing,asreportedbyClevelandet ing Information) summarize the data collected from different al. (2015), in their study on candidemia during the 2008–2013 studies. period.Thismaybepartiallyduetochangesinantifungaltreat- Flucytosine,anucleosideanalogue,isnowrarelyuseddue mentstrategies,notably,theincreaseduseofechinocandinsas toitsnarrowtherapeuticindex.Becauseoftherapidandfre- primarytherapyforcandidemia.Thisstrain-dependentflucona- quentacquisitionofresistance,thismoleculemustnotbeused zolesusceptibilityphenomenonisquiteuniqueamongCandida inmonotherapy.Nevertheless,itisoneofthemostactiveanti- Angoulvantetal. 9 species. This makes it difficult to predict susceptibility or re- mentisnowdrivenbythefearofC.glabrata’.Inmanyways,C.ni- sistance based only onspecies identification, as isoverall the variensisandC.bracarensis,tworecentlydescribedNakaseomyces ruleforotherpathogenicCandida.Accordingtothemolecular species,mimicthetraitsofC.glabrata.Whilethetrueprevalence mechanism(s)involved,resistancemaybecrossed,ornot,with ofthesespeciesremainedtobedetermined,itisclearthatthey other azole derivatives, including the more recent ones such areratherrarecomparedtoC.glabrata.Additionaldataarere- as voriconazole and posaconazole (Espinel-Ingroff et al. 2005; quiredtobettercharacterizetheecologicalnichesandclinical Lortholaryetal.2007;Pfalleretal.2010c).82%ofthefluconazole- featuresofinfectionsduetothesepathogens,aswellasmolec- resistantstrainswere reported tobe resistanttovoriconazole ularmechanismsinvolvedinazoleresistance. (Pfalleretal.2010c)and70%ofthemreportedtoberesistantto posaconazole(Sanguinettietal.2005). SUPPLEMENTARYDATA Data on C. nivariensis and C. bracarensis susceptibility pro- files to azoles are still limited. An overview of the published SupplementarydataareavailableatFEMSYRonline. dataispresentedFig.4andTableS2(SupportingInformation). D Some strains exhibit high MICs to fluconazole alone or to all o w azoles,suggestingthatthesamemechanismsofresistanceas ACKNOWLEDGEMENTS nlo inC.glabratamightbeinvolved.Furtherstudies,usingtheC.ni- a variensisandC.bracarensisgenomedata,thatarenowavailable, Wethank MarieElisabethBougnoux, Frederic Dalle,EricDan- ded mightbeusefultoconfirmthishypothesis. naouiandFredericGrenouilletforsharingtheirdataonisola- fro tionandidentificationofC.nivariensisandC.bracarensis.Weare m Finally,echinocandins(caspofungin,anidulafunginandmi- gratefultoCecileFairheadandMoniqueBolotinfortheirhelpful h cgcoaafdluecndegllbi-nyw)taahlrleestFyhKneStmhgeoesnsitsersbe.ycDeiunnethlyitboaitvtihaniegliartbheleexcdßer-lulgeglnus.tcTathonleesyryainnnthchieab,sittehfueennse-- rCeoandfliinctgoafnindtaerdevsitc.eN.onedeclared. ttps://aca drugs became widely used from the 2000s. 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